The Hormone Handbook - 2° Ed.pdf

The keys to safe hormone therapies: How to do it and how to solve therapy problems

The Worldwide Bestseller: 2 "d edition NEW: 6 major hormones: IGF-1, VP, MSH, OXYT, PTH, INS MORE:

+

30% practical information & updated references

NEW: Crucial data on cancer-protective hormones & lab test anomalies

Thierry Hertoghe/ MD lnternational Medicai Books- Publications

The

Hormone Handbook by

Dr Thierry Hertoghe

A quick reference guide therapy for the physician The keys to safe hormone replacement therapíes Also adapted for patients who want to understand he details of their treatments

ISBN 978-2-9599713-5-8, May 2010, Luxemburg, SA lnternational Medicai Books/Archimedial, 4b route d'Arlon, L-8399, Windhof, Luxemburg

Copyrights:

© Copyright: This book is under the copyrights' legislation. Ali rights reserved, for ali countries and parts of the world. No part of this book may be copied in any form without written permission of the author or editor. Trespassers will be pursuit.

Dedication

The Hormone Handbook is dedicated to ali the physicians of the world who have devoted endless hours to the health care of patients, continuously seeking for truth and improvement in their search for increasingly better health care, and thought me so generously their science

The Hormone Handbook is in particular dedicated to my father who devoted his life to better medicine and was my great master in medícine

The Hormone Handbook is equally dedicated to my patients who through the medicai problems they bring me and the solutions they find by themselves, are my greatest teachers

Acknowledgement The author expresses his deep recognition to Dr Kendra Pearsall, who has done a major work in rewriting the first edition of the book, Dr Holger Rasmussen, Dr Suzie Shuder, and Thomas Cauwley and Steffen Beyer who have helped further in the correction of the second edition.

Contributors Drs Benoit Everard, Benoit Poutet, Théràse Hertoghe, Bernard Duboé, Marie François, Marie-Christine Lhermitte, Patrick Truong, Charlotte Godefroit.

A WORD OF CAUTION The bits of advíce in this book do not replace the physician, nor his competence, common sense or professional responsibility. Ali treatments described in the book, except for life style management, are meant to be supervised by a physician. The responsibility for treating patients relíes on both the physícian and the patient.

The

patient's responsibility is to follow the treatment protocol of the physician and to immediately report any problem so that it can be adequately corrected.

GOALS, SOURCES and LIMITS of the HORMONE HANDBOOK: The Hormone Handbook is based on the personal experience of the author and colleagues, and an extensiva scíentific database. The book is meant to be a practical guide to help physicians successfully treat patients with hormone replacement therapy and help them teach patients what they need to know about their treatment. lnforming patients about their hormone deficiencies, lab tests, treatments, possible problems, and ways to improve lifestyle and diet often greatly improves patient motivation and satisfaction.

lt also improves safety and efficacy of hormone treatment because well­

informed patients participate in supervising the treatment. A good cooperation between patient and doctor allows for a quick intervention if something goes wrong. For this reason the book has also been adapted for patients. As medicai science and experience continually progress, some of the information will be replaced by more accurate data.

Therefore the information presented here should not be

considered as definitíve, nor, at ali times, infallible. Following the recommendations in this book will probably minimize any serious adverse effects. Nevertheless, as the human body is complex and individuais have varied reactions, treatment results may be unpredictable.

The author, therefore, cannot assure complete

safety at ali times. Treating patients is a difficult task requiring highly professional expertise. Each treatment must be indivídualízed to the patient. The personalization of treatment cannot be provided by one book. In a strict sense, each patient would need a book.

IMPORTANT WARNING: In arder to help physicians detect and treat hormone deficiencies, optimal and deficient values are presented in the book that do not necessarily correspond to the reference values

of laboratories. They are based on the subjective personal experience of the author and colleagues. Therefore, they should not constitute the sole base on which a corrective hormone treatment is decided. Lab test values whatever they are, constitute only one of the ínformation to gather, besides clinicai signs and symptoms, and possibly other tests before decídíng on a treatment.

Hormone Handbook: Contents How to read the charts U Detection of hormone deficiencies How to diagnose hormone deficiencies? Short or extensiva check? Aren't laboratory tests sufficient? Which hormone deficiencies to look for first? Which lab tests: Blood, 24-hour urine or saliva tests? What can be measured in a 24-hour urine What do you check in an initial assessment? What about toxicology tests? How to interpret lab tests? When does a hormone deficiency start? What is an overt deficiency? What are borderline deficiencies? Must borderline hormone deficiencies be treated? What is an optimal hormone levei? What are reference ranges? Erroneous ranges? What are lhe optimal reference ranges? What are optimal and deficient values? How do you interpret lab tests? Cancer detection: Primarily, which cancers should you look for and how? 11/ Treatment of hormone deficiencies

Replacement or corrective therapy? Do hormone treatments suppress the activity of the endocrine glands? How to treat hormone deficiencies 1) Make the treatment safe: 1. Use physiological doses 2. Use bio-identical hormones 3. Choose the best type and brand of products 4. Administer the hormones by the safes! and most efficient route 5. Simultaneously correct ali important hormone deficiencies 6. Correctly start the treatment 7. Perform regular follow-ups 2) Make the treatment more efficient 1. First step: Above ali, improve diet, environment and lifestyle 2. Second step: correct the hormone deficiencies

IIU Follow-up of hormone treatments How do you follow-up with hormone therapies When to have the patient return What to check during follow-up How often do you perform lab testing What to do just before lhe test

1

3 3 4 4 5 7 8 1O 1o 1O 1O 10 11 11 11 14 14 14 15 17

19 19 20 20 20 21 21 23 25 28 28 29 29 30

33

35 35 35 36 36

When to do the laboratory tests during lhe follow-up

36

What laboratory tests should you do

36

Which tests are more difficult to interpret during a follow-up

38

When to do lab tests without overdoing it

39

How to adjust the dose of a hormone treatment during follow-up

39

What to do when lhe dose is too high

39

IV! Hormone therapies for deficiencies

41

1.

Melatonin

43

2.

Growth hormone in adults

53

3.

MSH

75

4.

Oxytocin

91

5.

Vasopressin

107

6.

Thyroid

123

7.

Calcitonin

143

8.

Parathormone

153

9.

IGF-1

167

Cortisol and glucocorticoids

183

1O. 11.

DHEA and androstenedione

205

12.

Pregnenolone

221

13.

Aldosterone

231

14.

lnsulin

247

15.

Estrogen and progesterone in women

267

16.

Testosterone in women

299

17.

Testosterone in men

317

18.

Progesterone in men

347

VI Treatment of particular problems:

359

A. Treatment of men's díseases:

361

The prostate: 1. How to lower excessive estradiol leveis 2.

How to treat benign prostate hypertrophy

361 362

3.

What to do for prostate cancer patients

364 365

4.

How to lreat Peyronie's disease

367

B. Treatment of women's diseases: 1. How to correct excessive body hair and "male pattern" hair loss in women

369

2. How to treat endometriosis

369 372

3. How to !real uterine cancer patients

373

4-7. Treatment of benign breast cysts, breast cancer, menorrhagia, uterine fibroids

374

8. How to treat ovarian cysts

375

VI/ Quick Overviews

377

1.

Mental and emotional complaints of hormone deficiencies

379

2.

Physical complaints of hormone deficiencies

382

3. 4.

Physical signs of hormone deficiencies Disease susceptibility

386

5.

Laboratory tests: the initial hormone assessment

392

391

6.

Laboratory tests: the follow-up of hormone therapies

400

7.

Corrective hormone therapies: the best hormone medications and doses

407

8.

The hormone diet

413

VIl/ Hormone References and bibliography

421

Hormone References 1.

Melatonin

423

Melatonin treatment and pineal gland inhibition

438

Melatonin: absence of serious scientific studies in humans?

439

Melatonin deficiencies with melatonin (metabolite) leveis within lhe

443

reference range 2.

Growth hormone in Adults

444

GH treatment's influence on GH endogenous secretion

465

Exercise as an alternative to GH treatment

465

GH treatment and muscle strength

466

GH treatment and functional capacities, metabolic rale,

466

GH treatment and adverse effects, lhe diabetes controversy

467

GH and cardiovascular system GH and cancer

469

GH and life span

476

3.

MSH

479

4.

Oxytocin

485

5.

Vasopressin

496

6.

Thyroid hormones

504

Serum TSH: is lhe TSH serum measurement alone sufficient for diagnosis and follow-up of thyroid deficiency?

518

471

Does thyroid treatment definitely suppress the thyroid gland?

528

Mild thyroid failure: to treat or not to treat Controversy on lhe best thyroid treatment: T4 or T4-T3?

529

Thyroid treatment and lhe heart

537

Thyroid therapy and bone density

540

Thyroid hormone deficiencies with thyroid tests within the reference

541

534

range: to treat or not to treat? 7.

Calcitonin No inhibition of endogenous calcitonin secretion by intranasal and

8.

intramuscular calcitonin Parathormone

a

�M IGF-1 and growth hormone deficiencies with thyroid tests within

562 568 569 m 586

reference ranges: to treat or not to treat? 1O.

Cortisol and glucocorticoids Cortisol or glucocorticoid treatment and adrenal suppression

599 613

Glucocorticoids and bone density

616

Memory loss and Alzheimer's disease: doubts on glucocorticoid use?

619

Cortisol deficiencies with serum cortisol levels within lhe reference

621

range: to treat or not to treat?

11.

DHEA and androstenedione

625

DHEA and adrenal suppression

643

DHEA and prostate cancer

643

DHEA and breast cancer

646

DHEA deficiencies with serum DHEA leveis within the reference range:

650

to treat or not to treat? Androstenedione deficiency with serum androstenedione leveis within

656

the reference range: to treat or not to treat? 12.

Pregnenolone

657

13.

Aldosterone

660

14.

lnsulin

665

15.

Estrogen and progesterone in women

677

Controversy on lhe use or avoidance of female HRT in women I. Arguments against the use of non-bio-identical estrogens and progestogens in women 11. Arguments in favour of the use of bio-identical estrogens and bio-identical progesterone in women 111. Arguments in favour of lhe use of female hormones in women (as well the bio-identical as lhe non-bio-identical): the therapy may be neutra! or even protect against breast cancer IV. Arguments in favour of the use of tema/e hormones in women with female hormone deficiency: the therapy may preserve and improve body, mind and lonegevity

702

Estrogen deficiencies with serum estrogen leveis within the reference range: to treat or not to treat? Progesterone deficiencies with serum progesterone leveis or its urinary metabolite within lhe reference range: to treat or not to treat? Serum FSH leveis within lhe reference range associated to disease 16. Testosterone in women

Testosterone deficiencies in women with serum testosterone leveis

702 709 716

720 734 738 740 743 752

within the reference range: to treat or not to treat? 17. Testosterone in men

755

Testosterone and testicular suppression

778

Testosterone and prostate cancer

779

Testosterone deficiencies in men with serum testosterone leveis within

796

the reference range: to treat or not to treat? 18. Progesterone in men

809

Bibliography

813

Recommended books for physicians

813

Recommended books for lhe general public

815

Articles and books by the author

816

VIII/Hormone therapy seminars, laboratories and compounding

819

pharmacies IX/Index

821

How to read the charts Before reading further, please read the following explanations to fully understand the charts.

Bright yellow highlighted areas indicate the major complaints, signs, tests or treatments related to the hormone deficiency based on the author's experie ce

�

Reference ranges or 95% confidence

Deficient or pathological leveis reflect a hormone deficiency or other endocrine pathology. For some tests such as serum TSH, a high levei reflects an en ocrine deficiency.

intervals of young adults reflect endocrine states found in 95% of a young adult population. The ranges of young adults are considered as the best reference range, the one that is the closest to the optimal one, although many leveis, low or high within this

�

:

range are not v lues of optimal health.

' '

' SERUM TESTS for 80TH GENDERS ' ' ' ' Endogenous Probably ' ' Reference Range HORMONE Deficient &for Test TEST\ Optimal of STATUS ' Pathological Value ' ' young adults ' Trend ' - !:e\leÍs ' ' Growth 114-492 IJQ/1 ' 0-250 300-350 -Essential IGF-1 --- CÔw hormone 15-65 nmoi/L' 39-46 0-33 -- ' '' ' ' .: ' � -' Optimal levels reflect lhe endocrine status for Test or therapy Lab test value: 3 categorias healthy adults of average size and weight (70-80 leveis in kg men, 55-65 kg women). They are estimations of quotes, based on grams are based on the author's personal experience and of lhe author's typed in some of his colleagues. not on thoroughly experience, are used standard investigated studies as they do not yet exist. to indicate a test or print, • therapy value: The optimal levels are generally the ones the whereas - either low, individual had in his youth. As big-tall persons leveis in med(ium) or high had in youth higher leveis of anabolic moles are - either essential for hormones such as growth hormone and IGF-1, typed in tests that are the testosterone, DHEA, leveis that permitted to italic to most helpful, or grow big, they need higher leveis also !ater on distinguish auxiliary for tests in adulthood to maintain their tissues tight and them better. that may be of firm, while the contrary is true for small ' '

_

•

_

persons who may feel optimal at lower leveis

interest for the

The optimal value for each test may slightly

diagnosis, but often

differ for each individual from the one indicated in the hormone handbook, because of individual differences in metabolism and hormone receptors that may require different hormone leveis. Nevertheless, most patients feel good, having no symptoms or signs of hormone dysfunction when they have leveis close to or at the optimal leveis.

are not indispensable - either 1

o

(first), 2o

(second) or 3° (third)

option to indicate in decreasing order of usefulness-efficacy of a treatment for most patients.

I.

Detection of Hormone Deficiencies

How to Diagnose Hormone Deficiencies

How do you detect hormone deficiencies? Hormone deficiencies can be recognized by the evidence found on the patient's body and past health history, current complaints, laboratory tests and possibly in some cases by medicai imaging testing.

What should be included in a hormone therapy consultation? The average hormone therapy consultation starts with an interview that consists of gathering information about the patient's past and present complaints, important medicai events of the past, both personal and familial ones pertinent to the patient. Also, it is important to check the diet and look for environmental pollutants, primarily food and indoor air pollution. Review any previous

laboratory tests.

Essential to a good endocrine

assessment is the physical

examination of 1 O to 20 minutes. The consultation concludes with ordering new laboratory tests and if necessary medicai imaging tests.

At this first consultation dietary counseling is given. At

the second consultation, treatment protocols are written out for the patient with explanations for each treatment.

Short or extensiva check? A short 5 to 15 minutes check-up only allows enough time to read lab results and to request further medicai testing.

This is not sufficient for a good hormone assessment. Please avoid

sending patients to medicai centers specialized in hormone therapy where short consultations are the routine. A sufficient hormone therapy consultation takes about one hour.

lt may be shortened to 45

minutes with advanced computer programs where the patient can fill out hormone-related questionnaires beforehand.

3

Aren't laboratory tests sufficient?

No, clearly not. Most laboratory tests only give partia! information on one or two steps in the chain of reactions before a hormone enters a cell. What laboratories can give is an idea of the production of a hormone, or of the amount of hormone found in blood, and possibly how much of it is available for uptake by target cells. Such information may or may not reflect what is important. The tests that evaluate what really matters are rare, namely the hormone activity inside the body's cells, also termed the metabolic impact of the hormone. A thorough medicai history and physical exam may more accurately evaluate the patient's metabolic activity. Many hormones are so powerful that they not only determine brain function, but also strongly influence height, weight and shape. Therefore, when you as a physician follow a patient for hormone therapy, you should always check the patient's body, look for physical signs and evaluate his emotional state. Which hormone deficiencies do you look for first?

Many hormones are important to health. For many physicians and patients who are neophytes in this medicai domain and want to know more about it, it is better to start learning one hormone deficiency and treatment at a time. A good choice would be to start mastering thyroid hormone deficiency and its treatment first. Thyroid hormones are potent hormones that boost the secretions of many other influential hormones such as the pituitary hormone named growth hormone, the adrenal hormones (cortisol, DHEA...) and the sex hormones (especially estrogens, progesterone, testosterone). Correction of a thyroid hormone deficiency inevitably improves the leveis of other hormones. Nevertheless, thyroid therapy should be started with caution, particularly in those with heart problems, cortisol deficiency and/or who are heavy coffee drinkers. See the chapter on thyroid hormones for more information. The order of priority in learning of hormone treatments that may work best for physicians is presented in the table below: Suggested order of priority in learning hormone

therapies for neophyte physicians and patients

10 20 30 40 50 60 r

ao go

10° 11° 12° 13 ° 14

Thyroid hormone therapy Testosterone theraQYin men Safe female hormone therapy in women Melatonin treatment Pregnenolone DHEA therapy Oxytocin therapy Safe cortisol replacement Fludrocortisone - aldosterone therapy Growth hormone therapy MSH-Iike therapies Vasopressin therapy Parathormone and calcitonin therapy IGF-1 therapy lnsulin therapy and others

The suggested priority is based on my personal experience in training physicians. lt is efficient. We could suggest first treating with DHEA and pregnenolone that have weaker effects and do not produce major secondary effects. However, efficacy and satisfaction with these treatments alone are often insufficient compared to that of thyroid, sex hormones and growth hormone treatments.

4

Which lab tests: blood, urine or saliva? For many hormone deficiencies, blood tests alone are ínadequate. A 24-hour urine test is the ideal complement to blood tests,

when the laboratory uses accurate testing such as

radioimmunoassay or gas chromatographic testing instead of using calorimetry. Calorimetric tests are outdated, but regrettably are still used by half of the laboratories that do urine lesting. Saliva tests are useful when no blood or urine tests are available or when severa! successive measurements have to be made at different times during a day, e.g. circadian rhythm evaluation or during a month such as the analysís of the leveis of female hormones during the menstrual cycle. Proponents of saliva tests say thal in contras! to most blood tests, saliva tests evaluate only what is ímportant, namely the (free) fraction of hormones lhat enter target cells. Despite this advantage, saliva tests rank for hormone evaluation in third posilion behind blood and a 24-hour urine tesls. One important reason herefor is lhe very large reference range (this will include many abnormal values within the normal range). Another problem with saliva testing - that it shares with blood testing - is lhe vast variations in free fraction of a hormone throughout a 24-hour period. Compared to a 24-hour urine test, many factors may explain why blood and saliva hormone leveis generally do nol adequately reflect physical, mental and inside-the-cells (intracellular) hormone status. Among these factors are the lack of information they provide on the production and metabolic activity of hormones for a 24-hour period, and the important circadian fluctuations of hormone leveis in blood and saliva. Moreover, there are test kit limitations, etc. 24-hour urine tests for hormones overcome many of the problems inherent in blood tests, and thus better reflect the cellular hormone status and are more effective in detecting milder forms of hormone deficiencies. Severa! reasons, shown in the comparativa table below, explain why. Compared to blood tests, baseline urine hormone and hormone metabolite excretions are, in our experience, relatively stable. They do not fluctuate very much from day to day, provided, of course, that the urine is correctly collected.

In addition, urine gives only information about the

"free" hormones and metabolites that are found in blood, those that are not bound and sequestrated by transporting proteins. Thanks to this, urine tests provide good information on what really matters, on the fraction of hormones in the blood ready to enter the body's cells. These features allow an understanding of why urine collections are invaluable not only for measurement of the 24-hour production and bio-availability of hormones for the body's cells, but they also give information about the 24hour metabolic impact of the hormones through measurement of hormone metabolites. The urinary excretion of hormone metabolites reveals information on hormone metabolic activity. This 24-hour information is not available in blood and saliva tests that are merely momentary snapshots of what happens in blood. Because of ali these properties, the observations of some scientific studies and our experience of 24-hour urine hormone testing, we find that the 24-hour urine test often gives more reliable values that match the mental and physical (clinicai) hormone status of the patient more reliably than blood or saliva tests.

5

The combination of blood and urine tests form, in our experience, the best approach for assessment and follow-up of most hormone deficiencies. The pros and cons of each of the different types of tests are listed in the table below. Blood, 24-hour, Urine and Saliva hormone tests CHARACTERISTICS

Blood

24-hour urine

Saliva

INFORMATION on HORMONES - Production

(24-hour)

- Blood levei

(momentary) (mean 24 h.) - Urinary excretion (24 h.) - Blood levei - Total

Often inadequate Adequate lnadequate lnadequate Variable

Adequa te

lnadequate

lnadequate lnadequate Adequate lnadequate

Variable lnadequate lnadequate

(bound & unbound fractions) - Free or bioavailable fractions

- Metabolic activity

- Circadian rhythm

Often inadequate

Adequate

1 lnadequate

Adequate lnformation on adrenal cortex hormones and the principal melatonin metabolite

Adequate if tests are repeated during the day

lnadequate

Variable Often adequate

lnadequate

Adequate

PATIENT

- Compliance

Good, except for those who have syringe phobia

- Discomfort

lnjection pain, having to go to the laboratory

Good, if patient gets information on how to do it & on the test's importance Long duration (24 h.); to do in sedentary and relaxed conditions

Good, especially for those who have syringe phobia Often multiple testing during days or weeks

Note: 1 Except for androgen metabolic activity, which may be eva/uated by measuring androstanediol glucuronide

6

What can be measured in a 24-hour urine?

Many hormone and hormone metabolite excretions are worth measuring in the urine. Hormones that are mainly secreted and metabolized during the night such as growth hormone and melatonin's major metabolite, 6-sulfatoxy-melatonin, can be measured also by a night-time urine collection.

But, doing this does not add any scientific value, and forces the patient to

collect their urine twice, one collection purely for night-time hormone metabolites, and another one for the hormones that are secreted both day and night. The hormones and their metabolites that can be measured in a 24-hour urine, are reviewed in the table below: 24-hour urine hormone tests Endocrine gland

Hormone

Pituitary

Growth hormone 6-sulfatoxy-melatonin

Pineal

(Melatonin's major metabolite) Triiodothyronine

Thyroid Adrenal cortex

Thyroxine Glucocorticoids

Cortisol

17-hydroxy-steroids

Androgens

DHEA

17-keto-steroids

Mineral corticoids

Aldosterone Estradiol

Ovaries

Estrone Estriol

Testicles

Metabolite

Testosterone

7

2-hydroxy-estrone 16-alpha -hydroxy-estrone 4-methoxy-estrone 4-hydroxy-estrone Androsterone Etiocholanolone

What do you check in an initial assessment?

The following table shows the laboratory tests we consider the most useful for an initial investigation. lt is divided into tests we advise doing systematically in persons suspected of multiple problems and those to do occasionally when a further investigation is helpful. Suggested Laboratory Tests for the lnitial Assessment

OCCASIONAL TESTS

STANDARD TESTS Blood Cells •

•

Hemoglobin, Hematocrit, red blood cells (MCV; MCHC, MHC) Leukocytes, differential

Rheumatism

For men: uric acid Kidneys (renal function) Creatinine Urea (BUN)

Rheumatism & lnflammation • • •

•

•

•

•

Kidneys

•

Lipids

Triglycerides Total cholesterol HDL cholesterol Atherogenic ratio total/HDL Homocysteine Sugar (glucose metabolism) Glucose (fasting) lnsulin (fasting)

•

•

•

•

•

•

•

•

•

•

•

Magnesium (erythrocyte) Sodium

Vitamins • • • •

VitaminA Vitamin E Vitamin 812 Red blood cell (erythrocyte) folic acid (Vitamin B9)

Trace Elements • •

Ferritin (iron) Zinc

LDL cholesterol VLDL cholesterol Lipoprotein a Fatty acid profile (omega-3, trans-fatty acids)

6,

9 and

Sugar

•

•

Creatinine Clearance (with adjustment for weight and height)

Lipids

•

Minerais

Sedimentation rate CRP Rheumatoid factor Waller-Rose

Glycosylated hemoglobinA 1 c

Minerais •

Potassium

Vitamins •

Carotene

Vitamin C

Coenzyme 01 O

•

Oxidative Stress Profile

Glutathion peroxidase, carotene, myeloperoxidase, etc.

•

Trace Elements

Copper

•

8

The following table shows the hormone tests useful for an initial assessment. The essential tests are highlighted in yellow colour, whereas tests to do occasionally, only when a person's signs and complaints require further investigation, are not highlighted in colar. Recommended Hormone Tests for an lnitial Assessment •

Pituitary hormones

24-hour URINE TESTS

BLOODTESTS

HORMONES • • • •

•

GH LH FSH ACTH Prolactin

•

Pineal h. • •

Thyroid hormones

• • • • •

Liver GH axis hormone

• • • • •

Adrenal hormones

• • • • • • •

•

TSH

•

Free T3, Free T4

Anti-thyroperoxidase (ATPO) Thyroglobulin

•

Cortisol (total)

•

Transcortin (CBG) 1 Free cortisol

•

DHEA sulfate

•

Androstenedione Aldosterone after activity Sodium

homones

•

1

• • •

Potassium

•

Pregnenolone sulfate

•

Estradiol

•

•

•

lodine

IGF-1 (somatomedin C) IGF-BP-3

•

Male

Note:

•

Calcitonin

hormones

•

Free T3 Free T4

Thyroid antibodies:

Female

•

6-sulfatoxy-melatonin

Anti-thyroglobulin (ATG)

•

•

GH

Progesterone (premenopausal

2151 day of the menstrual cycle)

Testosterone

•

•

Free testosterone

Free Cortisol 17-hydroxy-steroids Free DHEA 17-keto-steroids Aldosterone Sodium Potassium Phosphorus Free Estradiol, estrone, estriol 16-alpha -hydroxy-estrone 2-hydroxy-estrone 4-methoxy-estrone 4-hydroxy-estrone Pregnandiol Free Testosterone

SHBG Androstanediol glucuronide (or if not available: dihydrotestosterone)

The free cortisol is calculated from a formula based on the ratio total cortisol- CBG.

9

What about toxicology tests? Toxicology tests: More and more people suffer from environmental illness.

Environmental

pollution may cause hormone problems or aggravate existing ones. Sources of pollution such as pesticides and other toxins in food and water, toxic indoor furniture, excessive radiation caused by electrical appliances, air conditioning and outdoor pollutants, have increased over the years and adversely influenced hormone leveis. In this book, we have not included toxicology tests for two reasons. First, there are more than 60,000 toxic substances known to date, too many to test for.

Second, with the help of an

adequate questionnaire and knowledge about what is the most toxic and what is not, it is often possible to find out or deduce without lab tests for many persons what is toxic and may cause a problem.

This knowledge alone may be sufficient to take adequate measures of avoiding or

removing the toxic source.

Although the matter is important, it exceeds the scope of The

Hormone Handbook.

How to interpret lab tests? In order to correctly interpret laboratory tests, it is important for the reader to understand some basic principies.

When does a hormone deficiency start?

A hormone deficiency starts as soon as physical signs, complaints and lab test results typical of hormone deficiency are found and that can be corrected by hormone therapy (without producing a state of hormone excess).

What is an overt deficiency?

An overt hormone deficiency is a severe deficiency with hormone leveis that are clearly low, in particular lower than the lower reference value.

lts signs and complaints are usually obvious

and generally have a greater intensity than those of borderline deficiencies.

What are borderline deficiencies?

Borderline deficiencies are states that lie between clear-cut (overt) deficiencies and the optimal state.

Other names for borderline deficiencies are suboptimal states, marginal, mild, minimal,

subclinical or intermediate (degrees of) deficiencies. As a rule, borderline deficiencies show blood, urine or saliva hormone leveis that are still within the reference range. The leveis are lower than the upper reference value, but higher than the lower reference value. complaints.

Some borderline hormone deficiencies generate a lot of signs and

Individual variations in optimal leveis for a specific hormone or inaccurate

reference ranges (for a whole category of patients taking the test) may explain such discrepancy.

10

Must borderline hormone deficiencies be treated? In the past, the general approach for hormone therapy was to treat only overt deficiencies and to wait and see what happens with borderline deficiencies. lf it developed further into an overt deficiency, then a treatment was started, otherwise it was not. Currently, an increasingly greater number of physicians are treating not only overt deficiencies, but also the borderline ones, in particular those that produce typical signs and complaints of deficiency.

The aim is to prevent premature aging and other health problems caused by a

hormone deficiency, even a mild one. This approach is the one adopted in this book.

What is an optimal hormone levei? In the past, ali values situated inside the reference range, somewhere between the upper and lower reference values, were considered to be optimal hormone leveis.

This concept lacks

supporting scientific evidence. Actually, more and more the prevailing concept is that optímal hormone leveis may vary trom person to person. For the average person of average weight and height, the optimal hormone levei grossly corresponds to the mean leveis found in young adults. Thus, it is a value situated halfway between the youthful lower and upper reference values.

An optimal hormone levei

should be a levei that allows an individual to be free of the complaints and physical signs of a hormone deficiency, without provoking any signs of excess.

In a laboratory test, it is often -

based on our experience - a hormone levei that is at the same levei or slightly higher than the average levei of young adults. lt is this concept that is used in this book for the determination of optimal hormone leveis, a concept that is based on subjective practical experience with patients, not on theoretical reference ranges.

What are reference ranges? Erroneous ranges? The reference range, presented by a laboratory on a lab protocol, contains 95% of ali the values (generally) found in the patients going to that particular laboratory. lt corresponds to the values situated within two standard deviations from the mean. The way reference ranges are obtained has been heavily criticized. They often are too broad, are unjustifiably adapted to age, are made for groups of individuais but do not take into account that optimal values may be different from one individual to another, and that some leveis within a reference range may be unhealthy for an individual. ldeally, reference ranges should indicate who is healthy and who is not, but they do not. The ideal reference range should contain only values that reflect health for any person and exclude values that reflect disease. levei.

This is impossible.

Each person has his own optimal hormone

For some individuais the levei needs to be moderately higher than the mean levei of

young persons and for some it needs to be a little lower.

11

The principal criticisms against the actual reference ranges are presented in the following table.

Criticisms of Laboratory Reference Ranges: Part 1 Population used to create a reference range

Explanation The reference ranges of hormone tests may vary from laboratory to laboratory, because each laboratory is obligated to determine its own reference range for every test. ranges contain usually many

These reference

people who are not optimally

healthy. Why? Because to establish reference ranges for each test, a laboratory does not bring together 3000 optimally healthy subjects. lt is simpler and much more inexpensive to base it on the test results of the patients whose doctors had requested the A mix of

(a few) healthy Health

and (many) unhealthy persons

particular test.

These patients are generally not healthy people,

because most physicians arder a hormone test for patients only when they suspect a deficiency or an excess of a specific hormone.

When physicians arder follow-up laboratory tests they

are more likely to arder tests when they suspect the dose to be incorrect for patients, rather than when patients look clinically healthy. The percentage of sick individuais that help determine a reference ranges is even higher than years ago because of the increasing pressure put on physicians by national and private insurance companies to minimize the number of tests in arder to reduce costs.

Tests must be restricted to what is absolutely necessary

and justified.

In other words, physicians are told only to arder

those hormone tests that have a great chance of being abnormal, and encouraged to do tests only in clearly sick patients. Percentage of patients

95 percent of ali people undergoing the tests will have hormone

with hormone leveis

leveis inside the reference range. That number is toa high! There

•

is only a 5% chance of having a test result outside the reference

lnside the reference

range, 2.5% under and 2.5% above. 95 %

considered

to

be

healthy

values,

lf reference ranges are solely

2.5%

of

patients

undergoing a hormone test are to be considered (diagnosed) as

range

abnormally low, while it is apparent that more individuais than that suffer from hormone deficiency. A good example is the extremely low reference range for estradiol

•

in women after menopause (10-40 pg/ml), a reference range

Below the lower reference value

where ali women, yes, ali, who have values inside the range are 2.5 %

estradiol-deficient!

Compare that range with the 100-21O pg/ml

reference range of women in the second (luteal) phase of their menstrual cycle and the 30-150 pg/ml range of the first (follicular) phase.

12

Cri ti ci sms of Labor atory Refer enc e Ranges: Part 2 Population used to create a reference range

Explanation Most reference ranges for hormones are lower for older individuais and these values are often considered to be a range of healthy values. This concept means that even though your hormone leveis drop as you age, the lower leveis, nevertheless, may be considered healthy! No scientific study proves this. Many studies demonstrate the opposite: lower values in individuais are often associated with an increased risk of disease and a lower quality of life. Moreover, adapting reference ranges to (older) age is even more surprising in face of the fact that older individuais have bodies that relatively maintain their size (height, volume and weight). Their size is usually quite similar to what it was in young adulthood. Many are even heavier and have a larger volume! Logically, the same sized or

Age

Adapt ed to age

larger body requires at least the same hormone leveis to remain as healthy as it was in the youthful years, not to mention that the body undergoes with age a progressive reduction in the number and sensitivity of the cellular receptors for many hormones, which may necessitate in elderly persons the presence of leveis of hormones higher than those found in young people to obtain similar hormonal effects as in young people. The adjustment of the reference range for DHEA sulfate, for example, to the age of the patient illustrates how aberrant it is for the older patient. In men age 70+ years the DHEA reference range is approximately 8-135 J.lg/dl, while in men aged 17 to 30, it usually is around 200-61 O J.lg/dl. lf the age-adjusted DHEA reference ranges are considered to be healthy values, than an old man with a DHEA sulfate levei at 250 J.lg/dl, a low value for a younger man, would be sick from DHEA excess!!! Excessively broad reference ranges will contain leveis of healthy

Broadnes s

and unhealthy persons. lf such reference ranges are considered as ranges of healthy values, many hormone deficiencies will be missed

(important difference between upper

as individuais with signs and symptoms of hormone deficiency have To o broad

a greater chance of seeing their leveis situated inside the reference range. The broad reference range of 3-9 ng/1 in the blood for free T3 (active

and

thyroid hormone), is a good example. Persons with free T3 at 9 ng/1

lower

have three times more T3 than individuais at 3. lsn't it nonsense to

reference)

consider both as equally normal and not needing therapy? A reference range is not a range of optimal hormone leveis or even

Optimal hormone leveis

Noor wrong dat a

of healthy ones. By definition, it is just representative of the leveis of the 95% of the people whose results have been used to determine the reference range. An optimal hormone levei for one person, may be too high o r too low for another.

13

Laboratory tests have also heavily been criticized for the lack of correlation between the hormone leveis on the lab tests and the actual amount of hormones in the target cells which is the true determinant of a patient's signs and symptoms. For ali these reasons, reference ranges are not ranges of optimal, or even of healthy hormone leveis. lf reference ranges are used as ranges of healthy values, many hormone deficiencies will be missed. Both physicians and patients will be misled to erroneously conclude that the aging and suffering patient is "normal" and should not receive hormone replacement therapy because he would not need it.

What are the optimal reference ranges? Reference ranges for young adults are much more likely to correspond to optimal healthy values than those for elderly persons. Practical experience teaches us that an average sized person often feels better when his hormone leveis are situated around the average levei of young adults. Experience and logic teaches us that big (tall and muscular) persons who have developed a bigger body thanks to higher leveis of anabolic hormones, generally need higher leveis of these hormones, somewhere in-between the average and upper reference value of young adults. Anabolic hormone leveis should be proportional to the person's muscle and bone mass.

The bigger individuais are, the higher the anabolic hormone leveis should be.

In

contrast, smaller and thinner persons have enough with lower than average leveis of anabolic hormones. Anabolic hormones are the hormones that in youth have built up the body to its actual adult size. Growth hormone, IGF-1, DHEA and the sex hormones are the major anabolic hormones.

What are optimal and deficient values? In the Hormone Handbook, optimal and deficient lab ranges have been estimated based on the extensive experience of many physicians who specialize in hormone therapy. The ranges are designed to help the physician interpret lab tests, and suggest a possible treatment direction.

How do you interpret lab tests? Laboratory tests have to be systematically interpreted in the light of the hormone-related signs and complaints found during physical examination and through an interview.

This

approach permits detection of not only the rare severe deficiencies, but also the much more frequent milder borderline deficiencies. Borderline low hormone leveis in persons with characteristic signs and complaints of hormone deficiency, should be considered as (borderline) deficient leveis and the patient be accordingly treated. Chances are high that signs and complaints of the hormone deficiency will disappear with therapy without seeing any excessive hormone leveis showing up in follow-up lab tests.

14

Cancer detection: Primarily, which cancers should you look for and how?

We advise doing the following cancer screening: lf suspicion

Cancer screening

Additional tests

Occasionally, when necessary Thyroid cancer

Lung cancer

lnterview, ultrasound imaging, blood thyroglobulin, calcitonin, nodule oaloation lnterview, radiography of thorax (everv vear for smokers)

Scintigraphy

Routinely after the age of 40-50 years

Breast cancer

Ovarian cancer

Uterine cancer

Prostate cancer

Testicular cancer Rectal and Colon cancer

Notes:

1

lnterview, breast palpation (twice a year), mammography (every 2 years or sooner if suspicion)1, ultrasound imaging, blood CEA (and CA 15.3) Genetic tvoinq Abdominal palpation, ultrasound imaqinq lnterview (for unexpected blood loss), abdominal palpation echography, qenetic typinq lnterview (for unexpected blood loss or urine retention), rectal examination, qenetic tvoinq lnterview, testicular examination (everv vear) lnterview, genetic typing

Biopsy, CA 15.3

CT scan Biopsy

Biopsy Transluminal ultrasound imaging Stool analysis, rectoscopy, colonoscopy, biopsy

Controversies exist. Some data has suggested that mammography could increase

the risk of breast cancer, which is why some physicians do not recommend it without sufficient reason such as the presence of a suspected mass in the breast.

Alternatively, some physicians have proposed doing a combination of PET scans and CT scans every two years. Unlike mammography, the PET and CT are able to detect tumors of a few millimeters of size. Although the radiation exposure is similar to that of a mammography, it has nonetheless been considered still too high to permit preventiva prospectiva studies on healthy volunteers.

15

11.

Treatment of Hormone Deficiencies

Replacement or corrective therapy?

The word hormone replacement or hormone substitution is wrong for most hormone treatments.

Hormone replacement means replacing the existing (endogenous) hormone

produced by the human body itself by (exogenous) hormones that come from the outside. One example of hormone replacement is using the birth contrai pill. The pill blocks the internai sex hormone production by the avaries and replaces these hormones with synthetic estrogens and progestogens that are different from the natural ones. Another example of hormone replacement is when the body does not produce a hormone and so the patient is given hormone treatment. Complete shortages are found after total remova! by surgery or total extinction of endocrine glands such as is the case for the avaries with menopause. Most hormone therapies add hormones in addition to the body's own hormones to reach an optimal levei. There is a certain degree of suppression and thus replacement, but on average only 10-40% of the natural hormone production is suppressed and the suppression is temporary. Therefore, the term "corrective" is a better way to describe most hormone therapies as it includes both hormone replacement and non-replacement therapies. We will throughout the book preferably use the

term "corrective hormone therapy (or therapies)" where others

would use "replacement" or "substitutive". Nevertheless, because of the widespread use of the word "replacement" for corrective hormone therapies, both terminologies may be used in this book when corrective therapies are meant.

Do hormone treatments suppress the activity of the endocrine glands?

Small physiologic doses of hormones such as those used to correct deficiencies are safe and healthy. They cause a small decrease in endogenous hormone production that generally does not exceed 30-40%. The suppression is thus partia!, not total, and temporary. The mild suppression of the endocrine gland(s) is caused by a feedback mechanism that alerts the body that adequate hormone leveis are present so that less needs to be produced. Thus, a corrective hormone therapy allows the endocrine gland to calm down and avoid overworking. lnitially, before treatment, the endocrine glands are working at their maximal capacity but this is still not sufficient to provide the body with enough hormones to be healthy. The absence of corrective hormone treatment forces the endocrine glands to work maximally to minimize deficiency problems and the risk of glandular exhaustion exists such as the case of adrenal burn-out. "Hormone doping" or taking excessive hormone doses to improve athletic performance, is not safe and should be avoided.

19

How to treat hormone deficiencies? Safe and efficient hormone treatment abides by the rules set forth in the table below:

How to make the hormone treatment safe and efficient First, make it safe

Second, make it efficient

1.

Take physiological doses

1.

lmprove diet, environment and lifestyle

2.

Take bio-identical hormones

2.

Correct the hormone deficiencies

3. 4.

Choose the best type and brand

•

Apply the safety principies

of products

•

Correct ali deficiencies

Take the hormone medication by

•

the safest and most efficient way 5.

Simultaneously correct ali

•

important hormone deficiencies 6.

Correctly start the treatment

7.

Perform regular follow-ups

Fully involve the patient in the treatment and ask for his cooperation Patients should contact their physician when necessary

..

Balance judiciously the various hormone therapies with one another

Make the treatment safe 1. Use physiological doses

Physiological doses are doses that are a fraction of the normal daily secretion of a hormone up to the maximal daily secretion in young healthy adults. Supraphysiological (or pharmacological) doses are doses above the maximal daily secretion in young healthy adults. Overdoses (or excessive doses) are doses of a treatment that are too high for the individual who receives it. Overdoses can be supraphysiological or physiological but always exceed what is necessary to correct an individual's deficiency. Therefore, physicians should give the adequate physiological dose (also called the optimal dose for deficient patients), a dose that is not too high, nor too low. A physician can estimate the optimal dose by checking the patients' lab tests, complaints at interview and signs at physical exam.

20

2. Take bioidentical hormones

lmportant differences in action and safety exist between bioidentical hormones and non­ bioidentical hormones. Bioidentical hormones have a structure that is exactly the same as the structure of the hormone naturally secreted by the body. In contrast, the structure of non­ bioidentical (or modified) hormones differs from that of the natural hormone. Most are synthetically modified such as, for example, ethinylestradiol that is used in birth control pills. lt is a synthetic derivative of the natural female hormone, estradiol. Non-bioidentical hormones may also be natural hormones that come from another species such as conjugated estrogens that come from the urine of pregnant mares and differ from human estradiol. Non-bioidentical hormones have different structures from the natural-to-the-human-body or bioidentical hormones. The different structure can cause excessive binding or unstable and incomplete binding to the hormone receptor sites and therefore cause different effects. In addition, as the human liver was not meant to process these hormones, the breakdown of non­ bioidentical derivatives often takes place at a slower pace, permitting these hormones to accumulate in the body. In certain circumstances, this slow breakdown provides an advantage compared to bioidentical hormones that may be broken down too quickly. Nevertheless, the slow and difficult breakdown may lead to adverse effects as well such as liver damage by hormones accumulating in the liver or the promotion of breast cancer by synthetic progestogens. To illustrate such risk, the unwanted effects on the cardiovascular system of ethinylestradiol, the commonly used estrogen of the birth control pill, are presented in the table below. Observed adverse effects of Ethinylestradiol (birth control pill) on blood vessels • • •

•

Thickening of the inner wall (intima media) of arteries and veins in animais and humans lncrease in lif>ids: trigly_cerides, very_low density lip_�otein cholesterol lncrease in blood pressure, particularly the diastolic blood pressure (that is much more associated with disease than the systolic p_ressurel lncrease in blood viscosity and increased risk of blood clots as a result of an increased tendency to cause the aggregation of blood platelets (thrombocytes) and to lower the leveis of anti-thrombin 11( (a blood coagulation-reducing substance)

21

3. Choose the best type and brand of products Most pharmaceutical companies produce non-bioidentical hormones instead of bioidentical hormones because they can obtain a patent on them, while they cannot for bioidentical hormones. For the reasons stated above, non-bioidentical hormones are not the most suitable for long-term use. When ordering bioidentical hormones from a compounding pharmacy, it is better to use those compounding pharmacies that have experience in compounding bioidentical hormone preparations. lf they seem to hesitate when asked to compound a typical hormone preparation, it is a sign that they are not used to compounding that preparation and may not be able to formulate the best preparation for you. In the following table a list of the best options for hormone preparations for each deficiency following my personal experience is reviewed. For more detailed information on each hormone deficiency and suggested products, please reter to that particular chapter.

Best types and brands of hormone treatments Hormone deficiency

2"d choice

151 choice

Growth

Norditropine, Omnitrope, Saizen,

hormone

Genotropin, Zomacton®

Humatrope, Umatrope®

MSH

Subcutaneous Melanotan li

Melanotan I, Bremelanotide

Oxytocin

Sublingual oxytocin

Subcutaneous oxytocin, (intranasal)

Vasopressin

Oral desmopressin tablets

lntransal vasopressin

Melatonin

Most sublingual tablets 0.1 to 1 mg tablets, marketed by nutritional companies

Thyroid hormones Calcitonin

Oral melatonin marketed by nutritional companies Novothyral, Euthyral, Thyrolar®

Armour Thyroid® Subcutaneous or lntramuscular injections: Calcynar, Miacalcic

Nasal: Miacalcic®

Parathormone

Subcut. teriparatide, parathormone

Cortisol

Hydrocortisone marketed under a

Prednisolone marketed under a variety of

variety of names by severa!

names by severa! pharmaceutical firms, Medro!® (methylprednisolone)

pharmaceutical firms

DHEA Fludrocortisone (Synthetically modified aldosterone)

Estradiol

-

Most oral capsules produced by compounding pharmacies are good Florinef®, oral capsules produced

Capsules obtainable in health food stores or through the Internet (but on doctor's prescription) Aldosterone (bio-identical as tablets or oral

by compounding pharmacies on

capsules produced by compounding

prescription

pharmacies on prescription)

Estrogel, Oestrogel, Oestrodose, Gynokadin®

Estradiol gel in compounding pharmacies

IGF-1

Subcutaneous IGF-1

Subcutaneous IGF-1

lnsulin

Subcut short/intermediate insulin

Subcut. ultrashort-/long-acting insulin

Progesterone

Prometrium, Utrogestan, Utrogest, Progestan®

+

IGF-BP-3

Duphaston, Lutenyl® Testocaps, Andriol, Proviron; Testoviron

Testosterone

Testosterone liposomal gel

depot, Androtardyl, Androgel® (but only for

available by prescription from

women at the lowest Androgel dose or for men with mild testosterone deficiency at the highest

quality compounding pharmacies

dose), Andractim®

22

4. Administer the hormone medication by the safest and most efficient route

Hormones can be administered by different routes: oral, sublingual, buccal, nasal, transdermal, vaginal, rectal, subcutaneous, intramuscular or intravenous. The main routes of administration for hormones are described in the following table. Main routes of administration for hormones Routes of

How to take

intake

the medication

Where the hormones are absorbed

The hormones are absorbed in the gut; before Oral

Put it in the mouth and swallow it

reaching the bloodstream many go first through the liver where they can be inactivated or may accumulate and exert excessive activity

Sublingual

Placed under the tongue and let it melt Place it against the

Buccal

gums as lozenges and let it melt

About half of the hormones are absorbed through the mucous membranes of the mouth, half are swallowed and absorbed later on by the gut. The hormones are absorbed through the

Nasal

Use as a nasal spray

mucous membranes of the nose. After absorption through the mucosa they penetrate the bloodstream. The hormones slowly diffuse through the skin,

Transdermal

Apply it as cream or

get stored in the fat under the skin and from

(percutanous)

gel on the skin

there are progressively released into the bloodstream.

Subcutaneous

lntramuscular

lnject it under the skin

Vaginal

skin, and then progressively released into the bloodstream.

lnject it in the

The hormones are stored in muscles and from

muscles (generally

there are progressively released into the

of the buttocks or

bloodstream. Depot forms offer prolonged

deltoid of the

effects by slowly releasing the hormone into

shoulders) lntravenous

The hormones are injected, stored under the

lnject it in the veins

the bloodstream. The hormones are directly injected into the bloodstream.

Place it in the vagina

The hormones are absorbed through the

as ovules or

vaginal mucous membranes and from there

capsules

get into the bloodstream.

To maximize efficacy and safety of hormone treatments, physicians should choose whenever possible the best way to administer them, even if it is more time-consuming for the patient.

23

The best ways to take the medications are summarized for each hormone in the following table. Preferable routes of intake of hormone medications Hormone treatment

151 choice Subcutaneous

injection

Growth hormone (Mos! pharmaceutical products are Qood)

MSH-derivatives

Subcutaneous

injection

Oxytocin

Sublingual

Vasopressin

Oral

Melatonin

Sublingual

Thyroid hormones

Oral Nasal

Calcitonin Parathormone IGF-1

(more comfortable} Subcutaneous

injection

DHEA

Oral

Fludrocortisone

Oral

lnsulin Estradiol Progesterone (bioidentical) Testosterone

(because of inefficacy or adverse effects)

lntranasal spray lntranasal spray Subcutan. injection Oral tablets (lntraven. injection for delivery) lntranasal spray (Subcutaneous injection) Oral (lntraven. injection for coma patients) lntramuscular injection (cheaper and more efficient) lntramuscular injection Oral

injection Oral

To avoid

Oral sublingual, nasal (through lntramuscular injection nose mucous membranes) Nutropin (depot) routes are inefficient

Subcutaneous

Cortisol

Aldosterone

2"d choice

(lntravenous or intramuscular injection for emergencies) Sublingual, Transdermal (but at very high doses)

Sublingual (local risk of gum erosion)

Oral Subcutaneous

injection Transdermal

lntranasal Oral (not yet on lhe market) Nasal Oral, (sublingual} (Sublingual for occasional use)

Vaginal

Oral

Oral progestogens such as medroxyprogesterone acetate and others with adverse effects

Transdermal

lntramuscular injection (Oral and sublingual for occasional use)

Oral methyl-testosterone and other 17-alkyl derivatives with liver toxicity, (Proviron® at high doses)

24

5. Simultaneously correct ali important hormone deficiencies

Hormones are designed to be in balance with one another. A major goal of the treatment is to have a good balance among ali hormones. Most hormones stimulate or slow down the production or effects of other hormones. A fundamental principie to achieve good balancing is that it is often safer and more efficient to treat ali important hormone deficiencies when starting a treatment, than to treat only one and do the rest !ater. For example, thyroid and growth hormone replacement treatments are often not well tolerated if a person has a cortisol deficiency. In addition, usually estradiol is not tolerated and unsafe without administering progesterone in conjunction. The physician must have in mind that severe hormone deficiencies cause many problems when left untreated, including making a person intolerant to replacement therapies for other hormone deficiencies. The most important effects a hormone treatment can have on other hormone activities are summarized in the following table. Corrective hormone therapies that are not well tolerated

because of another hormone deficiency that is left untreated Corrective Hormone therapy

Endocrine deficiency that lntolerance to the hormone therapy makes the hormone 1 Degree Hormone imbalance: therapy not well-tolerated

Melatonin

+±

therapy GH -IGF-1

therapy

Cortisol deficiency

+++

Oxytocin

+±

therapy MSH-Iike

therapy

Cortisol deficiency

+±

Melatonin, growth hormone (GH), IGF-1 and oxytocin treatment may aggravate the cortisol deficiency by reducing cortisol production and leveis. Cortisol-deficient patients react to Meianotan 11® with nausea, allergies, hyperpiÇJmented spots The thyroid treatment aggravates the cortisol deficiency increasing by cortisol catabolism; => Even small doses in thyroid treatment of result hyperthyroid episodes of excess T3

Thyroid

+++

Cortisol deficiency

therapy

because

in

cortisol

deficiency

the

conversion of thyroid hormone T4 to the

T3 accelerated. active is very Hyperthyroid episodes more frequently occur in stressful conditions when more cortisol is needed. +

Estradiol deficiency

Calcitonin

therapy

Cortisol deficiency (?)

+±

Hyperthyroid episodes, because a low estradiol levei increases the conversion of T4 into the active T3. At excessive doses of calcitonin, patients report suffering from a state that resembles overt cortisol deficiency with nausea.

Note: 1 A borderlíne or severe hormone defícíency that causes íntolerance íf ít remaíns untreated.

25

Corrective Hormone therapy

Endocrine deficiency

that causes the hormone therapy not to be well-tolerated1

lntolerance to the hormone therapy Degree

Hormone imbalance

The

Thyroid deficiency

++

treatment aggravates the by reducing the conversion of T4 in T3 cortisol

thyroid

The

deficiency

cortisol

treatment

aggravates

the

DHEA deficiency by slowing down the

DHEA deficiency

+

Cortisol

therapy

production of ACTH, and thereby slowing down the secretion of ali other adrenal cortex hormones, including DHEA. The cortisol treatment increases tissue breakdown by increasing the ratio catabolic (cortisol)/anabolic (DHEA) ratio. treatment aggravates the by reducing deficiency, ACTH production, thereby reducing the secretion of ali adrenal cortex hormones, Persons with including aldosterone. borderline low aldosterone leveis may fali The

cortisol

aldosterone

Aldosterone deficiency

+++

into severe aldosterone deficiency that appears intolerable to them.

The

DHEA

treatment

aggravates

the

cortisol deficiency by mildly reduce ACTH DHEA

therapy

Cortisol deficiency

+±

production, thereby reducing the secretion of ali adrenal cortex hormones, including cortisol. The mild reduction of cortisol secretion may be felt as intolerable by very sensitive persons with low cortisol leveis prior to treatment. The fludrocortisone treatment aggravates

the cortisol deficiency by mildly reducing Fludrocortisone

therapy

lnsulin

Cortisol deficiency

+±

Thyroid deficiency

+

Cortisol deficiency

+±

therapy DHEA deficiency

+

Estradiol deficiency

+

Testosterone deficiency

+

26

ACTH production, thereby reducing the secretion of ali adrenal cortex hormones, including cortisol. The mild reduction of cortisol secretion may be felt as intolerable by very sensitive persons with low cortisol leveis prior to treatment. A T3 deficit facilitates insulin deficiency and poor response to insulin. lnsulin quick produces hypoglycemia in cortisol deficient patients. Their diabetes is very difficult to manage quickly going from ('unstable' hyperhypoglycemia to diabetes). A deficit in DHEA and sexual hormones facilitates insulin deficiency and a poor response to insulin.

Corrective Hormone therapy

Endocrine deficiency that causes the

hormone therapy not to be well-tolerated1

lntolerance to the hormone therapy Degree

Hormone imbalance Progesterone

Progesterone

deficiency

deficiency

leads

to

an

insufficient conversion of the estradiol into ++++

weak estrone, resulting in an accumulation

of potent estradiol brought along by the estradiol

treatment,

resulting in signs of

estradiol overdose +

(Trans­ dermal

Thyroid deficiency

E2) ++

(Oral

Estradiol therapy

estro­

(women)

gen)

The

estradiol

treatment

aggravates

the

thyroid deficiency causing weight gain and swelling by reducing the leveis of thyroid hormones

mechanism:

thereby

in

target

an

increasing

sequestration

cells

increase

of

the

by

a

binding

and

conversion.

estradiol

thus

thyroid hormones in the

blood, and a reduction of the T4 The

double

of serum TBG,

treatment

to T3

aggravates

the

testosterone deficiency, possibly leading to a decreased muscle mass. Estrogens reduce the testosterone activity in the muscle cells by

Testosterone deficiency

a +

double

mechanism:

by

increasing

the

production and serum levei of SHBG, which increases the binding and thus sequestration

of testosterone in the blood and reduces

intracellular testosterone, and possibly by

blocking the androgen receptor in the target cells.

The progesterone treatment aggravates the Estradiol deficiency

++

Proge­

deficiency

by

accelerating

the

estrone.

sterone therapy

estradiol

conversion of estradiol into the weak estrogen

Aldosterone deficiency

The progesterone treatment aggravates the +±

aldosterone

deficiency

with

vertigo

and

dizziness because progesterone blocks the

aldosterone receptors in kidney cells.

The testosterone treatment aggravates the estradiol deficiency with body hair growth.

Testosterone reduces the estradiol activity by

Testo­ sterone therapy

Estradiol (women)

+±

a double mechanism: by a progesterone-like

effect

with

acceleration

of

conversion

of

estradiol into the weak estrone and possibly

by blocking the estrogen receptors in target cells.

27

6. Correctly start the treatment

About half of the hormone treatments need to be carefully started at low doses. Subsequently, the dose should be progressively increased over weeks. 'Take your time" should be the recommended strategy. Starting at low doses is essential in corrective thyroid therapy. For another half of the treatments, the best way to assure efficacy and good tolerance is to start directly at the dose that is presumed adequate, or in case of doubt at a slightly lower dose. Such strategy is essential to start cortisol and sex hormone (especially female hormone) corrective therapy. Vou find here below an overview of the principal strategies for the most frequent hormone replacement therapies. How to start corrective hormone therapies Corrective hormone

Dosing

Preferable route

therapy Melatonin Oxytocin Vasopressin Melanotan 11 Growth Hormone IGF-1 Thyroid hormones

Sublingual Sublingual Oral Subcutaneous injection

Start at low doses and then gradually increase (lower doses for persons with low cortisol leveis)

Start at low doses and then gradually increase (for persons with low cortisol levels) or begin Subcutaneous injection directly at higher dose and gradually decrease to the adequate dose (for persons with good or high cortisol levels) Oral Start at low doses and then increase every 3 to days up to the adequate dose

lntranasal lntramuscular injection. Subcutaneous injection lnsulin Subcutaneous injection Parathormone Cortisol Oral Oral DHEA (Sublingual) Fludrocortisone Oral: Transdermal Estradiol Vaginal Progesterone (bioidentical) Oral Transdermal

30

Calcitonin

Testosterone

Start at the presumed adequate dose or slightly lower, and then adjust the treatment following patient's reactions

May be started at higher than normal doses in urgent situations (cardiovascular problem or impotency) and then tapered off to a lower dose

lntramuscular injection

7. Perform regular follow-ups

Patients who receive hormone replacement should be regularly checked. We recommend regular follow-up visits every 6 to 9 months once the initial therapy is producing stable effects, or anytime when adjustments are necessary due to changes in diet, work, sports, sleep, disease and stress.

28

2. Make the treatment more efficient 1. First step: Above ali, improve the diet, environment and lifestyle

lmprove the patient's diet before any other changes are made. The patient should eat a diet that is optimal for healthy endocrine function; the Paleolithic diet based on fruits, vegetables, meat, poultry and fish, improves best the efficacy of a hormone therapy in most patients. Dairy products such as milk, yoghurt and cheese, from the cow, goat, sheep or horse are among the worst foods to eat for the endocrine system. They disturb hormone activities by a variety of mechanisms such as digestive problems, allergies, yeast overgrowth, blood acidification, liver overload, etc. Also unsprouted grains such as bread, cereais, pasta, baked goods, are unfit for optimal hormone activities because they often cause digestive problems with gluten, gliadin allergies, yeast overgrowth, inhibition of digestive enzymes, etc.). High glycemic index carbohydrates such as sugar, starches, sweets, chocolate, cake, corn flakes, muesli, biscuits, soft drinks, alcohol, and also the added sugar in ham, sausage, and salami, tend to ruin the benefits of various hormone treatments by promoting yeast overgrowth and slowing down the secretions of at least 6 hormones (ali the hormones able to increase the blood sugar levei such as cortisol, growth hormone, testosterone, DHEA, androstenedione and estradiol). The following table presents the effects of various types of foods and drinks on hormones. High dietary intake Good Hormone activities

Protein

(meat, poultry, eggs, fish) ij

Melatonin activity Growth/IGF-1

activity Thyroid

activity activity DHEA activity_

Cortisol

Aldosterone Estradiol

activi!Y_ lnsulin

activity

Progesterone

activity Testosterone

activity Notes:

reduces

Good Bad

Carbo-

Protein

hydrates

(milk products) ij

(lowsugar fruits, veQetables) ij

?

O?

Bad Carbohydrates (sugar, sweets, unsprouted cereais)

ij ?

Alcohol

Fats

(saturated)

ij ij severely ? reduces severely lncreases/ reduces reduces reduces? reduces reduces increases reduces increases

reduces/ O? increases reduces reduces increases increases reduces O? O? increases reduces reduces? o

increases reduces reduces reduces

increases

reduces

o

reduces

reduces

increases

improves

worsens

O?

worsens

worsens

improves/ worsen_!?l

increases

reduces

o

reduces

reduces

increases

increases

reduces

o

reduces

reduces

lncreases

increases

reduces

The abbreviations "reduces" means "lowers" the activity, "increases" that it increases it, has no effect and blank spaces ar "?" that its effect is currently unknown.

"O" that it

29

Furthermore, it is essential to decrease the amount of pollution in the patient's environment. Many pollutants damage and weaken endocrine glands and can favor cancer development. Also baking at low temperatures (maximum of 90°-1 00 C, 194-212° F) or by steaming, and boiling, avoids the production of many toxins such as heterocyclic aromatic hexosamines that o

are carcinogens and are produced when food is cooked at high temperatures. lmprove the lifestyle. Minimize stress. Get daily physical activity.

2. Second step: Correct the hormone deficiencies

1)

Apply the above mentioned safety principies that are efficacy principies as well:

Physiological doses,

bioidentical hormones,

best brand,

best

product,

safest

route,

progressive start, regular follow-up, etc. 2) Correct ali deficiencies:

Nutritional therapies should be given for nutritional deficiencies. A single hormone therapy is the treatment for a single hormone deficiency.

However,

whenever multiple hormone

deficiencies are found, they should ali be treated if possible. 3) Fully involve the patient in the treatment to have him cooperate lnform the individual as complete as possible on the what's, how's and why's of the

detected deficiencies and how to treat them.

Give him explanations on cause and

consequences of the hormone deficiencies, on the signs and symptoms of over- and underdoses of the treatment and on the most frequent other possible treatment problems. The information boosts the patient's interest for the treatment and transforms him or her into a hard-working and reliable partner in maximizing the results of therapy. Depending on the quality of the information given, the patient will be able to report to the physician that something is wrong and thereby become able to help in correcting any problem as soon as it starts. Adapt the treatment to the patient's compliance and motivation to be treated.

Strategically, it may be a losing situation for a physician to insist on treating a moderate deficiency if the patient for whatever reason refuses to be treated. lnsisting a little too much may make that the patient rebel and not only make him or her refuse a given hormone treatment, but also refuse to follow ali other treatments that are criticai to his or her health.

4)

Patients should contact their physician when necessary

Side effects may occur. Questions of importance may rise in the head of the patient. When a patient quickly contacts his physician for answers and solutions, most problems are quickly solved.

A close collaboration greatly enhances the patient's trust and ease with the

treatment. 5) Balance judiciously the hormone therapies with one another

A good knowledge of the effects of a hormone therapy on other endocrine activities helps the physician to balance and optimize hormone treatments.

Often, dosages of a hormone

therapy may be reduced when other corrective hormone treatments are given that increase the efficacy of the treatment. On the other hand, the dosage of the hormone treatment may need to be increased, if the second hormone treatment reduces the efficiency of the original hormone therapy.

30

The principal effects as they appear in practice are summarized in the following table. Effects of hormone therapies on the activity of other hormones Meia-

Net

tonin

effect

u

Melaton.

Corti-

u

u

u

stim.

Thyroid

activity

T3, T4

stim.?

activity

GH activity

GH

1

Cortisol

activity DHEA

activity IGF-1 activity lnsulin

activit/

Estradiol

activity

Progest.

activity

Testost.

activity

Inh. stim.

stim.1

stim.1

inh.

inh.

stim./ lnh.5

?

?

stim.

stim. ?

stim.

stim.

stim.

inh./ stim.

stim.

in h.

stim.3

stim.

inh.

stim.

stim.

inh.?

stim.4

stim./ inh.

sol

DHEA IGF-1

u

?

?

stim.

stim.

stimJO / inh.

stim.1

stim.1

stim.1

inh./0

inh.

inh.?

?

inh.?

inh. stim./ O/inh.6 stim./0/ inh.6 stim./ O/inh.6 stim./ O/inh.6 stim./ O/inh.6

u

?

Inh. stimJ O/inh.6 stim./ O/inh.5

u

lnsulin

stim.

stim.

ProEstradiol

geste -rone

Testosterone

u

u

u

stim. transd. E27 stim.? inh. (oral E) stim. only stim. transd. E27

? stim.

inh.

stim.1

stim.1

inh. esp. oral E7 inh. esp. oral E stim. transd. E27 stim.(tr.E2)7 inh. (oral E)

inh.8

stim.

?

stim.

stim.

stim.

?

stim.

inh./ 79 stim '

inh./ 10 (stim) stim./ (inh.)

stim.

stim.

stim.

stim.

stim./ (inh.)

stim./ (inh.)

stim.

stim.

stim./ inh.

stim.

stim.

stim./ (inh.)

inh.

inh./

(stim)'

Abbreviations: "inh." means inhibits or /owers, "stim." that it stimulates!increases, "O" means absence of effect and "?" signifies yet unknown.

Hormone therapies often have "stim"ulating ar "inh"ibiting

effects on other hormone activities, changes in hormone activity that can be recognized by patients. Notes:

1

Severa/ hormone therapies increase thyroid activity by accelerating the conversion of thyroid hormone T4

into the much more aclive T3. lt is noteworthy that a minimum amount of T3 itself is necessary for lhe conversion. 2 A stimulation of insu/in activity improvement such as an increase in insulin activity and sensitivity or a reduction =

3

4

in insulin resistance in insulin-resistant patients or increased insulin production in insulin-deficient persons. GH stimulates ovulation, boosting both estradio/ and progesterone production in women. GH increases lhe amount of testosterone that diiffuses form the blood into the target cells by reducing the binding of testosterone to SHBG, lhe blood transporter of ma/e hormones via a lowering of lhe blood leveis of SHBG.. By

this mechanism, GH lowers the leveis of testosterone in the blood, but increases them inside of the target cells, boosting testosterone's physical effects. 5 At low, physiologic doses, thyroid hormones reduce cortisol action; at high and excessive doses thyroid hormones increase lhe breakdown of cortiso/ and thus reduce cortiso/ activity. In most cases, cortisol therapy does not reduce other hormone activities when given at low doses to correct a deficiency, but prolonged intake of excessive doses may cause inhibition of hormone activity. Transdermal estradiol has often a completely different impact on other hormone activities than oral estrogens, as it does not much increase lhe blood leveis of lhe (hormone) binding proteins. Oral estrogens reduce hormone activities by increasing lhe hormone (transporting) binding proteins in blood, thereby increasing the binding of lhe hormones, an effect that ends up in reducing the amount of bioavai/able hormones that can enter the cel/s. 8 Progesterone can reduce the salt-retaining effects of cortisol by its diuretic effect. 9 Progesterone's main role is to reduce estradio/ levels in men and women, but at the same time progesterone may amplify some beneficiai effects of estradiol in women. 10 Testosterone works in women as a progestogen and generally reduces estradiol activity, but in men and some women after menopause who do not take tema/e hormone replacement, testosterone may convert into estradiol through lhe enzyme aromatase and, thus, increase lhe estradiol levels.

31

111.

Follow-Up of Hormone Treatments

How do you follow up with hormone therapies? When to have the patient return

We recommend holding the first two consultations one month apart. The first consultation is for diagnosis (detection of hormone and other abnormalities, which includes the prescription of laboratory tests). The second consultation is for reading the laboratory test results and outlining the treatment regimen.

The one-month interval leaves time enough to receive the

results of all lab tests. Later on, follow-up consultations can take place successively two, six and fourteen months after the start of the treatment.

After the patient is stabilized, later consultations should take

place every six to nine months. The minimal time between two consultations should not be less than two months because that is about the time necessary to see any important changes with most hormone therapies. The first consultations in time and content are overviewed in the following table. Consultation

Time

Type

What to check or prescribe •

Check the answers of the patient to the selfreport questionnaires, including: - Past and present health (medicai history

First day

1st consultation

including família! history, complaints)

Diagnosis

- Diet choices and habits e o

=>

diet advice

Procede to the physical examination Review previous lab and imaging tests

=>

prescribe additional and more extensive hormone lab tests in blood and 24-hour urine •

Check the results of the hormone lab tests =>

One month later 2"d consultation

prescribe the hormone treatment,

explaining the patient how to start and

Treatment

contrai the therapy, mentioning any possible unwanted effects

2-3 months after

therapy start 6 months after

thera()y start 12 to 14 months after therapy start

3'd consultation 4th consultation 5th consultation

1st follow-up

o

Prescribe a limited number of blood tests for

•

Check health problems during the last three

contrai of testosterone, DHEA, .. treatments months, the actual complaints, diet changes,

of treatment 2"d follow-up

lab test results, body examination •

3'd follow-up

Every 6 to 9

6th and later

41h and later

months

consultations

follow-ups

Prescribe a number of blood and 24-hour urine tests for contrai of hormone treatments and other abnormal tests in previous checks

•

Adjust hormone treatments and diet, possibly adding new hormone therapies for correction of hormone deficiencies that initially seemed less urgent

What to check during the follow-up?

The physician should review any complaints of the patient, physically examine him/her and check the results of lab tests. Checking the patient's complaints and examining his/her body are important as they reflect the hormone states, the degree of impact the hormone treatments have on the patient.

35

How often do you perform lab testing? ldeally, laboratory tests should be done three to four weeks before each consultation so that results are in the patient's chart at the time of the visit. For patients who do not have insurance coverage and cannot afford the expense of the tests, repeating the test every other consultation with a limited blood check may often suffice providing that the physician carefully monitors for hormone-related complaints and physical signs, and is able to recognize signs of even minor changes in hormone states.

What to do just before the test? Remain calm and sedentary. No morning jogging, nor sexual intercourse or hurrying through a traffic jam before the blood test, as this would eievate the stress hormones and mislead the physician in this interpretation of the lab tests. The physician must know the baseline hormone leveis, not the stress-activated ones. The patient should come to the laboratory having not eaten, on an empty stomach, but in well­ hydrated state, having drunk water, one half to two thirds of a liter of water (not coffee) an hour or two before the blood test. This avoids possible misinterpretation of lab tests caused by dehydration, a condition that misleadingly increases the concentration of the hormones that are bound to them. How? When a person is dehydrated, the water content diminishes in the blood vessels, while the concentration of blood binding proteins that are too large to get out of the blood vessels increases, and thereby that of the hormones that are bound to them.

When to do the laboratory tests during the follow-up? As hormone leveis peak during the first two to nine hours after hormone administration, it is not advisable to check blood leveis during those hours, but !ater. For oral DHEA and pregnenolone, and transdermal testosterone (and transdermal estrogen in women with hysterectomy), it is best to check the leveis 8 to 14 hours after the treatment has been taken, when the blood leveis have stabilized to leveis that are more or less the 24-hour average ones, the leveis that are of interest to evaiuate the effect of the hormone treatment. In order to do this, it is wise to ask the patient to switch over from a morning administration to an administration before bedtime during the three days before the blood test. The blood is taken in the morning after the third evening intake.

For thyroid therapy, take blood 24 hours after the last intake on the next

morning, as an evening intake of lhe medication may preveni lhe patient of sleeping well.

What laboratory tests should you do? Every year or two, doing an extensive laboratory assessment such as lhe first initial laboratory assessment is very helpful. For more information on the tests that are useful for a first initial assessment, please return to the subchapter "What do you check in an initial assessment?" at the beginning of the chapter "introduction". Except for the aforementioned extensive lab checkups, the laboratory tests useful for most follow-ups are more limited. Reanalyzing the blood tests of the main hormones such as sex hormones, IGF-1, thyroid hormones, DHEA sulfate, etc.), retesting some basic biology tests such as serum lipids and glucose and checking ali the tests lha! showed abnormalities lhe first time, may suffice. Of course, these tests should compliment the essential interview and physical examination.

36

The minimal range of tests to regularly check during follow-up, are listed in the table below: Minimum tests for follow-up ESSENTIAL SIMPLE BLOOD TESTS Kidne_y_s_írenal function) • •

Creatinine Urea (BUN)

Minerais • •

Lipids

Magnesium (erythrocytic) Sodium

Vitamins

• Triglycerides Vitamin E • • Total cholesterol Vitamin 812 • • HDL cholesterol Vitamin 89 in red blood cells • (erythrocyte folic acid) Atherogenic ratio totai/HDL Sugar (glucose metabolism) Trace Elements • fasting Glucose or Hemoglobin A1 c • Cancer Tests Ferritin (iron) • • Zinc For men: PSA, free and total • For women: CEA or CA15.3 •

ESSENTIAL BLOOD HORMONE TESTS Thyroid

TSH Free T3 Free T4

• • •

GH- Liver - IGF-1 Axis

•

IGF-1 (somatomedin C) IGF-8P-3

• •

Adrenal Hormones

DHEA sulfate Sodium • Potassium Pregnenolone (sulfate)

• • •

Female Hormones •

•

Estradiol (in men and women) day of the menstrual cycle Progesterone (mainly for women at the 2151)

Mate Hormones • • •

Testosterone SHBG Androstanediol glucucoronide (or if not available: Dihydrotestosterone)

Pancreatic hormone •

lnsulin

24-hour URINE TESTS (optional in follow-up) Thyroid

Free T3 Free T4

• • •

Pituitary Hormones

•

GH

Adrenal Hormones

17-ketosteroids· 17-hydroxysteroids·

• •

Note:

Female Hormones •

16-alpha -hydroxy-estrone

Mate Hormones •

Free Testosterone

OTHER ESSENTIAL TESTS: ali other

tests with abnormal values on previous reports .

The 17-ketosteroids and 17-hydroxysteroids are breakdown products (metabolites) of DHEA and cortisol, respectively. They are of /esser interest when oral treatments of DHEA and cortiso/ are given. As explained in the next page, these treatments profoundly disturb the urine tests because of the arrival in the urine of excessive amounts of the hormones and their breakdown products, that do not reflect real metabolic activity but just excessive tiver breakdown of cortisol and DHEA. ·

37

Which tests are more difficult to interpret during follow-up?

For follow-up, blood tests of TSH, free T3 and T4, cortisol and some other hormones may be difficult to interpret. The hormone treatment increases the fluctuations of the hormone leveis in the blood, and more precisely generates peak leveis just after absorption of the medication and Jower-than-normal levels 24 hours after. For follow-up in well-balanced treatments, 24-hour urine analyses of cortisol, DHEA and their metabolites (the 17-hydroxysteroids and 17-ketosteroids respectively) as well as of pregnandiol (metabolite of progesterone) may show abnormally high leveis that do not reflect the metabolic activity. The high urinary excretion of cortisol and DHEA is due to excessive losses of cortisol and DHEA in the urine, losses that take place when these hormones just after absorption enter the bloodstream at high leveis that exceed the binding capacity of the transporting binding proteins. The high leveis of metabolites found in the urine during oral hormone treatments come from the important breakdown and thus spilling by the liver of the hormones after absorption, breakdown products that will then be found as supplementary amounts in the urine that do not reflect metabolic activity.

Laboratory Tests that cause problems when used for follow-up Where Blood

Test

Cause

•

TS H

The corrective hormone treatment makes these

•

Free T3 & T4

hormone leveis fluctuate more often and more

•

Cortisol

intensely. During

oral

cortisol

and

DHEA

treatment,

excessive amounts of cortisol and DHEA are excreted in the urine because of the high peak Urine

•

DHEA

•

cortisol

leveis that occur after arrival in the bloodstream following absorption from the gut. The excessive cortisol and DHEA overwhelm the capacity of the blood binding proteins to bind them. The unbound hormones

increase

temporarily

in

excessive

amounts, and Qet excreted in the urine too easilv. •

•

•

17-hydroxysteroids

After absorption in the intestinal tract the liver

(cortisol metabolites)

breaks down much of the cortisol and DHEA,

17-ketosteroids

before these hormones enter the bloodstream.

(DHEA metabolites)

This unutilized and broken down cortisol and

Pregnandiol

(progesterone metabolite)

DHEA will be excreted as breakdown products in the urine. These excessive urinary metabolites do not reflect increases of cortisol or DHEA metabolic activity.

38

How to adjust the dose of a hormone treatment based on the results of the follow-up exams and lab tests. To adjust the dose of a hormone treatment up to optimal levels, please physically examine the patient and review hormone-related complaints and lab tests.

Look for signs of hormone

deficiencies or excess. This "clinicai" examination matters for the follow-up at least as much as the laboratory tests which only point out if there is a major hormone excess or deficiency in patients.

The clinicai information is crucial for finer adjustments of the dose of hormones, in

particular to distinguish between doses that are slightly too low or too high. lf signs of deficiency are found, increase the dosage. lf overdose signs are found and no other causes for these signs are discovered, then lower the dose. Please do not forget to check for other causes of inadequate dosage. The intake of caffeinated drinks during a thyroid treatment, for example, can cause thyroid overdose signs because of the high amounts of caffeine in these drinks.

What to do when the dose is too high? lt depends on the extent of the overdose.

When it is major, it may be necessary to stop the

hormone treatment for one or two days (but not more) in order to accelerate the return to the optimal state. The cessation is advisable for major excesses of thyroid, growth and male hormone treatments.

However, it is not generally advisable for therapies with oral cortisol or

transdermal estradiol whose effects do not persist more than 24 hours. lowering the dose is often the best tolerated approach.

39

In such situations,

IV.

Hormone Therapies for Deficiencies

Chapter One

Melatonin Deficiency and Treatment

A Patient with Overt Melatonin Deficiency Melanie and her sleep troubles Melanie is a 42-year-old Caucasian woman who looks a little older than her age. Almost ali the time, some anxiety shines through her eyes and her face looks slightly contracted, expressions of her tension and neNousness. lt is not easy for Melanie to relax. Her muscles feel tense ali day and she has to make a conscious effort to relax her muscles. Her blood pressure tends to be somewhat higher than normal, peaking at 150/90. At night in bed, it is difficult for Melanie to fali asleep. She tries hard but it usually takes an hour or more before she succeeds. Any noise that occurs during the night wili wake her up and once woken up, she has a hard time faliing asleep again. Her husband says she's agitated when she sleeps, because she moves ali the time in her bed.

Periodically, although she hates it, she

takes sleeping pilis. Because of her poor sleep, she feels sleepy in the morning. At breakfast, she takes a lot of coffee to stay awake, but restrains from taking any after lunch, because she knows that this will greatly aggravate her sleeping problem. When traveliing over long times across time zones, she suffers from jet lag. She feels sleepy during the day, while she is wide-awake at night. Most of Melanie's problems are typical of a person with melatonin deficiency.

To better

understand what this deficiency means and how to treat it, let us review some basic information.

43

Melatonin: lmportant lnformation Roles of Melatonin Melatonin induces sleep.

lt shortens the time to fali asleep, but has little to no effect on the

deep sleep and rapid eye movement phases.

lt does induce at night a profound relaxation of

muscles and nerves, which makes the sleep better.

Melatonin acts as an anti-spasmodic for

the intestinal tract, relaxing it when it is contracted and tense. lt protects against free radicais by its antioxidant property, possibly slowing down the aging process and the appearance of various age-related diseases. Melatonin helps in setting the pace for circadian rhythms such as the sleep-wake, temperature and hormone cycles. lts action on circadian rhythms is less powerful than that of sunlight and activity, but nevertheless significant enough to explain the beneficiai effects of melatonin supplements against j et lag. Melatonin can increase the serum leveis of growth hormone, and also of thyroid hormones, by increasing the conversion of poorly active thyroid hormone T4 into the active thyroid hormone T3. Furthermore, it calms down excessive cortisol activity. Last but not least, melatonin may help pregnancy by boosting female hormone production, a paradoxical effect, as it tends to suppress female hormone production in the non-pregnant state.

Production of Melatonin Daily melatonin production by the pineal gland is estimated at 30-100

Principal metabolite of Melatonin:

119

per day.

6-sulfatoxy-melatonin, measurable in the urine

Leveis of Melatonin The

highest

leveis of melatonin are observed at night and are due to an intensive production

by the pineal gland during sleep. The

lowest

leveis of melatonin are found during the day: one-third to one-sixth of night-time

leveis. They are mainly due to melatonin secretion by the intestinal tract.

Factors that increase the night-time melatonin production Having the eyes closed, total darkness, exposure to strong morning light.

Melatonin leveis decrease with age The highest night-time melatonin leveis occur in childhood, before puberty. During puberty, there is a steep decline during puberty.

In adulthood, there is a slow but progressive decline.

By age 80, a person has a 70-80% drop in the melatonin blood levei during the night when compared to that of a young adult.

44

I. Melatonin Deficiency: DIAGNOSIS

How do you detect Melatonin Deficiency?

The best way to detect melatonin deficiency is to combine severa! approaches. Review the patient's past medicai history, diseases and complaints. Search for physical signs, and obtain laboratory tests typical for melatonin deficiency.

1. Onset of Melatonin Deficiency When did the melatonin deficiency start (past medicai history)? lt is possible in some cases to know if a person had a melatonin deficiency as early as childhood. The main differences are summarized in the following table. Determining the Onset of Melatonin Deficiency Onset Physical appearance Sleep Sleep-wake cycle

In adulthood

In childhood • •

Precocious puberty

•

Disturbed sleep began

•

Delayed sleep phase · syndrome in childhood

Disturbed sleep started in adulthood

in childhood •

Premature aging

•

Delayed sleep phase syndrome in adulthood

· Note: The delayed sleep phase syndrome is the tendency to go late to bed and wake up late. After this quick check, it is important to inquire about the timing of the patient complaints.

2. Timing When do melatonin complaints occur?

Most signs and complaints of melatonin deficiency appear at night as sleep disturbances and the next day with signs and behavior indicating that the patient did not sleep well. The next step is to check for the complaints of melatonin deficiency.

45

3. Complaints of Melatonin Deficiency What are the usual complaints of melatonin deficiency? The patient who suffers from melatonin deficiency expresses complaints that, similar to the physical signs, mainly result from a poor sleep and an excess in muscle tension, circadian rhythm disturbances or from an increase in free radical damage. The principal symptoms suggestive of melatonin deficiency are listed in the following table:

Complaints suggestive of Melatonin Deficiency PHYSICAL Sleep

• •

Muscles

•

Physical

•

appearance

•

Energy/vitality

•

Intestinal tract

• •

Agitation Restless leQs syndrome at niQht Tense muscles, especially at night Premature aging in adults Precocious puberty in children Fatigue Abdominal pain Intestinal spasms (hyperactivity) MENTAL

Poor sleep: •

Sleep

• • • •

Sleep-wake cycle

•

•

Mood

•

•

A superficial, anxious, agitated sleep with a lot of anxious thinking Easily waking up during the night Difficulties to fali asleep and fali back asleep Poor dreaming lmportant jet lag symptoms when going to another time zone Delayed sleep phase syndrome (tendency to go to bed late and wake up late) Anxiety, lack of serenity, inner peace of mind, especially at night Depression, especially seasonal affective disorder Excessive emotionality, irritability

With this basic knowledge we can now examine the details of the body of patients suspected of having a melatonin deficiency

46

3. Physical Signs of Melatonin Deficiency What are the signs that suggest melatonin deficiency? Signs of melatonin deficiency have not been abundantly described in the literature. However, three major types of physical signs may predominate: those resulting from poor sleep and muscle tension due to the lack of melatonin's sleep-promoting and muscle relaxing effects, those for disturbance of circadian rhythms including hormone cycles and resulting hormone deficiencies and imbalances, and those caused by free radical damage due to the lack of its antioxidant action. Possible Signs of Melatonin Deficiency TYPES

Circadian rhythm disturbances

Lack of relaxation

Behavior

•

Nervous behavior Prematurely aged*

Face/bocly_ Eyes

•

Anxious eyes

Muscle

•

Tense muscles

•

•

Heart BP

Free radical damage

• •

Looking tired, having not slept well (bags under the eyes, ...) Bradycardia (slow heartbeat) Faint heartbeat

High blood pressure

Note: * pale, ear/y graying, flabby muscles, etc.

After checking for complaints and for typical body signs of melatonin deficiency, it is important to look for diseases that may develop more easily with a melatonin deficiency.

4. Disease Susceptibility Which diseases develop easier in persons with melatonin deficiency? Human and animal studies have suggested that melatonin deficiency may contribute to diseases such as jet lag, high blood pressure (arterial hypertension), heart disease (ischemic coronary disease, heart arrhythmias), obesity, diabetes, osteoporosis, colitis, infections (due to a lower immunity), breast and prostate cancer, Alzheimer's disease, Parkinson's disease.

5. Lab tests for Melatonin The best lab test for melatonin is measuring its major metabolite 6-s-melatonin in 24-hour urine. Lab Tests for Detection of Melatonin Deficiency Route Urine Saliva Saliva

Optimal value

Test

24-hr or 8-hr overnight collection at 2-3 p.m. at 2-3 a.m.

6-sulfatoxymelatonin Melatonin

>40 6 55-70

Melatonin

47

Probable Deficiency

References

Test Value

35

1 0-55 1-19/day

High

0-4 40

1-8 pg/ml 25-80 pg/ml

Medi um

o-

o-

11. Melatonin Deficiency: TREATMENT

Melatonin Medications Sublingual tablets or drops of a solution of melatonin are the most efficient treatment for

melatonin deficiency. Compared to oral melatonin, the sublingual route presents three advantages: a faster action as it is quicker absorbed into the bloodstream, a more reliable and constant action as the absorption of a sublingual form is greater, while the absorption of oral melatonin is more irregular, easily disturbed by digestive troubles, and a much smaller (one­ third to one-fifth) dose requirement as apparently more is absorbed. Melatonin Treatment Route

Sublingual

Oral

Product

Speed

Doses

Melatonin

Fast release

0.05-1 mg/day

(0.1-0.3 on average)

Fast release

(often 1 mg/day)

Melatonin

Slow release

Value

0.5-3 mg/day

1-5 mg/day

Observation

High

First effects 10-15 minutes after intake

Med

First effects 30-60 minutes after intake

Low

Often too long action (continued drowsiness 1 hour after awakening)

How to Begin Melatonin Therapy We recommend beginning with a low dose and then to increase or decrease the dose following the reactions of the patient. lf a patient reacts strongly by sleeping firmly the first three or four hours and then waking up too early, with excessive sweating, heart pounding and then is unable to fali back asleep for two to four hours, s/he has definitely overdosed. The dose should be considerably lowered to a third or a quarter of the initial dose. How to Start Melatonin Treatment Melatonin

When to take?

Adrenal status

Starting Dose

Optimal dose

(cortisol leveis) Sublingual

10--30 min. before bedtime

Weak (low

Oral

30--60 min. before bedtime

Weak

Oral slow release

60--120 min. before bedtime

cortisol)

Normal Normal Weak to normal

48

0.1--0.2 mg 0.25-0.3 mg 0.5-1 mg 1-3 mQ 0.5--2 mg

0.05--0.5 mg per day 0.1-1 mg per day 0.25-1.5 mg per day 0.5-5 mQ per day 0.5-5 mg per day

Progress with Melatonin Treatment How much time is needed to improve with treatment? Melatonin therapy can be very quick in its effects: it often works from the first night on. lmprovement may be more noticeable two or three weeks after the start of the treatment.

lndications for Melatonin Treatment Permanent indications: Ali degrees of melatonin deficiency Occasional indications: 1. Circadian rhythm disorders: •

Jet lag

2. Conditions with increased free radical production: •

Stressful periods

•

Cerebral vascular accidents (stroke)

•

Myocardial infarction

•

Heart arrhythmia.

Contraindications to Melatonin Treatment Absolute contraindications:

No absoluta contraindication exists to our knowledge to melatonin treatment. Relative contraindications: •

Arthritis

•

Autoimmune diseases

•

Pregnancy

As melatonin can counter cortisol activity, it is wise to be prudent with melatonin with diseases where needs in cortisol are greater. lf no cortisol or glucocorticoid treatment is given with these diseases, avoiding melatonin altogether may sometimes be the safer solution. Doses higher than 1 O mg per day may inhibit the ovaries so that the use of high doses of melatonin in pregnancy is contra-indicated.

49

How to Boost Night-time Melatonin First, you can boost melatonin by improving the lifestyle, including eating a better diet.

What is important to do and to avoid for optimizing melatonin leveis is summarized in the following table. How to optimize Night-time Melatonin activity and treatment When During the day

in the office or living room

•

•

•

•

Evening •

At night

in the bedroom

{conditions that reduce melatonin production)

WhatTo Avoid

WhatTo Do

• •

•

lncrease morning daylight, thereby increasing day/night contrast. Expose the eyes to bright morning sunlight {using a sunlamp on cloudy days). Spend time outside during the brightest part of the day{1 O a.m.-2 p.m.) Relaxation in the evening:

Spend some time relaxing every day, especially in the evening Maximize darkness at night, thereby increasing daylight-night-time darkness contrast: Make the bedroom pitch black Use black-out drapes or blinds Block out any light coming from digital clocks, nightlights or light coming in from the window Use an eye mask

•

•

Diet: Avoid alcohol and, caffeinated drinks {coffee, tea, cola) Smoking:

Avoid tobacco

•

Avoid stressful activities in the evening {esp. emotional stress)

•

Avoid sleeping next to electrical devices {clock, radio, ventilator, etc.) Avoid living under or close to high current electrical

•

cables

Secondly, melatonin leveis can be increased by correcting other hormone dysfunctions that relate to melatonin.

Hormone replacement therapies that can influence melatonin production and its effects on the body1 are summarized in the following table. lnfluence of Hormone ReplacementTherapies on Melatonin Melatonin Stimulators • •

Melatonin lnhibitors

{use if necessary) Transdermal estradiol in menopausa! women Growth hormone1

• •

{avoid or use minimally) Glucocorticoids at high doses Thyroid hormones

Note: 1 Based on reports from patients and physicians. This information needs to be confirmed by scientific studies.

50

Follow-Up: How to do the best follow-up? 1. Find the adequate dose: Most melatonin sold is in tablet form or capsules containing excessive doses for the sublingual route. The optimal dose may vary widely from one individual to the other. The most frequent conditions for dose adjustment are listed in following table.

When to adapt the Dose of Melatonin? INCREASE the Dose

When •

Permanently Occasionally

•

lntensive emotional stress - increase the dose by 50-150%

•

Jet lag increase by 100-200% the first 3 days after arrival, then by 50-100% the next 3 days Cortisol (glucocorticoidl_excess

•

Occasional

(25-200% more) lnsufficient melatonin effects

/permanent conditions •

LOWER the Dose •

(25-75% less) Excessive melatonin effects

•

Unstressed, holidays

•

lncreased physical activity

•

Transdermal estradiol Hypothyroidism Growth hormone therapy 1

• •

Note: 1 This information needs to be confirmed by scientific research

How to treat jet lag: Double or triple the dose the first three days after arrival and take 1.5-2 times the dose during the next three days. Then go back to the regular dose. What to do at the end of a very emotionally stressful day:

lncrease the dose by 50-150%

before bedtime. 2. Avoid overdosing and underdosing:

This is done primarily by checking signs and complaints of melatonin over- or underdosage. When do you check? The patient should monitor himself for improper dosing every day and the physician should follow-up with the patient every two to nine months. The main complaints of melatonin overdosing are reviewed in the table below. Melatonin Overdose Signs

Frequency

Most frequent

•

followed by an early wake-up • often strong heart beats with excessive sweating when waking up • great difficulty of falling back asleep • feeling of having a heavy head in the morning Very lntense dreaming, awakening with great difficulty to distinguish reality from dreams Excessiva sleep of 9 to 11 hours with difficult awaking Shorter but deep sleep of 3-4 hours •

Rare

•

Rare

•

3. Correct any problems during follow-up quickly and efficiently

51

111. Melatonin PROBLEM SOLVER How do you solve problems that occur during treatment? No dangerous side-effects are known to be caused by use of melatonin, but some unpleasant ones may occur.

Besides the classical signs of melatonin excess (overdosing), the most

frequent problem results from an inhibition of cortisol activity by melatonin which is a particularly annoying effect as low cortisol can cause so many undesirable effects. The possible problems and what to do about them are explained in the following tables. Problems possibly due to Melatonin Overdose OVERDOSEPROBLEM?

POSSIBLE CAUSE -

Shorter but deep sleep of

3-4 hours, followed by

SOLUTION

Melatonin overdose: The strong

-

an early wake-up

-

often strong heart beats

hyperthyroidism resulting from

with some excess sweating

melatonin's excessive stimulation

when waking up

of the conversion of weakly active

-

Reduce the

1.

heart beats accompanied by

dose of

excessive sweating are due to

great difficulty of falling

thyroid hormone T4 to active T3,

back asleep

3-4 hours after intake of melatonin.

feeling of a heavy head in the morning

-

melatonin by 75%.

Check for any

2.

borderline high thyroid or growth

1

hormone therapy

Another, but rare, possibility:

and reduce these

GH excess caused by melatonin's

if necessary.

activation of the GH axis. lntense dreaming Awakening but with great difficulty to distinguish

Melatonin overdose

Reduce dose of

reality from dreams

melatonin, often by

Excessive sleep of 9-11 hours with difficult

3 to 4 times less Melatonin overdose

wakinQ in the morning Note:

1

Normally, low doses of melatonín stímulate thyroíd actívíty 6-8 hours after íntake wíthout sígns of

excess thyroíd hormones but wíth the feelíng of havíng a refreshíng wake-up.

In contrast, when

melatonín dosage ís excessíve, a transíent hyperthyroídísm may occur quíckly, 3 to 4 hours after íntake, duríng the níght, awakeníng the patíent at a too ear/y hour.

Problems possibly due to Cortisol Deficiency PROBLEM

POSSIBLE CAUSE Cortisol deficiency:

• • •

Headaches Low blood pressure Fatigue especially when standing up

Melatonin therapy, even, at physiological doses, may further decrease cortisol leveis in persons with borderline or overtly low cortisol levels causing fullblown cortisol deficiency

52

SOLUTION Take lower doses of melatonin: 2 to 4 times lower. Correct the cortisol deficiency if symptoms of cortisol deficiency persist, take ± 30 mg hydrocortisone per day, for men, 20 for women, or a synthetic derivative if indicated. See chapter on cortisol for more info.

Chapter Two

Growth Hormone Deficiency and Treatment A Typical Patient with Growth Hormone Deficiency Fred and his exhaustion Fred, a big man at 6'1, 180 lbs

(1

meter 85, 82 kilos), worked hard most of his life. However,

recently he felt the weight of his 57 years. For two or three years, things were changing.

His sense of inner peace was progressively

vanishing and replaced by a permanent feeling of anxiety unfamiliar to him. He was losing his energy. Years ago he worked well beyond the hours required of him and had even been thought of as a workaholic. workday.

Now, he could barely make it through the hours of a normal

His employer started to complain. Fred's sleep pattern had also changed.

He

needed more sleep. Even eight to nine hours of sleep was inadequate for him to fully recover and regain his energy. His physical appearance had also changed. He found it hard to look at himself in the mirror. Where had the young guy gone? His cheeks now sagged and his eyelids drooped. Even his lips were thinning.

And it wasn't any better with the rest of his body. Where had the large

muscles he was so proud of, gone? They seemed to be replaced by fat, fat everywhere. particular, his fat belly disturbed him and, unfortunately, dieting didn't really help. What is Fred suffering from? Most of Fred's problems are typical of growth hormone (GH) deficiency. In order to better understand what this deficiency means and what you can do about it, let's get some basic information first.

53

In

GROWTH HORMONE: lmportant lnformation Roles of Growth Hormone (GH) GH is a major hormone with prominent roles. First, GH is a major anabolic hormone that powerfully builds the body and is responsible for a great part of the growth that takes place during childhood and puberty. GH increases the size and volume of brain, skin, hair, muscles, bones and internai organs. Without growth hormone, we would ali be dwarfs!

In adults, growth hormone substantially helps to maintain the

appropriate volume and tone of the skin, muscle and bone. A decrease in growth hormone production causes an acceleration of the aging process: our skin, muscle and tissues begin to atrophy and sag, wrinkles and fat begin to replace our once smooth skin and muscles. Second, GH increases the function, repair and health of muscles, heart, lungs, liver, kidneys, joints, nerves and the brain.

GH's mental and emotional impact is substantial because GH

stimulates the parasympathetic nerves, which contain many mood-calming neurons. Thanks to this effect many patients on GH treatment report feeling calmer, experiencing feelings of inner peace and a clear increase in the overall quality of life, and ability to concentrate and cope with stress. Via these mechanisms, GH may relieve depression, anxiety and nervousness.

Leveis of Growth Hormone By far, the highest GH leveis in the blood are found during the first three to four hours of

sleep at night in men and women. During the day, no detectable blood GH leveis are found in men, except three to tive small bursts of GH.

In contrast, women generally have a low but

detectable and relatively constant baseline GH levei throughout the day.

Production of Growth Hormone The majority of GH is produced during the first three to four hours of the sleep by the pituitary gland.

GH production peaks in adolescence, reaching about 1,500 �g per day.

In well­

developed young men and women at age 25, production averages about 350 �g per day. Tall, large muscular athletes generally produce substantially more than small, thin and poorly muscled adults.

Production and Leveis of Growth Hormone Decline with Age From age 30 on, GH's production and leveis decline at a sharper rate than most other hormones do, about 1-3 % a year. One study showed at age 40 an average production of about 200 �g a day for lean men, but 80 �g in obese men!

IGF-1 or Somatomedin C lnsulin-like growth factor 1 or IGF-1, also named somatomedin C, is a hormone, produced by the liver under stimulation of GH and intake of food, protein in particular.

IGF-1 mediates and

thus produces a large part, but not ali, of GH's effects. Measuring serum IGF-1 leveis is a good marker of GH activity because it has more stable blood leveis than GH during the daytime.

In

contrast, daytime leveis of serum GH are only useful to screen for acromegaly, where a pituitary tumor produces huge amounts of GH during both the day and night. They are not accurate in other people because they are very low compared to the high night-time leveis. lt takes one month of GH treatment for serum IGF-1 to increase and stabilize at a higher levei.

54

I. Growth Hormone Deficiency: DIAGNOSIS How do you detect GH deficiency?

The best way to detect GH deficiency is to combine severa! approaches: review the patient's past medicai history, diseases and complaints, search for physical signs, and obtain laboratory tests typical for GH deficiency (including medicai imaging if needed).

1. Onset of G H Deficiency When did the growth hormone deficiency start? To answer this question, physicians should interview and examine the patient. People who are GH deficient since childhood, are small with thin bones and muscles. Their bodies are relatively sexually immature. Complaints of a low quality of life are present but are usually less severe than in subjects who developed GH deficiency !ater in adulthood. This may be because people with early GH deficiency have adapted to their state not having known any other condition. The differences between child onset and adult onset GH deficiency are listed in the table below. Determining the Onset of Growth Hormone Deficiency ONSET General

Height Face, eyebrows,

nose, jaw bones, chin, hands, feet Muscles, Bones

Adulthood

Childhood •

Major physical impact (dwarf)

•

Less severe emotional impact

•

Short stature

•

Dwarf

• •

• •

Sex organs

•

Body Hair

•

Quality of life

•

•

Small Thin

• •

•

• •

Thin and small Sexual immaturity Small genitais: micro-phallus, micro-clitoris Sexual immaturity Less body hair, the pattern is prepubescent or pubescent Moderately impaired

• • •

• •

•

Major emotional impact

Physical impact is less severe (Qremature aging) Normal height, but beginning to hunch over (up to severe kyphosis) Normal-sized but thinning and sagging Atrophy Sexual maturity Normal sized genitais, but atrophying Sexual maturity Diffuse thinning of body hair, but adult hair pattern Severely impaired

After this check it is important to inquire about the timing and location of the patient's complaints.

55

2. Timing and Location When and where do GH signs and complaints manifest? When? Symptoms of a growth hormone deficiency persist throughout the day, but will considerably worsen if the patient has not slept enough (8 to 1 O hours). Sleep deprivation will cause these patients to feel exhausted. Where? GH deficiency primarily affects skin, muscles and banes. However, genital areas may also be affected in men and women with early GH deficiency, from childhood onward. Genitalia are sexually immature and body hair is restricted to much smaller areas.

With this basic knowledge, we can now examine the details of the body of patients suspected of having a GH deficiency

3. Physical Signs of GH Deficiency What are the signs that suggest GH deficiency in an adult? These physical signs are summarized in the following table. Physical Signs suggestive of Adult Growth Hormone Deficiency Body

Hair

•

Sparse thin hair

•

Prematurely aged body

Face

•

Droopy eyelids

•

Obese body

•

Sagging cheeks

•

•

Thin lips

•

•

Neck Shoulders

•

Thin nose with the tip pointing downward Thin jaw banes

•

Loose skin folds under the chin

•

Small or smaller shoulders

•

Thin muscles

Arms

•

Hands

• •

•

•

•

Droopy triceps Thin muscles Thin fingers (atrophic metacarpal banes)

Trunk

•

Abdomen

•

Back

Thighs

Stretch marks on the abdomen

• •

(reduced muscle tone at lhe palm of lhe hands, esp. just beneath lhe thumb and under lhe little finger)

Feet

The next step is to check for the complaints of GH deficiency.

56

A fat, droopy abdomen Kyphosis (hunchback)

•

Atrophied palm and hypothenar eminence

Small difference between maximal expiratory and inspiratory circumference of the chest

•

•

Nails with striae (longitudinal !ines)

Small sexually immature body (childhood- onset)

•

•

Prolonged skin folds after pinching the skin at the back of the hand

Normal-sized, sexual aging or atrophying body (adulthoodonset GH deficiency)

Hyperlordosis (increased lumbar curve) lncreased subscapular skin fold Sagging back muscles that look like drapery folds Sagging inner thighs Fatty "cushions" (fat deposits) above the knees

•

Reduced foot arch or flat feet

•

Muscular atrophy of foot sole

4. Complaints of GH Deficiency What are the usual complaints of GH deficiency? Growth hormone has major effects on the mind and mood. Severe growth hormone deficiency, especially when the deficiency started in adulthood, considerably impairs the quality of life. Some patients experience it as a severe collapse. People who acquire GH deficiency in adulthood suffer more severely, possibly because they remember how much better their lives were before the deficiency started. The principal complaints of GH deficiency are summarized in the following table. Complaints suggestive of Adult Growth Hormone Deficiency MENTAL COMPLAINTS

Quality of life

• •

Mood

• •

Self-esteem

• • •

Efficacy

• • • •

Social behavior

• • •

Stress

•

Poor quality of life, feels unwell Lack of inner peace Chronic anxiety, without any reason Tendency to be depressed Low self-esteem Lack of self-confidence Great difficulty in performing multiple tasks Feeling powerless Lack of concentration Lack of self-control Excessive emotional reactions, sharp verbal retorts Dramatizing, outbursts of panic and anxiety Tendency to social isolation lmpaired social status (lower professional position, lower income, poor social integration, often without partner, living still with parents) Poor stress tolerance; may collapse from minor stress

PHYSICAL COMPLAINTS

Health Physical appearance Feet

• • • • • •

Energy/vitality

• •

Temperature Sex (men) Sleep Food

• • • • •

Poor health Degradation of physical appearance Muscle and skin: thinning, loosening and weakness Obesity Sore feet after lonQ walksl_caused tJy_colla_m;ed arches) Exhaustion with poor or no recovery Difficulty in recovering when not having slept enough Feeling of rapidly aging, feeling of profound physical degradation Cold intolerance Erectile dysfunction: lack of volume and persistence of erections Light sleep Excessive need for sleep- 9 hours or more Poor appetite for meat (because of the low anabolic state that decreases the appetite for protein)

After checking for complaints and for typical body signs of GH deficiency, it is important to look for other diseases that may develop more easily with a GH deficiency.

57

5. Disease Susceptibility Which diseases develop easier in persons with GH deficiency? The following diseases may evolve more easily in patients with a GH deficiency: cardiovascular diseases (including high cholesterol, heart failure, atherosclerosis, hypertension), obesity, type 2 diabetes, and possibly Parkinson's disease and to a lesser degree Alzheimer's disease as these two illnesses seem to mildly respond to GH replacement.

6. Lab Tests for Growth Hormone Because many signs and complaints of GH deficiency can also be caused by a male hormone deficiency such as muscle wasting and obesity, laboratory tests are essential to differentiate between a deficiency of either of the two hormones. Lab tests will also help clarify the extent of GH deficiency. The principal tests for detection of GH deficiency are summarized in the following table. Laboratory Tests for Detection of Growth Hormone Deficiency Optimal3

Test

?

ãi

0-250

0-33

1

220-300

0-180

IGF B P-3

1 (binding protein)

29-40

0-24

3000

> 4000

75

>100

1

114-492 l..lQIL

15-65 nmoi/L 2000-4000 l..lQ/1

50-100 nmoi/L

Basal GH

Women: 0-1.5

0-6 ng/ml

(daytime)

Women>

Women: 0-70

0-280 pmol/ml

> 25

>1165

Notes:

114-492 l..lQ/1

15-65 nmoi/L

Women >1

Stimulated GH2

.c: Cl) r:: III:J' ·.:::: N :l

Value

39-46

-

o o

Test

(21-30 vrs)

300-350

IGF-1-women "O

References

C)

IGF-1-men (somatomedin

Probably GH Deficient

> 2000

GH

>95

0- 15

High High

ng/ml

=

119/L; stable

leveis, no! influenced by meals; essential to test with IGF-BP-3

High leveis reduce bioavailable IGF-1 Women have often

Low

detectable daytime leveis, men rarelv

>10 ng/ml

4

0-3.3 for insur

0-700 0-153 for insur4

High

Comment

The test to obtain

Low

insurance coverage for GH treatmenT4

>465 pmol/ml

0-1500

0-3500 ng/24h

Low -

0-70

0-165 nmol/24h

Med

Value depends largely on quality of laboratorv test

" " > means "more than"; "<" means "less than"

/GF-1 shou/d imperative/y be measured by RIA (radioimmunoassay) to get the accurate /GF-1 leve/ and not by the

more recent, but unreliable technique called chemoluminescence.

Unfortunately, most /aboratories nowadays use

the chemoluminescence method that does not require the use of an expert physician in radioactive tests and a

2

special safe and approved /aboratory unit for radioactive material.

The secretion of GH can be stimulated by GHRH, insulin, arginine, L-Dopa, clonidine, propanolol, g/ucagon or

exercise.

These tests are generally required by insurance companies to confirm the diagnosis before

reimbursement.

3

In some patients,

these tests may help determine if treatment with growth hormone

secretogogues can be successful to treat GH deficiency.

The optimal value proposed here corresponds to the average value found in young healthy adults of average size.

Large and tal/ persons have higher optimal GH values (approximately

350-450 for large men, 300-350 for large 180-

women), converse/y, short and thin people have lower optimal GH values (about 200-300 for sma/1 men and

250 for sma/1 women).

4 Reimbursement for GH treatment is obtained when serum GH after stimulation is below

58

3.3 nglml or 10 lU/m/.

11. GH Deficiency: TREATMENT GH Medications Growth hormone deficiency is best treated by injections of growth hormone. products are on the market. Most of them are of equal quality.

The following

Growth Hormone Medications Product Genotonorm Genotropin Mini-Quick

Humatrope, Umatrope

Company Delivery Vials of 1.3 mg Pen (5.3, 12 mg) Pfizer Syringes of 0.2, 0.4, 0.6, ..up to 1.8, 2 mg

Eli-Lilly

Vials of 5 mg

GeneScience

Maxomat

Sanofi

Norditropin

Novo Nordisk

(Nordipen)

briefly not refrigerated, remains good

Vials of 5 & 10 mg

Supplied with 2 or 10 ml diluent

depot

Vials of 13.5, 18, 22.5 mg

Omnitrope

Sandoz

Vials of 5 mg Vials of 1.33 mg Vials of 5 & 8.8 mg

Serono

Pen of 8.8 mg

(one-click, cool-click) Serostim Somatotropin

Zomacton

Serono ( U SA) Eurohormone Ferring

High

Low?

Hig_h High

Genentech

Saizen

Individual ready to use syringes- ideal for travelers unable to keep GH refrigerated, not more expensive Some patients have found that Humatrope may quickly lose its potency once the vial has been opened for longer than lhe period of time recommended by lhe producer

Supplied with 2 ml of bacteriostatic water Vials of 1.3 mg Supplied with 1 ml of bacteriostatic water Vials of 1.33 mg Pen of 5, 10, 15 mg The stability of GH in Nordipen vials, even if

Vials of 1O mg

(Nutropin) Pen 1 O mg

Nutropin

High Hig_h

Good product

Med

Genentech

Nutropin

V alue

Less used

Possibly lonQer potency than reQular vials Not registered in lhe USA or Europe; possible product contrai problems; once the vial is started => quick potency loss

Pen of 6, 12, 24 mg Jintropin

Observation

Once a month subcutaneous injection, good for poorly compliant patient; in 2007 to 2010 out of production Excellent quality, stable at room temperature if accidentally left out of lhe refrigerator, cheapest (-10 to -25%) Supplied with 1 ml bacteriostatic water Supplied with 5 or 10 ml of diluent A cheap pen using spring pressure and needles, you push on a button and the needle is pushed into lhe skin (one-click) or a needle-free device (cool-click)

Vials of4, 5, 1O mg Supplied with 1 ml vial of sterile water Device with needle Pen (Serojet) Vials of 81U Vials of4 mg Pen of 10 mg (Zomajet)

Low

High High

Med High Hig_h High High High Hig_h

Black market, same remarks as for Jintropin, less potent than regular brands

Low

Supplied with 1 or 3.5 ml of diluent

Hig_h

A pen using air pressure (no needles), needs correct handling

High

lmportant note: The product quality column is a subjective evaluation of the product based on personal experience and reports from patients and colleagues. No responsibility is taken for the information. The aim is exclusively to provide physicians with practical information; See also the warning in the beginning of the book.

59

What is the best way to inject GH? How to inject GH 1.

Use a thin needle

2. Use a new needle each time. The needles of most injection pens may be reused for two or three consecutive days, but each time a needle is reused the needle becomes more dull which may cause pain and difficulty penetrating the skin.

3. Inseri the needle subcutaneously, but do not penetrate the muscle. An oblique injection angle just under the epidermis avoids penetrating and

Howto inject GH

damaging muscles. 4.

Inseri delicately and avoid pinching the skin between two fingers which may cause bruising.

5. Change the injection site regularly. For instance, starl injecting on the lateral side of the abdomen and every day move the injection site lower by two finger-widths until the pubis is almost reached. Repeat this pattern at the middle abdomen, and opposite lateral abdomen until ali the parls of the abdomen have been injected. Next, proceed to the lateral upper thigh following the same spacing until the lower third of the thigh is reached, then starl at the upper front of the thigh and then go to the other thigh.

lnjection sites Via I users

Abdomen, thigh (ventral and externai sides), side of the buttocks To avoid infecting the via!, keep the rubber top of the via! covered with the attached aluminum tab. Absolutely avoid inserling a used needle back into the via!: you are almost cerlain to inject infectious germs and contaminate the via!. In general, one droplet will leak from the needle once you have injected the

Pen users

solution and removed the needle from the pen. Do not worry. This is positive as it rinses away any unwanted infectious germs. Most manufacturers add extra GH to the via! to compensate for this loss.

Women

Women usually need higher doses

Obese patients

that are

(20 to 35% more).

Massive obese patients seem to be relatively GH-resistant. They need doses

50% to 200% higher than lean patients.

Patients with corlisol deficiency may badly react to GH, as GH furlher reduces

Cortisol deficient patients

their production of corlisol. Even if they are supplemented with glucocorlidoids, they may still not well tolerate GH, so that it is wise to starl treating such patients at lower doses than for the average patient (see furlher pages for more information).

Children

Children who are GH deficient need on the average about seven times higher doses of GH than adults.

60

How to begin GH treatment? There are two different ways to start growth hormone treatment: at a "high" or at a "low" dose regimen. The best method depends on firstly, the strength of the adrenal glands (reflected by

the lab test leveis of cortisol and its urinary 17-hydroxy-metabolites and by the patient's signs

and symptoms) and secondly, the degree of urgency to obtain quick results.

GH treatment is poorly tolerated in persons with low cortisol leveis. When GH is given, cortisol

leveis decrease by 10-40%, which is too much for people with borderline low leveis. In these persons, besides giving cortisol replacement therapy, we recommend starting GH therapy at

lower doses than usual. To avoid problems it is best in most cases to start with a lower dose and then gradually increase the dose.

Two different ways of starting GH treatment according to the strength of the adrenal glands are represented in the following two tables.

STRONG ADRENALS

(High to average cortisol and 17-OH-steroids without signs or complaints of cortisol deficiency) PRINCIPLES •

higher dose and

gradually

Take GH every day before

bedtime only

OR 1/3 of the dose in the

morning, 2/3 in the evening;

increase by

Before

•

patient about

the signs of GH

overdose so

that he can

report them

quickly if they

occur and thus

Saizen (1.33 mg/ml

=

Saizen: 5 mg/5 ml

3.9

(0.5 mg/ml

IU/ml after reconstitution) 1 0.25 ml/day

1.5 IU/ml)

mÇJ

I.U. DOSE:

mÇJ 0.33

=

1

0.66 ml/day

0.33

0.5

0.33 ml/day

0.165

0.165 ml/day

0.0825

I.U. 1 0.5

2"d month 3'd month 3'd, ih &

Follow-up consults: the patient is examined and GH dose

months

Optimal dose (on average): 0.06 ml - 0.30 ml/day

0.125 ml/day 0.165 0.06 ml/day

0.0825

0.25

0.25

h 15t month adjusted, either increased or decreased depending upon needs 4h & t later lncrease the dose by 0.06 ml every 1O days; INJECTION PEN:

INJECTION PEN:

Before

lnform the

VIAL:

Zomacton, Norditropin,

GH DOSE:

1st month

0.1O mg every month

GH TREATMENT VIAL:

bedtime

reduce

•

TIME

Start GH at a

bedtime

Norditropin Simplex (Nordi-

pen) (5 mg/vial One click

GH DOSE:

1st month

2"d month 3'd month 3'd, i &

7 clicks/day 4 clicks/day 2 clicks

=

=

1.5 mllvial)

0.05 mg) mg

Saizen (one.click pen)

(8.8 mg/vial One click

I.U.

0.35 mg 1.05 0.20 mÇJ 0.60

0.10 mg 0.30

=

=

1.51 ml/vial)

0.11-0.12 mg

DOSE

mg

3 clicks/day 0.35 mg 2 clicks/day 0.23 mÇJ 1 click/day

0.12 mg

I.U. 1.05 0.69 0.36

Follow-up consults: the patient is examined and GH dose

h 15t month adjusted, either increased or decreased dependinQ upon needs 4h & t lncrease the dose by 0.1O mg every month; later

the dose can be months Optimal dose (on averaQe): 0.1-0.4 mg/day lowered Later: Follow-up consultations every 6-9 months

Note: 10.01 ml

=

0.0133 mg

=

0.0399 lU; 1 mg (milligram) of GH

61

=

3 lU (international units)

DEFICIENT or Moderately weak ADRENALS (Patient with average to low cortisol and

17-OH-steroid leveis, with or without signs and complaints of cortisol deficiency) PRINCIPLES •

•

•

•

•

TIMING

GH TREATMENT VIAL:

Start GH at a lower dose and gradually increase

VIA L:

Zomacton, Norditropin, Saizen: 5 mg/5 ml Saizen (1.33 mg/ml = 4 IU/ml (0.5 mg/ml = 1.5 IU/ml) Before after reconstitution) 1 bedtime GH DOSE mg I.U. DOSE: y mg I.U. 1st 10 days 0.02 ml/day 0.05 mllday 0.075 0.027 0.08 0.025 0.15 2"a 10 days 0.04ml/day 0.05 0.10 ml/day 0.050 0.16 lnject every 0.225 0.15 ml/day 0.075 0.08 0.25 3'd 10 days 0.06 ml/day day before 4 2"a- tn month 0.08 ml/day 0.11 0.1 0.20 ml/day 0.32 0.3 bedtime 4t n month Follow-up consultation: check and adjust doses (eventually 1 'd /3 of the 0.10 ml/day 0.375 0.125 stn month 0.13 0.25 ml/day 0.4 dose in the stn month 0.45 0.12 ml/day 0.16 0.30 ml/day 0.15 0.48 morning, 0.35 ml/day i" month 0.525 0.14 ml/day 0.175 0.19 0.56 %rds in the sth month 0.21 0.2 0.40 ml/day 0.64 0.6 0.16 ml/day gth evening) 0.72 0.225 month 0.18 ml/day 0.675 0.24 0.45 ml/day 4rt \ stn & 6th 1 Follow-up consults: patient is examined and GH dose lncrease month adjusted, either increased or decreased depending on needs; the dose by lncrease the daily dose with 0.02 ml every 1O to 30 days; 0.02 ml Optimal dose (average): 0.06 ml- 0.30 ml/day every Before INJECTION PEN: INJECTION PEN: 10 days Norditropin Simplex (+ Nordipen) Saizen (one.click pen) bedtime lnform the patient about GH overdose signs so that he can report them quickly if they occur and lower the dose

Omnitrope (+ Omnitrope pen)

(5 mg/vial

=

One click

1.5 ml/vial) 0.05 mg

(8.8mg/vial

One click

=

=

1.51 ml/vial) 0.11-0.12 mg

=

DOSE I.U. I.U. mg 0.15 0.18 1 click/2 days 0.06 2"a 15 days 1 click/day 0.12 0.36 0.3 2"d to 4th mo. 0.3 or alternate 1 & 0.12 0.36 or 0.45 2 clicks/day 0.18 0.54 4t n month Follow-up consultation: check and adjust doses h 5t month 2 clicks/day 4 clicks/day 0.23 0.69 0.20 0.6 t 0.25 s n month 0.87 Alternate 2 & 0.29 0.75 5 clicks/day 3 clicks/day & sth Correct 3 clicks/day 1.05 7 months 6 clicks/day 0.35 0.30 0.9 any cortisol 4t" stn & 16tn Follow-up consultations: the GH dose is adjusted, , deficit month lncrease the dose with 0.1O mg every month; Optimal Dose (on averaQe): 0.1 - 0.4 mQ/day 1st 15 days

GH DOSE 1 click/day 2 clicks/day 2 or 3 clicks/day

mg 0.05 0.10 0.10 or 0.15

Later: Follow-up consultations every 6-9 months Severe adrenal deficiency

lncrease two times slower and remain at lower doses

even if patient is treated for the adrenal deficiency:

lncrease the daily dose with 0.01 ml every 1O days or 0.05 mg every 30 days

=>

go up to maximum of 0.06 ml - 0.1O mg/day before the next follow-up.

62

How can you naturally boost GH treatment? First, improve the lifestyle and, in particular, the diet. The principal lifestyle recommendations for the patient to increase GH production or effects, are summarized in the following table. How to optimize GH activity and treatment What?

WhatTo Avoid

WhatTo Do

1. Eat sufficient calories 2. Follow a "Paleolithic" diet: fruits, vegetables, meat, poultry, eggs, fish1 3. Add amino acids (e.g. 2 g/day of glutamine in old & young persons, 7 g/day of arginine in young-lean subjects, lysine, etc.) 4. Eat organic foods2

Diet

Weight

•

Sleep

•

Stay lean

1. Avoid alcohol, vinegar, caffeinated drinks3 2. Avoid sugar, sweets, cookies, bread, pastas and other cereais 3. Avoid milk products

• •

Get adequate sleep

Stress

•

Abuse

• •

Avoid being overweight Avoid sleep deprivation Avoid excessive prolonged stress Avoid tobacco smoking Avoid marijuana and other drugs

Notes: 1 A high protein intake may actual/y /ower GH leveis in b!ood, but at the same time increase /GF-1 leveis. A higher (bioavailable) /GF-1/eve/ signifies that GH activity is increased as /GF-1, which is made in the liver under the influence of GH in /iver cells, is actually the best marker for GH activity; pesticides may a/ter GH secretion and effect;

3

2

Certain

Oecaffeinated drinks (where the caffeine has been

extracted by the safe method based on water and carbonic acid), may be an acceptab/e alternative.

Second, correct other hormone deficiencies. Many hormones can enhance GH production and its effects on the body. The principal hormone replacement therapies that can increase the secretion of growth hormone and/or its action, and those that can reduce or inhibit GH secretion, are summarized in the following table. Corrective hormone therapies that influence Growth Hormone Therapies Strong

Mild

GH/IGF-1 stimulators

stimulators

Mild

Strong GH/IGF-1

inhibitors

inhibitors • •

• • • • •

Testosterone, other androgens Estrogens (transdermal or injectable) Progesterone and progestogens Thyroid hormone Melatonin IGF-1 lnsulin (for insulin deficiency)

• •

• •

•

DHEA Cortisol at physiological doses Vasopressin Parathyroid hormone EPO

63

•

•

Cortisol, other glucosteroids at very high dosages Oral estrogens

•

Endogenous insulin (in the case of insulin resistance)

Growth Hormone Secretagogues In my experience most growth hormone secretagogues, including amino acids, GHRP (growth hormone releasing peptides), niacin, and other chemical substances, only work well in young adults, under 35, who do not really need them! This is because in order for the secretagogues to work, the person has to have enough healthy GH-secreting cells in the pituitary gland to be able to secrete supplementary quantities of GH, but if a person has this, he is not GH deficient and does not need to supplement GH. When GH secretagogues do work, their beneficiai effects seem to wane after six to ten weeks. For this reason the patient needs to stop the secretagogues for a period equal to the period of intake, in order to continue to have improvement. Nearly ali patients who have taken GH secretagogues said they feel better, generally strikingly better, when they begin to receive GH injections. lt seems that the improvement with secretagogues is temporary and only a small fraction of the improvement obtained with GH injection therapy. In conclusion, when there is a documented GH deficiency GH injections are the treatment of choice and GH secretagogues, if used, are only a complementary treatment to GH injections. In fact, the best GH-secretagogues are other hormones. Testosterone, transdermal estradiol (but not oral estrogens), thyroid hormones and melatonin are probably the best stimulators of GH secretion. Most of the GH secretagogues have to be taken before a normal GH secretion occurs, especially at bedtime and before exercise. An overview of the GH secretagogues is presented in the table below. GH Secretagogues, Table 1: Various compounds Route

Subcuta -neous injection Oral or nasal spray

Oral

Oral

Secretagogue GHRH

(GH releasing hormone) GHRP-6

Niacin

(Vit. 83)

Mechanism

Stimulates GH production directly

50-300 119/day

Stimulates GH production directly

1 0-50 119/day

lncreases GH secretion

0.2-1 g/day before sleeping

GHB

lncreases GH

(y-OH-

secretion, GABA precursor

butyrate)

Oral

L-Dopa

Transdermal

Trans-Dtropin®

Optimal daily doses

0.5-1 g/day before sleep

Dopamine lncreases GH secretion

125-500 mg/day before sleep

May increase serum GH

10-40 drops/day

64

Comment

Good data, but at prize and comparable dose to GH injections GHRH seems to have only about 50-60% of the efficacy of GH injections Short duration of action, magnitude of GH response seems less than with conventional GH injections Mild to good GH response but only in thin to normal weight patients; may cause a "niacin flush" for 20' (histamine release with artery dilatation); liver damage exceptionally from 0.8 g up. Potent GH response; may increase prolactin and sleepiness, cause muscle spasms and twitching Potent GH response; doses higher than 0.5 g/day may cause side-effects: nausea, vomiting, dizziness, orthostatic hypotension, arrhythmia, confusion, psychosis, depression, GIT bleeding lnsufficient data; is claimed to increase GH but not IGF-1

GH Secretagogues, Table 2: Aminoacids Secretagogue

Mechanism

Optimal daily doses

Arginine

lnhibits somatostatin release ; increases effects of GHRH when given together

7-12 g one hour before sleep or exercise

Highest GH response in young adults 20-35 years with low body fat and high aerobic capacity_

lncreases GH secretion

2.5-5 g/day before sleep

Highest GH response in young adults 20-35 years with low body fat and high aerobic capacity. Doses > 6 g/day may cause diarrhea

Lysine

lncreases GH secretion

1-3 g/day on an empty stomach one hour before sleep or exercise

Works only in young adults and about 1O times better in combination with arginine; Doses > 6 g/day may cause diarrhea

Glycine

lncreases GH secretion

5-7 g/day one hour before sleep or exercise

Good GH response, well-tolerated

L-tryptophan

Serotonin precursor that increases GH secretion during sleep

5-10 9 before sleep

Small response accompanied by drowsiness and sleepiness

Oral

L-glutamine

lncreases GH secretion

2 g/day before sleep

Good GH response, works also in older adults (32-64 yrs), virtually no side-effects

Oral

Commercial formulas: pro-HGH, symbiotropin, aminotropin-6, etc.

Mixture of amino acids with a GHRP or an inhibitor of somatostatin secretion

Route

Oral

Oral

Oral

Oral

Oral

Ornithine

65

Comment

See recommended

dosage by the producer

Works better in young adults

GH Secretagogues, Table 3: Other hormones, the most potent GH secretagogues Secretagogue

Mechanism

Thyroid hormones

lncreases GH secretion and serum IGF-1

Oral, sublingual

Melatonin

lncreases GH secretion

Oral

DHEA

lncreases serum IGF-1

Testosterone

Probably the most potent increase of GH secretion and serum IGF-1

Route

Oral

Transdermal IM, oral Transdermal

Dihydrotestosterone

Little or no increase of GH secretion

Transdermal

Estradiol

lncreases GH secretion and serum IGF-1

Subcutaneous injections

lnsulin

lncreases serum IGF-1

Optimal daily doses

Comment

Efficient at physiological doses (see corresponding chapters for doses and time of intake)

See corresponding chapters

Refer to expert

lndications for GH Treatment Growth hormone deficiency is the principal and almost only indication. Certain patients with cardiac failure who have good adrenals seem to also benefit from receiving GH treatment, whether they have been diagnosed GH deficient or not.

Contraindications to GH Treatment Currently, GH treatment is contraindicated in persons with aclive malignancy, benign intracranial hypertension and proliferative retinopathy. GH is not contraindicated during pregnancy at physiological doses in growth hormone-deficient women. lt is worth noting that the placenta produces GH so that lower treatment doses may be necessart during the second and third trimester of lhe pregnancy. Caution is nevertheless recommended.

Progress with GH Treatment How much time is needed for lhe first improvements to be fel!? GH treatment usually takes weeks before lhe first improvements appear. Quicker results can be obtained by starting at higher doses. In general, mos! of lhe improvements are fel! during lhe second, third and fourth months. Unlike mos! other hormone treatments, many patients continue to improve for two to three years after lhe start of treatment, even at doses equal to or lower than lhe initial ones, especially in people who have made major diet and lifestyle adjustments.

66

Follow-up of GH Treatment

1. Adjust doses up to the optimal dose:

The optimal GH dose may vary in various conditions. The most frequent conditions that may require a permanent or occasional dose adjustment in a patient already undergoing treatment are listed in the following table. When to adapt the Dose of GH Dose

lncrease the Dose

Lower the Dose

(50 to 200% more) • •

Chronic conditions

{25 to 75% less)

lnsufficient GH effects

•

Excessive GH effects

Low IGF-1 (and normal

•

Excessively high IGF-1 (and low to normal

to high IGF-BP-3) in

IGF-BP-3) in blood (near or above the upper

blood

reference value of young adults) •

•

Persistent (untreated) cortisol deficiency Type 1 and 2 diabetes (risk of aggravation during the first year)

•

Oral estrogen

•

treatment Acute to

•

conditions

(HRT, birth control pills)

chronic •

Persistent (untreated) hypothyroidism

•

lncreased physical

•

Melatonin treatment

•

Thyroid hormone treatment

•

Type 2 diabetes

•

DHEA treatment (rarely)

•

Decrease in physical activities (Sedentary,

activity •

•

Acute Conditions

• •

Testosterone, dihydrotestosterone or other androgen treatment

lntensive stress After surgery (if leveis of cortisol are sufficienl, olherwise GH will further lower lhe leveis of lhe indispensable hormone cortisol!)

bedridden) •

•

lnfections (e.g. flu, mononucleosis, ...) because of the danger of lowering cortisol leveis (a possible effect of GH therapy)

•

Allergies such as asthma, ear-nose-throat infections, skin rashes, etc. {because of the danger of lowering cortisol with GH)

Abdominal bloating (Amino acid

Unstressed, holidays, vacations

•

Crisis of rheumatoid arthritis (because of the danger of lowering cortisol with GH)

malabsorption)

The effects of GH or its production can be increased in patients by correcting other hormone deficiencies in them. Thus, many replacement therapies boost the effects of GH treatment so efficiently that often 30 to 80% lower doses of growth hormone are necessary to correct the GH deficiency.

In my experience, the most potent of these therapies is testosterone treatment.

67

2. Pertorm lab tests during follow-up.

The tests that can be done during follow-up are reviewed in the following table. Serum IGF-1 and IGF-BP-3, its binding protein, are the most helpful tests and often the only ones to do during follow-up. An increase in GH action is expressed by an elevation of plasma IGF-1 and, in particular, of the ratio plasma IGF-1/IGF-BP-3. Lab Tests for Follow-up of Growth Hormone Treatment

Type

Levei • •

Serum • •

24-hour urine Note:

*

•

Test Value

GH

Useless*

GH after stimulation with insulin, GHRH, arginine-vasopressin, etc.

Useless for follow-up

IGF-1

High

IGF-BP-3

High

GH

Medium

When to do it?

Second to fourth month after the start of the treatment

Except for follow-up of acromegaly treatment

As the cancer risk for intestinal cancer seems to be increased for patients with high serum IGF1 and low serum IGF-BP-3, it is wise to monitor these two lab tests closely and aim to bring both of these leveis close to the mean value of young adults. A normal GH treatment increases both serum IGF-1 and IGF-BP-3 (several studies suggest that high serum IGF-BP-3 are cancer protective), and thus should not be a cause for concern.

3. Avoid overdosing.

Signs and complaints of GH overdose should be well known by the patient and avoided. lf they occur, he should be taught how to reduce the dose. In an emergency, with some major intolerance, he may stop treatment for one or two days. The principal overdose signs and symptoms and what to do about them, are reviewed in the following table. Time lag before overdose signs appear after the start of the GH treatment After 3 to 4 days of GH excess

After 1 month or more ,

After 6-12 months

GH overdose signs • • • •

Edema of the feet, hands (possibly nose, lips, eyelids) Tingling fingers (carpal tunnel syndrome), tingling nose Excessiva muscle development (esp. shoulders and pelvis) Acromegaly (increased size of hands, feet, nose, etc.)

Note: 1 At GH doses about 5 to 30 times the doses used in GH rep/acement therapy for GH deficiency

4. Solve problems quickly and efficiently: See next section to know how to do it.

68

111. GH Problem Solver How do you solve problems that occur during treatment? The problems that are found most frequently are listed in the following tables. Problems due to an excessive GH dose: Problems possibly related to GH Overdose GHOVERDOSE •

Feet, hand (and possibly nose, lip, eyelid) edema

•

Tingling fingers, tingling nose

APPARENT CAUSE GH overdose causes excessive fluid retention,

SOLUTION

1.

aldosterone system (that

(1-3

grams a day) that counterbalance

partially by increasing the activity of the renin-

Take potassium supplements the sodium excess

2.

lf taking potassium is not sufficient, lower the dose of GH

leads to water retention) Testosterone and GH overdose. How? The excess

•

Excessive

GH lowers serum sex

muscle

hormone binding protein

development,

(SHBG), the transporting

1.

Reduce the dose o f GH

especially

binding protein of androgens

When lowering the dose of GH does not

shoulders and

in the blood.

sufficiently reduce the muscle

pelvis. This sign

A low SHBG sets androgens

overdevelopment and the patient is on

requires more

free and increases the blood

androgen therapy:

than one month

leveis of unbound

of GH overdose

bioavailable testosterone,

to develop.

resulting in a global increase

2.

Reduce the dose of androgens

of (intracellular) androgens in the target cells These signs almost never occur during normal GH replacement. The doses used are too small to cause them. The best solution is prevention: use only small physiologic doses. •

Acromegaly (enlarged hands, feet, etc.)

Extreme long-term (at least 6

1.

to 8 months) GH overdose =>

drastically by

increases the size of the

50-75%. After ali

swelling has disappeared, begin GH

extremities (nose, chin, hands, feet, etc. )

Mild acromegaly: stop G H for 6 weeks, or reduce the dose

at a 2.

30

to

50%

lower dose

Severe acromegaly (esp. in athletes who are doping with GH): stop for

34 months, or reduce the dose by 7590%, then after ali swelling has

disappeared, begin GH at a fraction,

1 0-40%

69

of the initial dose.

Problems caused by the GH treatment's stimulation of various hormone activities

GH can increase thyroid, androgen, estrogen and aldosterone activities. lt can slow down the activity of cortisol which is essential to blood pressure and stress resistance, and insulin which maintains the blood sugar leveis. Problems may occur from time to time during GH treatment because of the changes brought about by GH. The principal ones are listed below. Problems due to female hormone excess: Rare Problems with GH

I

PROBLEM

POSSIBLE CAUSE

SOLUTION

FEMALE HORMONE EXCESS (Hyperestrogenism) •

•

Breast enlargement

(Women)

Excessive breast development caused by lncreased leveis of free estradiol (E2) in the breast cells via a lowering of SHBG, transporting protein of sex hormones, due to GH therapy

•

• •

Reduce the dose of estrogen if using estrogen therapy Reduce the dose of GH or lncrease the dose of androgens (testosterone, DHEA, DHT)

lncrease the dose of locally and systemically administered DHT (better anti-glandular action than testosterone) and progesterone (transdermal progesterone and DHT) 2. Reduce the dose of testosterone, increase the dose of androgens that do not convert into estradiol (DHT, synthetic testosterone derivatives.) 1.

•

•

PseudoGynecomastia

(Men)

•

Breast development caused by GH therapy through high estradiol leveis in breast cells Breast edema caused by excess estradiol

Problems due to hyperthyroidism (excess in thyroid hormones):

Problems caused by GH's stimulation of thyroid activity PROBLEM

POSSIBLE CAUSE

SOLUTION

Lower the dose of thyroid hormones in thyroid patients 2. Lower the dose of GH (if no thyroid hormone is given or if lowering or even stopping the thyroid hormone preparation does not sufficiently correct the problem) 1. Administer GH in the morning rather than before bedtime 2. Reduce dose of thyroid or GH 1.

•

Excess heat, sweating

(especially at night), hunger

•

Difficulty falling asleep

Hyperthyroidism caused by GH through an excessive conversion of T4 into the active thyroid hormone T3

Hyperthyroidism caused by GH

70

Problems caused by GH's ability to stimulate androgen activity: Problems caused by GH's stimulation of androgen metabolic activities (hyperandrogenism) MALE HORMONE EXCESS •

POSSIBLE CAUSE

PROBLEM

1. •

SOLUTION

Excessive stimulation of the

Excessively

catecholamine /sympathetic

aggressive,

nervous system by excessive tissue leveis of T3 due to GH treatment

excess self-esteem

2.

Excessive leveis of androgens in

1.

Reduce the dose of thyroid hormone and/or androgens

2.

Reduce dose of GH treatment

1.

Adjust the diet: avoid sweets

brain cells caused by GH therapy Excessive production of sebum (oil) by the skin during GH treatment. GH

(especially chocolate) and

improves the uptake of androgens by

dairy products (especially

sebum cells, which produce the skin's •

Acne, oily skin

yogurt) as they may stimulate

oily layer. GH makes this possible by lowering blood leveis of SHBG, thus freeing up androgens that rapidly enter the target cells. The high androgen leveis in the sebum

sebum production 2.

3. Possibly reduce GH if results are still insufficient

cells overstimulate sebum production. Excessive stimulation of hair follicles

1.

by GH. How? GH reduces SHBG, the transport binding protein for •

lncreased body hair

2.

3.

cells such as the body hair producing

Excessive and persistent

1.

sensitivity (not painful, but unpleasant by its overwhelming nature)

Excessive stimulation of the

1.

erections 2.

Reduce dose of androgens (testosterone, DHEA, DHT, etc.)

which calms the mood but promotes

penis

Possibly reduce GH if the problem persists.

parasympathetic nervous system

erections and

lf necessary: block the conversion of testosterone to dihydrotestosterone

4.

growth. •

Reduce the dose of androgens (testosterone, DHEA. etc.)

eagerly enter and overwhelm target cells, resulting in increased body hair

Avoid using dihydrotestosterone (DHT)

androgens, and thereby sets many androgens free. These androgens will

Reduce dose of androgens (testosterone, DHEA, etc.)

2.

lf necessary: reduce the

Excessive increase in androgen

conversion to DHT by

receptors in the glans penis and

finasteride (Proscar®) or similar compounds

other highly sensitive genital areas under GH therapy

3.

71

Reduce the dose of GH

Problems due to cortisol deficiency or insulin resistance:

Problems of Reduction of Other Hormone Activities by GH Treatment PROBLEM

I

POSSIBLE CAUSE

SOLUTION

CORTISOL DEFICIENCY (Hypocortisolism) 1.

lmmune depression caused •

Severe flu,

Correct the cortisol deficiency with cortisol supplements or increase

by overt cortisol deficiency

the dose (if the patient is already

with GH therapy

on glucocorticoid therapy)

bronchitis or

(GH excessively lowers

other infection for

cortisol levels

5 to 6 weeks

borderline low cortisol levels

treatment with cortisol does not solve

collapse

the problem:

=>

=>

patients with /f no cortisol treatment is given or the

immune

depression) 2. •

Low stress resistance

•

Low blood pressure

•

Postura I dizziness,

•

Fatigue when stressed

•

Headaches,

•

Other signs of intolerance

1. Cortisol deficiency with GH

therapy (GH excessively lowers cortisol leveis

1. Correct the cortisol deficiency by

cortisol supplements, or if the

=>

patient is already on glucocorticoid

patients with borderline low cortisol levels collapse into a clear cortisol deficiency (syndrome) 2. Allergy to the GH

preparation (probably to the substances of the preparation other than GH such as solvents, etc.)

Reduce the dose of GH therapy

therapy, increase the dose 2. Choose another brand of GH

if no cortisol treatment is given or the treatment with cortisol does not solve the problem: 3. Reduce the dose of GH therapy

INSULIN DEFICIENCY (lnsulin Resistance) GH can mildly increase serum glucose. The increase occurs temporarily in diabetics during the first few months and then blood sugar goes back to •

Hyperglycemia

normal.

(diabetic

Note: in healthy persons GH is

patients)

very safe at physiological

slowly increase the dose by 0.05

doses. In order to increase

mg every 3 to 4 weeks.

•

glycemia and insulin, supraphysiological doses of GH up to 1 O to 30 times higher than usual should be given to healthy volunteers.

72

In diabetics, start GH treatment at low doses of 0.05 mg a day, then

About the Hormone Fears Cancer Risk and GH Treatment As GH makes tissues grow, there is some concern whether GH treatment could increase the risk of cancer. In children taking GH, no significant increase in the risk of cancer (even in leukemia and lymphoma) has been found. In children with brain tumors, GH treatment reduced the 5-year mortality by 50% and the brain tumor recurrence by 40%. In patients with advanced gastrointestinal cancers treated with GH injections, the duration of survival after surgery was (not significantly) increased by two months, but the recurrence and remission period were significantly increased. A study of more than 1000 patients with acromegaly (excess GH) showed that the overall cancer incidence was actually lower than in the general population, including breast and prostate cancer. However, some studies on acromegalic patients showed an increase in the incidence of colon cancer. In acromegaly, leveis of plasma IGF- 1 are extremely high, far above those found in patients treated with physiological doses of GH. The GH production in acromegalic patient may exceed by ten to hundred times the normal daily production. Data from acromegalic patients may not be as relevant to GH treatment with physiological doses of GH­ deficient patients. Nevertheless, the studies on acromegalic patients seem to support the increase in prostate cancer observed in about a sixth of the studies in men with high IGF- 1 leveis and the increase in breast cancer incidence observed in about a a half of the studies in women with high IGF-13 leveis. In fact, a sixth of the studies in men have shown high IGF- 1 leveis to be protective against prostate cancer, while the other studies showed neutra! effects. Moreover, rodent studies have shown that malignant prostate tumors may secrete IGF- 1 and there is some suspicion that breast cancer tumors may do it too. This finding suggests that the higher IGF- 1 leveis found in prostate and breast cancer patients is a consequence and a marker of the cancer, and not a cause or favoring factor. lt is worth noting that a study in women with breast cancer showed that malignant breast tissue has two to four times less receptors for IGF- 1 than benign breast tissue, suggesting that there is an IGF-1 resistance in breast cancer patients, similar to the insulin resistance observed in type 2 diabetic patients. This finding further suggests that it might be unlikely that high IGF-1 leveis would cause the cancer as the breast tissue of breast cancer patients is poorly responsive to IG F-1. lt may even suggest that breast cancer patients have deficient IGF- 1 activity and that low rather than high IGF-1 effect may favor the development of breast cancer. What happens to patients who have severe growth hormone deficiency? In fact, patients with hypopituitarism and thus GH deficiency have an increased cancer risk and mortality up to two to five times the normal risk. GH treatment of these patients reduces their risk by half for ali forms of cancer, except intestinal cancer. Anecdotal reports of GH treatment in terminal cancer patients seem reassuring as well.

lt

appears that GH treatment may, besides increasing the quality of life, slow down tumor progression and increase the duration of survival. Unfortunately, these anecdotal cases are not sufficient to draw definite conclusions and recommendations. lf any risk does exist however, this increased risk may not exist for patients on low dose GH treatment for GH deficiency which aims to restare the GH leveis back to normal. lt is also important to remember that GH is a powerful stimulator of the immune system, an effect that may help prevent or treat cancer.

73

Chapter three

MSH {Melanocyte-stimulating hormone)

Deficiency & Treatment

A Typical Patient with MSH Deficiency Vance and his sunburns and declining sexuality: Vance, of Caucasian race, used to tan well in the sun as a child and young adult. After the age of 40 he started to hesitate to expose his skin to the sun because he started to sunburn easily. His sexual potency remained high until his mid forties, after which he observed a weakening when he had sexual intercourse. Once every two months, when he was tired or too tired to have sex every day he would have trouble with erection or ejaculation. This put the idea in his head that his sexual potency was declining. lt made him feel less sure of himself and his potency. He had to use sexual fantasy more to stimulate his erection and ejaculate. In general he became less interested in sex. He put on weight more easily and in particular accumulated fat on his lower belly, which surprised him as he was on adequate hormone replacement therapy. These hormones; testosterone, growth hormone and DHEA, should have prevented fat accumulation. What is Vance suffering from? Vance is likely suffering from MSH deficiency. In order to better understand this deficiency, let's first provide some basic information.

75

MSH: lmportant lnformation Melanocyte-stimulating hormone:

Melanocyte-stimulating hormone or MSH is a peptide hormone that is derived from a bigger molecule called pro-opiomelanocortin.

Pro-opiomelanocortin is a precursor molecule made in

lhe pituitary gland that splits into alpha-, beta- and gamma-melanocyte-stimulating hormone, ACTH and beta-endorphins. Alpha-melanocyte-stimulating hormone is lhe most abundant MSH hormone in our blood and lhe most aclive MSH for skin pigmentation. MSH deficiency is often found in patients with deficiencies in other pro-opiomelanocortin-derived molecules such as ACTH (ACTH deficiency causes adrenal cortex deficiency) or beta-endorphin (beta-endorphin deficits increase pain sensitivity and lower mood), or in individuais whose protein intake is deficient (causing a depletion of amino acids necessary to produce peptides such as MSH). Roles of MSH:

MSH has many major beneficiai actions: 1.

MSH protects the skin against sunburn and melanoma: MSH protects against sunburn

by stimulating the production of the pigment melanin by melanocytes (melanin-producing cells) when lhe skin is exposed to sun. MSH may protect against melanoma by reducing the proliferation of human melanoma cancer cells. 2.

MSH may protect hair against graying. The possible anti-grey hair effect of MSH is

supported by various events. Firstly, grey and white hairs are produced when MSH receptors are blocked by antagonists. Secondly, treatment with MSH of severa! animal species with

premature

graying fur,

reverses the

greying.

Nevertheless,

anecdotal

experience in humans has not yet been confirmed in this capacity. Possibly, a treatment associating MSH with other pigment-enhancing hormones such as ACTH may produce better, synergic effects against greying. 3.

MSH reduces appetite, playing a role against bulimia and obesity.

4.

MSH reduces inflammation, opposes fibrosis and possibly decreases eczema.

5.

MSH potently boosts female and male sexuality, making the whole body more sexually sensitive. MSH has potent beneficiai mechanical or 'physical' effects on sexuality. Psycho­ sexual aspects of sexuality such as sexual drive and erotic fantasies are also enhanced by MSH in women and men. Some sexologists repor! that lhe administration of an alpha-MSH analogue boosts sexuality in women far more than any other hormone. lt enhances the sensitivity of the skin to sexual caress, as sexual arousal, vaginal lubrification, clitoris sensitivity, orgasmic capacity and other aspects of sexuality in women. In female rats, MSH increases the attractiveness of sexual odors of females for male rats. In men, administration daily or three times per week is reported to increase the frequency, duration and volume of erection, and make sexual intercourse easier and more successful. At least one repor! says it is better than Viagra®.

6.

MSH may help us live longer. In patients with AIDS, a premature aging syndrome,

the

serum MSH leveis correlate positively with 6-month survival. Further evidence for MSH's potential to extend life is found in a study that shows that lhe mortality of people that are likely low in MSH such as subjects with grey hair is slightly higher than in individuais of lhe same age without grey hair.

76

Production and serum leveis of MSH

The daily secretion of MSH has to our knowledge not been investigated in humans, but may approximate the 50 119 per day, an estimation based on the doses efficiently used in human studies with injectable MSH or an analog are considered. The leveis of MSH decrease with age:

In humans, serum leveis have been found to be significantly lower in healthy elderly patients compared to young adults. In rats, MSH has been shown to decline in brain tissues, but not in the serum.

Factors that increase MSH production:

A diet sufficiently rich in animal proteins, which provides amino-acids, increases the production of MSH. Malnutrition, fasting or low protein diets such as vegan diets do the opposite. Melanocortin receptors

Five known different melanocortin receptors have been discovered, each with differing specificities for melanocortins:[ •

MC1 R is associated with pigmentation genetics.

•

MC2R is also known as the ACTH receptor or corticotropin receptor because it is specific

for ACTH alone. •

MC3R is involved in the anti-inflammatory effects, mildly involved in sexuality

•

MC4R o

lnvolved in appetite reduction; Defects in MC4R

=

a cause of autosomal

dominant obesity, accounting for 6% of ali cases of early-onset obesity.[5]

•

o

Also highly involved in sexuality

o

lnvolved in anti-inflammatory effects.

MCSR is possibly involved in immune system stimulation, anxiety reduction, correct function

of exocrine glands, including sebaceous glands). Principal types of MSH:

Melanocyte-stimulating hormone belongs to a group calied the melanocortins. This group includes ACTH, alpha-MSH, beta-MSH (longest structure of the MSH's) and gamma-MSH (sortest structures of the MSH's.; these peptides are ali cleavage products of a large precursor peptide calied pro-opiomelanocortin (POMC). Alpha-MSH is the most important melanocortin for pigmentation. Among the most know synthetic derivatives: Melanotan I and 11, and bremelanotide (formerly PT-141 ), a metabolic derivative of melanotan 11 that lacks the terminal amide NH2 group, replaced by a hydroxyl OH group. •

Synthetic analogues of alpha-MSH have been developed for human use: melanotan I (or afamelanotide), melanotan 11 and bremelanotide.

Melanotan 11 and bremelanotide have

more potent effects on sexuality. Melanotan I is being investigated as a method of photoprotection in patients with erythropoietic protoporphyria, polymorphous light eruption, actinic keratosis and squamous celi carcinoma (a form of skin cancer. Melanotan 11 causes enhanced libido and erections in most male test subjects and arousal with corresponding

77

genital involvement in most female test subjects.

Unlike Viagra and other related

medications, it does not act upon the vascular system, but directly increases sexual desire via the nervous system. Bremelanotide (formerly PT-141) seems to have equivalent or higher potency than melanotan 11 on sexuality. The use of bremelanotide has raised concerns of increased blood pressure by intranasal route, not by subcutaneous route. The different melanocyte-stimulating hormones and their synthetic derivatives are represented with their characteristics in the table below:

Melanocyte-stimulating hormones and their derivativas Mole-

Amino acids

Type

Mole-

13 amino acids :

CnH10s Ac-Ser-Tyr-Ser-Met-Giu1665.87 N2o02oS His-Phe-Arg-Trp-Giy-LysPro-Vai

a-MSH

22 amino acids : Ala-Giu-Lys-Lys-Asp-GiuGly-Pro-Tyr-Arg-Met-GiuHis-Phe-Arg-Trp-Giy-SerPro-Pro-Lys-Asp

13-MSH (longer)

MCR

Anti-

Potency

inflam-

on

Appetite

matory

melanine-

potency

production

reduction

++

++

++

+ (?)

+

±

+

+ (?)

+

+

NO

?

MC2R

++

+ (+)

NO

+(+)

MC1R

?

+++

No elfect

No elfect

+

+++

+ (mainly limited to the initial stage)

+++

+ (?)

+

± (?)

+++

(melanocu lar cor!in weight Formula receptor) cu lar

Effects on sexuality

MC1R MC3R MC4R MC5R (MC1R)

2,661

MC3R MC4R

y-MSH (shorter)

12 amino acids: Tyr-Vai-Met-Gly-His-PheArg-Trp-Asp-Arg-Phe-Giy

1571

ACTH

39 amino acids

4,541

(MC1R) MCR 3

c21oH315 NS?Os,S,

Synthetic derivatives

Melanotan

I, I

13 amino acid residues: Ac-Ser-Tyr-

or afamelanotide

Ser-Nie-Giu-His-0-Phe- 1646.9 Arg-Trp-Giy-Lys-Pro-ValNH2

Melanotan 11,

7 amino acid residues : Ac-Nie-

Melanocortin

Melonocortin 11,

cyclic structure

cyclo[Asp-His-0-PheArg-Trp-Lys]-NH2

C?BH111 N21019

MC1R 1024.18 CsoHagN

o

1509

MC3R MC4R (MC5R)

7 amino acid

residues:

Bremelanotide

formerly PT-141 , cyclic structure, developed from melanotan 11

Ac-Nie-cyc/o[Asp-His-0Phe-Arg-Trp-Lys]-OH or cyc/o-[Nie4, Asp5, OPhe7, Lys10]alpha-MSH-

(4-10).

1025.2

CsoHaaN 14010

(MC1R) MCR3 MCR4

lt is a metabolite oi Melanotan 11 that Jacks lhe C-terminal amide function.

Note: Beneficiai effects are noted as 'no effect", '±' (means mild effect), '+ ' (moderate effect), ' ' ++ (potent effect). A question mark '?' means that the information needs confirmation.

78

I. MSH Deficiency: Diagnosis How do you detect MSH deficiency?

lndications in past health, physical signs, patient complaints, concurring diseases, lab tests and possible medicai imaging produce the best picture for detection and evaluation of the degree of MSH deficiency.

1. Onset of MSH deficiency When in life does a patient of Caucasian race start to develop an MSH deficiency? A Caucasian patient who easily gets sunburn and was never able to tan well, has an MSH (activity) deficit since childhood. People with red hair and some people with very white skin have an inability to become brown in the sun, while their MSH leveis may increase in a normal manner in the sun. Their problem is that the baseline levei of MSH is lower than in normal tanning individuais and that they fail to increase their melanin production at higher MSH leveis due to mutations in the MC1 R gene and a lower levei of the enzyme tyrosinase that stimulates melanin formation. The same is valid for blond-haired individuais, although their ability to brown in the sun is better. In adult-onset MSH deficiency, patients had normal tanning in the sun in childhood, but gradually lost the ability to tan in the sun as adults, starting to sunburn more and more easily with age. At the same time, sexuality progressively decreased in these individuais. The differences between the two types are summarized in the following table: Determining the Onset of MSH deficiency Onset Skin color

Since Childhood • •

Sun tanning

• •

Hair

• •

Body

Inflam-

•

mation Sexual

•

Since Adulthood

White skin

•

Great difficulty or inability to brown in the sun Easily sunburns

•

•

Needs high protection sun lotions (<:: SPF30) Often red or blond hair

•

•

Possibly overweight or obese sincE childhood because of excessive appetite History of inflammatory diseases in childhood: conjunctivitis, eczema, allergies, celiac disease, etc. Normal to low and stable developed sexuality

•

•

•

Past

•

Recurrent infections as a child

History

•

Learning disabilities

•

Darker skin, but became paler Gradually decreasing ability to tan in the sun, was previously normal lncreased tendency to sunburn Need for moderately protective sunscreens (> SPF12) Darker hair, brown-black, but graying Overweight due to progressively increasing appetite, has progressively appeared and worsened in adult years No or recent history of inflammatory diseases Normal sexuality, which is progressively declining in its intensity and potency Normal health and school performance as a child

After this first check-up please determine the timing and location of the patient's complaints.

79

2. Timing and location: When do complaints of MSH deficiency appear? Typically, the signs and complaints of MSH

deficiency are remarkably more intense and frequent when exposed to the sun, at meal-times (with an excessiva hunger) and during sexual intercourse. Where? Physical signs of MSH deficiency are usually ditfusely spread ali over the body,

especially on the skin.

3. Complaints of MSH deficiency The principal complaints of MSH deficiency are summarized in the following table: Complaints of MSH deficiency PHYSICAL Complaints

MENTAL Complaints Behavior

Learning

Sex

(Men & women)

•

Possible lower resistance to stress

•

Poor memory

•

Poor school pertormance

•

•

Health

•

•

Body •

Low(er) sexual arousal, drive

Energy

Low(er) frequency and intensity of erotic fantasies

Vitality

•

• •

•

Sex

(Women)

• • •

•

•

Sex (Men)

•

•

Low(er) skin sensitivity to sexual caress

Food

Less sexual arousal Less vaginal lubrification Difficulties in vaginal opening for penis insertion

Hair

Low(er) orgasmic capacity

Erectile dysfunction: lower frequency, and especially duration and strength of erections, less ejaculate volume

Skin

Diges-

Low(er) capacities for sexual intercourse

tive

Permanent silent doubts about sexual capacities and pertormance

Joints

Prone to weight gain - due to excessiva appetite Overweight or obese Lack of freshness, lack of the fresh feeling of being in the spring or on a sunny holiday Feeling overworked Excessiva appetite for food (a certain degree of bulimia with tendency toward being overweight)

•

Flat hair, lacking volume

•

Absent or decrease in curling hair

•

Paler hair:

•

Early graying or whitening hair

•

Blond or red hair

•

White (Caucasian) skin

•

Difficulty or inability to tan in the sun

•

Easily sunburned

•

Nails

Possible proneness to infections and inflammations

Needs sun lotions that offer a high protection (� SPF15)

•

Brittle nails, lacking strength

•

Gastro-enteritis, colitis, celiac disease

•

Possible muscle loosening (MSH deficiency provides /ower leveis of GH, the hormone of musc/e firmness)

Muscles

80

•

Possible joint pains (arthralgia), especially under stressful conditions

4. Physical Signs of MSH deficiency What physical signs may help you to recognize an MSH-deficiency on a patient? The physical signs of MSH deficiency are listed in the following table:

Physical Signs of MSH deficiency Face

Hair

•

White or oale face

•

Skin

•

Flat hair, lacking volume

•

Absent or decrease in

Nails

curling hair

Behavior

•

Paler hair: o

Early graying or

•

Body

•

Blond

Red hair Overweight

Brittle, weak nails

•

Stressed, nervous

•

whitening hair o

Possibly sun-burned skin

•

•

Mental

White skin

•

•

Blood

Memory loss Learning difficulties High diastolic blood pressure

pressure

•

Tendency to high blood oressure with salt intake

The next step is to check for any diseases related to MSH deficiency

5. Diseases more likely with MSH deficiency What diseases are more likely to be found in MSH-deficient patients? Some studies suggest that the following diseases may develop easier in patients with low MSH leveis:

arterial

hypertension

sensitive

to

salt

intake,

obesity,

learning

disabilities

inflammatory diseases After this check laboratory tests should normally be asked, but they may be ... unavailable.

81

and

6. MSH Lab Tests In general, there are no regular laboratories that measure MSH leveis, only some research labs do MSH tests for research purposes. Once the tests become available, based on the available information, we would recommend in prioríty to perform the measurement of the serum levei of alpha-MSH Which laboratory tests are most useful to confirm MSH deficiency? In general a blood test:

Laboratory Tests for MSH Where?

Test Men

Serum

Alpha-MSH Women

Beta-MSH Serum

Possibly

Optimal*

Deficient*

References

20

0-10

10-45 pQ/ml

12

0- 6

6-27 pmol/ml

14

0- 6

3-30 pg/ml 1.8-18 pmol/ml

8

0- 4

Morning

30

0-18

13-38 pg/ml

(9AM)

23

0-14

10-29pmo/lml

9

0- 5

4-18 pQ/ml

Evening (9 PM)

Med.

Low

3-14 pmol/ml

7

0- 4

Gamma-

1.9

0-

1. 1

0.8-2.4 pg/ml

MSH

1.2

0-

0.7

0.5-1.5 pmo//1

ACTH

Test Value

40

0-28

20-80 pg/ml

9

0- 6

4.4-17.6 pmo//1

Low (?) Med

lmportant notes: lt is líkely that test kits will improve once they become widely available in traditional

•

laboratories. The developments of better test kits may change the reference range, making changes also necessary in optimal and deficíent leveis. For the serum levei of gamma-MSH leveis great differences in serum leveis of gamma-MSH

•

in humans have been reported in the literature from fmoi/L to pmoi/L (this is a 1 000-fold difference in serum levei). We have retained as reference range and unit, the levei that seemed us to most likely and acceptable levei. *

Higher leveis may be seen with sun exposure

7.

Which imaging tests help detect MSH abnormalities?

Medicai imaging is rarely of value: Magnetic resonance imaging centered on the sella turcica and the pituitary gland: rare cases of pituitary tumor may compress and damage the pituitary cells that secrete MSH.

82

11. MSH: TREATMENT MSH medications The principie medications available are summarized in the following table: Optimal Dose Route

Subcutaneous lntranasal & Subcutaneous

(SC) Subcutaneous

Medication

(Average)

Dose partition

over the day

0.100 to 1 mg/day Melanotan 11 ®) 50 to 400 (10 mg vials) llQ/day (SC) 0.2 to 1 mg/day Bremelanotide (intranasal) (10 mg vials) 1 00-400 llQiday (SC)

1x/day or 2 to 3x per week

MSH

1x/day

Melanotan I

10-20 1.19/day

Efficient dose range

Drug

for most patients 0.1 -0.5 mg/day 50- 200 1.19 per day

Value

Effects

Med High

0.1 to 2 mg/day

High

1O 11. 9/day

Med

Fast onset (30' to 2h}, prolonged effects (6-72h h}

How to start MSH-Iike Therapies: Subcutaneous injections:

First, place in front of you two vials: one with powder containing Melanotan I or 11/Bremelanotide® and one with bacteriostatic solution (salty water solution usually containing 0.9% benzylethanol). Mix the powder with the solution after extracting with a syringe 1 ml of bacteriostatic solution from its vial and having injected it into the 1 O mg melanotan I or 11 or bremelanotide powder vial. Note that both vials are covered by silver/aluminium. Take off the silver centre part the covers the top but operation). The extraction of bacteriostatic solution out of its vial and the injection of 1ml of it into the powder vial must occur with the needle of a syringe through the center of the rubber top. The silver borders that seal the rubber top to the two glass vials must remain in place to assure sterility of their content. Do not take them off. As Melanotan 11 must be injected into the body, please inject a smaller dose the first injection such as 0.01 ml 0.1 mg) - a good precaution to spot any allergy that would contra-indicate the treatment. An allergic reaction is rare as MSH has some anti-allergenic and anti-inflammatory proprieties of its own. lf an allergy occurs, it might be due to the additive of the bacteriostatic solution. =

After this check, when everything goes well, you can slowly go over to the injection of higher doses. Two methods can be used: 1. 2.

A first month of daily injections of 0.01 ml to 0.05 ml (0.1 to 0.5 mg) per day, then followed in the following months by an injection every three days of 0.02 to 0.1O ml (0.2 to 1 mg). Or start right away with two to three times per week injections of 0.01 ml to 0.1 O ml.

83

People with darker skin (African or Asian origin) who take Melanotan 11 or Bremelanotide for their effects on sexuality, should take

0.05 to 0.1 O ml (0.1 to 0.5 mg) of Melanotan

11 or

0.1 to 2

mg/day Bremelanotide occasionally six hours before sex, and not more than once or twice a week. This method may work well for sexuality as tha action of Melanotan 11 or Bremelanotide may perists for two to three days after injection. Doing so may avoid any excessive tanning of the skin.

lntranasal sprays Applying the Melanotan li and Bremelanotide through into the nostrils may work, but is usually less efficient because the solutions have to pass the nasal mucosa first before acting on the body. Moreover, starting with a very low dose may be difficult here as one spray generally contains a higher amount of the solution. In case a person has already a tanned skin, dilute the solution with more than one ml of the bacteriostatic solution to avoid excessive tanning by too high doses. lncrease the dose later on if effects on sexuality are not good enough and tanning is not excessive.

Progress with MSH-Iike Therapies: Progress can occur quickly in Caucasians. After a first week, a slight to much darker skin tan may appear, following the proneness of the skin to tan, followed in the next two to three weeks by a progressively darker tan. Some patients who already have a darker skin can become dark brown at the end of the first week. Doses of

0.05 to 0.1 O ml may improve the sexuality the first day of intake and last for two to

three days maximum. About six hours after the injection a climax in sexual arousal may appear. Regular treatment with the MSH-Iike therapies may yield increasingly better results.

lndications for MSH- Melanotan 11- Bremelanotide Treatment Permanent indication: Ali degrees of MSH deficiency Occasional indications: •

A patient prone to sunburn can have a MSH/Melanotan 11 treatment three to four weeks before anticipated sun exposure as this will to help to avoid sunburn. (Melanotan I can also be used for this indication)

•

Decreased sex drive and potency in men and women

Contraindications to MSH - Melanotan I

-

Melanotan 11

Bremelanotide Treatment Relative contraindications: •

Hyperpigmented spots, melasma, dark skin (as the treatment makes them darker

•

Pregnancy and lactation (absence of studies showing its safety in this indication)

•

For Bremelanotide: arterial hypertension

84

-

How can you boost MSH - Melanotan I - Melanotan 11 - BremelanotideTreatment? Before administering a treatment, the first step is to improve various lifestyle factors that can reduce the deficiency. The most important booster of MSH and MSH-Iike therapies is sun exposure. Eating a 2,500 cal/day diet helps too. The table below shows the most important interventions to improve MSH leveis or the beneficiai effects of MSH-Iike therapies.

How to optimize MSH activity and treatment WhatTo Do •

Sun

• •

Diet

•

Sun exposure

WhatTo Avoid

1

•

1 Fluorescent light Eat sufficient calorias (at least 2

1 ,500-2,500 cal/day)

•

Eat organic foods (free of 3

•

4 Sunscreens 2 Low caloria diets 5 Alcohol

pesticides) •

Activity

Physical exercise

Notes: 1

2 3

Sun exposure and even fluorescent light increases a/pha-MSH leveis

f!?.

Eating, ingesting food and ca/ories increases the serum a ha-MSH leve/ Certain pesticides may a/ter MSH secretion and/or effect Sunscreens reduce pigmentation by MSH­ Iike preparations, een the pigmentation that appears with indoor light.

5 Alcoho/

reduces the secretion of MSH from the pituitary glands of rodents;

Second, correct any other hormone deficiency of importance for MSH activity. Severa! hormones augment MSH production and its effects on the body. When deficiencies in these other hormones are being corrected, the dose requirements for MSH decrease. The principal hormone replacement therapies that increase or decrease the secretion of MSH and their actions are summarized in the following table. Hormones whose secretion is stimulated by MSH: lnfluence of various hormone therapies on leveis and/or activity of MSH and MSH-Iike medications Strong MSH Stimulators •

Testosterone and other androgens

•

Mild

Transdermal estradiol

Strong MSH

Stimulators

•

lnsulin

•

Leptin

Mild

lnhibitors •

Melatonin

•

Cortisol and other glucocorticoids at high dosages

•

Dopamine

85

lnhibitors •

Hydrocortisone or synthetic glucocorticoid treatment at-low doses

Follow-up of MSH-Iike Treatments 1. Find the adequate dose:

Various conditions may change the optimal dose and require temporary or permanent adjustments. The most frequent conditions are summarized in the following table: When to adapt the dose of Melanotan I or 11/ Bremelanotide Dose

lncrease the dose

Lower the dose

(20 to 200% more) •

lnsufficient MSH serum levei and effects

•

Caucasians who easily sunburn (skin types 1 and 2) and are exposed to sun 1 People with paler skin and activities on snow or in the water (swimming pool, lake, sea, ocean) In the mountains2 Low-calorie diee

•

Conditions

• • •

Alcohol consumption3

•

Melatonin treatment at high doses3

•

Hydrocortisone or synthetic Glucocorticoid treatment at high doses3

(20 to 80% less) •

•

Excessive MSH serum leveis and effects People with darker skin (skin types 4 and 5)

•

Sun exposure4

•

Excessive stress4 HiÇJh calorie diet4 Untreated cortisol deficiencl Testosterone or other male hormone treatment4

• •

•

•

Estradiol treatment4

Notes: 1 because of the supplementary sun reflection (neeed for more melanogenesis; 2 because of the stronger UV /ight; 3 may /ower production of pro-opiomelanocortin, precursor to MSH, and thus MSH; 4 stimulates production of pro-opiomelanocortin, precursor to MSH, and thus MSH.

2. Lab tests:

When is the best time to perform lab tests during follow-up?

When lab tests will be available, ideally, labs should be measured 6 to 12 hours after the last injection of MSH. A minimum of six hours after the last dose is required before taking a blood sample, as the MSH leveis peak shortly after the injection and then the leveis become more constant. Which lab tests help to control MSH treatment?

Actually, no traditional laboratories measure alpha-MSH, oríly research laboratories. But if you find one, the following test might be recommended when pure alpha-MSH is used as a treatment (pure MSH is actually also only available for animal experiences). The serum MSH test is normally not able to detect the MSH derivatives as Melanotan I or Melanotan 11 or Bremelanotide as their molecular structure is different from the original MSH molecule. The information needs checking once the serum MSH test becomes commonly available in specialized or traditional labs.

86

Recommended Lab Tests For Follow-Up Medication used

Blood

Melanotan I or 11 or Bremelanotide

Currently no test available

MSH

Serum MSH (research labs)

3. Avoid MSH overdosing and underdosing: Monitoring and dose adjustment should be based on signs and symptoms. When lab

tests for measurement of Melanotan I or 11 or Bremelanotide, or possibly MSH become available, they might help to adjust the dose in the course of the treatment, but their usefulness is restricted to the assessment of gross excesses or deficiencies. They should not help as much as clinicai assessment for fine tuning the dose from a sub-optimal state to the optimal state where the patient is symptom-free. When do you check for signs and symptoms of MSH over- or underdosage?

The patient should monitor his MSH status day by day (effect on sexuality and skin tanning for example) and go to the physician for a check every two to nine months. lt is of utmost importance to sufficiently inform patients about the signs of MSH excess or deficiency so that they can assist the physician with dose adjustments and adjust their dose themselves in case of an adverse event. The principal signs and symptoms of MSH overdose are outlined in the table below.

COMPLAINTS of MSH OVERDOSE Skin

•

•

Face

•

Sexually

Becomes darker than intended Slight swelling possible (Cushingoid -as in cortisol excess) Excessiva stimulation

•

Excessiva sensitivity

•

Excessiva potency

Appetite

•

Nausea

•

Loss of appetite

•

Weight & appetite

Excessiva weight loss despite excessiva food and fluid intake

•

Excessiva hunger

•

Excessiva thirst

PHYSICAL SIGNS of MSH OVERDOSE Excessive behavior

Weight

• •

•

Nervousness

Skin

Excessiva weight loss by anorexia

pressure

Blood

•

•

Excessiva pigmentation Further excessiva darkening of pigmentation spots Blood pressure drop

When signs and symptoms of overdose occur, stop the MSH treatment for three days in case of excessiva sexual stimulation or for one to three months in case of excessiva darkening of the skin. lt takes three months for the Caucasian skin to come back to its original tint. 4. Solve problems quickly: Check the problem solver for a detailed description.

87

111. MSH PROBLEM SOLVER How to solve problems that occur during treatment? The most common problems associated with Melanotan I or 11 or Bremelanotide or MSH treatment and their possible causes and solutions are outlined in this section.

Problems possibly related to MSH Overdose or other causes PROBLEM •

First, stop the Melanotan I or 11

Excessiva skin

•

•

SOLUTION

CAUSE

darkening

or Bremelanotide or MSH therapy:

Nausea (esp. in older people)

•

for one day three days in case of nausea

•

for one to three months in case of

Excessiva sexual stimulation (high

or sexual stimulation Melanotan I or 11 or Bremelanotide

excessive darkening of the skin. lt takes

or MSH overdose

three months for the Caucasian skin to come back to its original tint.

libido, with excess lubricationof vagina

After one to three months, restart the

or glans penis,

treatment at a lower dose, often half of the

etc.) •

lrritability,

Can come from sexual

anger,

frustration due to sexual

excessive

overstimulation or a

reactions

•

initial dose.

Headaches (rare)

partner with too low libido

Treat the cause: 1.

Lower the dose of the Melanotan 11 or Bremelanotide treatment

2.

Dialogue and psychotherapy of the couple

Treat the cause:

1.

MSH overdose

2.

Cortisol deficiency

3.

Chemical

1.

Lower the dose of MSH derivativa

2.

Correct cortisol deficiency (hydrocortisone, prednisolone or

contamination

methylprednisolone)

(additives of the bacteriostatic solution)?

3. Eliminate the source of chemical pollution

•

Further darkening of hyperpigmented spots, melasma

•

Correction of the cortisol deficiency with Often Addison disease

prednisolone (a cortisol-derivative that has a

withcortisol deficit, causing

more permanent 24h effect than lhe bio-identical

excessive secretion of

hydrocortisone)1x a day, or with

ACTH and ACTH-induced

hydrocortisone 4x per day may harmonize

lncrease in size of hyperpigmentation seborrhoeic warts

the pigmentation and fade the irregular

I pigmentation spots

Melanotan li works in combination with testosterone to increase

•

sebum production by •

Excessiva body scent

sebaceous glands of the skin . •

lt is in the sebum that

Reduce the dose of the Melanotan 11 or Bremelanotide or MSH therapy Reduce the dose of testosterone in the

pheromones are secreted,

case the patient takes a corrective

which may provide a stronger

testosterone treatment.

scent, that is generally a sexual scent.

88

Problems possibly related to allergic reactions or stimulation of other hormone secretions PROBLEM •

Red flushing over the face

•

CAUSE •

Skin rash over the body

•

Red skin rash at the site of injection •

•

Chest pain

•

Nausea

•

Headaches

•

Abundant menstruation

(menorrhagia) •

Painful menstruation

(dysmenorrhea)

SOLUTION

Allergic reaction to Melanotan I or 11 or Bremelanotide or to an additive in the solution (the benzylalcohol of the bacteriostatic solution for example) Possibly overdose in Melanotan I or 11 or Bremelanotide for the red flush, nausea or headaches

Treat the cause: 1.

Lower the dose of the MSH derivativa, or stop it

2.

Correct cortisol deficiency

(hydrocortisone, prednisolone or methylprednisolone) that increases the risk of allergic reactions 3.

Take medication against

(cetirizine (Zyrtec®) for example): efficient therapy allergy

lmbalance between the leveis of estradiol and progesterone 1. Supply progesterone to as the therapy tends to reduce menstruation 2. Lower the dose of the MSH excessively stimulate the production of estradiol, but derivativa, or stop it not that of progesterone

89

Chapter four

Oxytocin Deficiency and Treatment Case Studies of Patients with Oxytocin-Deficiency Celine and her difficulties to achieve orgasm and deep love Celine, a 42-year old woman, felt somewhat detached from men, making it difficult for her to stick to a relationship when the understanding did not go perfectly well. Even her girlfriends found her to be a bit too cool or even too cold, not smiling enough to consider her as a close friend and see her often. She was the typical intellectual, introvert type. Celine herself found, her life to be fairly chilly, lacking the warmth and pleasure that is found in romantic or familial relationships exposed in some films and that many people were openly showing. She didn't feel at ease when others exposed their emotions. She had the impression that they were exaggerating or faking the warm-hearted feelings they were showing. She became more and more a loner. Being solitary was, she felt, the best way not to be disturbed by the emotions displayed by demonstrative people. Sexually, she had another problem she did not openly talk about: a great difficulty to achieve an orgasm, even with experienced and zealous partners. Wener and his inability to ejaculate Werner, a 60-year old man, was a good lover with apparently good sexual potency for his age. He usually had strong erections, stronger and more persistent than other men of his age. However, for the last six years something fundamental in his sexuality had appeared. He could almost never ejaculate, never have an orgasm however hard he tried, however great a lover he was for his partner. Trials of testosterone and growth hormone treatments did not do much for this potency. Every six to ten months he occasionally achieved a poor, low intensity ejaculation, but this was a real exception in the desert. His sexual condition continued until a treatment was found that made him ejaculate eight times out of ten intercourses!

What was affecting Celine and Werner? Most of the problems Celine and Werner faced are typical of oxytocin deficiency. To better understand what this deficiency means and what can be done about it, let us review some basic information on oxytocin.

91

OXTOCIN: lmportant lnformation Role of Oxytocin in both sexes Psychosocial effects of Oxytocin: 1.

Oxytocin stimulates sociability, friendliness and deeper bonds between people more than any other hormone.

lt makes people more warm-hearted, trustful and enjoy the

company of others, not only that of humans but also of animais such as domestic pets. Oxytocin's capacity to make people want to be more social with each other may be useful for patients with autism or schizophrenia. In this category of patients low leveis of oxytocin are often found and oxytocin treatment has been shown to reduce social withdrawal and repetitive behavior. 2.

Oxytocin may improve the mood, making people smile more in the presence of others.

3.

Oxytocin reduces anxiety, especially for social encounters.

For psychosocial effects, oxytocin acts either as a neurotransmitter in the brain, for its actions on sociability for example, while for more physical actions on the skin, the heart and other peripheral tissues the hormone acts by direct action. Physical effects of Oxytocin: 1.

Oxytocin can prevent ischemia by dilating the diameter of arteries, including the coronary arteries of the heart, where oxytocin has been anecdotally reported to reduce chest pain caused by angina pectoris. Subcutaneous or intramuscular injections of oxytocin may provide a red-rose flush of the cheeks and earlobes.

2.

By the same vasodilatory effect, oxytocin can lower the blood pressure.

3.

Oxytocin may speed up wound healing, possibly by increasing blood supply to the wound thanks to its vasodilatating effects.

4. 5.

Oxytocin speeds up orgasm and increases attachment between lovers. Oxytocin

stimulates

sexual

drive,

sexual

behavior

and

warm

feelings,

including

attachment, between partners. 6.

Oxytocin increases pleasure at orgasm.

7.

Oxytocin may relax muscles and reduce pain, beneficiai effects that may be of

8.

Oxytocin stimulates anabolism by increasing the production of anabolic hormones such

considerable help to patients with fibromyalgia. as IGF-1 and testosterone and its conversion into dihydrotestosterone. At the same time, it reduces catabolism, the breakdown of tissues, by reducing the production of ACTH and cortisol, the major catabolic hormone. The most frequent side effects at excessive oxytocin doses are in fact cortisol deficiency symptoms such as flu-like fatigue, poor stress resistance, etc. Specific roles of Oxytocin in women: 1.

Oxytocin increases vaginal lubrification, vaginal and anal contractions during sexual intercourse.

2.

lt facilitates orgasm: women have quicker and more intense orgasm when taking oxytocin. Oxytocin intensifies uterine and vaginal contractions that climax at orgasm, and heightens subjective pleasure. Oxytocin also makes the occurrence of new, multiple orgasms easier after a first one.

92

3.

After orgasm, contrary to men, oxytocin awakens women and makes them easier remind positive sexual experiences, especially the most romantic ones, effects that are opposite to those reported by men after an orgasm. Full of oxytocin, men fali asleep after orgasm and have a hard time remembering any details of their recent lave experience.

4.

Oxytocin helps delivery at birth by increasing the contractions of the uterine body to expel the baby out of the uterus.

5. 6.

Oxytocin stimulates breastfeeding by contracting the milk-producing glands of the breast. lt may protect against breast, ovarian and endometrial cancer as oxytocin reduces the proliferation of human breast, ovarian and endometrial cancer cells in laboratory settings. lt also may reduce the degree of malignancy of ovarian cancer as reported in experiments with oxytocin on female animais, which show that oxytocin reduced local invasion and formation of metastases of ovarian carcinomas.

Specific roles of Oxytocin in men: Oxytocin performs in men many roles, some of which are listed below: 1.

Oxytocin

increases

the

sensitivity

of

the

penis

to

sexual

contact.

lt

increaseslubricationof the glans penis, the frequency of erections. In rodents, rabbits and monkeys oxytocin injections into the brain increase the volume and intensity of erections. Oxytocin is less efficient for penile erection in men when given through the oral, sublingual or intranasal route, in particular less efficient to increase the volume and persistence of an erection than promising reports in animal experiences may have make us think. Oxytocin's sexual enhancement is proportionately greater in sexually sluggish rats. In healthy men, when the flaccid penis becomes tumescent and erect, the leveis of oxytocin gradually increase in the corpora cavernosa of the penis and in the systemic blood. Oxytocin leveis further increase from tumescence to rigidity in the cavernous blood but remain unaltered in the systemic blood. During detumescence, oxytocin leveis in the cavernous blood decline, whereas those in the systemic blood tend to increase causing sleepiness in men after intercourse. 2.

Oxytocin makes men achieve ejaculation by repetitive contractions of the seminiferous tubules, the seminal vesicles, the epididymis and the muscular capsule around the prostate. Oxytocin is a more potent inducer of contractile activity than adrenergic agonists. At ejaculation, a burst of oxytocin is secreted from the posterior lobe of the pituitary gland, the neurohypophysis, into the systemic circulation and sets off contractions of the whole male reproductive tract.

3.

Oxytocin stimulates sperm release. lt increases the number of spermatozoids after a first ejaculation, by stimulating contractions of the reproductive tract and thus increasing sperm passage. The effect dies off when frequent ejaculations occur during the same day.

4.

Oxytocin stimulates in men yawning, sleepiness and forgetfulness just after ejaculation.

5.

Oxytocin may increase the healthy volume of the accessory sex glands, including the prostate by increasing the height and volume of the epithelial secretory glandular cells of the prostate and enlarging the diameter of the lumen of the glands. lt differentiates human glandular epithelial cells of the prostate by increasing the activity of the 5-alpha-reductase enzyme in them. In contrast, oxytocin inhibits the unwelcome proliferation of stromal cells of the prostate in presence of sex hormones, an effect opposite to what happens in prostate stromal hyperplasia, which causes most cases of prostate hypertrophy. Some studies have shown inhibitory effects of oxytocin on the proliferation of prostate epithelial cells in cell cultures when sex hormones were added.

93

Oxytocin Production: Where? Specific areas of the hypothalamus, named the paraventricular and supraoptic nuclei, produce oxytocin. From these nuclei, oxytocin is transported through axons of neurons into the posterior lobe of the pituitary gland, where it accumulates and is secreted into the bloodstream. Oxytocin is also produced locally in peripheral tissues such as the heart, testicles, avaries - in particular in the corpus luteum, uterus, placenta, amnion, etc. There is growing evidence that oxytocin is produced locally in the prostate as far higher oxytocin leveis are found in the prostate than in the plasma. Men with higher androgen leveis have higher leveis of oxytocin in their prostate suggesting that higher androgen leveis stimulate local production of oxytocin by the prostate.

How much? The daily production of oxytocin in young healthy adults is possibly between one and two international units {lU) per day, an estimation based upon information gathered from the doses that are efficient in oxytocin treatment. Higher amounts are produced in people who engage in frequent sexual intercourse. Doses above the 5 to 1 O lU per day are produced in breastfeeding women or during delivery.

Factors that affect Oxytocin Production and/or Leveis Factors that increase oxytocin leveis are physical contact, hugging, massage, noise, reading, singing, physical activity, sexual contacts, cohabitation and eating. Factors that lower oxytocin leveis are loneliness, anxiety, depression, chronic stress and sex hormone deficiencies.

Oxytocin effects and leveis decrease with age Oxytocin activity declines with advancing age, making the need for oxytocin supplementation progressively greater with age. While the decrease in number of cells producing oxytocin has not been confirmed in humans, it has been repeatedly reported in rats. Other indications confirm the age-related decline in oxytocin activity. Firstly, the cells that produce oxytocin become less and less responsive to stimuli, resulting in insufficient production of oxytocin when additional amounts are necessary such as in social and familial encounters and sexual activities for example. Secondly, the leveis of oxytocin decrease in central areas of the brain that are important for emotions such as the septum and hippocampus. Leveis of oxytocin have not been reported to decline significantly with age in the blood, nor in the pituitary gland or hypothalamus. Thirdly, the oxytocin receptors on the target cells, necessary for oxytocin action, decrease in number with age, making it necessary for elderly people to have higher than normal oxytocin leveis to saturate the receptors and benefit from sufficient oxytocin action, a compensation that does not spontaneously occur in elderly persons .

Precursors of oxytocin Next to oxytocin, precursors of oxtyocin bound to peptides fixed at the C-terminal ending have been found in the blood such as oxytocin-glycine, oxytocin-glycine-lysine and oxytocin-lysine­ arginine. The leveis of these poorly active peptides are higher in autistic children, while the serum leveis of the more efficient oxytocin are lower.

94

I. Oxytocin Deficiency: DIAGNOSIS Oxytocin deficiency is established by findings coming from the patient's medicai history,

complaints, physical examination and laboratory tests.

1. Onset of Oxytocin Deficiency When did the oxtyocin deficiency start? To find out, ask the patient how he behaved in the company of others as a child, adolescent and adult. Patients with oxytocin deficiency since childhood have usually been socially isolated: few or no friends, tendency to play alone as a child, irritable when having to meet other people in games and parties. They rarely smile or laugh. Some react and force their smile to look sympathetic. Children with severe oxytocin deficiency show autistic traits, and may become schizophrenic as adults. Adults who progressively acquire oxytocin deficiency in the course of an endless period of chronic stress, or suddenly after a major trauma such as a car accident, surgery in the hypothalamic-pituitary area or the loss of a loved one, were socially well integrated in childhood and young adulthood, but later lost their happy smile and became more isolated, colder, or even purely asocial. The basic differences between the two types are summarized in the following table: How to Determine the onset of Oxytocin Deficiency Onset Social

Childhood-onset

Never good at social involvement/interactions

•

Greater social involvement, but less than before

•

Preference for solitary activities; poor teamwork

•

Teamwork possible, but less easy than before

•

contacts Games, sports, job Marital

•

Rarely married, and if married, is considered as 'cold' by the partner

•

ls married, but marriage has become less happy Often divorced

•

No or poor circle of friends

•

Larger circle of friends, but decreasing

•

Never had real close friends

•

•

Friends are distant friends

•

lntrovert since childhood Always cold

status Circle of friends Character

Adulthood-onset

•

•

•

Retains mainly old friends, but very few if any new friends Warm hearted before, now has become more introverted and colder

Cold, smile less face Pale, never flushing face

•

Smile less, unhappy face

•

•

Pale, rarely flushing face

Sex drive

•

Poorly developed

•

Sexual

•

Poorly developed

potency

•

Sex is physical pleasure, not a romantic experience

Face

•

(men) Orgasm

•

(women) Orgasm

•

(Men) Glans pen is History

• •

•

Never or almost never achieved orgasm

• •

Since end of puberty: poor or absence of ejaculation Dry glans penis with sex

•

•

Has never been very warmhearted and sociable

95

•

Developed sex drive but declininQ More developed sexual potency, but declining Sex feels less fantastic than before Had easy orgasms, but the ability has clearly declined later on Decreased ability to ejaculate or loss of ejaculation Drier ÇJians penis with sex Was warmhearted and sociable before, but !ater became colder

2. Timing and Location: When do signs and complaints of oxytocin deficiency manifest themselves? They are present

throughout the day, in particular the lower sociability symptoms but sexual signs may be more evident during sexual activity, as the patient appears a little too cold. Where? Several tissues can be affected by oxytocin deficiency, but predominantly those

related to the skin (paleness), breast and genital areas (decline in sexual sensitivity) and brain (tendency to social isolation and other psychological symptoms).

3. Complaints of Oxytocin Deficiency The most common complaints in oxytocin deficiency are listed in the table below. Physical complaints of Oxytocin Deficiency Physical appearance

•

Paleness

•

No or poorly emotional manifestations

Pain

•

Easier pain perception

•

Excess pain sensitivity Lower sex drive and arousal

•

Absent, rare or forced smile

•

•

Pale face, unable to flush

•

Few or no ejaculations

•

Fibromyalgia: muscle pains

•

tendons

•

Tensed muscles

Low ejaculation volume, poor sperm count (due to absent or poor prostate capsule contractions)

Sleep

•

Disturbed sleep

•

•

Absence of uterine contractions to start delivering the baby

Sex feels as though physical/mechanical and not as an intense romantic lave experience

Face Muscles

End-term pregnancy Breast-

Sex

and 'tender (tendon) points'

and

•

feeding

(men)

Sex

lnability to breast feed (poor (women) milk ejection despite breasts full of milk)

•

Absence or rareness of orgasm

•

Needs > 20 minutes to achieve orgasm

•

Low or lower orgasmic intensity

•

Absence of multiple orgasms

Mental complaints of Oxytocin Deficiency in Men Behavior

Mood

Character

•

lrritability

•

Affectionless

•

lrritable when someone interrupts him or her

•

Stress

Low mood, no intense joy, life is felt as 'not funny'

Social

•

Excessive sensitivity to difficulties

•

Unnecessary, futile worry

•

Excessive anxiety, fear

•

Easily feels disturbed by others

•

Lack of interest in others

•

Greater need for solitude

•

Few social contacts, withdrawn No close friends, not even the partner No or poor circle of acquaintances

•

lntrovert

•

lntellectual, not emotional

•

•

Excessively (emotionally) detached from others

•

•

Not warm-hearteds

•

Unfriendly

•

Suspicious, untrusting

•

Paranoid trend

Job

Married

96

•

Tendency for solitary work

•

No or poor teamwork

•

Unmarried or divorced

4. Physical Signs of Oxytocin Deficiency What are the physical signs of oxytocin deficiency? The principal physical signs of oxytocin deficiency that can be seen at physical examination are summarized in the following table: Physical Signs of Oxytocin Deficiency •

Physical appearance

• • • • •

Face

•

Eyes

• • •

Skin

Pale face and body Joyless No or poorly emotional face Expressionless body lntellectual, rational type Absence or rareness of a smile Pale cheeks that don't flush Dry eyes (conjunctiva sicca) Pale skin Tiny, little skin folds (due to dehydration) spread over the face and other areas

• •

Behavior

• • •

Mood

•

Muscles

•

Muscles,

•

tendons

lrritability Unemotional attitude Asocial Unkind, unpleasant Unattractive personality Unhappy attitude Tensed Painful tender (tendon) points (fibromyalgia)

Note: Oxytocin has some water-retaining effects similar to vasopressin, the lack of oxytocin may consequently make the skin lose water. *

lf Oxytocin deficiencies are apparent in a person, he or she should be examined to see if the following diseases might be occurring.

5. Disease Susceptibility Long-term oxytocin deficiency may increase susceptibility to the following disorders: cardiovascular diseases (myocardial infarction, coronary insufficiency), lower fertility, poor wound healing, depression, anxiety disorders, sexual impotence or frigidity, autism and schizophrenia.

6. Medicai lmaging Tests Which medicai imaging tests should be done to check for complications of long-term oxytocin deficiency? The following imaging test may reveal complications of acute oxytocin deficiency: Ultrasound of the uterus at time of delivery in pregnant women: absence or weakness of

uterine contractions.

97

7. Lab Tests for Oxytocin Deficiency The blood test is the best test to screen for oxytocin deficiency. The optimal conditions under which to perform blood or urine tests are sedentary conditions to obtain baseline leveis. Patients should avoid intense physical activities such as sexual intercourse, vigorous exercise or emotional stress 24 to 72 hours before the test, as it may temporarily modify the oxytocin leveis. The following blood lab test is helpful to confirm the diagnosis of Oxytocin deficiency. Blood Lab Tests for Oxytocin Test.

Sex

Optimal1

Men

7-15

Womend

7-18

Oxytocin

Probably deficient2

References3

Below 5

1-17.1 pmol/1

Test Value4

1-17 pg/ml

pg/ml or pmol/1

1-22 pg/ml

Medium

1-22.2 pmol/1

Notes: 1 pg/ml 1.01 pmol/1 1 The optimal leve/ is the leve/ where the patient is often free of complaints and signs of oxytocin deficiency 2 Ranges of deficient values in oxytocin 3 References of adu/ts aged 20 to 49 years 4 The test value is the estimated (by the author) usefulness in practice =

Difficulty to do the test: Actually the test is dane in research settings, but some laboratories are trying to make it available for medicai use.

When to do Lab Tests during Follow-up The blood test for follow-up of oxytocin supplementation should be obtained at the following times:

•

•

Wait 6 to 9 hours after taking an oxytocin sublingual tablet, intranasal spray or a subcutaneous injection before checking blood. Wait 8 to 12 hours after taking a slow release oral oxytocin tablet before checking blood.

The patient should take oxytocin at bedtime on 3 nights before the blood test.

98

11/ Oxytocin Deficiency: TREATMENT Medications for Oxytocin Treatment In the following table, various treatments for oxytocin deficiency are listed. The treatments that, in our experience, work better are highlighted with a yellow background. Dose and frec uency following the indication Value

Route

Drug

Sublingual

Oxytocin

Oral

(compounding pharmacy)

Slow released Oxytocin

High

Med.

(compounding pharmacy)

lntranasal

Oxytocin spray (Syntocinon® 1 puff 8 lU, 40 putls/vial))

Low

=

Subcutaneous lntravenous

Oxytocin (Syntocinon® ; 1 O lU vials)

Oxytocin Syntocinon® )

High High

Social binding

Sexual activity

5 to 1 0 IU/day morning & evening

51U/day in morning, 5 to 1 01U2h before sex

1 to 3 puffs/day , most before bedtime

1 puff of 8 lU in the morning, 1 to 3 puffs in the evening

Not indicated

Not indicated

1 O to 20 IU/day2 h before sex

Not indicated

Fibromyalgia

Autism, Schizophrenic traits

5 to 40 IU/day in2 to 3 divided doses (morning, lunch & evening)

Not indicated

1 0 to 40 IU/day 2x/ day*

Not indicated

1 0 to20 IU/day

Breast Labor, feeding Delivery

1 0 to 30 IU/day

1 to 3 puffs twice a day

Not indicated

Not indicated

Not

Not

indicated

indicated

Not

Not

Not

indicated

indicated

indicated

3-30 lU

Change the Dose or Type of Medication? Various deficiencies may require changing the product or adjusting the dose of oxytocin. The most frequent of these conditions are summarized in the following table. When to adapt the dose or to change medication? •

More severe deficiencies

•

Fibromyalgia

•

Frequent sexual activity

•

Frequent social encounters

•

Autism, schizophrenia

Subcutaneous or intramuscular injections may do better than oral or sublingual forms Require higher doses of oxytocin: increase (temporarily) daily doses from 25% up to 100% higher than the normal dose

99

What is the best route for Oxytocin Treatment? Controversy exists on the best route of administration for oxytocin. The principal administration routes for oxytocin are discussed in the underlying table.

Routes for Oxytocin administration Route

lndication

Explanation Oral forms are usually less efficient because the liver breaks down much of the ingested oxytocin. The intestinal

As slow-re/eased torm:

absorption of oral oxytocin varies according to the health

Oral

state of the digestive system. People who have digestive

•

Mild fibromyalgia

troubles, often reflected by abdominal pain or bloating, will

•

Sociability

poorly absorb oxytocin.

improvement

lf it is well compounded, a slow-release form may

•

constitute an interesting alternative for patients with mild fibromyalgia or when the aim is to improve sociability and

increase

social or even romantic attachment. The sublingual route allows a quicker and more stable absorption of oxytocin. However, the effects also tend to

•

•

recommended as an aid for the delivery of a baby at the

Sublingual

With the sublingual route, part of the oxytocin is absorbed through the buccal mucosa, while another part is

increase •

Low mood

•

Autism/ Schizophrenic traits

swallowed and absorbed in the intestines. The oxytocin that penetrates through the mouth mucosa goes directly

•

•

of oxytocin through the liver after oral ingestion that is the case of most of the oral oxytocin, causes an important

nasal

Poor absorption of oxytocin through this route.

intensity of orgasm

•

Breastfeeding

•

Women: to increase the number and

spray

intensity of orgasms Subcutaneous injections of oxytocin are used for more severe conditions, which fail to work with sublingual

Subcu-

tablets: fibromyalgia, labor (to speed up delivery) or

taneous lnjections

severe frigidity or anorgasmia . Oxytocin injections have a moderate risk of allergic reaction and should be tried in

• •

•

lntravenous administration of oxytocin is reseNed for delivery and its use is restricted to hospitais.

100

Pregnant women: Women: severe frigidity or anorgasmia .

the solution at home.

lntra-

Severe fibromyalgia labor/delivery

the office first before permitting the patient to self-inject

venous injections

Women: increase in number and

breakdown and inactivation of most of the oxytocin.

lntra-

Men: improvement of ejaculation

into the bloodstream. Overall, the effect of the sublingual route is superior to that of the oral route, as the passage

Social or romantic attachment

end of the pregnancy as higher doses are necessary in this urgent condition.

Sociability improvement

wear off more quickly. Therefore, a second administration during the day is recommended. Sublingual oxytocin is not

Social or romantic attachment

•

Pregnant women: labor/delivery

lndications for Oxytocin Treatment Acute, occasional, short-term indications for use of oxytocin at higher doses: Sexual failure (in particular to improve orgasm/ejaculation), angina pectoris, birth delivery and breastfeeding. Chronic, long-term indications: Treatment of ali degrees of oxytocin deficiency, in particular in presence of predominant symptoms such as an abnormally low sociability;

autism,

schizophrenia, depressive states, anxiety disorders and paranoid tendencies with high cortisol leveis (but be careful as many people with paranoid tendency have low cortisol levels).

Contraindications to Oxytocin Treatment in Men There are two fundamental contraindications to oxytocin treatment: Absolute contraindication for subcutaneous or intravenous administration: •

Individuais who have an allergic reaction to a first trial of oxytocin in the office (have adrenaline shots ready in the office). The allergic reaction is rare, but may require an injection of adrenaline.

Relative contraindication: •

Patients with untreated cortisol deficiency - as oxytocin may decrease cortisol levels.

•

Patients with vasopressin excess (rare) as they retain water and may not tolerate the moderate water-retaining effects of high doses of oxytocin.

•

Do not administer oxytocin to a man before driving a car or any other high risk activity as oxytocin may induce drowsiness and decrease the concentration in men, much less in women.

•

Acute active prostate infection or the obstruction of urinary flow by an enlarged prostate as oxytocin may temporarily increase the prostate volume usually in a healthy way by increasing the size of the small prostatic glands.

•

Men with premature ejaculation should avoid oxytocin treatment because it may shorten the time to ejaculation.

How to start Oxytocin Treatment For daily use of oxytocin oral or sublingual tablets, it is better to start with low dosage oxytocin (a low dose is 2.5 to 5 lU per day) and then titrate the dose upward until a dose is obtained that brings complete relief of the deficiency. The reason for a prudent start at low doses is oxytocin's capacity to decrease cortisol leveis. Particularly, patients with typical physical signs of cortisol deficiency such as a hollow face and a thin body have a higher risk of badly reacting to oxytocin. They will do better with a lower dose of oxytocin. For acute uses such as during delivery or with chest pain caused by coronary insufficiency, the quick administration of a dose of 10 to 20 lU or more by subcutaneous or intravenous injection may help well.

101

Progress with Oxytocin Treatment How quick can a treatment with oxytocin work in a patient? Oxytocin treatment may quickly help a patient. Sociability may already improve 5 to 1 O hours after taking oxytocin the first time. For ejaculation, 5 to 1 O lU of oxytocin may work fast too. Men may ejaculate better in the evening after one morning and one evening intake of oxytocin. For fibromyalgia, effects take longer before obtaining a 24 hour permanent pain relief. When used for fibromyalgia an initial three hour pain relief is experienced, similar to the three hour pain relief experienced after orgasm (due to the higher leveis of oxytocin after orgasm). lf for some indications, oxytocin may quickly help with a single intake, for most indications and in most people its effects are better when regularly taken day by day. Faster and greater improvements are achieved with sublingual oxytocin than with the oral slow release or intranasal forms that are routes of administration that generally are not very efficient to improve sexual problems. Better improvement is obtained when the diet is healthy and well­ balanced. Coffee and alcohol intake may oppose the effects.

How to naturally enhance Oxytocin Effects Before treating with oxytocin, the patient should receive the recommendation to increase the body's oxytocin production by improvements in diet and other lifestyle factors. The same interventions may enhance the beneficiai effects of a treatment with oxytocin. The principal lifestyle factors to enhance oxytocin treatment are outlined in the following table: How to optimize Oxytocin activity and treatment Do what increases oxytocin leveis •

Diet

•

• •

Consume enough calories; don't fast Follow a "Paleolithic" diet: fruit, vegetables, meat, poultry, eggs, 1 fish Eat organic foods

Exercise Leisure

•

Living with people we love Live in family Being touched and hugged Massage Search sexual contact, have sexual intercourse Moderate exercise every day Singing, reading, music

Stress

•

Encourage relaxation

Social contacts

• •

Physical contacts

• •

•

•

Avoid what reduces oxytocin leveis Avoid alcohol, vinegar, caffeinated drinks Avoid sugar, sweets, soft drinks, cookies, bread, pasta and other cereais Avoid cereal fiber (whole grain bread, bran flakes) Avoid living alone Avoid aggressive, stressful j::>eople

•

Avoid being hit or harmed

•

Sedentary lifestyle

•

•

•

•

•

•

Drug Abuse

•

Avoid excessive chronic stress (especially prolonged) Avoid tobacco smoking Avoid marijuana and other drugs 1

1 Drug addiction resu/ts in symptoms of /oneliness, poor sociability, /ow resistance to stress, anxiety, violent reactions that in animal experience have been proven to be reversed by oxytocin. Notes:

102

The second step is to correct any other hormone abnormalities that influence oxytocin. Many hormones can boost or reduce oxytocin production and its effects in the body. The principal hormone replacement therapies that influence the secretion of oxytocin and/or its action are listed in the following table:

lnfluence of hormone replacement therapies on Oxytocin Strong stimulator of oxytocin

•

Estradiol

Mild stimulators •

Testosterone

•

Thyroid hormone

•

Melatonin (?)*

•

MSH

Mild inhibitor

Strong oxytocin inhibitor •

Glucocorticoids

•

Melatonin (?)*

at high doses

Note: Melatonin has some inhibitory and stimulatory actions on oxytocin's activity

Oxytocin and Prostate, Breast and Ovarian Cancer Leveis of oxytocin in prostate cancer patients are about half of those found in patient with benign prostate hypertrophy, suggesting a protective effect of oxytocin against prostate cancer. In laboratory cancer cell cultures and in living animais, oxytocin reduces the proliferation of breast, ovarian and endometrial cancer and the dissemination of ovarian cancer, suggesting a protective role of oxytocin in genital cancers.

Follow-up of Oxytocin Treatment 1.

Find the optimal dose: When a patient receives a treatment with oxytocin for oxytocin deficiency in combination with a growth hormone treatment for growth hormone deficiency, a testosterone treatment for testosterone deficiency or with an estradiol treatment for estradiol deficiency, the doses of oxytocin usually have to be 10 to 30% lower. This is due to testosterone and estradiol's stimulating effects on the oxytocin production.

When to adapt the dose of Oxytocin Dose Oxytocin Therapy

Diet, Lifestyle factors

lncrease the dose of oxytocin

Lower the dose of oxytocin

(by 25% to 150%)

(by 25 to 50%)

•

lnsufficient oxytocin effects

•

•

Low-calorie diet

•

High-calorie diet

•

Intensiva and/or chronic stress

•

lncreased physical activity,

Excessiva oxytocin effects

•

Decrease in physical activities

participation in moderate-

•

Sedentary lifestyle, prolonged

intensity sports for leisure

rest, bedridden

•

Unstressed states, vacation

•

Wounds

•

Massage

•

Transdermal estradiol

•

Testosterone treatment

Hormone

•

Adult growth hormone deficiency

dysfunctions

•

Estradiol deficiency

or treatments

•

Testosterone deficiency

treatment

103

2. Avoid under- and overdosing:

lt is highly recommended for the patient to recognize the signs and symptoms of oxytocin deficiency and overdose so that he can help his physician adjust the treatment and reduce

the dose himself if side-effects are severe. In particular, attention should be given to the signs and symptoms of oxytocin overdose listed in the following table: Typical Signs of Oxytocin Excess Latency

Type Head

First few hours or days

•

• • •

Sex •

•

usually several weeks 1-2

months

Skin,

•

feet,

•

ankles Emotions

•

Signs

Cause

Flushing of face and ears

Vasodilatation of the cheek arteries caused by oxytocin excess

Excessive sexual arousal, libido Excessive genital sensitivity Excessive vaginal lubrication{women) Excessive lubrication of the glans penis {men) Premature ejaculation Fluid retention in skin, feet, ankles Lack of bleeding when the skin is cut Sticky, excessively affectionate behavior

Excessive stimulation of genital areas and sexual brain areas by oxytocin

Fluid retention caused by has which oxytocin, vasopressin-like effects Excessive stimulation of brain areas related to social bondinQ by oxytocin

3. Perform lab tests

The tests should be done about 6 to 14 hours after the last intake depending on the route of administration. Slow release forms are slower to be absorbed and require a blood check for control of the oxytocin levei 8 to 14 hours after intake, later than for sublingual tablets.

4. Solve problems at follow-up examination quickly and efficiently:

See Problem Solver for tables with reviews of the most frequent problems that may occur during oxytocin replacement and their solutions.

104

11/ Oxytocin PROBLEM SOLVER How to solve problems that may occur during oxytocin treatment: Problems due to oxytocin excess: Problems due to Oxytocin excess or other factors PROBLEM

CAUSES

SOLUTION

•

Excessive

Excessive stimulation of blood flow in the skin by the administered oxytocin during subcutaneous injections or intravenous administration Excessive oxytocin that

sexual arousal

excessively stimulates

•

Sticky,

corresponding brain areas

affectionate

related to sexuality or social

•

Red, flushing face

behavior

•

Premature ejaculation

•

Skin edema

•

Feet edema

•

Reduce the dose of oxytocin

•

Reduce the dose of oxytocin

bonding

Oxytocin stimulates contractions of the prostate muscle capsule, seminal vesicles, and other parts of the male reproductive tract, speedinQ up ejaculation Excessive salt and fluid retention from vasopressin-like effects at higher doses of oxytocin

•

Reduce the dose of oxytocin or stop the treatment 1. Take potassium (1-3 g per day) /f edema persists despite potassium intake: 2. Reduce the dose of oxytocin

Problems due to an oxytocin deficiency: Problems due to Oxytocin Deficiency or other factors

Too low dose

• •

lnefficient preparation •

Absence of any effect

A poor diet blocks the effects of oxytocin Other hormone deficiency (estradiol, GH, testosterone,

• •

lncrease the dose of oxytocin Stop the inefficient intranasal, oral or sublingual oxytocin lncrease the dose of oxytocin Take a better brand of sublingual oxytocin, possibly use subcutaneous injections

•

Avoid alcohol and caffeinated beverages

•

Avoid a low calorie diet

•

• •

Correct the estradiol deficiency in women with a combination of transdermal estradiol and oral or vaginal micronized progesterone Correct the testosterone deficiency in men Correct the growth hormone or IG F-1 deficiency

105

Problems due to the excessive conversion of testosterone into dihydrotestosterone

under the impulse of oxytocin (this is a rare phenomenon): Problems due to excessive conversion of testosterone into dihydrotestosterone •

Excessive body

hair

follicles

without

by

otherwise sexual performance may be at

Excessive

by long-term oxytocin use

body hair

to

(hirsutism)

predisposed

months)

12

(6

•

some

women

will

testosterone

•

into

sebaceous skin

•

Excessive body scent

by

may

by

glands

the

of

increasing

increases to

testosterone

Reduce

the

dose

of

DHEA),

androgens avoid

using

Reduce the dose of oxytocin

and

conversion

the

testosterone

•

to

Reduce

the

dose

of

testosterone

or

dihydrotestosterone in case one of these

dihydrotestosterone, which

(meat

of

increase

of

hormones

meat

dihydrotestosterone

production

production its

less

(testosterone, •

Oxytocin

supplementation,

dihydrotestosterone)

dihydrotestosterone (DHT)

sebum

Eat

conversion

have excessive conversion of

testosterone

risk!)

dihydrotestosterone caused •

Finasteride 1 to 2.5 mg/day (do not give

of

stimulation

treatments is given

stimulate

•

sebum production. lt is in

Reduce the dose of oxytocin

the sebum that pheromones are

secreted,

which

may

provide the scent, that is generally a sexual scent.

Problems due to an excessive lowering of the cortisol leveis under the impact of oxytocin:

Physical Problems due to Cortisol deficiency (favored by oxytocin supplementation) PROBLEM •

Flu-like fatigue

•

Allergic reactions

SOLUTION

CAUSES

•

•

lrritability

•

Poor resistance

Correct the adrenal deficiency, in particular cortisol deficiency

Lowering of cortisol level s

•

Reduce the dose of oxytocin or stop the treatment

to stress

106

Chapter five

Vasopressin Deficiency and Treatment

Case study of a patient with Vasopressin deficiency Suzie, with her head in the clouds Suzie was drinking a lot of water. 'For health', thought her friends. But Suzie drank because she was thirsty. Almost immediately after she drunk water, she had to run to the bathroom. She did not seem to keep the water inside of her body. Although she drank a lot of water, she looked dehydrated. Her eyes were deeply sunken in her orbits. Her skin looked as there was not enough water in it. Here and there small dehydrated folds appeared that she tried to lessen with a special skin lotion from one of the great French couturiers and to mask with a high quality face powder. At night, she woke up every two to three hours, pressed by an urgent need to urinate large volumes of urine. The interrupted sleep made her tired throughout the day. She learned to avoid drinking any fluid before going outdoors for shopping or to any other place where she wasn't sure to quickly find toilets. Suzie also presented with difficulties to learn. She was trying to learn Spanish, but it seemed harder than ever, although she felt she had the skills to do it. What is Suzie suffering from? Most of Suzie's problems are typical of vasopressin deficiency. To better understand what this deficiency means and what can be done about it, let us review some basic information about vasopressin.

107

VASOPRESSIN: Basic lnformation

lnformation about its roles 1.

Water retention in skin and blood vessels. Vasopressin's major role is to keep water in

the body. Two thirds of the human body is made up of water and vasopressin is lhe most potent hormone to keep water inside of lhe body. To achieve this, vasopressin blocks water excretion in lhe kidneys in a different way than aldosterone does. Aldosterone keeps water in lhe body indirectly through sodium retention, which attracts water by osmotic forces), whilst vasopressin makes lhe kidneys directly retain water, without retaining sodium. 1.

Prevention of blood loss: In case of bleeding (hemorrhages), vasopressin considerably

helps to keep blood inside of lhe capillaries and blood vessels, preventing any excessive blood loss, a property that is life-saving in surgery and physical trauma. 2.

Memory improvement: Vasopressin improves memory and in particular learning. People

with vasopressin deficiency are forgetful.

Vasopressin Production:

Daily secretion of vasopressin averages about 100 to 150 119 a day in young healthy adults. Vasopressin is produced by lhe hypothalamus and from there migrates through axons of neurons into lhe posterior pituitary gland where it accumulates and is secreted into lhe bloodstream.

Vasopressin Leveis:

Vasopressin leveis are higher during night time. What increases the production of Vasopressin?

Vasopressin production is increased during physical activity, in stress situations, with high protein diets and decreases with age. The excretion of vasopressin decreases with age and target cells become less responsive for vasopressin with age.

108

1/ VASOPRESSIN DEFICIENCY: DIAGNOSIS How do you recognize Vasopressin Deficiency?

To detect vasopressin deficiency, it is important to recognize the typical signs and complaints of the deficiency, as well as to do some laboratory tests.

1. Onset of Vasopressin Deficiency When did the vasopressin deficiency start? Older vasopressin deficiencies are often of a more severe degree. Finding out when the deficiency began helps the physician to evaluate the severity of the deficiency and to get clues on the dose of vasopressin he will need to prescribe. The way to discern the onset is to interview the patient and search for typical vasopressin deficiency signs and complaints that may have appeared many years ago, possibly even in childhood. The differences between childhood and adulthood-onset vasopressin deficiencies are reviewed in the following table.

Determining the Onset of Vasopressin Deficiency Childhood

Onset

Physical Signs

• •

Complaints

Adulthood

of signs severe Less Often more severe signs of dehydration dehydration, except when the such as: vasopressin deficiency is acquired by surgery or other • Deeply sunken eyes physical trauma in the • Dry tongue hypothalamus or pituitary gland.

•

• •

Exaggerated thirst Urgent need to quickly run to the bathroom after drinking Disturbed sleep because of the recurrent need to go to the bathroom to urinate during the night (nocturia)

No such complaints in childhood

Bedwetting (enuresis) Difficult learning at school

After this quick check it is important to inquire about the timing and location of the patient's complaints and signs.

109

2. Timing and Location When do vasopressin deficiency complaints manifest themselves? Vasopressin deficiency complaints appear most frequently at night when a person fies down for a prolonged period of time. In healthy people, higher amounts of vasopressin are made during bed rest at night. lt is during this period that complaints of vasopressin deficiency are more pronounced. Where do the physical signs of vasopressin deficiency appear most frequently? They are found on the skin under form of dehydrated skin folds, in the eyes as sunken eyes in the orbits and at urination discernible as excessively large volumes of urine. With this knowledge it is important to check the patient's complaints and signs.

3. Differences: Vasopressin

�

Aldosterone

Differences between the two major fluid retaining hormones Onset

Aldosterone deficiency

Position

•

Complaints increase standing up

Thirst

•

lmportant thirst+±:

Nocturia Daily urinary water loss lmpact on minerais Highest secretion

Learning and memory

•

Excessive urines+±: 1 to 2 litres/day more than usual Changes the salt balance: • Sodium retention • Potassium excretion

Greater thirst +++ Frequent nighttime urinary urgency ++±

•

Greater urinary loss +++:

•

2 to 8 litres/day

• •

• • •

•

Blood

Sleep

Sometimes nighttime urination +

•

•

•

disturbance

•

Complaints increase when laying down

•

Hearing

pressure

Vasopressin deficiency •

•

•

During the day Triggered by upright positions: standing up or prolonged sitting No specific effect on memory lmproves clear thinking lmproves visual focusing lmproves hearing, especially reduces the age-related decline in hearinÇJ (presbyacusis) Potent increase in blood pressure ++ Higher risk of high blood pressure at overdose ± No or moderate sleep disturbances because of a mild need to go to the bathroom at night (maximum 1x/night)

110

No change in salt status (but excess can dilute the salts and cause low blood sodium) • •

•

•

•

•

•

•

At night Triggered by lying down flat lmproves learning and memory retention No improvement of visual focusinÇJ No effect on hearing Poor or no effect on blood pressure ± Low risk of high blood pressure at overdose ++± Greater sleep disturbance because of the urgency to go to the bathroom several times at night (1 to 5x/night)

4. Complaints of Vasopressin Deficiency How does a person with vasopressin deficiency feel? Typically, individuais with vasopressin deficiency are forgetful, thirsty and feel recurrent pressing needs to go to the bathroom to urinate. As vasopressin is the principal water-retaining hormone, a lack of the hormone makes people lose a lot of fluid in the urine. In people with low vasopressin, there is less water in the blood vessels, and thus a reduced supply of blood, nutrients and oxygen to brain cells, making learning more difficult for the patient. As vasopressin is also an important neurotransmitter in the brain, some of the memory loss may also be explained by a decline in vasopressin's neurotransmitter activity.

The principal complaints suggestive of vasopressin deficiency are listed in the table below:

Complaints of Vasopressin Deficiency When

MENTAL Concentration Behavior

•

Easily distracted

•

Forgetful

•

Difficulty in memorizinQ and learninQ

stressful

Difficulties to learn and adapt to new situations

situations

•

Highest frequency in

PHYSICAL •

Behavior

Thirst

Urine

Tendency to drink a lot during the day and through the night

•

Tendency to go to the bathroom quickly

•

Thirsty ali the time

•

• •

Highest frequency in stressful

Strong tendency to drink important quantities of situations and water and other liquids Polyuria during the day (> 5x during daytime) Nocturia at night (� 2x/night)

111

flat position

5. Physical signs of Vasopressin Deficiency What is the appearance of a person with vasopressin deficiency? He or she looks dehydrated. Cause

Physical Signs of Vasopressin Deficiency Face

• •

Eyes

• •

Dehydration

Tongue

•

•

Skin •

Sharp wrinkles Sunken eyes, deep in orbit Crow feet wrinkles at the corner of the eyes Soft eyes (eye ball feels soft to pressure because of low eyeball pressure) Tongue with teeth marks visible at tongue borders (tongue indentations) Tiny skin folds (caused by dehydration), more apparent when the skin is extended by pressure with a finger tip Prolonged stiff skin fold after pinching the skin of the back of the hand {skin tentinQ)

6. Disease Susceptibility Does vasopressin deficiency cause any other health conditions? Several diseases may be aggravated or possibly caused by the dehydration that accompanies vasopressin deficiency, in particular cardiovascular diseases (thromboses, coronary heart disease) and possibly dementia. Furthermore, untreated vasopressin puts the patient at high risk of excessive wound bleeding, possibly dramatic blood fosses in surgery or multiple trauma accidents. After having clinically evaluated the patient, it may be important to perform laboratory tests. However the test to measure the blood levei of vasopressin is not currently available in most medicallaboratories, but mainly used in research settings.

112

7. Lab tests for Vasopressin deficiency Test conditions: 12-hour urine without drinking

IMPORTANT NOTE: We advise the patient to:

1. 2. 3.

4.

Be calm, sedentary, avoiding any stress or heavy physical activities Consume a normal amount of salt for the average population Sweat normally (not excessively) No drinking during the 12 hour test period

To check vasopressin leveis with lab tests, measure the baseline vasopressin leveis, obtained in conditions free of important stress or physical activity. An average salt intake: Lab tests for vasopressin are to be checked with a normally salted

diet. Lab Tests for Vasopressin Deficiency Tissue

Lab Test

Serum

Vasopressin

Urine

Optimal

12h urine Volume (night) 24 h urine Volume (total)

2-3 1.8-2.8 0.6-0.81 1.51

Probably

References

Deficient*

0-1.5 1.4 > 1.21 > 2.31

to 4.7 pg/ml to 4.3 !)moi!L 0.3-1.3 U24h 0.6-2.5 U24h

O

o-

O

Test Value

Med Med Med

Fluid drinking influences vasopressin secretion:

Optimal and deficient leveis in vasopressin in laboratory tests differ according to the water intake. When people do not drink enough, the production and leveis of vasopressin increase to prevent water depletion by slowing down urinary water loss. This mechanism compensates for the lack of drinking and assures that enough fluid remains in the body. When people drink plenty of water, vasopressin secretion and leveis drop to prevent excessive water accumulation. In many obese people, however, water drinking does not suppress vasopressin secretion well, causing excessive fluid retention and edema. Low-Fiuid lntake

(< 1 liter per day) Tissue

Test

Ser um

Vasopressin 12h Urine

Urine

Volume (night)* 24 h Urine Volume (total)*

Optimal

Probably Deficient

High-Fiuid lntake >

2 liters per day

Optimal

Probably Deficient

References

4

0-3

1-2

0-1

O

to 4.7 pg/ml

3.7

0-2.8

0.9-1.8

0-0.9

O

to 4.3 pmoi/L

0.4

>

0.8

1-1.51

>

1.81

0.3-1.31/24h

0.81/24h

>

1. 61/day

2-2.51

>

31

0.6-2.5 l/24h

Note: The urine volume that is to consider optimal or deficient depends on the amount of fluid

drunk. Values presented on the table above are therefore only suggestive of water intakes of 0.5 to 11/day for low fluid intakes and 2 to 2.51/day for high fluid intakes.

113

11/ Vasopressin Deficiency: TREATMENT Vasopressin Medications: The basic recommendation for a patient who is 90in9 to take vasopressin is to reduce fluid intake whilst takin9 the medication. Generally, desmopressin, a synthetic derivativa of vasopressin, is considered the dru9 of choice because it has a 12-hour action; whereas, bio-identical vasopressin is quickly metabolized and thus needs to be 9iven in three to five divided doses per day. Moreover, bio­ identical vasopressin is not readily available in pharmacies. Medications for Vasopressin Deficiency Doses (sedentary) Route

Product

Desmopressin

(Minirin®: 30 tablets of 100, 200 or 400 1-19; Desmopressin®: 100 tablets of 200 1-19)

Oral

Morning

Evening

(no intake or smaller dose in lhe mornin!:ll

(2h or jus! before bedtime)

o to lA - 1 tablets

(50-150 1-19)/day (starting dose % to Y2 tablet (50 �g per day) =

0-6 drops/mornin9 Desmopressin solution

lntra-

(Minirin®)

nasal

Desmopressin Spray (Minirin®) Subcutaneous Desmopressin

(4 1-19/vial of 1ml)

lntravenous Subcut.

Vasopressin

IM

(Pitressin® 20U/ml: vials of 0.5 & 1.0 ml)

IV

lA 2 tablets (50-400 1-19)/day

Drug Value

-

(starting dose %tablet (100 �gper day) =

1- 2x

per day

Hi9h

1-6 drops/evenin9

(±1O to 60 1-19); (±30 to 60 1-19); mean: 1 drop/mornin9 mean: 2 drops/evening (±1o 119)

How often

(±20 119)

Recommendation: lt is often better to instill the drops directly from lhe bottle top deep into lhe nose without using the accompanying tube de/ivered by the pharmaceutica/ company

1 - 2x per day

1 - 2x 1 to 4 puffs/day /day (20-80 119/day) (20-40 119) 1 to 2 �9 1-2x /d 1 to 2 1-19 30' before sur9ery: 4 1-19 subcutaneous or IV 0.3 119/k9 in 15' à 30' in intravenous infusion (50 ml diluent for adults and children > 1O k9) 2 - 4x 5-20 u 5-20 u /day Abd. distention: 5 U, then 10 U every 3-4h O, 1 to 2 puffs/day

LowMed

LowMed Med Hi9h for acute uses

Vasodilatatory shock: 0.01-0.04 units/min

Note: The equivalency between oral and intranasal desmopressin is 1 O or 20 to 1, which means that a tablet of 200 �g desmopressin is equivalent to 1 O to 20 �g of desmopressin nasal spray. Doses higher than 0.04 U/min. of vasopressin may lead to cardiac arrest. *

114

How to start Vasopressin/Desmopressin Treatment? For most patients, the starting dose is % to V2 a tablet bedtime.

{50 to 100 119) of desmopressin before

There are two exceptions to the rule: •

Patients who easily swell may need to start vasopressin at two-fold lower doses: start with

25 119 of oral desmopressin. •

In life-threatening hemorrhages in the emergency rooms patients receive high doses of vasopressin of 2 to 8 119 intravenous to prevent bleeding to death (which corresponds to a dose of

400 to 1200 119/day as oral tablets).

Once or twice daily desmopressin? Once the evening dose is established, an additional morning dose may be necessary for many patients as the effect of desmopressin dies off after about

12 hours. The morning dose is in general

half of the evening dose.

Ali patients need to take an evening dose, but not ali require a morning intake.

Fluid restriction Ali patients, in particular those who are used to drinking a lot of water, should restrict fluid intake to 1h to %rds of a liter during the hour before and the six hours after desmopressin intake once they take desmopressin at doses higher than a quarter of a tablet or one drop of the nasal solution. This recommendation is particularly true for the higher dose of vasopressin that is usualiy taken in the evening.

Slowly increase the dose of desmopressin When desmopressin is well-tolerated, but beneficiai effects are insufficient, the dosage can be slowly increased by a quarter of a tablet more every three to four days. The need for urination at night should decrease to maximaliy once a night. The usual evening dose for mild deficiencies is

150 119 of a desmopressin tablet.

Take desmopressin two hours before bedtime The reduction in nighttime urination is best when

the evening dose is taken two hours before bed time as two hours are needed for desmopressin to fully express its water-retaining effects.

When should the routine dose be increased or decreased? Doses should be increased in conditions where more vasopressin is needed such as heavy sweating, severe stress, excessive bleeding during surgery, or multiple trauma accidents, etc.

115

Progress with Vasopressin/Desmopressin Treatment How long does it take before the patient notices improvement?

The first improvement appears after an hour. Clear improvement is generally within two hours. In some patients, the efficacy seems to increase after several weeks of desmopressin intake, thus it may require patience before benefiting from ali the effects at a lower dose of desmopressin. Learning is improved when desmopressin is taken just before beginning a seminar or lecture day.

lndications: Vasopressin deficiency (diabetes insipidus) Bleeding disorder (Hemophilia) Heavy hemorrhages Vasodilatatory shock Bedwetting Nocturia

Contraindications to treatment Caution is recommended with individuais whose feet, ankles and/or hands easily swell as these signs may mildly exacerbate with vasopressin replacement. However this recommendation is less imperativa than for aldosterone treatment. People who keep on drinking large volumes of water are at risk of water intoxication and must restrict their water intake to normal amounts to receive vasopressin medication.

116

How to naturally boost Vasopressin: Firstly, lifestyle changes can have a very positive effect on this condition.

The principal lifestyle factors for boosting the effects of desmopressin treatment or of the body's own (endogenous) vasopressin are summarized in the following table: How to optimize Vasopressin Activity and Treatment What to Avoid

What to Do

What •

•

Fluid

Drink more water

(2 or more 1/day)

•

when slill in vasopressin deficiency1

and vegetables (vegelable soup)-

Drink moderate amounts of waler (1.5

induces dieresis, especially in the

lilers/day) when on vasopressin 1 lreatmenl • •

Food

evening

Eat organic foods2 Eat sufficient (animal) protein-rich foods such as low temperatura cooked red meat, poultry, eggs3

Position

•

Regularly stand up during the day.

Movement

•

Move regularly during the day

Stress

Avoid excessive consumplion of fruils

4

•

Avoid drinks that make the kidneys excrete more fluid: coffee, tea, soft drinks, alcohol, etc.

•

Avoid lying down in flat position for prolonged periods during the dal

•

Avoid exposure to prolonged stress, including intensive sports4

Notes: 1

Waler is lhe importanl chemical for vasopressin aclion. An insufficienl waler inlake decreases

2

Peslicides may damage the hypothalamus and piluilary gland; lhereby lowering vasopressin secrelion.

3

vasopressin's effecls on body waler. Dielary proleins can increase vasopressin produclion, whose produclion needs lhe amino acids that come from lhe protein (amino acids are lhe building blocks for vasopressin synlhesis).

4 Laying down in fiai posilion and slress slimulale lhe produclion of Vasopressin. However, in patienls wilh vasopressin deficiency, these conditions may further deplete lhe body's vasopressin stores, which are already low in lhe deficiency slale.

Secondly, correct other hormone dysfunctions that impair vasopressin production or

effects.

lnfluence of Hormone Therapies on Vasopressin activity and/or production Strong

Mild

Stimulators

Stimulators •

•

Aldosterone

• •

Mild

Strong

lnhibitors

lnhibitors

Oxytocin Testosterone

• •

Estrogen (estradiol)

117

Progesterone Thyroid hormones

Follow-up of Vasopressin/Desmopressin Treatment How do you follow up once the treatment has started? 1. Find the optimal dose:

Monitoring and dose adjustment should be based on signs and notes of improvement, carefully avoiding any excess. The following conditions may also necessitate dose adjustments:

When to adapt the dose of Desmopressin lncrease the dose

Lower the dose

(by 1JI to Y2 of 200 llQ tablets) •

• • • •

(with 1JI to 3JI of 200 llQ tablets)

Signs of persistent vasopressin deficiency: nocturia, polyuria, thirst, etc. Prolonged laying down, bedridden lntensive stress High altitude Low fluid intake

•

•

•

Signs of excess vasopressin: headache, swellings Relaxed conditions, vacations (holidays)

calm

High fluid intake

2. Avoid overdosing:

The patient should be educated to recognize the signs and complaints of vasopressin overdose so he can notify the physician and lower his dose. The main signs and complaints of vasopressin excess are reviewed in the table below:

Vasopressin - Desmopressin Excess Consequence

Nasal mucosa edema Brain edema (resulting from osmotic water shifts into the brain) Blood dilution (hypo-osmolality - hyponatremia)

Complaints • •

• • •

•

• •

Signs

Excessive nasal discharge Snoring Headaches

•

•

Nausea More severe degree of vasopressin excess: disorientation, confusion, obtundation (less than full mental capacity) Swellings Oliguria (urination during the day) Oligodipsia (reduced thirst)

•

•

• •

lncreased serous nasal discharge Swollen face More severe degree of vasopressin excess: confused behavior, focal neurologic deficits, seizures Excessively turgescent skin Swollen face Swollen ankles and feet

Note: lmportant symptoms of hypo-osmolality do not occur until the serum sodium falls below 125 mEq/1. The severity of symptoms ran be roughly correlated with the degree of hypo-osmolality.

118

3. Perform lab tests: What lab tests are recommended for follow-up?

Most tests are of little use for vasopressin treatment follow-up. Vasopressin leveis are not generally used in monitoring vasopressin treatment efficacy as the treatment consists of providing a synthetic derivative of vasopressin that because of the difference in molecular structure with the natural vasopressin may not be measured by the vasopressin measurement test.

Possible Laboratory test for follow-up of Desmopressin treatment Product used Desmopressin

I I

I Urine (24-hour) I (total urine volume, vasopressinl

Blood

------

4. Solve problems during follow-up quickly and efficiently: Reter to the next section titled "Vasopressin Problem Solver" for more information.

119

111/ Vasopressin PROBLEM SOLVER How do you solve problems that may occur during treatment?

Problems related to overdosing: Problems related to Vasopressin Overdose POSSIBLE CAUSES (in order of frequency)

PROBLEM? •

•

Excessive nasal discharge

SOLUTION •

Nasal edema

Reduce the dose of desmopressin by 30 to 70% less

Snoring

•

Take potassium supplements

•

Reduce the dose of desmopressin

Vasopressin excess may raise the intracranial pressure •

(brain edema), which can

Headaches

cause headaches. •

Excessiva fluid intake •

Amplification of an already

lncreased blood pressure

Reduce fluid intake: drink less or stop drinking fluids

existing arterial hypertension, should not occur in people

• •

lncrease fruit and vegetable intake in the diet, take potassium supplements.

without high blood pressure •

Excessiva fluid intake

Stop or lower the dose of desmopressin

Reduce fluid intake: drink less or stop drinking fluid

An overdose of vasopressin retains water in the skin, •

•

giving a 'tensed skin

Swollen skin (skin of

Stop or reduce dose of desmopressin

sensation'

hands, feet,

•

face, limbs)

lncrease intake of fruit and vegetables (rich in potassium)

Low fruit and vegetable

•

Take potassium supplements (acts as a

•

Transiently use a diuretic: stimulates fluid

intake

diuretic) : 1 to 3 grams per day excretion in the urine

•

A feeling of being under pressure

•

•

Confused look Confused behavior

desmopressin excess

•

causes fluid retention that

•

puts brain tissues under

Reduce the dose of desmopressin Reduce fluid intake: drink less or stop drinking fluids

pressure •

•

Vasopressin or

Vasopressin or desmopressin excess causes brain edema, which compressas brain structures and impairs the brain function

120

• •

Stop or reduce dose of desmopressin Reduce fluid intake: drink less or stop drinking fluids

Other problems with vasopressin or desmopressin due to the diet or medication may occur

and their solution discussed in the table below. Problems due to the Diet or Medication PROBLEM

POSSIBLE CAUSES

SOLUTION Correct the diet:

•

•

Excessive fluid intake

•

Reduce fluid intake

(possibly due to a high

•

Reduce intake of water-rich

•

lncrease salt intake (helps retain

vegetables and fruit

intake of water-rich

No improvement

vegetables and fruit)

from the treatment.

water in the body) •

Diuretic use: the diuretic increase the water loss in the urine

121

•

Stop or reduce the diuretic

Chapter six

Thyroid Deficiency & Treatment

A Typical Patient with Thyroid Deficiency (Hypothyroidism) Svetlana and her weight problems As a child, Svetlana had a tendency to put on weight. Her parents tried hard to make her lose weight by having her practice sports and adj ust her diet but with little success. She grew up at a delayed rate compared to others.

In the morning, as a child, she had difficulties getting out of

bed and felt better after some time and activity.

She was a slow child, slow in thinking and

understanding, was known at school for her concentration difficulties and had a hard time to catch up on her school work. Another problem she faced was that she always felt cold, even in the summer. As an adult, her problems worsened. Her face became puffier over the years, especially in the morning. She now feels swollen ali over, although her diet is strict and low in calories. Anyway, whatever the diet, her tremendous efforts to decrease her weight are hardly ever rewarded. Her skin and hair are rough and dry. She often has a bad temper, especially in the morning. She feels depressed. What is Svetlana suffering from? Svetlana is most probably suffering from thyroid deficiency. In order to better understand this deficiency, let's first explain some basic information.

123

Thyroid: lmportant lnformation Thyroxine and triiodothyronine There are two major thyroid hormones, thyroxine or T4 , which has four iodine atoms, and triiodothyronine or T3, which has three iodine atoms.

T3 is the most active thyroid hormone

and the most widely distributed thyroid hormone in the body. lts distribution volume is five times greater than that of T4. T3 is by far the main thyroid hormone in the target cells. In contrast, T4 is the most abundant thyroid hormone of the blood: it is approximately 65 times more abundant in the serum than T3.

lt is mainly a precursor hormone that has to be broken down to T3 to

become fully active in the cells. Roles of Thyroid Hormones Thyroid hormones have various beneficiai actions. First, thyroid hormones increase blood flow, heart rate, heat production, metabolism, energy production and consumption, speed of thinking, intestinal motility, thirst, urination, HDL (good) cholesterol, immune defences against various infections and cancer, and many other functions. Second, thyroid hormones beneficially decrease total and LDL (bad) cholesterol, diastolic blood pressure, the amount of "myxoedema", the edema consisting of mucous waste products outside the cells that is typical of thyroid deficiency, and accelerate the elimination of old defectiva enzymes and other waste products inside of the cells. Production of Thyroid Hormones The daily secretion of T4 is 80 to100 11g and of T3 is 20 11g by the thyroid gland; most of the T3, about 35 11g per day, does not come from the thyroid gland but from peripheral conversion of T4 into T3, mainly in the liver. Factors that increase Thyroid Hormone production Eating high caloria diets, fruits and vegetables can increase thyroid activity. Eating sugar does too, although transitorily, an effect that perhaps explains why certain people like eating sugar. In contrast, eating too much protein (meat and poultry), or eating very little (such as is the case in low caloria diets, fasting or malnutrition) can considerably lower thyroid activity by slowing down the conversion of T4 to T3 that is so essential to optimal thyroid activity, and by lowering the production of both thyroid hormones by the thyroid gland. The leveis of thyroid hormones decrease with age Both thyroid hormone leveis gradually decline with age: that of T4 decreases approximately 1020% from age 25 to 75 and that of T3 decreases by 25%. Principal metabolites of Thyroid Hormones: Metabolites of thyroid hormones include rT3 or reverse T3 that can partially block T3 activity, T2 or diiodothyronine (two iodine atoms), T1 or monoiodothyronine (one iodine atom), thyronine (no iodine atom).

124

Ta or

I. Hypothyroidism: Diagnosis How do you detect hypothyroidism?

lndications in past health, physical signs, patient's complaints, concurring diseases, lab tests, and possible medicai imaging will offer the best picture for detection and evaluation of the degree of thyroid deficiency.

1. Onset of Hypothyroidism When did the thyroid deficiency start? A first look at a person who has hypothyroidism may inform you whether his or her thyroid deficiency started in childhood or later in adulthood. Persons with adult onset thyroid deficiency have a normal height, and normal sized arms and legs, whereas individuais with a child onset deficiency are shorter with a bigger trunk, shorter arms and legs, and thicker muscles. These differences are summarized in the following table: Determining the Onset of Hypothyroidism Childhood Height •

Body

Adulthood

Short • •

Normal

Thick trunk Larger chest and abdomen Smaller limbs

•

Relatively normal trunk but swollen and obese

•

Obese

•

Smaller

•

•

Hyperlaxity of finQers

•

Normal laxity

Feet

•

Flat feet

•

Normal arch of foot

Spine

•

Scoliosis, hyperlordosis

•

Hyperlordosis

•

Thick

•

Normal to thick

•

Poor sexual characteristics

•

Normal-sized but atrophic

•

Heavy birth weight •

Normal health as a child

Hands

Skin, bones & muscles

Sexual

Past Medicai History

• •

•

Normal size

Delayed growth, development, puberty Recurrent infections as a child (possibly tuberculosis, pneumonia) Learning disabilities

After this first check, please inquire about the timing and location of the patient's complaints.

2. Timing, Location: When and where do signs and complaints of hypothyroidism appear? When? Typically, signs and complaints of thyroid deficiency are remarkably more intense

and frequent in the morning and at rest. Where? Physical signs of hypothyroidism are usually diffusely spread ali over the body.

125

3. Complaints of Hypothyroidism The principal complaints of hypothyroidism are summarized in the following table: PHVSICAL Complaints of Hypothyroidism Health Appearance Energy/ Vitality

• • • • • • • •

Temperatura

• • • •

Sleep

• •

Food Water balance

• • • • •

Ha ir

• •

Head

• •

Voice

•

Skin

•

Nails

•

Digestiva

• • •

Joints and muscles

• • • •

Prone to ear, nose and throat infections Prone to weight gain, but difficult weight loss when dieting Overweight, obesity Swollen ali over Morning fatigue, fatigue when taking a rest Feels best in the evening and when physically or mentally active Lethargy, apathy lntolerance to cold, easily shivers (because of the cold) Needs to wear supplementary warm clothes in ali seasons Poor circulation (white fingers in winter) lntolerance to heat, inability to sweat in a hot climate Snoring when sleeping at night (sleep apnea) Difficulties getting out of bed in the morning Somnolence (sleepy during the day, especially when resting) Poor appetite for food (a certain degree of anorexia but with obesity) Excessive intake of caffeinated drinks (used for energy) Oligodipsia (decreased thirst) Oliguria (decreased urination) Dry hair Slow growing hair Diffuse hair loss Diffuse headaches ; Migraine headaches Tinnitus (ear buzzing) Morning hoarse voice Dry skin Brittle, slow growing nails Bloated abdomen (often dolichocolon), dyspepsia (slow digestion) Constipation Muscle and joint stiffness upon waking Diffuse myalgia and arthralgia, more important in the morning Feet and leg cramps at night Carpal tunnel syndrome Low back pain MENTAL Complaints of Hypothyroidism

Behavior Mood

• • • •

Memory

• •

Slowness Apathy (lack of interest, initiative) Morning depression Slow thinking and slow reactions Easily distracted, poor concentration, poor attention Poor memorv, poor school performance

126

4. Physical Signs of Hypothyroidism How does a hypothyroid patient look like? The physical signs of hypothyroidism are listed in the following table: PHYSICAL SIGNS of Hypothyroidism Body

Hair

• •

Puffy Overweight

Behavior

•

•

Dry, thick, brittle hair

•

Memory loss

•

Diffuse hair loss

•

Attention deficit

•

Puffy face

•

Concentration difficulties

Loss of outer third of the eyebrow

•

Apathy

Mood

•

Depression

•

Swollen eyelids

Voice

•

Hoarseness in the morning

•

Swollen lips, tongue

Hearing

•

Otosclerosis (hearing loss)

•

Abnormal-sized thyroid gland:

Lungs

•

Face

Mental

•

Neck: Thyroid

•

Atrophic

•

Thyroid hyperplasia

•

Goiter

•

•

Arms

Elbows

Abdomen Calves

Dry, rough skin (follicular hyperkeratosis) Thick muscles

•

Keratosis (dry, scaly skin)

• • •

Heart

Nodule(s)

•

•

Hands

Sluggish, slow thinking and moving

•

•

Brittle, slow growing nails

•

Bloating due to achlorhydria Constipation Thick swollen calves

•

Non-pitting edema

• •

Feet • •

Faint heart sounds High diastolic blood pressure

•

Skin

•

•

•

Tendon

Cold feet

reflexes

Swollen feet (pitting or non- pitting edema)

Bradycardia

•

pressure

Excessive laxity of the fingers

Dyspnea Slow and superficial breathing (hypoventilation)

•

•

Yellowish palms (carotenemia)

•

•

Blood

Cold hands Swollen hands

•

•

•

Narrow differential blood pressure (small difference between systolic and low diastolic blood pressure) Slow pulse rate Carotenemia (yellowing of the palms and soles ) Dry skin on face, elbows, legs Follicular keratosis

Slow Achilles tendon reflexes (pathogonomonic) Other slow reflexes: patellar (knee) reflex)

Carotenemia Flat feet

The next step is to check for any diseases related to thyroid deficiency.

127

5. Disease Susceptibility What diseases are hypothyroid patients susceptible to? Some studies suggest that the following diseases may develop easier in patients with low

thyroid hormone leveis: cardiovascular diseases such as hypertension, hypercholesterolemia, heart failure, infertility, obesity, diabetes, depression, memory loss, Alzheimer's disease, respiratory infections (ear-nose-throat infections, flu, bronchitis, pneumonia, tuberculosis, etc.) and possibly cancer. After this check it is essential to require lab tests.

6. Thyroid Lab Tests Which lab tests are the most useful to confirm thyroid deficiency? The lab tests listed in the underlying table are the most recommended ones. Laboratory Tests for Thyroid Hormones

TSH1 Free T3

(fT3)

Free T4 Thyroid

Blood

Possibly

Optimal

Test

(fT4) 2

antibodies

ATG ATPO J TSI

Thyroglobulin

2!2.5 0-2.4

0.4-2.5 mU/ml4 1.8-3. 7 nQ/L

3.9-5.2

0-3.7

2.8-5.7 pmoi/L

1.3-1.8

0-1.2

0.8-1.8 ng/dl

16.7-23.2

0-15.5

10.3-27.7pmoi/L

o o o <10

2!20 2!20 2!5 >15

0-50 U/ml 0-50 U/ml 0-10 U/ml 0-25 ng/ml

the initial TSH levei

stimulation

Urine

� 1Ox initial TSH

Notes:

"

2! "

Med Low Med Med Low

thyroidism < 5x

2000 1.6-1.9

Free T4

Med

Med

Secondary hypo-

1400-

24h

Test Value

Prímary hypothyr.

0.9-1.3 Free T3

References

1 2.5-3.4

5-9.99 X

TSH after TRH

Deficient

2000-2500

0-0.85

0.5-1.7 j1g/24h

0-1300

800-2500pmol/24h

0-1.4

0.4-2.5 j1g/24h

0-1800

550-3160 pmol/24h

High Low

means equal to or greater than

1 Thyroid Stimulating Hormone;

2

ATG (anti-thyroglobulin antibodies), ATPO (anti-thyro,peroxidase 3 TSI is high with hyperthyroidism; new TSH

antibodies), TSI (thyroid stimulating immunoglobulins);

references of the National Academy of Clinicai Biochemistry to detect borderline hypothyroidism.

Other tests such as imaging tests may be useful, in particular when the thyroid gland is enlarged or presents nodules.

128

7. Which imaging tests to detect thyroid abnormalities? 1. Ultrasound examination of the thyroid: to detect and investigate further nodules. Finding thyroid nodules is important as thyroid therapy may reduce the size and development of nodules.

With age, most thyroid glands have heterogeneous active and non-active zones

with nodules developing in the thyroid glands of up to more than 90% of elderly persons, when examined by ultrasound at autopsy. 2. Radiography of trachea and esophagus: this is used only in case of a goiter with the aim of evaluating if the goiter narrows the lumen of the trachea and esophagus. 3. Radiography of the thorax: can be done in patients with severe hypothyroidism to check if there is any cardiomegaly or pericardial effusion that is caused by thyroid deficiency. 4. Echocardiography of the heart: may be useful for checking the presence of a mitral valve prolapse as it is more frequent in hypothyroidism 5. Electromyography (EMG)

-

Hypothyroidism causes slow nerve conduction

129

11. Hypothyroidism: TREATMENT Medications for Hypothyroidism The principie medications available are summarized in the followin9 table: Daily

Q) ::;,

...

o a:

Medication

Triiodothyronine

(T3) Fast release (Cytomel, Cytonel®)

Optimal

over (Avera9e) the day In divided doses 40119 4x per day Dose

T3 Slow release

(Compoundin9 pharmacies)

Oral

Thyroxine (T4)

(Levothyrox, Euthyrax, Elthyrone, L-Thyroxine, etc.)

Synthetic T3- T4

(Novothyral, Euthyral, Thyrolar®)

Efficient dose range

for most patients 1o -75 119 per day

Value

Low

1-2 X per day

50-300 119/day

Low

1X per day 100-150119 (early mornin9)

25-300 119/day

Low

1 to 1Y2 tablets

1-2x /day (mornin9 & lunch)

Y2 to 2 tablets

Medium

75-120 m9

1X per day (early mornin9)

30-240 m9/day

Hi9h

150119

Desiccated thyroid

(Armour, Erfa Thyroid®)

Dose partition

Effects

Fast onset (30 min.); short effects (3-4 h) Slower onset {hours) and lon9er effects (4-8 h); low absorption => need for hi9h doses Slower onset to activity (1O days), less effective than medications containing T3 Hi9h mornin9 /lower evenin9 activity Animal ori9in, 9entler action, better 24-hour constant action1

Note: 1 The best source of thyroid is from pork (because of its higher T3 content), second best is from beef, third best is from sheep. A great deal of thyroid hormones in desiccated thyroid powder of animal origin is thyroglobulin. Thyrog/obulin is a huge protein that is slowly absorbed and once it reaches the b/oodstream, it s/ow/y re/eases the thyroid hormones that are bound to it. Many patients find that desiccated thyroid has more persistent beneficiai effects that last for a 24-hour period with a constant T3T4, content. Synthetic T3-T4 medications are too quickly absorbed so that the effects come quickly (thanks to the absorption of quick-working T3) but also tend to disappear very quick/y with not enough in the evening..

130

Why T3-T4 medications may be the first choice for Adult Thyroid Therapy

Because they work better! This is what many patients and physicians firmly believe after trying both types of medications (T3-T4 and T4 alone preparations). Foliowing certain physicians, T4 alone preparations seem to work weli in patients with thyroid deficiency but at doses that suppress TSH, the hormone that stimulates the thyroid gland to produce thyroid hormones. No solid studies exist to our knowledge, which show T4 products to work clearly better than T3-T4. Some studies show a better tolerance, but not efficacy.

The main arguments,which explain why treatments that provide the two main thyroid hormones T4 and T3 work better than treatments relying on T4 only, are listed in the foliowing table. Reasons why T3-T4 medications may be superior to T4 alone medications T3-T4 medications work better than T4 medications in the following areas: 1. 2.

Lowering the total cholesterol Restoring a normal Achilles tendon reflex

3.

Prevention of goiter formation

4. lmprovement in overali symf)toms(at least in some - not ali - studies ). There are no studies that really show T4 preparations to work better than T3-T4. Some studies do show a better tolerance, but not efficacy. T3-T4 medications achieve better T3 tissue leveis in the followin_g areas: 5.

In blood: T4 medications must increase serum T4 to the upper reference value to obtain an average blood levei of T3, while this is not the case for T3-T4 medications.

6.

In target tissues (heart, lung, spleen, muscle, adrenals, avaries): In hypothyroid rat studies T4 supplements alone fail to obtain T3- euthyroidism, contrasting sharply with T3-T4 treatment that brings the tissue T3 concentration to a healthier T3-euthyroid levei

T3-T4 medications may be more stable in potency: 7.

Higher potency: T3 is relatively stable, whereas the potency of T4 preparations can vary

8.

Greater stability: synthetic T3 and registered animal preparations such as Armour Thyroid® have greater stability compared to T4.

The intestinal absorption of T3, which is found in T3-T4 medications, is better and more constant than that of T4, which is the sole active ingredient of T4 alone preparations. 9.

The absorption of T4 is poor and variable (35-67%), whereas T3 is very weli absorbed (95%).

T3-T4 medications may better improve the conversion of T4 into T3 and thus provide higher T3 tissue leveis: 1 O. Many conditions inhibit the conversion of T 4 to active T3 such as aging, hormone deficiencies

(including T3 deficiency, stress, digestive troubles, etc.) and make it unlikely for T4 preparations to be sufficiently converted to T3. lnterestingly, researchers have demonstrated that a minimal amount of T3 is necessary to convert sufficient amounts of T4 into T3. For these reasons, it is justifiable to add T3 to T4 in the thyroid medication to assure minimal T3 leveis and a good T4 to T3 conversion.

T3 is the most important hormone not T4: 11. T3 is the active hormone in target cells, not T4. Moreover, T3 is the dominant thyroid

hormone in ali bocly cells with a five times greater distribution volume than T4. 12. Mortality studies in humans and animais show that it is, in general, the levei of T3 - not of T4,

which determines survival.

131

How to start Thyroid Therapy The golden rule is to start low and then slowly increase. lf the patient has a cortisol deficiency or if his thyroid deficiency is severe, start thyroid therapy on even lower doses and increase the doses at a slower pace. Paradoxically, the greater the thyroid deficiency, the lower the dose to start on and the slower the pace of increase in dosage should be, as otherwise the patient may suffer acutely of symptoms of cardiac intolerance. Hypothyroid patients with cortisol deficiency

Cortisol deficiency often makes patients intolerant to thyroid treatment, because in this condition T4 converts excessively into T3, thereby pushing the hypothyroid patient quickly into a state of hyperthyroidism. In some extreme cases, the intolerance can be so severe that the patient suffers from severe signs of hyperthyroidism even at very low doses of thyroid hormones. These patients need to get the cortisol deficiency treated with hydrocortisone or glucocorticoids first or concurrently to the onset of thyroid treatment. In mild cases, thyroid treatment can stimulate the adrenal glands to produce more cortisol so that cortisol replacement can be postponed or even avoided in these patients. But as this is not the rule, prudence should be practiced at ali times. How to gradually increase the dose of T4-T3 medications A schedule on how to do it is presented in the following table.

How to Start Synthetic T4-T3 Medication NOVOTHYRAL-THYROLAR-EUTHYRALQl) When?

• •

The 1st two weeks

The 2"d two weeks The 3'd two weeks

The next 2 to 3 months

Next consultation

�

14 tablet per day

�

Y2 tablet per day % tablet per day

� �

•

during summe�

•

thin I cortisol-deficient

•

Take the tablet 15 minutes before breakfast Chew it before swa/lowing1

patients

�

during the winte�

�

First follow-up consultation

(2 to 3 months after starting)

The next 4 months

Month 3 to treatment

Next consultation

Second follow-up consultation (6 months after the start)

6 of thyroid

Climb up to a maximum of % tablet per day and remain on it until the next consultation lncrease up to 1 tablet per day and remain there until the next consultation Check the thyroid status of the patient with interview, physical exam and lab tests => advise the patient if there is a need to reduce, maintain or increase the dose. lf a higher dose is needed => increase the daily dose with 14 tablet every 2 weeks (in big people every 1 O days, but in sensitive persons every 3 weeks,) up_to 1 Y2 to 1 % tabletlday Control the adequacy of the dose with interview, physical exam and lab tests => determine if a higher or lower dose is necessary

132

How to Start Desiccated Animal Thyroid (T4-T3 medications) Time before the next increase in dose depends on the cortisol level Thin & small Average Big & tall patients; sized patients; patients Patients with Patients with low cortisol high cortisol 7 days 1"tPeriod 14 days 10 days 7 days 2"d Period 14 days 10 days 3'd Period 14 days 7 days 10 days 4t"Period 14 days 7 days 10 days

n 5t Period

6tn Period

10 days

14 days

10 days

14 days

2 to 3 months after start:

First follow-up consultation

3th to 6th month of

thyroid treatment

6 months after start:

Second follow-up consultation

7 days

7 days

ARMOUR- ERFA THYROID® and

other desiccated preparations • •

Take 10-20 min. before breakfast 1 Chew before swallowing

Dose 15 mg!day (= � grain) per day 30 mg!day (= Y2 grain) per day 45 mg!day (= 3f.l grain) per day 60 mg/day (= 1 grain) per day:

Low cortisol patients should remain on lower doses of ± 60 mg until the next consultation. 75 mg/day (1� grain) per day:

lf the weather is hor, remain on mg until the next consultation.

75

90 mg/day (1% grain) per day

lf the weather is cold, increase up to 90 mg until the next consultation. Adjust thyroid dose to the patient's needs, as estimated by interview, physical exam and lab tests. lf necessary, increase the thyroid dose with 15 mg (14 grain) every 10 days (or 7 or 14 days) up to 120 mg (2 grains) per day Adjust thyroid dose if needed based on the interview, physical exam and lab results.

Notes: 1' 2

Chewing or letting the thyroid medication melt under the tongue 20 minutes before breakfast improves its intestinal absorption. Higher doses are usual/y necessary during co/d weather (winter) and /ower doses in hot weather (summer). The difference between winter and summer is !4 to Y2 tablet per day.

How do you switch over from a medication with Thyroxine {T4) alone to one with T4 and T3? Avoid abrupt switches from one to the other. Take your time. Slowly increase the T4-T3 medication over a period of 6 to 12 weeks, while at the same time slowly decrease the T4medication.

133

The followin9 table presents an example on how to switch over: How to switch over fromThyroxine (T4) alone toT4-T3 medication lnitial Status (w/ solelyT4)

Chan9e dose every ...

Switch

T4 (e. 9· of a patient on 100 119)

T3-T4 medication

INCREASE by 15 m9 (14 of a grain) per day of desiccated thyroid. e.9. a patient on100119 ofT4: /fone product is 1st week: 15 mQ/day of thyroid From lowered, 2"0 week: 30 mQ/day of thyroid Thyroxine one 3ra week: 45 mg/day of thyroid (T4) alone n increased 4 1 week: 60 m9/day of thyroid to n 1 Every 5 1O days: 75 m9/day of thyroid Desiccated 10 days Thereafter: thyroid Every 7days

Nearly normal thyroid

(lhe patient is free or nearly free of mental and physical signs and symptoms of From thyroid Thyroxine dysfunction) {T4) alone

to Synthetic T4-T3

LOWERT4 by 25 1..19 of T4 /day

+ + +

75 11!:1 of T4 50119 ofT4 25119 ofT4 STOPT4

lfthe dose Remain at 75 m9/day or increase to a ofonlyone maximum of 90 m9/day (before the medication is increased next consultation)

Every INCREASE BY 14 tablet/day of synth. 10 days T3-T4, e.9. a patient on100119 of T4

oneproduct is lowered, one increased

Every 14days lfonlyone medication

Principie

First days

LOWERT4 by 25 1..19 of T4 /day

1st1O days: 14 of tablet/day ofT3-T4+ 75 1..19/day ofT4 2"01O days: 112 of tablet/dayT3-T4 + 5011Q/day ofT4 ra 3 10 days: 3A of tablet/day T3-T4 + 25 119/day of T4 41" 10days: 1 tablet/dayT3-T4 & STOPT4 51"10 days: 1 tablet/dayT3-T4 & Thereafter, remain at 1 tablet/day T3T4 or increase to a maximum of 114

INCREASE ONLYT3-T4 Do not chan9e T4at the start Take desiccat. thyroid up to 30 mg/day Every 1st 10 days: 15 m9/day thyroid + 100119 ofT4 10 days FromT4to + 100119 ofT4 2"d1O days: 30 mg/day thyroid Desiccated LOWERT4 by Next, follow instructions above for (The patient Then thyroid 25 normal thyroid (every 7 days increase 1..19 every 7 has evident every thyroid by 15 m9): successively 45 days e.9.,75 119 mental and 7 days 60- 75 m9 thyroid, etc, and reduce T4 of T4, etc. physical signs and Take synthetic T4-T3 up to Y2 T4unchan9ed symptoms of tablet/day Every thyroid 1st14 days: 14 tablet/day of T3-T4 + 100119 of T4 FromT4to 14 days dysfunction; Synthetic 2"d14 days: Y2 tablet/day of T3-T4 + 100119 ofT4 and lowT3 75 11!:1 ofT4 Next, follow instructions above for a T4T - 3 Then and T4 in the normal thyroid. For the next 1O days: every 50119 ofT4 lab tests) 10 days %, then 1 tabletT3-T4 then .. & 25 119T4 => stop

Overt Low Thyroid

Lookfor

Persons with low cortisol with si9ns of overdose

•

Make the switch slower to avoid intolerance such as chan9in9 doses every10-14 days rather than every 7 days, or

•

lncrease theT4-T3 medication by smaller doses

•

S top the T4 preparation, continue the T4-T3 medication

•

lf overdose persists after 3- 4 days, reduce the T4-T3 dose

134

lndications for Thyroid Treatment Permanent indication: Ali degrees of thyroid deficiency Occasional indications for T3 supplementation: Heart transplants (there is a higher success

rate if both the heart donor and receiver receive T3 supplementation) ; Some patients with refractory depression on anti-depressant medication and who do not improve sufficiently.

Contraindications to Thyroid Treatment Absolute contraindication: Normal thyroid function (euthyroidism). Absence of any degree of

thyroid deficiency (this becomes evident because intake of thyroid creates overdose signs). Relative contraindications:

•

Severe uncorrected cortisol deficiency

•

Recent myocardial infarction and other acute heart diseases. lf a patient suffers from both myocardial infarction and hypothyroidism, priority should be given to treat the myocardial

infarction. Treat the hypothyroidism only two months later at lower doses and increase the

doses at a much slower pace, increasing for example the thyroid hormone by one-third of normal. An exception to the rule is extreme low thyroid function, where very small doses

are essential for survival, possibly accompanied by a beta-blocker to avoid cardiac

intolerance.

How can you boost Thyroid Treatment First of ali, improve the lifestyle and the diet in particular. The principal lifestyle factors are summarized in the following table: How to optimize thyroid activity and treatment WhatTo Avoid

WhatTo Do • •

Diet

Eat calories (at least 1 ,500-2,500 cal/day)

•

Avoid low-calorie, low-fat diets ,

vegetables, but modest amounts of protein 1 and fat such as meat, poultry, eggs, fish

•

Avoid "industrialized" foods:

•

Eat organic foods2

•

Eat foods rich in iron3 (red meat), and

iodine (seafood, seaweed (kelp, dulse)) Sleep

•

fasting, skipping meals

Eat "Paleolithic" foods: plenty of fruits and

Sleep sufficiently

Stress

• •

Alcohol, vinegar, caffeinated drinks4 Milk products

•

Excess animal protein (meat, etc.)1

•

Fiber-rich cereais (whole grain bread,

•

Avoid sleep deprivation

•

Avoid prolonged chronic stress,

•

bran flakes, ...)5

Avoid excessive physical activity6

Notes: 1 A minimal amount of protein is necessary for opti m al thyroid performance, but excessive amounts of protein, in particular excess meat, slow down the conversion of T4 to active T3, and thus inhibit thyroid function; 2 Certain pesticides may a/ter thyroid secretion andlor effects; 3 lron sipnificantly accelerates the conversion of T4 into the active thyroid hormone T3 and thus increases thyroid activity; Decaffeinated drinks (where the caffeine has been extracted by the safer method based on water and carbonic acid) may be an acceptable alternative. Unfortunately, unlike decaffeinated coffee or tea packages where the caffeine extraction method is often printed on the cover of the package, it is generally not mentioned on packages of other decaffeinated drinks; 5 Studies suggest that fiber-rich cereais may considerably lower the absorption of the T4 (in the thyroid medication) in the intestinal 6 tract, making thyroid medication less efficient; These conditions are accompanied by an overconsumption of thvroid hormones andlor a decrease in thyroid hormone production by the thyroid gland.

135

Second, correct any other hormone deficiency of importance for thyroid activity. Many hormones augment thyroid production and its effects on the body. When severa! other hormone deficiencies are being corrected at the same time, the optimal thyroid dose is usually 30-80% /ess! The lesser need for thyroid hormones in multiple hormone treated subjects is due to the fact that many of the other hormone supplements boost the activity of the thyroid gland and the conversion of poorly active T4 into active T3 (see table below to know which ones). The most potent one is growth hormone treatment. The principal hormone replacement therapies that increase or decrease the secretion of thyroid hormones and their actions is summarized in the following table. lnfluence of various hormone therapies on the thyroid hormone levels/activity

Strong Thyroid

Mild

Stimulators

•

•

Strong Thyroid

Stimulators

•

DHEA

Growth hormone,

•

Androstenedione

IGF-1

•

Melatonin

Testosterone and

•

other androgens

Progesterone

•

Cortisol at small

synthetic Estrogens

2 •

lnsulin in patients with insulin deficiency

•

Oral bio-

•

Erythropoietin (theoretical)

Cortisol and other

Transdermal or injectable

identical or

ohvsioloaic doses •

Mild lnhibitors

lnhibitors

•

1

Estradiol •

Cortisol at small doses2

•

lnsulin in patients with

glucocorticoids

insulin

at very high

resistance

dosaaes

{theoretical)

Notes: 1

Paradoxical/y, a potent increase in thyroid action can be obtained for many hormones, as is the case for severa/ food or nutritional supp/ements by mainly increasing the leveis of active thyroid hormone T3, whi/e at the same time leveis of poorly active T4 decline.

2

Cause? The thyroid treatment itself

acce/erates the conversion of T4 into T3. Sma/1 doses of cortiso/ may slightly boost or calm down thyroid activity depending on the patient's thyroid status. One study showed that these safe doses tend to normalize thyroid activity--decreasing excessive leveis of thyroid hormones, while increasing deficient leveis.

Progress during Thyroid Treatment How much time is needed for noticeable improvement with thyroid treatment? Progress takes time. In general, the first improvements emerge during the second month and patients continue improving during the third and fourth months. One of the reasons for the slow progress is that thyroid treatment is started at low doses in order to let the body adapt and to avoid intolerance. However, low doses do not permit spectacular effects. Nevertheless, some patients quickly feel improvement after two weeks or even after a few days.

The quick improvement is a very

positiva sign and is a predictor of further marked improvements with excellent tolerance.

136

Follow-up of Thyroid Treatment

What do you do next, once treatment has begun?

1. Find the adequate dose:

Various conditions may change the optimal dose and require temporary or permanent adjustments. The most frequent conditions are summarized in the following table: When to adapt the Dose of Thyroid Hormones lncrease the dose

Dose

Conditions

Lower the dose

(5-20% more)

(5-20% less) Excessiva thyroid blood leveis and effects

•

lnsufficient thyroid effects

•

•

Winter

•

Summer

•

In the mountains

•

At the seaside

•

Excessiva physical activity

•

Excessiva stress

•

High-protein diet

•

High vegetable and fruit diet

•

Low vegetable and fruit diet

•

•

Low-calorie diet

•

•

Beta-blocker treatment

•

•

Oral estrogen treatment

•

•

(birth control pill, HRT)

• •

Sleep deprivation Situations that require a sharp mind: speeches, TV talk shows, exams

Low protein diet Caffeinated drinks (Coffee, tea, cola) Untreated cortisol deficiency Testosterone or other male hormone treatment in women

•

Growth hormone treatment

•

lnsulin treatment

1

Note: Some physicians and patients have reported that taking a supplementary sma/1 dose of T3 (1015 pg) or of T3-T4 preparation (15-30 mg of Armour Thyroid or !4 of a tablet of synthetic T3-T4) one or two hours before a situation requiring a sharp memory and quick rep/ies, have been very helpful. This information concerns only patients already on thyroid treatment.

137

2. Lab tests: When is the best time to perform lab tests? ldeally, the labs are measured 24 hours after the last dose of thyroid. A minimum of nine hours after the last dose is required before taking a blood sample, as the thyroid hormone leveis peak above the upper reference after intake of thyroid hormones. Which lab tests help to control thyroid treatment? The following tests are recommended: Recommended Lab Tests For Follow-Up Medication used Desiccated thyroid Synthetic T3-T4 T4 (alone) T3 (alone)

Urine (24-hour)

Blood Serum TSH, free T4, free T3

(To do 24 hours after last thyroid dose) Serum TSH, free T4, free T3,

Free T3, T4

(rarely thyroglobulin)1

(To do 24 hours after last thyroid dose) Serum TSH, free T3

Free T3

1 Notes: Thyroglobulin is measured in thyroid cancer patients (as an increase in thyroglobu/in may indicate a thyroid cancer recurrence) and in patients with goiters. What are the optimal test results for follow-up? 1.

Blood leveis and 24-hour urine leveis of thyroid hormones T4 and in particular T3 should be in the normal reference range.

2.

Blood leveis of TSH should be in the normal reference range between 0.4-2.5 miU/ml (guidelines of the National Academy of Clinicai Biochemestry), but some rare studies have shown that about one-third of patients have a clinicai presentation of euthyroidism, while the serum TSH is suppressed under the 0.4 miU/ml. These patients have a pituitary TSH deficiency (secondary hypothyroidism). When thyroid hormone leveis are normalized, their weak pituitary gland will stop producing TSH.

138

3. Avoid thyroid overdosing and underdosing.

Monitoring and dose adjustment should be based on signs and symptoms. Lab tests help, but their usefulness is restricted to observe gross excesses and will not help the fine tuning of the dose from a suboptimal to the optimal state where the patient is symptom-free. When do you check for signs and symptoms of thyroid over or underdosage?

The patient should monitor his thyroid status every day and go to the physician for a check every two to nine months. lt is of uttermost importance to sufficiently inform the patients about the signs of thyroid excess or deficiency so that they can assist the physician with dose adjustments and can adjust their dose themselves in case of an adverse event. The principal signs and symptoms of thyroid overdosage are outlined in the following table. THYROID OVERDOSE COMPLAINTS • •

Nervousness

• • •

Excessiva quickness Weakness Sleep

• •

• •

•

Nervousness Anxiety lrritability Agg ressiveness lnner feeling of trembling Tachycardia Early morning waking

•

•

Overheating •

•

Weight & appetite

Fatigue Muscle weakness Sleep disorders

• •

Digestiva unrest

•

Excessive, diffuse and permanent sweating lncreased sweating after minor physical efforts such as walking up the stairs Excessive heat production, having it too warm Excessive weight loss despite excessive food and fluid intake Excessive hunger Excessive thirst Diarrhea

THYROID OVERDOSAGE SIGNS • •

Excessiva behavior

•

•

Weight

•

Nervousness Excessive emotional reactions Quick reactions, movements Quick speech, thinking Excessive weight loss

Face Eyes Trunk Skin Blood

•

Heart

•

Tachycardia Heavy heart palpitations (cardiac overactivity)

•

•

• • • •

pressure Fingers Tendons

4. Solve problems quickly

139

• •

Thinning of face and body (emaciation) Excessively bright eyes (adrenaline look) Diffuse sweating Overheating Baby-soft wet skin High differential blood pressure (high systolic and low diastolic BP) Trembling fingers Quick Achilles tendon reflexes

111. THYROID PROBLEM SOLVER How to solve problems that occur during treatment? The most common problems associated with thyroid treatment, their possible causes and solutions, are outlined in this section.

Problems possibly related to thyroid treatment overdose

I

OVERDOSE PROBLEM

CAUSE

SOLUTION

What to do if the patient suffers from more than two of the symptoms mentioned below The first thing to do is to determine the

Doing everything too quickly:

onset of hyperthyroidism.

•

Waking up too early

•

Moving too quickly

•

Speaking & thinking too quickly

•

(Over)reacting too quickly

•

•

an increase in thyroid hormone dose and are mild and sparse, are generally transient and an adaptation

Rapid heart rate, beats,

that subsides after 2-3 days.

especially after climbing up stairs •

Treatment? Wait 2-3 days more.

lntense pounding heart •

Being nervous, overexcited: •

lrritable, aggressive

•

Trembling fingers

dose and are severe and frequent, are generally persistent and are

Thyroid

indicativa of thyroid excess

Overdose

Being hot •

Symptoms that begin 4-5 days after an increase in thyroid hormone

Nervous, anxious

•

Symptoms that start 1-2 days after

Treatment?

(hyper-

Overheated

•

Sweating ali over & continuously

•

Wet and baby-soft skin

•

thyroidism)

Stop ali caffeinated drinks (coffee, tea, cola)

•

Reduce the dose by:

•

lA to Y2 tablet (or more) of

Overeating and overdrinking, but

Novothyrai®,Thyrolar or

losing weight:

Euthyral®etc.)

•

Loosing weight ++

•

15 to 30 mg less of Armour Thyroid®

•

Excess hunger

•

25 to 50 119 less of L-Thyroxine®

•

Excess thirst

(Synthroid, Euthyrox, Thyrax®, etc.) •

Weakness: •

Muscle weakness

•

Fatigue

•

lnsomnia

lf severe signs and symptoms persist, stop the thyroid hormone

for 1 or 2 days then restart treatment at a lower dose.

What to do if the patient suffers from only one or two of the symptoms mentioned above •

•

•

Excessive aggression

May be the first sign of

Lower the dose of thyroid treatment

too quick reactions

overdose, esp. in women

by 15-35%

lntense sweating at

Clear excess of thyroid

Stop thyroid hormone for one or two

night, overheating

hormones, may happen in

days (allows the hyperthyroid

lntense feeling of inner trembling, trembling fingers

•

Excessive hunger, attacks of hypoglycemia

the hot summer when

condition to pass quickly}, and then

thyroid hormones need to

start again the thyroid hormone

be decreased

treatment at a 20-30 % lower dose

May be the first sign of thyroid hormone excess, in particular in lean and

underweight persons

140

Lower the dose of thyroid hormones the next day (and after) by 10-20% of dose

What to do in case of an emergency with severe and stressful signs of thyroid overdose? Reduce the dose.

lf overdose symptoms are too intense such as tachycardia, anxiety,

insomnia, extreme nervousness, the patient should stop the thyroid medication for one or two days. Stopping the thyroid for two days will not dramatically drop the patient into a state of complete absence of thyroid activity, as the half-life of the T4 hormone drug is long: one week! The exceptional case would be for patients who have had total thyroidectomy and who are on T3 only hormone therapy, where stopping the treatment is totally contraindicated. Problems with thyroid hormones may also be related to problems with other hormones such as

cortisol, estrogens, or to wrong dietary intake as shown in the following tables:

Problems possibly related to lnefficacy or Cortisol Deficiency PROBLEM •

Cardiac symptoms

SOLUTION

POSSIBLE CAUSES Search for other signs: 1. Cortisol deficiency when

even at low doses

Treat the cause: 1. Correct the cortisol

deficiency:

other signs of low cortisol (low

of thyroid

•

blood pressure, allergies,

hormones: signs

patients

anger, low resistance to stress,

that the heart does

•

history of intolerance for

not tolerate thyroid

disease

2. Thyroid overdose if other

tachycardia,

•

signs and complaints of excess

palpitations,

excessiva sweating, anxiety,

pain, etc.,

etc.) are observed.

Methyl-prednisolone (Medrol®) if there is

thyroid hormones (overheating,

nervousness, chest

Prednisolone in case of chronic inflammatory

medications, etc.) are found.

medication:

Hydrocortisone for most

tendency to swell 2. Lower the dose of thyroid

medication Treat the cause:

•

Headaches

•

lrritability, anger,

1.

Lower the dose of thyroid

2.

Correct cortisol deficiency

hormone 4. Thyroid hormone overdose

excessive

5.

Cortisol deficiency

reactions,

6.

Chemical contamination

with hydrocortisone, prednisolone or

aggressiveness,

methylprednisolone

nervousness,

3.

quarrelsome •

•

•

Diarrhea

Treat the cause:

Excessiva magnesium or iron intake

•

Yeast (or bacterial) infection

•

Thyroid hormone overdose (if

treat intestinal yeast or bacterial infections, avoid allergy-causing foods

other signs of thyroid hormone •

excess are found)

•

Cortisol deficiency (in presence

•

of other signs of low cortisol) •

Food allergy

141

Lower or stop magnesium intake, correct food intake,

Food intolerance

•

Eliminate the source of chemical pollution

Lower thyroid hormone Correct the cortisol deficiency

Problems possibly related to low estrogen or diet PROBLEM

SOLUTION

POSSIBLE CAUSES

ESTROGEN DEFICIENCY • •

Hot flushes,

Estrogen deficiency aggravated by intake of

droopy breasts,

1 . Correct the estrogen deficiency with estradiol and progesterone.

thyroid hormones.

pale face,

Thyroid hormones

polymenorrhea,

accelerate the breakdown

amenorrhea

2. lf not sufficient, then lower the

dose of thyroid hormones.

of estrogens into inactive metabolites. DIET •

•

Weight stagnation

•

during low-calorie

and high protein intake

ancl/or high-

slow down the conversion

lncrease the dose of thyroid hormone by 15-30% during the

8oth a low-calorie diet

weight loss diet after a week of dieting. Use only a T4-T3 thyroid

protein/low-carb

of T4 to T3. Lower tissue

diets

amounts of T3 slow down

medication (animal desiccated

the basal metabolism.

thyroid or synthetic T3-T4), not a T4

•

medication

142

Chapter seven

Calcitonin Deficiency and Treatment

A case study of a Patient with Calcitonin deficiency David and his spontaneous fractures David, a tall, lean man of 60 years has had a thyroid goiter removed 15 years ago. The goiter was a benign tumor, but large and unsightly. The surgeon almost completely removed the thyroid gland.

After the operation, David felt well, everything went smoothly and David no

longer had breathing problems caused by compression of the trachea by the goiter. David was prescribed a thyroid medication that seemed adequate. Anyway, David was not a big complainer. Troubles had to be important before he would complain.

But something unusual

had happened recently. A year ago he had fallen on his hand and broke his wrist easily, a bit too easily. lt hurt tremendously. David found that the last years his pain threshold had lowered. Pain felt more intense than before, he didn't know why.

Nine months later, David made a

wrong step and fell down the stairs. His back hurt terribly. Vertebral crushes were discovered at radiography. A more extensiva investigation by DEXA showed bone density decrease, close to osteoporosis. Most of David's problems are typical of calcitonin deficiency.

To better understand what this

deficiency means and what can be done about it, let us review some basic information.

143

Calcitonin: lmportant lnformation

Roles of Calcitonin Calcitonin, the hormone made by the C cells of the thyroid gland, helps prevent osteoporosis. lt reduces bone resorption by inhibiting the bone-resorbing osteoclasts and increases bone density.

Production of Calcitonin To our knowledge, daily baseline production of calcitonin has not been investigated yet. A dose of

50 to 200 lU per day may be enough to improve bone anabolism.

Factors that increase the effects of Calcitonin Calcium intake stimulates calcitonin production, while vitamin D, in particular 1 ,25-(0H)2vitamin D, reduces calcitonin production.

Eating plenty of protein and taking calcium

supplements greatly improve the anabolic effects of calcitonin on the bone.

Likewise,

malnutrition deprives calcitonin of essential building material to exert its anabolic bone effects and should therefore be avoided.

Calcitonin leveis decrease with age Serum leveis of calcitonin gradually decrease with age.

144

I. Calcitonin Deficiency: DIAGNOSIS How do you detect calcitonin deficiency?

lndications in past health, physical signs, patient complaints, concurring diseases, lab tests, and possible medicai imaging will offer the best picture for detection and evaluation of the degree of calcitonin deficiency.

1. Onset of Calcitonin Deficiency When did the calcitonin deficiency start? There are two ways for a calcitonin deficiency to start. First, a very slow way is the age-related decline that accelerates at menopause in women or when a man has a testosterone deficiency. Second, a fast way is when the thyroid is damaged such as being partially or totally removed, or irradiated (generally by radioactive iodine). The main differences are summarized in the following table. Determining the Onset of Calcitonin Deficiency Onset Patient's age Appearance

After surgery or other trauma of the thyroid

Age-related decline

Any age: any patient (child, adult or elderly person) who has undergone thyroidectomy or thyroid irradiation

Elderly men Postmenopausal women

Acute, sudden, from one day to the other

Slow, Qrogressive

thyroidectomy scar, or

Thyroid gland atrophy at Physical signs palpation

thyroid gland atrophy

Osteoporosis

1 O to 20 years after thyroid damage

Only at old age

After this quick check, inquire about the timing and location of the patient complaints.

2. Timing and Location When and where do calcitonin signs and complaints occur? When?

In most cases, a calcitonin deficiency does not produce symptoms throughout a person's life, remaining unnoticed at the background. In two circumstances a calcitonin deficiency may result in adverse consequences for the patient: •

Bone trauma where the calcitonin deficiency, through a loss in bone density, facilitates

•

Stress that triggers migraines is a second condition where persons with calcitonin

pathological fractures such as vertebral crushes, and increased pain sensitivity.

deficiency may suffer more. Calcitonin supplementation may help to reverse this condition. Where? Mainly on bones (vertebrae, limbs) and nervous tissue (brain, nerves).

The next step is to check for the complaints of calcitonin deficiency.

145

3. Complaints of Calcitonin deficiency A patient afflicted by calcitonin deficiency may suffer from complaints coming from two origins: bone and nervous tissue. The principal symptoms suggestive of calcitonin deficiency are listed in the following table:

Complaints suggestive of Calcitonin Deficiency PHYSICAL Head

Back

Muscles

•

Miaraine

•

Cervicalgia (neck pain)

•

Dorsalgia (middle back pain)

•

Lumbalgia (lower back pain)

•

Proneness to vertebral crushes

•

Nervous tension

•

Aches lncreased pain sensitivity,

•

Nervous system

esoeciallv for back oain

PSYCHIC Behavior

Possibly an excessiva proneness to pain

•

Knowing more about the patient's complaints, we can now search for physical signs suggestive of calcitonin deficiency

4. Physical Signs of Calcitonin Deficiency Most presumed signs of calcitonin deficiency are signs related to the bones, in particular signs of osteoporosis, especially of the spine, such as increased kyphosis.

Possible signs of Calcitonin deficiency Thyroid gland Bone signs

Nervous system

•

Thyroid gland atrophy at palpation

•

Thvroidectomv scar

•

Kyphosis

•

Remnants of bone fractures

•

Vertebral crushes, other fractures

•

Vertebral disc hernia

•

Nervous behavior

After checking for complaints and physical signs of calcitonin deficiency, it is important to look for the diseases that may be facilitated by calcitonin deficiency.

146

5. Disease Susceptibility Which diseases develop easier in persons with calcitonin deficiency? One major disease: osteoporosis.

6. Lab Tests for Calcitonin Deficiency What is the best lab test for calcitonin deficiency? The laboratory test to detect a calcitonin deficiency is the measurement of its serum levei after 2 to 3 days of a diet relatively restricted in calcium (no calcium supplements, relative avoidance of calcium-rich foods such as seafood and milk products). The calcium restriction is necessary as an increased intake of calcium in the diet sharply increases the serum levei of calcitonin above baseline

Route

Test Calcitonin*

Caleium Serum

(morning)

value *

Calcitonin

References

Deficiency 0-4

8

O- 15 pg/ml

9.5

>

10.1

8.6 - 10.5 mg/dl

2.4

>2.58

2.1 - 2. 7 mmoi/L

lonized

5.0

Calcium

1.25

Phosphorus

Probable

Optimal

> >

5.2

4.6 - 5.4 mg/dl

1.30

1.15-1.35 mmoi/L

3.5

0-3

2.7- 4.5 mg/dl

1.15

0-0.97

0.87-1.45 mmoi/L

Test Value

Medium Low Medium Medium

Note: *Medul/ary thyroid cancer is characterized by an increased se rum leve/ of calcitonin above 100 pglml.

7. Paramedical tests: DEXA (dual-energy X-ray absorptiometry, or osteodensitometry): checks the bone density at various sides. In case of long-term calcitonin deficiency, osteopenia or even mild osteoporosis may be observed.

147

11. Calcitonin Deficiency: TREATMENT Calcitonin Medications The most efficient treatment for calcitonin deficiency is the intramuscular injection. lt is the first choice medication for acute vertebral crushes. Second best in efficacy and most convenient treatment is the calcitonin nasal spray. Calcitonin Treatment Route

Product Calcitonin

lntramuscular

Nasal

(Calsynar), Miacalcic®) Calcitonin

(Miacalcic®)

lndication

Doses

Osteoporosis

orper 2 days Acute 25-100 lU per day vertebral crushes Osteoporosis

Value

100 lU per day

100 - 200 lU per day

High

Medi um

lndications for Calcitonin Treatment General indication: Ali degrees of calcitonin deficiency Specific indication: Stress fractures, vertebral crushes, osteoly1ic metastases, phantom limb,

prolonged migraine

Contraindications to Calcitonin Treatment Absolute contraindications: No absolute contraindication to calcitonin treatment exists to our

knowledge. Relative contraindications: As some patients report cortisol deficiency-like complaints when taking excessive amounts of calcitonin, prudence is recommended with patients with low adrenal function that do not get adequate treatment for their adrenal problem. For these patients, begin calcitonin treatment with low doses and slowly increase to a higher dose as long as no side effects occur.

148

How to begin Calcitonin Therapy We recommend beginning with a low dose such as 25 lU per day for vertebral fractures, every two or three days in case of treatment of osteoporosis, and then to gradually increase by 25 lU (increasing the dose each day for acute vertebral fractures or every two to three days for osteoporosis). lf the patient has side-effects of nausea or dizziness reduce the dose by 25 lU or more. Some patients need or tolerate only 25 lU per day. These oversensitive persons may be deficient in cortisol, a condition which facilitates intolerance to many medications.

How to Start Calcitonin Treatment Route

Product

Starting

lndication

Optimal dose

Dose lntramuscular lntramuscular

Calcitonin (Calsynar®)

Migraine

Calcitonin

crushes

251U/day

Acute vertebral

(Calsynar, lntramuscular Miacalcic®)

Nasal

Calcitonin

I(Miacalcic®)

251U/day

Osteoporosis

251U/day or every 2 3 days

Osteoporosis

100 IU/day

Depends on the patient: 25-100 lU /day or 2 or 3 days Depends on the patient's sensitivity to calcitonin, status of calcitonin deficiency, severity of its adverse consequences: 25100 lU /day or every 2 or 3 days Depends on the patient: 50-200 IU/day

At the same dose, the intramuscular injections are about 3 times more potent (2.8 to 3.5 times).

Progress with Calcitonin Treatment How much time is needed to improve with treatment? •

For prolonged migraine: in 1 to 3 days calcitonin may neutralize the migraine.

•

For acute vertebral crushes: calcitonin can help get rid of the pain in 14 days.

•

For osteoporosis: improvements may be observed at DEXA after six to twelve months of

calcitonin treatment.

149

How to Boost Calcitonin First, you can boost calcitonin production and its effects by improving the lifestyle, including eating a better diet.

What is important to do and not to do to get optimal calcitonin leveis is summarized in the following table. Optimal Lifestyle for Calcitonin

•

Diet •

•

Physical activity

•

WhatTo Do

WhatTo Avoid

(conditions that increase calcitonin production or effects)

(conditions that reduce calcitonin production or effects)

Eat foods that are rich in proteins (meat, poultry, fish, eggs, etc.)

•

•

Eat foods that are rich in calcium (seafood, fish, etc.) Take calcium supplements

•

lncrease physical activity against gravity such as walking and leisure- jogging

•

Avoid malnutrition, avoid eating too little protein and calcium Avoid foods and drinks that may increase osteoporosis: e.g. sugar, sweets, soft drinks Avoid caffeinated beverages(coffee, tea, cola), etc. Avoid sedentarity

Second, calcitonin leveis can be increased by correcting other hormone dysfunctions that relate to calcitonin.

The hormone replacement therapies that can influence calcitonin production and its effects on the body are summarized in the following table. lnfluence of Hormone ReplacementTherapies on Calcitonin Calcitonin Stimulators

Calcitonin lnhibitors

•

Testosterone treatment

•

Transdermal estradiol in menopausa! women

150

•

1 ,25-(0H)2-Vitamin D

Follow-up of Calcitonin Treatment 1. Find the adequate dose.

After starting calcitonin at a low dose

(25 lU

per day), doses should be slowly increased and

titrated to the optimal dose that provides maximal effects without side effects. In case of acute vertebral crushes, the dose of calcitonin should quickly be increased by 25 lU a day or more up to

100

lU per day is reached or side effects occur.

The most frequent conditions for dose adjustment are reviewed in the following table. When to adapt the dose of calcitonin

Hormonal

(25to 75% less)

(25 to 200% more)

Excessiva calcitonin effects

•

lnsufficient calcitonin effects

•

•

Cortisol (glucocorticoid) treatment

•

Cortisol deficiency

of adrenal deficiency

•

Transdermal estradiol

•

Testosterone treatment

•

Protein- and calcium-rich diets

conditions Disease

Lower the dose

lncrease the dose

Dose

•

Severe osteoporosis

Diet

2. Avoid overdosing and underdosing.

This is primarily done by checking signs and complaints of calcitonin over- or underdosage. When to check? The patient should monitor himself for improper dosing every day and the physician should follow-up with the patient every two to nine months. The following table summarizes the main complaints of calcitonin overdosing. Calcitonin Overdosage Frequency Most frequent

Less frequent

Overdose Signs •

Nausea, vomiting

•

Lack of appetite

•

Feeling of being unwell, dizziness

•

Fatigue

•

Headaches

3. Correct any problems during follow-up quickly and efficiently

151

111. Calcitonin PROBLEM SOLVER

How to solve problems that occur during calcitonin treatment? The most frequent problems that may occur during treatment and their solutions are described in the following table.

Problems due to Cortisol Deficiency or Calcitonin Overdose PROBLEM

•

Nausea

POSSIBLE CAUSE

1. Cortisol

deficiency •

SOLUTION •

Reduce the calcitonin dose by 25 to 75 lU

•

Correct the cortisol deficiency at low doses

per day with hydrocortisone as it does not suppress

Lack of appetite, malaise, feelings of being unwell,

the activity of the adrenal cortex as much as a

2. Calcitonin

synthetic derivative and is at less risk of

overdose

aggravating any existing osteoporosis. Add

drowsiness,

DHEA to the glucocorticoid treatment and/or

headaches,

any other anabolic hormone in which the

fatigue, vomiting

patient may be deficient, to maintain a wellbalanced anabolic-catabolic ratio.

152

Chapter eight

Parathormone Deficiency and Treatment

A

case

study

of

a

patient

with

Parathormone

deficiency Andrew and his low bone density:

Andrew, a tall, strong man of 55 years was being treated with the best corrective hormone treatments by an experienced doctor. He was himself working in the pharmaceutical industry, but not as a physician and had easy access to hormone medications. He felt fine, as did his wife, who also followed adequate hormone treatments. Out of curiosity he and his wife got a DEXA, a bone mineral density scan. To their surprise, both had lowered bone mineral densities, while they were taking sex and growth hormone treatments for correction of their age-related deficits. He and his wife had thought they were almost invulnerable to such above-average bone losses. A blood analysis showed low leveis of parathormone. At that time, parathormone treatment as a synthetic derivativa had become newly available on the market. Both he and his wife tried the new treatment and achieved impressive 1 O to 12% increases in bone density during the first year of treatment! The bone density losses of Andrew and his wife are typical for parathormone deficiency. To better understand what this deficiency means and what can be done about it, let us review some basic information.

153

Parathormone: lmportant roles

Parathormone's major role is to maintain constant calcium leveis in the blood. As soon as

the calcium levei decreases in the serum, the levei of parathormone increases in the serum to correct the situation. When the serum calcium levei increases, the levei of parathormone decreases to permit the calcium levei to gradually lower and normalize. By keeping the caleium leveis constant in the blood, parathormone exerts two major roles: 1.

lt keeps nerves and muscles (including cardiac muscle) relaxed and well-functioning. When calcium leveis are too low, muscles tense and go into spasmic contractions that may ultimately lead to titanic contractions and death in extreme cases - such as surgical remova! of ali four parathyroid glands at the occasion of a total remova! of the thyroid gland (thyroidectomy) for thyroid cancer.

2.

lt helps prevent or reverse osteoporosis. By elevating the calcium levei in the blood, parathormone makes more calcium available for the bones. Parathormone increases the serum levei of calcium by stimulating calcium absorption in the intestine from food if the diet is rich enough in absorbable calcium and vitamin D leveis are sufficient to help absorb the calcium. However, with a diet poor in calcium or when the leveis of vitamin Dare low, parathormone causes unwanted bone density loss by increasing serum calcium leveis through extraction from the bones.

Production of Parathormone:

Parathormone is a hormone produced and secreted by the four parathyroid glands situated at the back of the thyroid gland. Daily baseline production has to our knowledge not been investigated. Based on studies of parathormone treatment, it is likely that parathormone is daily secreted in the range of 20 to 60 119 per day. A dose of 20 119 per day may be enough to improve bone density.

Factors that increase the effects of Parathormone: •

The intake of supplements of calcium and vitamin D, in particular 1 ,25-(0H)2-vitamin D intake

reduce

parathormone

production

and

leveis,

but

stimulate

the

action

of

parathormone, resulting in increased calcium leveis and bone density. •

The consumption of foods rich in calcium such as fruit, vegetables and seafood, usually increases calcium intake and absorption and thereby boost the anabolic action of parathormone on the bone. Most foods help as almost ali of them have calcium. Likewise, fasting and malnutrition deprives parathormone of essential building materiais to exert its anabolic bone effects and makes parathormone stimulate calcium resorption from the bones to maintain adequate blood calcium leveis, leading to bone density loss.

•

Sun exposure without sun creams triggers vitamin D synthesis in the skin, which elevates

vitamin D and calcium leveis in the blood, thereby optimizing the anabolic effects of parathormone.

154

Parathormone leveis increase with age in most people, but may decrease in patients receiving correct anabolic hormone treatments. With age, bones lose density and calcium caused by a progressive loss of anabolic hormones such as growth hormone and the sex hormones. The lower serum calcium leveis trigger with advancing age a gradual increase in parathormone in most individuais, which increases bone resorption to extract calcium out of the bones to maintain adequate calcium in the blood, on itself not a good sign of optimal calcium metabolism. In fact, in patients who receive adequate sex hormone, growth hormone and vitamin D supplementations to correct their age-related loss in anabolic hormones and nutrients, the serum levei of parathormone tends to gradually decline with age as for most other hormones. The cause is a progressive aging of the parathyroid glands as for most other endocrine glands.

155

I. Parathormone Deficiency: DIAGNOSIS How do you detect parathormone deficiency?

lndications in past health, physical signs, patient complaints, concurrent diseases, laboratory tests and possibly medicai imaging offer the best picture for detection and evaluation of the degree of parathormone deficiency.

1. Onset of Parathormone Deficiency When did the parathormone deficiency start? In the majority of cases, aging and surgery are the most common causes of parathormone deficiency. Paradoxically, aging progressively increases parathomone leveis in most people. This is due to a slow and progressive age-related decline in anabolic hormones such as growth hormone and the female and male hormones. These hormone deficiencies make bones and blood lose calcium. The lower calcium triggers the secretion of parathormone. Theage-related increase in parathormone does not occur in people adequately corrected withanabolic hormone supplementations. In a minority of parathormone deficiencies, the deficiency brusquely appears by partial or total removal or damage of the parathyroid glands during thyroidectomy or by irradiation - generally by radioactive iodine for treatment of thyroid cancer or hyperthyroidism. The main differences are summarized in the following table: Determining the Onset of Hypoparathyroidism (Parathormone Deficiency) Onset

Age-related decline

Patient's age

Patients under adequate treatment with anabolic hormones: • •

Appearance

•

After trauma such as surgery of the parathyroid gland •

Postmenopausal women •

Signs of osteoporosis: Physical signs

• •

Osteoporosis

•

adults or elderly people who underwent parathyroidectomy, thyroidectomy or thyroid irradiation

Elderly men

Slow, progressive

Any age: children (rarely), young

Acute, sudden, from one day to the next

•

Thyroidectomy scar, or

•

Thyroid gland atrophy

Signs of osteoporosis:

Thinner bones Proneness to bone fractures

• • •

Only at old age

156

Thinner bones Proneness to bone fractures O to 15 years after thyroid surgery or irradiation

2. Timing and Location When and where do parathormone deficiency signs and complaints occur? When? In most cases, a parathormone deficiency remains unnoticed in the background. In two

circumstances a parathormone deficiency may make a person acutely suffer: •

Spontaneous or pathological bone fractures such as vertebral crushes due to a loss in

•

Muscle spasms and nerve tingling due to stress, facilitated by parathormone deficiency.

bone density facilitated by parathormone deficiency. Parathormone supplementation may help to reverse this condition. Where? Signs and symptoms mainly occur on the tissues that are influenced by parathormone such as the bones (vertebrae, limbs), muscles (hands, arms, feet, legs and face) and nervous tissue (brain, nerves, especially those in the hands, feet and lips).

The next step is to check for the complaints of parathormone deficiency.

3. Complaints of Hypoparathyroidism A patient afflicted by hypoparathyroidism or parathormone deficiency may suffer from complaints coming from three origins: the nervous tissue, muscles and bones. The principal symptoms suggestive of parathormone deficiency are listed in the following table: Complaints suggestive of Hypoparathyroidism PSYCHIC comJ!Iaints Behavior

•

Decreased consciousness

Energy

•

Adomen

•

Fatigue

PHYSICAL complaints H air

•

Dry hair

Skin

•

Dry, scaly skin

Nails

• Brittle nails Children:

Teeth

Breathing

and

limbs

Muscles

Nervous system

•

weakened tooth enamel

•

delayed or absent tooth formation

•

Face

•

Breathing difficulties (due to muscular spasms of the larynx)

•

Hyperventilation

•

Asphyxia

•

Pain in the face, legs and feet

•

• •

Back

•

•

•

Tensed muscles

•

•

Spasmophilia, muscle cramps

•

•

Muscle aches

•

Fibromyalgia

•

Bones

Spasms through to convulsions and tetany

•

Abdominal pain Tingling and numbness of lips, fingers and toes Excessive tendon reflexes (patellar, Achilles' reflexes) Cervicalgia (neck pain) Dorsalgia (middle back pain) Lumbalgia (lower back pain) Vertebral crushes (proneness ) Soft, painful bones Proneness to spontaneous or pathological fractures Children: Rickets impaired growth

and

Once we know more about a patient's complaints, we can now search for physical signs suggestive of parathormone deficiency.

157

4. Physical Signs of Hypoparathyroidism Most presumed signs of parathormone deficiency are muscle signs such as regular spasms, and bone signs such as a bowed back due to osteoporosis. Possible signs of Hypoparathyroidism Thyroid

Bones

Muscles

Lungs Nervous system

•

Thyroid gland atrophy at palpation

•

Thyroidectomy scar

•

Bowed back (kyphosis)

•

Remnants of bone fractures

•

Vertebral crushes, other fractures

•

Vertebral disc hernia

•

Tensed muscles, especially of the chest, back and limbs

•

Spasmophilia - cramps: spasms of hand muscles caused by pressure (compressed with the blood pressure armband)

•

Fibromyalqia with positive tender points

•

Superficial breathing

•

Hyperventilation (faster breathing)

•

Nervous behaviour

After checking for complaints and physical signs of parathormone deficiency, it is important to look for diseases that may be facilitated by parathormone deficiency.

5. Disease Susceptibility Which diseases develop more easily in people with parathormone deficiency? Major diseases: hyperventilation.

osteoporosis

with

fractures

158

of

ali

types,

fibromyalgia,

spasmophilia,

6. Lab Tests for Hypoparathyroidism What is the best lab test for parathormone deficiency? The best laboratory test to detect a parathormone deficiency is the measurement of its serum levei after 2 to 3 days of a diet relatively restricted in calcium (no calcium supplements, relative avoidance of calcium-rich foods such as seafood and milk products). The calcium restriction is necessary as an increased intake of calcium in the diet may sharply reduce the baseline serum levei of parathormone.

Tissue

Test

Optimal

Parathormone* Caleium Serum (morning)

*

References

Deficiencv

30 9.5

< 9.0

10-55 pQ/ml 8.6 - 10.5 mg/dl

2.4

< 2.25

2.1 -2. 7 mmoi/L

0-20

lonized

5.0

�4.8

4.6 - 5.4 mg/dl

Calcium

1.25

<1.20

1.15-1.35 mmoi/L

3.5

0-3

2.7- 4.5 mQ/dL

1.15

0-0.97

0.87-1.45 mmoi/L

Vitamin 03

45

0-35*

18-481J.Q/L

(25-0H-03)

150

0-85*

82-217 J1mol/l

Phosphorus

Note :

value *

Probable Parathormone

Test Value HiQh High High Medium High

Vitamin O deficiency causes through low calcium leveis an increase in parathormone,

but at the same time it weakes the beneficiai action of parathormone action on the bones by decreasing the availability of calcium for the bones.

7. lmaging tests: The following tests may be useful: - DEXA (dual-energy X-ray absorptiometry, or osteodensitometry): checks the bone density -

at various sites. X-ray of any bones when a bone fracture is suspected due to osteopenia or even mild osteoporosis as these conditions can be caused by long-term parathormone deficiency.

159

11. Parathormone Deficiency: TREATMENT Parathormone Medications: The treatment for parathormone deficiency consists of administering subcutaneous injections of recombinant parathormone or its shorter active part, teriparatide. Parathormone Treatment Route

Product Parathormone

(Preotact®)1'3

Subcutaneous

injections

Transdermal

patch

lndication

• Osteoporosis • Bone fracture

14 doses

of 100 JJQ

Teriparatide

750

�g/3 ml:

(Forteo or Forsteo®)2.4

28 doses

Teriparatide

Patches of of 40 �g6

100

healing (pelvic fractures, distai radius, etc.)

of 20 �g

(ZP-TPH®)2'5

Doses

Value

1.61 mg/1.13 ml

20

to 200 �g/day

High

to 40 �g/day

High

40

�g/day

Highl

Notes:

12 ' Parathormone is the original hormone made oi 84 amino acids, while teriparatide is part oi it (34 amino acids).

3'41

5

6

click with the pen for Preotact

=

100 �g/day; 1 click with the pen for Forteo

=

20 �g/day). 2010.

The ZP-PTH patch is still in trial, not yet approved and is expected to be marketed for The ZP-PTH patch of 40 �g/day provides an efficient delivery oi

16 �g/day.

How to start Parathormone Therapy: We recommend beginning with a low dose of 20 �g per day to increase the bone density for a period of six months. After 6 months, a new DEXA scan of the bone density should show an increase of 3 to 6 % of bone density, otherwise the dose should be increased. lntermediate contrai laboratory tests of the serum calcium, phosphorous and parathormone leveis after one, three and five months of treatment should provide the lab tests to assure that the dose is not excessive (high calcium leveis or hypercalcaemia), in which case the treatment has to be decreased to one injection of 20 �g every two or three days. lf the dose is too low (the serum calcium leveis remain too low), then the dose should then be increased. How to start Parathormone Treatment Route

Product

Sub-

(Preotact®

Fractures

Cuta-

Teriparatide

Osteoporosis

20 �g/day or

Fractures

20

lndication

Parathormone Osteoporosis

neous

(Forteo or Forsteo®)

Starting Dose 100

�g/day o r every 2 days

100 �g/day

�g/day

every 2 days

Optimal dose

Often 100 �g/day, possibly 200 �g/day1 Often 20 �g/day, possibly 40 �g/day1

1

Note: The optimal dose depends on the patient's sensitivity to parathormone and degree oi parathormone deficiency

For evidence of progress after parathormone therapy: Measure the DEXA scan at 6 months and 12 months. Adjust therapy depending on the results obtained.

160

lndications for Parathormone Treatment: General indication: Ali degrees of parathormone deficiency Specific indication: Osteoporosis, pelvic, limb and stress fractures, vertebral crushes

Contraindications to Parathormone Treatment:

Absoluta contraindications

Parathyroid hormone treatment should not be initiated in patients: •

Absence of parathormone deficiency and osteopenia. There is no value in administering

•

Hyperparathyroidism (parathormone excess), pre-existing hypercalcemia (excess calcium

parathormone in these cases. in blood) •

lmportant hypersensitivity to PTH or excipients

•

Conditions that increase the risk of osteosarcoma (parathormone in 3 to 60 times the dose of 20°1-lQ/day in humans , has been reported to caus e osteosarcoma in rodents): history of radiation therapy to the skeleton, Paget's disease, unexplained elevations of bone­ specific alkaline phosphatase

•

Severe renal impairment, severe hepatic impairment

•

Pregnancy or breast-feeding (reproductive toxicity in rabbits at high doses)

Relativa contraindications: •

Minor intolerance or allergic reactions to parathormone. Preotact® and For(s)teo® contain metacresol, which may cause allergic reactions. The allergic reaction occurs more likely in cortisol-deficient patients. Correct the cortisol deficiency with low doses of hydrocortisone to block the allergy and tolerate the use of Forteo.

•

Parathormone and teriparatride should be used with caution in patients with active or previous urolithiasis and in patients receiving cardiac glucosides as there is a theoretical risk of aggravation of these diseases if hypercalcemia develops (increase in risk of urolithiasis, digitalis toxicity)

161

How to boost Parathormone Firstly, you can boost parathormone production and its effects by improving lifestyle factors, including eating healthier foods and drinks. The following table shows the diet and supplements which optimize parathormone leveis - both those that improve and those to avoid. Optimal lifestyle for Parathormone

•

•

Diet •

Supplements

• •

•

Sun exposure

Physical activity

•

WhatTo Do:

WhatTo Avoid:

(conditions that increase parathormone production or effects)

(conditions that reduce PTH production or effects)

Consume foods that are rich in proteins (meat, poultry, fish, eggs, etc.) Consume foods that are rich in calcium (seafood, fish, etc.) Consume foods that are rich in vitamin D (cod liver oil, butter, chicken skin, eggs, fatty fishes such as salmon, mackerel, tuna, sardines, herring etc.)

•

•

•

Avoid malnutrition, avoid eating too little protein and calcium Avoid foods and drinks that may increase calcium excretion in the urine and osteoporosis: e.g. sugar, sweets, soft drinks, caffeinated beverages (coffee, tea, cola) Avoid alcohol (reduces PTH)

Take calcium supplements Take vitamin D supplements (2000 to 4000 IU/day or more) Sun exposure; the skin makes vitamin D (± 5 to 1 O minutes in the sun every day with unprotected hands and face is sufficient for daily vitamin D production) lncrease physical activity against gravity such as walking and leisure-jogging (to increase bone density)

•

Avoid a sedentary lifestyle

Likewise, parathormone leveis or beneficiai effects can be increased by optimizing other hormone deficiencies and supplements that affect parathormone. For example, deficiencies of testosterone and estradiol reduce parathormone secretion or effects and their normalization improves parathormone production. Vitamin D and calcium supplements help despite their inhibitory action on parathormone secretion, by a greater stimulation of parathormone's beneficiai effects on new bone formation. lnfluence of Hormone ReplacementTherapies on Parathormone Parathormone activity Stimulators,

Parathormone lnhibitors of

Parathormone

production, but stimulators

secretion & activity

of its effects on the banes

lnhibitors

esp. on new bone formation •

IGF-1

•

Growth hormone

•

Transdermal (and oral) estradiol

• •

Testosterone treatment Calcitonin treatment

•

1 ,25-(0H)2-Vitamin D

•

(Calcium supplements)

162

•

?

Follow-up of Parathormone Treatment 1. Find the adequate dose:

After starting parathormone at 100 ll9 per day or teriparatride at 20 ll9 per day, the dose is generally maintained. lf at the next DEXA scan, bone density remains low, the dose may be maintained to maximally double the dose without producing major side effects. In case of osteoporosis, the dose of parathormone may be maintained during two years and possibly even longer because otherwise, if the treatment is interrupted, the bone density drops again. The most frequent conditions for dose adjustment are reviewed in the following table: When to adapt the dose of parathormone Dose

lncrease the dose

Lower the dose

(25 to 100% more)

(25 to 75 % less)

Parathormone • lnsufficient parathormone effects •

Severe osteoporosis Acute fractures

•

Diet high in calcium-rich foods

•

Disease Diet

•

Excessive parathormone effects

•

Diet low in calcium, protein, calorie

2. Do check-up lab tests: include the check of the serum leveis of parathromone, calcium

(total and ionized) and phosphorus 3. Avoid overdosing, underdosing and intolerance reactions:

This is primarily done by checking signs and complaints of parathormone over- or underdose, and recording any signs of intolerance. When to check them? The patient should monitor himself for improper dosing every day and the physician should follow-up with the patient every two to nine months. The following table summarizes the complaints of parathormone overdosing and intolerance. Parathormone lntolerance

Parathormone Overdosage Frequent?

Overdose Signs

Nausea, vomiting • Loss of appetite • Constipation

Mechanism

Frequent?

•

More

Minor fatigue, muscle weakness (lransienl lhe firsl

common (8-10%of cases)

•

(8-10%)

Headaches • Neck pain • Joint aches, limb pain

Less frequent

4 days of lhe lrealmenl) •

(often transient,

&

transient

usually limited beginning of the treatment)

Rare

swelling, dizziness++, trouble breathing.

Excess calcium reduces blood pressure

to

teriparatide injeclion, or any of its lransienl) wilhoul ilching excipients

with itching,

Confusion • Feeling of being unwell

Orthostatic hypotension • Dizziness • Tachycardia • Syncope

Excessive sensitivity

•Larger rash

to the

•

•

R are

Excess calei um

Less frequent

lntolerance Mechanism

•Rash at injection site (ai firsl

Very Rare

•Angioedema •Anaphy-

Allergyto teriparatide or any of its excipients

laxis

4. Correct any problems during follow-up quickly and efficiently: See problem-solver

163

111. Parathormone PROBLEM SOLVER How to solve problems that occur during parathormone treatment: The most frequent problems that may occur during treatment and their solutions are described in the following table:

Problems due to Parathormone Overdose or Cortisol Deficiency PROBLEM •

Nausea, vomiting

•

Loss of appetite

•

Constipation

•

POSSIBLE CAUSE

SOLUTION 1. Stop 2. Reduce taking

Minor fatigue, 1. Parathormone

days af the treatment)

overdose=>

Headaches

•

Neck pain

•

Joint aches

•

Limb oain

•

Confusion

•

Feeling of being

hypercalcemia =>

hypoglycemia,

Dizziness, syncope Tachycardia

the

parathormone

parathormone

or

dose

by

teriparatridet

any existing osteoporosis (except in cases of chronic inflammatory disease => Use prednisolone 2.5 to 7.5 mg/day or in case of hypertension, overweight or swelling of feet and/or hands: methylprednisolone 2 to 6 mg/day).

electrolyte imbalance and low blood pressure

Orthostatic

•

D

doses with hydrocortisone at 15 to 45 mg/day as it does not suppress the activity of the adrenal cortex as much as a synthetic derivative and is at less risk of aggravating

2. Cortisol deficiency

Add DHEA to the glucocorticoid treatment and/or any other anabolic hormone in which the patient may be deficient, to maintain a

hypotension •

vitamin

3. Correct the cortisol deficiency at low

unwell •

and

every other day.

muscle weakness (transient the first 4 •

calcium

supplementation

well-balanced anabolic-catabolic ratio. Search for underlying disease that causes the

•

Treat the underlying disease

hypercalcemia: Primary hyperparathyraidism, Paget's

•

bane disease, bane cancer, Cushing's syndrame, •

Persistent elevated serum and/or urinary calcium

Parathormone or teriparatride should be used with caution in patients with active or previous urolithiasis and in patients

hyperthyraidism, tuberculasis,

receiving cardiac glucosides.

Hadgkin's lymphama, adult T­ cell lymphama, mvelama, etc.

lf no underlying disease be excessive parathormone or teriparatride dosing, or excessive calcium, vitamin D or vitamin A supplementation

•

=>The cause may

164

Stop calcium, vitamin D and vitamin A supplementation

•

Reduce the frequency of parathormone dosing to 100 �g every other day and teriparatride to 20 �g every other day /f elevated leveis continue=> Stop PTH

lntolerance due to Cortisol Deficiency or other causes PROBLEM

•

SOLUTION

POSSIBLE CAUSE •

Not sterile clean injection

•

Excessive sensitivity to

•

injections

teriparatide or any of its

Rash at injection

excipients. Preotact®

site (at first injection, transient) without itching

•

•

cause aller9ic reactions.

Chan9e parathormone preparation (from teriparatride to full len9th parathormone,

Transient reaction limited to the first injection

lnject parathormone with clean needles and pen

and For(s)teo® contain metacresol, which may

lf not severe rash: continue injectin9, the rash will normally not appear in further

or vice-versa) .

1.

Correct the cortisol deficiency Correct the cortisol deficiency at low

doses with hydrocortisone as it does not suppress the activity of the adrenal cortex as much as a synthetic derivative and is at less risk of a99ravatin9 any existin9 osteoporosis. •

Rash with itching, swelling, dizziness++, trouble breathing

2.

Add DHEA to the 9lucocorticoid treatment and/or any other anabolic hormone in which the patient may be

Allergy to teriparatide or any

deficient, to maintain a well-balanced

of its excipients esp. metacresol, which may cause aller9ic reactions

anabolic-catabolic ratio. 3.

Chan9e parathormone preparation (from teriparatride to full len9th parathormone, or vice-versa)

•

4.

Avoid/stop the treatment PTH

1.

Stop the PTH treatment

2.

An9io-edema

Chan9e parathormone preparation (from teriparatride to full len9th

•

parathormone, or vice-versa) after

Anaphylaxis

checkin9 for metacresol aller9y Digitalis toxicity: Confusion, irregular pulse, palpitations, loss of appetite, nausea, vomiting, diarrhea, blind spots in vision, blurred vision, halos or rings of light around objects, difficulty breathing when lying down, excessive nighttime urination overall swelling

In patients receivin9 cardiac

1.

Stop the PTH treatment for a week

2.

Restart PTH at lower dose

=>

reduce

9lycosides:

the frequency of parathormone dosin9

parathormone

to 1 00 119 every other day and

=>

hypercalcemia

=>

di9italis toxicity

teriparatride to 20 119 every other day 3.

/f elevated serum caleium leveis continue => Stop PTH

165

Chapter nine

IGF-1 (lnsulin-like Growth Factor-1) Deficiency and Treatment A Typical Patient with IGF-1 Deficiency Melina and her quest for a perfect body and condition: Melina had always loved to do sports. Mother of four boys, for whom she had taken care alone, she had built up a successful business career and had always taken good care of herself. She didn't hesitate to pay expensive medicai and aesthetical bills to maintain her youthful energy and outlook. At age 58, despite high doses of growth hormone

-

0.8 mg per day, which is

expensive (about 35-40 euros a day) and a high protein diet, Melina felt she was mentally, emotionally and physically aging. She saw her skin become lax and thinner. With unease, she observed that her muscles became droopy, and remarked that her face lost some of its firmness. She felt less self-assured, more anxious, and she recovered with more difficulty each time she practiced sports. Even her thinking, although far better than average for a person of her age, was getting less clear and less creative. Solving problems was becoming a problem of itself. As her IGF-1 leveis remained low despite the high doses of growth hormone and a high protein diet, she was prescribed the newly registered IGF-1 preparation. Results were surprising. The IGF-1 treatment at low doses reversed ali the above-mentioned complaints in three months with a need to quickly reduce the dose of growth hormone to take at only a quarter of the previous dose. This reduction was necessary because her tissues, muscles and skin became too firm with the combination of growth hormone and IGF-1. Melina could not hide how enthusiastic she was with the new treatment that made her feel fully self-assured, fresh, energetic, calm, with tighter skin and muscles, and a much more youthful body. The IGF-1 made a big difference. Although IGF-1 is more expensive than growth hormone, the addition of both hormone treatments not only brought a major improvement in quality of life, health and physical appearance, but also reduced the expenses as much lower doses of each were necessary to obtain the better synergistic effect. Most of Melina's problems are typical of IGF1 deficiency. In order to better understand what this deficiency means and what to do about it, let's look at some basic information first.

167

IGF-1: lmportant lnformation lnsulin-like-growth-factor 1 or IGF-1 : lnsulin-like-growth-factor 1 or IGF-1, also called somatomedin C, belongs to a class of growth­ promoting hormones that are sensitive to the action of growth hormone. IGF-1 or somatomedin C is the major one and its production is strongly influenced by growth hormone. In blood, slightly more than two-thirds of IGF-1 circulates bound to a plasma protein called IGFBP-3 (insulin-like growth factor binding protein). Other IGF's include IGF-2 (somatomedin A). GH insensitivity leading to IGF-1 deficiency: A variety of factors may reduce the production of IGF-1 and cause an IGF-1deficiency: •

The consumption of foods that reduce growth hormone production or effects: a low protein intake, excessive sugar consumption, intake of alcohol and caffeinated beverages, etc.

• •

A deficient production of growth hormone (growth hormone deficiency) A low number or a defective structure of growth hormone receptors, which causes a relative insensitivity to the action of growth hormone

• •

•

An inhibition of growth hormone action by antibodies to growth hormone A deficient production of IGF-1 due to a relative incapacity to synthesize it (defective enzymes, etc.). Other diseases that may impair the production of IGF-1 (liver diseases - most of the IGF-1 in blood is produced in the liver, catabolic states).

Rarely, some babies are born with a major IGF-1 deficit that is not correctable after birth by growth hormone (neither by the endogenous production of growth hormone, nor by growth hormone injections). They are affected by Laron syndrome, IGF-1 deficiency due to a the insensitivity of the growth hormone receptor. Children with IGF-1

deficiency are generally born with a much smaller size than their

gestational age. They do not grow or grow very little after birth. Their face is markedly underdeveloped with a very small nose, and small ears, chin, fingers and toes. Ageing adults seem to slowly develop insensitivity to the action of growth hormone, which results in an IGf-1 deficiency. The insenvitivity to growth hormone is due to an inadequate intake of protein-rich foods necessary for IGF-1 production, and/or age-related declines in the number of growth hormone receptors and in the capacity to make IGF-1. Many older adults continually have low IGF-1 leveis in the serum despite taking high doses of growth hormone, which is the main stimulant of IGF-1 secretion. They need to be supplemented with IGF-1. Treatments combining growth hormone and IGF-1: Remarkably, the administration of both growth hormone and IGF-1 seems to show more potent synergetic effects in many adults than either hormone treatment alone. The synergy may help patients to stay at low, thus cheaper, doses of both hormones, while obtaining greater improvements in quality of life and physical appearance and more potent anabolic effects than they could achieve with either hormone treatment alone, even at high doses.

168

Roles of IGF-1: IGF-1 is a major hormone, possibly more potent than growth hormone: 1.

Anabolism and growth: IGF-1 is a major anabolic hormone that builds the body. lt provides volume and size to bones, muscles, internai organs, the skin, nails. IGF-1 is responsible for a great part of growth, not only during childhood and puberty, but also before birth. In the uterus, the presence of IGF-1 is essential for proper growth of the fetus, in contras! with growth hormone, which is not in utero necessary for prenatal growth. A child who is not able to make IGF-1, will not grow well. At adult age, he will only reach lhe height of a small dwarf, a mean 12 standard deviations below the mean, while in simple growth hormone deficiency the height is 'only' about 4 to 5 standard deviations below the mean).

2.

Physical appearance: IGF-1 may improve and even reverse a (great) part of the atrophy and sagging profile of the body, as well as the wrinkles, thinning of skin and excess fat that appears with age. The intake of sufficient amounts of protein-rich foods such as meat, fish, poultry and sprouted grains is essential for IGF-1's action on physical appearance, as it is for the action of growth hormone on the body.

3.

Organ functioning: IGF-1 maintains people in good health, and improves or may even repair the function of muscles and inner organs such as the heart, lungs, liver, kidneys, joints, nerves and brain.

4.

Mental and emotional improvement: IGF-1 may provide greater benefits than growth hormone on the mind and the emotions such as greater inner peace, self-assurance and self-confidence, leadership, capacity to solve problems and confront stressful conditions.

5.

lmprovement of the glycemia and insulinemia: A treatment with IGF-1 lowers glucose and insulin leveis. lt improves both diabetes type 1 and 2 with similar effects to those of insulin as the name insulin-like growth factor 1 implies. In contras!, a treatment with growth hormone may increase during the first year the blood sugar and insulin leveis of diabetic patients, because of a direct anti-insulin action. On the long run, after a year of treatment, type 2 diabetic patients have a decreased fat mass and increased lean mass with growth hormone treatment and benefit from an improved glucose contrai and reduced insulin treatment. Patients with type 1 diabetes have to lower the doses of insulin to inject when they take IGF-1 treatment, while with growth hormone they need to increase the dose of insulin during lhe first year, but no! afterwards.

Serum leveis of IGF-1 and test kits The serum levei of IGF-1 is relatively stable and does not show lhe great variations in concentration as growth hormone. Even meals do not fundamentally disturb the IGF-1 levei. Women have on the average a 20% lower levei of IGF-1 than men. Men have higher leveis of IGF-1 thanks to !heir 20 times higher levei of testosterone which boosts lhe secretion of growth hormone, lhe main stimulant of IGF-1 production. In mos! laboratories, test kits to measure lhe serum levei of IGF-1 are often poorly reliable as they are based on the chemo luminescence technique, a non radioactive technique that often provides erroneous leveis of IGF-1, which do no! reflect the real ones. The older radioactive radio-immuno-assay test is far more accurate and reliable. Production of IGF-1: Most of lhe IGF-1 found in lhe blood is made in lhe liver.

In well-developed young men and

women aged 25, production averages about 500 to 1000 11g per day. Tall, large muscular athletes generally produce substantially more IGF-1 than small, thin and less muscular adults. A decline of IGF-1 with age: From age 30 onwards, IGF-1's production and leveis decline at a rale of 1 to 2 % a year.

169

I. IGF-1 Deficiency: DIAGNOSIS How do you detect IGF-1 deficiency?

The best way to detect an IGF-1 deficiency is to combine several approaches: review the patient's past medicai history, diseases and complaints, search for physical signs, and do laboratory tests typical for IGF-1/GH deficiency, possibly include medicai imaging if needed.

1. Onset of IGF-1 Deficiency When did the IGF-1 deficiency start? To find out, physicians should interview and examine the patient. Subjects with an untreated prenatal IGF-1 deficiency are very small. Their face is small with underdeveloped facial features: a small nose, a small chin, tiny ears. The bones and muscles are thin and poorly developed. The body is relatively sexually immature. Complaints of a low quality of life and emotional disturbances are much greater in people with IGF-1 deficiency acquired later on in adulthood than in subjects with IGF-1 deficiency since childhood. People who developed an IGF-1 deficiency later on in adulthood know how much better life is with good IGF-1 leveis, while those with childhood-onset deficit have usually not known better. The differences between prenatal, childhood-onset and adult-onset IGF-1 deficiency are listed in the table below: Determining the onset of IGF-1 deficiency

ONSET

IGF-1 deficiency

IGF-1/Growth hormone deficiency

Prenatal

Childhood

• Greatest physical impact:

General

small dwarf, underdeveloped features • Emotional impact of

intermediate degree Height

Muscles, Bones

• Less severe emotional

impact

less severe: premature aging • Major emotional

impact

• Very small dwarf

• Dwarf

• Normal height

• Short stature

• Bowed back +++

• Underdeveloped nose,

jaws, chin, ears Hands, feet

impact (dwarf)

• Very short stature • Very small face

Face

• Major physical

Adulthood • Physical impact is

• Small face • Thin

• Very small hands and feet

• Small hands and feet

• Thinner and smaller than in

• Thin and small

childhood deficiency

muscles - bones

• Normal-sized • Atrophying chin, nose,

jaws, ears • Atrophying hands and

feet • Atrophied muscles -

bones

Sex organs

• Sexual immaturity

• Sexual immaturity

• Sexual maturity

• Very small genitais: micro-

• Small genitais: Micro-

• Normal sized genitais,

Quality of life

• Considerably impaired

phallus, micro-clitoris

phallus, micro-clitoris • Moderately impaired

but atrophying • Severely impaired

After this check inquire about the timing and location of the patient complaints.

170

2. Timing and Location:

When/where IGF-1 deficit signs and complaints?

When? Symptoms of an IGF-1 deficiency persist throughout the day, but will considerably

worsen if the patient has not eaten enough protein due to the resulting lower production and activities of amino acid-dependent IGF-1 ). Malnutrition will cause these patients to feel exhausted. Worsening is also encountered after sleep deprivation. Where? IGF-1 deficiency primarily affects skin, muscles and bones similar to growth hormone deficiency. Genital areas may also be affected in men and women with undersized genitais not well-developed in cases of early IGF-1 deficiency during childhood onwards. Genitalia are then sexually immature and body hair is restricted to much smaller areas.

With this basic knowledge, we can now examine the details of the body of patients suspected of having an IGF-1 deficiency.

3. Physical Signs of IGF-1 Deficiency What signs suggest IGF-1 deficiency in an adult? These physical signs are summarized in the following table. Most of these signs are also encountered in growth hormone deficiency. Physical Signs suggestive of IGF-1 Deficiency Hair

•

Childhood-onset /GF-1 deficit:

Sparse, thin hair

Prenata/1 early childhood IGF-deficit: •

•

Thinner eyebrows

•

Droopy eyelids

•

• • •

Neck Shoulders Arms

• • • •

•

Hands •

•

• •

•

Thin jaw bones Sagging cheeks

Trunk

Loose skin folds under the chin Small or smaller shoulders Thin muscles

Thinner fingers (atrophic metacarpal bones) Prolonged skin folds after pinching the skin at the back of the hand

Obesity (more in adult type) Superficial breathing: small difference between maximal expiratory and inspiratory circumference of the chest

•

A fat, droopy abdomen

men

•

Stretch marks on the abdomen

•

Back

Thighs

Normal-sized hands, but with thinner muscles

Normal-sized, sexually regressing appearance body

Abdo-

Poorly developed/ droopy triceps Small hands Short, thin fingers

Prematurely aged appearance

8oth types of /GF-1 deficits: •

Thin lips

Adulthood-onset /GF-1 deficit: •

Body

Thin nose with the tip pointing downward

Prenatal/early childhood IGF-deficit: •

Small, sexually immature body

Adulthood-onset /GF-1 deficit:

Small chin, jaws, nose,

Adulthood-onset /GF-1 deficiency

Face

•

•

•

lncreased subscapular skin fold

•

Sagging back muscles

• •

Sagging inner thighs Fatty "cushions" (fat deposits) above the knees

Prenatal/early childhood IGF-deficit :

Feet

•

Small feet with short, thin toes

•

Flat feet

•

•

Nails with longitudinal lines

•

•

Atrophied palm (low muscle tone)

•

The next step is to check for the complaints of IGF-1 deficiency.

171

Kyphosis (hunchback) Hyperlordosis (excess I um bar curve)

Adulthood-onset IGF-1 deficit: Reduced foot arch Muscular atrophy of foot sole

4. Complaints of IGF-1 Deficiency What are the usual complaints of IGF-1 deficiency? IGF-1 has a considerable beneficiai impact on the mind and mood, possibly a greater impact than growth hormone (GH). Severe IGF-1 deficiency, especially when the deficiency started later in adulthood, considerably impairs the quality of life. Some patients experience it as a severe collapse. People who acquire IGF-1/GH deficiency in adulthood suffer more than other patients with earlier IGF-1 deficiency, because they remember how much better their lives were before the deficiency started. The principal complaints of IGF-1 deficiency are summarized in the following table. Most symptoms of IGF-1 deficiency are similar to those of growth hormone deficiency. Complaints suggestive of IGF-1 Deficiency MENTAL

Life

Mood

•

Poor quality of life, feels unwell

•

Lack of inner peace

•

•

Selfesteem

Social behavior

appearance

•

Lack of concentration Lack of self-control

•

•

Stress

•

•

Feet

Feeling powerless

•

•

•

Great difficulty in performing multiple tasks

•

•

Diet

Tendency to be depressed Lack of self-confidence

•

•

•

•

•

•

Physical

Low self-esteem

•

Health

Chronic anxiety without clear reason

•

•

Efficacy

PHYSICAL

•

Excessiva emotional reactions, sharp verbal retorts Dramatizing, outbursts of panic and anxiety Tendency to social isolation

Energy/ vitality

Temperature

lmpaired social status: lower professional position, lower income

•

•

•

•

Poor social integration, often without partner, still living with parents Poor stress tolerance; may collapse in minor stress situations

Sex (men) •

Sleep

•

General poor health Degradation of physical appearance Thinner, loose skin Muscle atrophy, become droopy and weaker Obesity Sore feet after long walks (caused by collapsed foot arches) Exhaustion with poor or no recovery Difficulty in recovering when not having not slept enough Feeling of rapidly aging, feeling of profound physical degradation Cold intolerance Erectile dysfunction: lack of volume and persistence of erections Light sleep Excessive need for sleep 9 hours or more

•

Ambivalent appetite for sweets and sugar (in some it is excessiva, in others low)

Food

Poor appetite for meat (because of the low anabolic state that lowers the appetite for protein)

After checking for complaints and typical body signs of IGF-1 deficiency, look for diseases that may more easily develop with an IGF-1 deficiency.

172

5. Disease Susceptibility The following diseases may evolve more easily in patients with an IGF-1 deficiency: type 1 and

2 diabetes, cardiovascular diseases (including high cholesterol, heart failure, atherosclerosis and hypertension), obesity, possibly Parkinson's disease and to a lesser degree Alzheimer's

disease (as these two illnesses may moderately respond to IGF-1 replacement).

6. Lab Tests for IGF-1 Because many signs and complaints of IGF-1 deficiency can also be caused by a male

hormone deficiency such as muscle wasting and obesity, laboratory tests are essential to differentiate between a deficiency of either of the two hormones. Lab tests will also help clarify the extent of IGF-1 deficiency. The principal tests for detection of IGF-1 deficiency are summarized in the table below:

Laboratory Tests for Detection of IGF-1 Deficiency ?

Test IGF-1-men1 (somatomedin C)

IGF-1-women 1

2 Optimal

Probably GH Deficient

300-350

0-250

39-46

0-33

220-300

0-180

29-40

0-24

3000

> 4000

References {21-30 yrs) 114-492 llQ/ 1 15-65 nmoi/L

114-492

llQIL

15-65 nmoi/L

Test

Comment

Value

High

ng/ml

=

119/L;

stable leveis, not influenced b y

High

meals; essential test with IGF-BP-3

High leveis IGF-BP-3 (binding

Blood

protein}1

Basal GH (daytime)

Stimulated GH3

24h ur. GH

reduce

2000-4000 1-1911 High

>

75

100

Women

Women:

>1

0-1.5

> 25

> 2000

<

0-15

3.3 after insulin stimulation <

1500

bioavailable IGF-

1 (by retaining

IGF-1 too long in

50-100 nmoi/L

the serum)

Women often have

0-6 ng/ml

Low

detectable daytime leveis, men rarely do

>10 ng/ml

(> 465 pmol/1) 0-3500 ng /24h

Low LowMed

lnfo. see growth hormone chapter Value depends largely on test kit quality

Notes: ">" means more than. 1

/GF- 1 shou/d be imperative/y measured by RIA (radioimmunoassay) to get the accurate /GF-1 leve/ and not by the more recent, but unre/iable technique called chemoluminescence. Unfortunately, most laboratories nowadays use the chemoluminescence method that does not require the use of an expert

2

physician in radioactive tests and a specia/ safe, approved /aboratory unit for radioactive material. The optimal value proposed here corresponds to the average value found in young healthy adults of average size. Large and tal/ persons have higher optima/ /GF-1 values (approximately 350-450 for /arge men, 300-350 for large women), converse/y, short and thin peop/e have /ower optimal /GF-1 values (about 200-300 for sma/1 men and 180-250 for sma/1 women).

173

11. IGF-1 Deficiency: TREATMENT IGF-1 Medications IGF-1 deficiency can be treated by injections of IGF-1 or growth hormone, except in growth hormone insensitivity syndromes where the patient will respond better to the direct injection of IGF-1. With age, people become less able to produce IGF-1 with growth hormone injections, and acquire a progressive need for IGF-1 suppelmentation, alone or combined to growth hormone. The following products are on the market. Most of them are of equal quality. IGF-1 Medications

Company Delivery

Product

�alue

Observation

For primary IGF-1 deficiencies (genetic, liver diseases, etc.) lncrelex (IGF-1 =

mecasermin)

lpleX (IGF-1

+

lpsen ffercica

IGFBP-3)

Vials of 40 mg (4 ml) Vials of 36 mg (0.6 ml)

lnject with subcutaneous insulin syringes 0.01 ml

0.1

=

mg, pre-mixed solution

lnject with subc. syringes 0.01 ml Supplied in boxes of 1 or 35 vials;

=

0.6 mg, pre-mixed

High

GH Medications to lncrease IGF-1 Genotonorm Genotropin

Pfizer

Mini-Quick Humatrope, Umatrope

GeneScience Sanofi

Jintropin Maxomat Norditropin Nutropin Nutropin

Eli-Lilly

depot

Omnitrope

Saizen

Serostim Zomacton

Novo Nordisk Genente ch Sandoz

Serono Serono (USA) Ferring

Vials of 1.3 mg Pen (5.3, 12 mq) Syringes of 0.2, 0.4, 0.6 up to 1.8, 2 mq

Less used

High

Good product

High

Ready-to-use syringes -for travelers unable to keep GH refrigerated

High

The experience of some patients is that Humatrope may quickly lose its potency once lhe vial has been opened for longer than lhe period of time recommended by lhe producer.

Low?

Pen of 6, 12 or 24 mg

Possibly longer potency than regular vials.

Med

Vials of 1O mg

Supplied with 1 ml vial of bacteriostatic water. Not registered in lhe USA or Europe, raises quality questions; reports of quick potency loss after opening lhe vial

Low?

Supplied with 2 ml of bacteriostatic water.

High

Vials of 5 mg

Vials of 1 .3 mg Vials of 1.33 mg Pen of 5, 10 or 15 mg (Nordipen) Vials of 5 & 10 mg Vials of 13.5, 18, 22.5 mg

poorly compliant patient

Vials of 5 mg in a package of 5 vials

Similar to Norditropin, but 25% cheaper, with an injection pen and no need to mix a solution with lhe powder,

Vials of 1.33 mg Vials of 5 & 8.8 mg Pen of 8.8 mg (one-click, cool-click) Vials of 4, 510 mg Pen (Serojet) Vials of 4 mg Pen of 10 mg (Zomajet)

Supplied with

1

ml of bacteriostatic water.

The stability of GH in Novopen vials, even if briefly not

refrigerated, remains good Supplied with 2 o r

1 O ml diluent

Once a month subcutaneous injection, good for

High High High

..!:!!.9.1!_ Med

High

Supplied with 1 ml bacteriostatic water.

High

Supplied with 5 or 1 O ml of diulent.

High

A cheap pen using spring pressure and needles, a button is pushed and the needle is pushed into the skin (one-click) ora needle-free device (coo/-click).

High

Supplied with

High

1

ml vial of sterile water.

Device with needle.

High

Supplied with 1 or 3.5 ml of diluent.

High

A pen using air pressure (no needles), -needs correct handling.

High

lmportant note: The product quality column is a subjective evaluation of the product based on personal experience and reports from patients and colleagues. No responsibility is taken for the information. The aim is exclusively to provide practical information for physicians 1 Mecaserim is recombinant IGF-1 with the same amino acid sequence as the endogenous IGF-1

174

The best way to inject IGF-1 Howto inject IGF-1 (lncrelex®): Patient lnstructions 1. 2.

Use a subcutaneous syringe with a thin needle Use a new syringe each time. You could possibly put the 0.01 ml to 0. 1O ml dose of the IGF-1 solution, which is necessary depending on the severity of the IGF-1 deficiency, for three to four days in a syringe, and each day inject the amount that is needed. In the meanwhile the syringe should be kept cool in the refrigerator. Take note that each time the syringe is re-used, its needle becomes duller. This dullness may cause pain and make it difficult to penetrate the skin.

3.

Howto inject GH

lnsert the needle of the syringe subcutaneously, but do not penetrate the muscle. An oblique injection angle just under the epidermis avoids penetrating and damaging muscles.

4.

lnsert delicately and avoid pinching the skin between two fingers which may cause bruising.

5.

Change the injection site regularly. For instance, start injecting on the lateral side of the abdomen and every day move the injection site lower by two finger-widths until the pubis is almost reached. Repeat this pattern on the middle abdomen and then at the opposite lateral side of the abdomen until ali the parts of the abdomen have been injected. Next, proceed to the lateral upper thigh following the same spacing until the lower third of the thigh is reached, then start at the upper front of the thigh and then go to the other thigh.

lnjection sites Via I users

Abdomen, thigh (ventral and externai sides), side of the buttocks. To avoid infecting the via!, keep the rubber top of the via! covered at its borders with the attached aluminum tab. Never insert a used needle back into the via!: you are almost certain to inject infectious germs and contaminate the via!.

Women

Women usually need higher doses (20 to 35% more).

Obese

Massive obese patients seem to be relatively IGF-1-resistant. They need doses

patients

that are 50 to 200% higher than lean patients. Patients with cortisol deficiency may react badly to IGF-1, as IGF-1 further

Cortisol

reduces the production of cortisol. Even with glucocorticoid supplemented, they

deficient

may still not well tolerate IGF-1. Therefore these patients should start the IGF-1 treatment at lower doses than used for the average patient (see further pages

patients

for more information). Children

Children who are IGF-1 deficient need on average about two to four times higher doses of IGF-1 than adults.

175

How to begin IGF-1 treatment Start at low doses. (Patient with average to low cortisol & 17-OH-steroid leveis, with or without signs and complaints of cortisol deficiency)

DEFICIENT or moderately weak ADRENALS

PRINCIPLES •

•

•

lfiming

IGF-1 TREATMENT: dose

(often children, rarely adults, require an additional dose in morning) Morning

Start IGF-1 at low doses and then gradually increase

Before evening meal if given alone Before bedtime if given with GH

(as GH neutralizes the hypoglycemia that IGF-1 can cause)

0.01 ml every 2 days Range of doses 2"d 10 days (0.01 ml/day) 0.01 ml/day generally useful for adults with partial 3'd10 days I (0.02 ml/day) 0.02 ml/day IGF-1 deficiency 2"a-3tn month (0.03 ml/day)_ 0.03 ml/day � 4tn month (0.04 ml/day) 0.04 ml/day Follow-up consultation: check and adjust doses. The mean dose for an adult with mild deficiency is 0.02 ml/day lncrease the 0.2 mg/day, higher IGF-1 deficiencies require higher dose by 0.01 4th month doses. However, doses of IGF-1 as low as 0.01ml every 2 ml/day every days may be sufficient for potent effects when the IGF-1 10 to 30 days is given in association with growth hormone due to the lnform the synergy between the two hormones 5th patient about month (0.05 ml/day) 0.05ml/day IGF-1 overdose stn month (0.06 ml/day) 0.06 ml/day Range of doses signs so that he i" month generally useful for (0.07 ml/day) 0.07 ml/day can report them stn month children (0.08 ml/day) 0.08 ml/day gth quickly if they I (0.1o ml/day) month 0.10 ml/day occur and Follow-up consults: The patient is examined and the lower the dose 4 h 8th & 6th IGF-1 dose is adjusted, either increased or decreased t , 1 depending on the needs and the reaction to the IGF-1 month treatment. lncrease the dose by 0.01 ml every 1O to 30 days. lnject every day before bedtime (possibly Y2 of the dose in the morning, Y2 in the evening)

1"t 10 days

=

•

Note:

1

0.01 ml of lncrelex

=

0.1 mg of IGF-1

Progress with IGF-1 Treatment How much time is needed for the first improvements to be felt? IGF-1 treatment usually takes weeks before the first improvements appear, although some patients feel improvement as early as three days. Quicker results can be obtained by starting at higher doses. In general, most of the improvements are felt during the second, third and fourth months. Similar to growth hormone treatment, many patients continue to improve for two to three years after the start of treatment even at doses equal to or lower than the initial ones, especially in people who make major diet and lifestyle adjustments.

176

How can you naturally increase the IGF-1 leveis? Firstly, improve the lifestyle and particularly the diet. The principal lifestyle recommendations for the patient that help him to increase his IGF-1 production or effects are summarized in the following table. How to optimize IGF-1 activity and treatment

•

Diet

WhatTo Avoid

WhatTo Do

What? •

•

Eat sufficient calories Follow a "Paleolithic" diet: especially protein-rich foods such as meat, poultry, eggs, fish*

•

•

Add amino acids (preferably a mixture of ali the important amino acids) 2 Eat orQanic foods

Weight

• •

Stay lean

Sleep

Avoid alcohol, vinegar, 3 caffeinated drinks

•

Avoid sugar, sweets, cookies, bread, pastas and other cereais

•

Avoid being overweight

•

Get adequate sleep

Stress

•

Abuse

•

Avoid sleep deprivation Avoid excessive prolonged stress Avoid tobacco smoking

•

Notes:

1

Avoid marijuana and other drugs

A high intake of protein-rich foods increases IGF-1 leveis. A higher (bioavailable) IGF-1 levei

signifies that IGF-1 activity is increased as IGF-1, which is made in the liver under the influence of growth hormone in the liver cells, is actually the best marker for IGF-1 activity; 2

Certain pesticides may alter IGF-1 secretion and effect;

3

Decaffeinated drinks (where the caffeine has

been extracted by the safe method based on water and carbonic acid), may be an acceptable alternative.

Secondly, correct other hormone deficiencies. Many hormones can enhance IGF-1 production and its effects on the body. The principal hormone replacement therapies that can increase the secretion of IGF-1 and/or its action, and those that can reduce or inhibit IGF-1 secretion, are summarized in the following table. Corrective hormone therapies that influence IGF-1 therapy

• •

• • •

• • •

Strong

Mild

IGF-1 stimulators

stimulators

Growth hormone lnsulin (esp. in people with low insulin leveis) Testosterone, other androgens DHEA Estrogens (transdermal or injectable} Progesterone and progestogens Thyroid hormone

Strong

• •

•

Cortisol at physiological doses Vasopressin Parathyroid hormone Melatonin

Alpha-MSH

177

inhibitors

inhibitors •

•

Mild

GH/IGF-1

•

Cortisol and other glucosteroids at high doses Oral estrogens (birth control pills, etc.)

• •

EPO (erythropoietin) Endogenous

insulin (in the case of insulin resistance)

lndications for IGF-1 Treatment IGF-1 deficiency is the principal indication; typically, growth-hormone/IGF-1-deficient children and adults whose IGF-1 leveis do not sufficiently increase with growth hormone treatment. Other indications: Malnutrition, weight loss, anorexia (small doses), prematura aging, difficulty to repair tissues, osteoarthritis, bone fractures that do not heal well, neurological disorders (paresias, paralysis). These conditions may benefit from the anabolic action of IGF-1.

Contraindications to IGF-1 Treatment Currently, IGF-1 treatment is contraindicated in people with active malignancy, in particular breast, prostate or colon cancer as higher IGF-1 leveis (with low IGF-BP-3's) have been associated with cancer. However, the recommendation is controversial as the tumor of breast cancer patients seems to have a major resistance to IGF-1; reflected by a 40 to 75 % lower number of IGF-1 receptors, suggesting that the lack of IGF-1 effects rather than the excess favors the appearance of breast cancer. IGF-1 is possibly not contraindicated during pregnancy at physiological doses in IGF-1-deficient women. However, caution is nevertheless recommended.

178

Follow-up of IGF-1 Treatment 1.

Adjust doses up to the optimal dose:

The optimai iGF-1 dose may vary in specific conditions. The most frequent conditions that may require a permanent or occasional dose adjustment in a patient already undergoing treatment are listed in the following table:

When to adapt the dose of IGF-1

• •

•

Chronic conditions

•

•

• •

Acute Conditions

Lower the Dose (25 to 75% less)

lncrease the Dose (50 to 200% more)

Dose

lnsufficient IGF-1 effects Low IGF-1 (and normal to high IGF-BP-3) in blood Type 1 and 2 diabetes (risk of aggravation during the first year) Oral estrogen treatment (HRT, birth contrai pills) lnsulin deficiency (diabetes type 1 ), not or insufficiently treated Hypothyroidism (untreated) Testosterone deficiency (untreated)

•

lncreased physical activity

•

lntensive stress

•

•

• •

•

• • •

•

•

•

During and after surgery Abdominal bloating (amino acid malabsorption)

•

Excessive IGF-1 effects Excessively high IGF-1 (and normal to low IGF-BP-3) in blood (near or above the upper reference value of young adults) Testosterone, dihydrotestosterone or other androgen treatment Melatonin treatment Thyroid hormone treatment DHEA treatment (rarely) Decrease in physical activities (sedentary, bedridden) Unstressed, holidays, vacations Allergies such as asthma, ear-nosethroat infections, skin rashes, etc. Crisis of rheumatoid arthritis {because of the risk of joint swelling)

The effects of IGF-1 or its production can be increased in patients by correcting other hormone deficiencies in them. Thus, many replacement therapies boost the effects of IGF-1 treatment so efficiently that often 30 to 90% lower doses of IGF-1 are necessary to correct the IGF-1 deficiency. In my experience, the most potent of these IGF-1-stimulating hormone therapies are growth hormone and insulin treatment.

179

2. Perform lab tests during follow-up:

The tests that can be done during follow-up are reviewed in the following table. Serum IGF-1 and IGF-BP-3, its binding protein, are the most helpful tests and often the only ones to do during follow-up. An increase in IGF-1 activity is expressed by an elevation of plasma IGF-1 and, in particular, of the ratio of plasma IGF-1 to IGF-BP-3. Lab Tests for Follow-up of IGF-1 Treatment

"J"y_pe Serum

•

Test Value

When to do the test?

IGF-1

High

•

IGF-BP-3

High

Second to fourth month after the start of the treatment

Levei

Note: These tests are a/so useful for follow-up of patients with acromegaly treated with a

growth hormone-blocking medication.

As the risk for intestinal cancer seems to increase in patients with a high serum levei of IGF-1 and a low serum IGF-BP-3 levei, it is wise to monitor these two lab tests closely and aim to bring both of these leveis close to the mean value of young adults. A normal IGF-1 treatment increases both serum IGF-1 and IGF-BP-3 (severa! studies suggest that high serum leveis of IGF-BP-3 are cancer protective), and thus should not be a cause for concern. 3. Avoid overdosing:

Signs and complaints of IGF-1 overdose should be well-known by the patient and avoided. lf they occur, he should be taught how to reduce the dose. In an emergency, with some major intolerance, he may stop the treatment completely for one or two days. The principal overdose signs and symptoms and what to do about them, are reviewed in the following table: IGF-1 EXCESS Time lag before overdose

COMPLAINTS

signs appear •

Same day as injection After 3 to 4 days of GH excess

•

Hypoglycemia: hunger, shakiness, nervousness, sweating, dizziness or light-headedness, sleepiness, confusion, difficulty speaking, anxiety, weakness Swelling of face, eyelids, tongue, legs, feet, etc.

Time lag before overdose

PHYSICAL SIGNS

signs appear •

After 3 to 4 days of GH excess

•

After 1 month or more

•

After 6-12 months1

•

Edema of the feet, hands

(possibly nose, lips, eyelids) (carpa! tunnel syndrome), tingling nose Excessive muscle development (esp. shoulders, pelvis) Acromegaly (increased size of hands, feet, nose, etc.) Tingling fingers

Notes: 1 Acromegaly at IGF doses about 3 to 30 times the doses used in /GF-1 rep/acement therapy for /GF-1 deficiency 4. Solve problems quickly and efficiently:

See next section to know how to do it.

180

111. IGF-1 PROBLEM SOLVER

How do you solve problems that occur during treatment? The problems that are encountered most frequently during IGF-1 treatment are listed in the following tables. Problems possibly related to IGF-1 overdose:

Problems possiblv related to IGF-1 Overdose IGF-1 OVERDOSE •

Feet, hand

(and possibly nose, lip and eyelid) edema •

Tingling fingers, tingling

•

APPARENT CAUSE IGF-1 (or growth hormone: GH) overdose causes excessive fluid

grams a day) that counterbalance the sodium excess

increasing the activity of the

2. lf taking potassium is not sufficient,

renin-aldosterone system

lower the dose of IGF-1 (or growth

(that leads to water

hormone)

retention)

Excessive

Tesloslerone and IGF-1 or GH

muscle

overdose. How? The excess

especially shoulders and pelvis. This sign requires more than one month of GH overdose to develop.

1. Take potassium supplements (1-3

retention, partially by

nose

development,

SOLUTION

IGF-1 or GH lowers serum sex

1.

Reduce the dose of IGF-1 (or growth hormone)

hormone binding prolein (SHBG), lhe lransporting binding prolein of androgens in lhe blood.

A low SHBG seis androgens free and increases lhe blood

/f it is not sufficient to reduce the muscle

overdevelopment and the patient is on androgen therapy:

leveis of unbound bioavailable lesloslerone resulling in a global increase of (inlracellular)

2.

Reduce the dose of androgens

androgens in lhe largel cells.

Signs of acromegaly almost never occur during normal IGF-1 or GH replacement. The doses used are too small to cause them.

Extreme long-term (at •

Acromegaly (enlarged hands, feet, etc.)

The best solution is prevention: use only small physiologic doses. 1. Mild acromegaly: stop IGF-1 (or GH) for 6 weeks, or reduce the dose

least 6 to 8 months) IGF-

drastically by 50-75%. After ali

1 (or GH) overdose=>

increases the size of the extremities (nose, chin, hands, feet, etc.)

swelling has disappeared, begin IGF-1 (or GH) at a 30 to 50% lower dose

2.

Severe acromegaly (especially in athletes who are doping themselves with IGF-1 (or GH): stop for 3-4 months, or reduce the dose by 7590%, then after ali swelling has disappeared, start IGF-1 at a fraction, 10-40% of the initial dose.

181

Problems of injection technique or changes of the blood sugar levei by IGF-1 Treatment

Problems of injection technique or changes of the blood sugar levei by IGF-1 Treatment PROBLEM •

•

POSSIBLE CAUSE

SOLUTION

Varous possible causes: Too brutal

Careful injection: gently extend

Pain, bruising,

injection, injection into a pinched

the skin and penetrate with the

swelling, red area

skin, too deep injection into the

needle sideways in the

at the site of the

muscles or too superficial iinjection

subcutaneous layer and

injection

into the epidermis, which makes the

remaiing there with the needle

skin swell, allergic reaction

during the time of injection

Hypoglycemia: hunger, shakiness, nervousness, sweating, dizziness or light-headedness, sleepiness, confusion, difficulty speaking, anxiety, weakness

IGF-1 can reduce serum glucose. In type

1

diabetic

insulin

patients

treatment,

taking insulin

requirements have to decrease. The reduction must take place in the first one or two months. Careful and regular glucose

monitoring

needs

to

of serum

take place in

diabetics, and hypoglycemia should

In

diabetics,

start

IGF-1

treatment at low doses of 0.01 ml (0.1 mg of IGF-1) every 2 days during two weeks, then slowly increase the dose by 0.01 ml per day or per two days every 2 to 4 weeks.

lead to dose reductions.

About the Hormone Fears

Cancer Risk and IGF-1 Treatment: As IGF-1 reduces apoptosis (death) of cancer cells and studies have shown an association of IGF-1 leveis in the serum with prostate, colon and in particular breast cancer, researchers have suggested that IGF-1 might promote cancer. lf IGF-1 reduces the death rate of cancer cells, it does this also for immune cells. Moreover, studies have shown protective associations between IGF-1 leveis and prostate cancer. In breast cancer, the tumor has been reported to be IGF-1 resistant as reflected by a major lowering of the number of IGF-1 and IGF-2 receptors in malignant breast tumors. In fact, patients with hypopituitarism and thus GH and IGF-1 deficiency have an increased cancer risk and mortality up to two to tive times the normal risk. lncreasing the leveis of IGF-1 of these patients with growth hormone treatment, which increases IGF-1 and in particular the amount of IGF-1 that is active and bioavailable for the target cells - reflected by an increase in the ratio IGF-1 to IGF-BP-3, reduces their risk by half from ali forms of cancer, except intestinal cancer.

182

Chapter ten

Cortisol and other Glucocorticoid Deficiency and Treatment

Case Report of a Patient with Cortisol Deficiency Cynthia and her outbursts of anger and anxiety Cynthia has always been thin. As a child, her classmates would tease her for being so "skinny." Part of the problem was that she was a very finicky eater. The only type of food that she liked and even craved was sweets, especially chocolate. Moreover, most foods made her nauseous or gave her colitis attacks (contracted and painful colon). She also suffered from allergies, skin rashes (including eczema), conjunctivitis, colds, and bronchitis, and even occasional asthma attacks. Emotionally, Cynthia was a very sensitive child, easily bursting into tears or anger when something bothered her. As an adult, things worsened. 8oth emotionally and physically she became even more fragile.

At work she generally contained herself and transformed ali her

negative feelings into neNousness and action. But her outbursts of anger and irritation dominated her family life as being neNous or upset was her way of living. Her doctor told her she was "driving on adrenaline". What is Cynthia suffering from? Cynthia is suffering from cortisol deficiency. In order to better understand this deficiency, let us review some basic information.

183

CORTISOL: lmportant lnformation Cortisol, hydrocortisone, cortisone and glucocorticoids Glucocorticoids is the family name for a group of hormones, natural or synthetic derivatives, that have the capacity to increase serum glucose and thereby to prevent hypoglycaemia. The natural ones are made by the adrenal cortex. Cortisol, hydrocortisone and compound F are synonyms for the same molecule: the human body's most potent glucocorticoid. Hydrocortisone is the name most often used for medication containing (exogeneous) cortisol.

Cortisol is the term used in general to designate the

(endogenous) hormone in blood. Cortisone is the natural precursor of cortisol and has approximately

80% of cortisol's activity.

Prednisone, prednisolone (the active form of prednisone), methylprednisolone (Medrai®), beta­ and dexamethasone, and so many other glucocorticoids on the market are synthetic derivatives of natural cortisol. Their structure is a modified version of cortisol to increase some of cortisol's properties.

Roles of Cortisol Cortisol keeps us alive thanks to three essential and powerful properties.

lt increases both

blood sugar (and thus energy leveis) and blood pressure, and neutralizes inflammation. The beneficiai effects of cortisol such as mood enhancement, dynamism,

work capacity, stress

resistance, stimulation of the immune defenses, anti-rheumatic action, anti-pain action

and

many others, rely on these fundamental functions. Another action of cortisol is to calm down any excessive activity of the sympathetic nervous system that produces adrenaline, the stimulating neurotransmitter. This explains why persons lacking cortisol often have high leveis of adrenaline. As they miss the energy and mood calming action brought about by cortisol, they tend to compensate by making more adrenaline, regularly exploding in emotional outbursts.

Production of Cortisol The daily secretion of cortisol in young healthy women is 15-25 mg per day and 25-35 mg per day in men. Cortisol is almost exclusively produced by the two adrenal glands from a layer called the zona fasciculata situated in the outer part of the adrenal cortex.

Studies have

discovered that the brain and intestines may be able to produce small quantities of cortisol as they have the necessary enzymatic equipment to do so. Cortisol leveis in blood are highest in the morning

(6-8 a.m.) and lowest in late afternoon or

evening.

Factors that increase Cortisol production Normal, appropriate stimulators of cortisol secretion during the day are activity, standing, stress, emotions, and bright sunlight, especially in the morning. At night, a high cortisol secretion is generally not needed. Melatonin and growth hormone are mainly secreted at night and reduce cortisol leveis, thereby helping individuais to sleep easier. Low night-time leveis of melatonin and growth hormone allow cortisol to remain inappropriately high at night, keeping individuais awake.

184

Cortisol activity decreases with age In several studies a lower cortisol secretion, lower cortisol metabolites (17-hydroxysteroids) and fewer cortisol receptors have been reported in the elderly population. The highest 24-hour urinary leveis of 17-0H-corticoids (cortisol metabolites, whose leveis reflect the metabolic impact of cortisol) are found in young adults but by age 80 there is an average decline of about 25%. Paradoxically, in other, but not ali, studies on elderly people higher evening and night-time serum cortisol leveis have been shown. The paradoxical association of a higher serum cortisol and lower cortisol metabolites in certain elderly people is caused by a reduction of the uptake of cortisol (metabolic clearance) with age by the target cells,

resulting in retention and

accumulation of cortisol in the blood vessels. As cortisol remains longer in blood, it penetrates the target cells less. Furthermore, the decrease of intracellular cortisol with age is aggravated by another problem. The target cells gradually lose cortisol receptors with age, becoming less able to respond to the intracellular cortisol, which causes a decline in the beneficiai effects of cortisol. Despite the decrease in beneficiai effects, adverse effects from cortisol may appear with age because the decline with age of anabolic hormones (that build up our body) such as the sex and growth hormones decline with age at a greater speed than catabolic hormones (which break down tissue products to liberate energy) such as cortisol.

In this way, an imbalance in

favor of catabolism emerges accelerating aging in elderly persons if the balance is not corrected by corrective hormone therapy.

Severe and mild Cortisol Deficiency Severe cortisol deficiency must be treated with cortisol, as it is a life-threatening condition and cortisol is essential to stay alive. A moderate cortisol deficiency should also be treated because it impairs health and is easily corrected with life-long cortisol treatment.

Sufficient cortisol is

essential to health and quality of life. On the other hand, prolonged treatment with high doses of cortisol can depress the immune system, lead to osteoporosis and other ailments, and thus become dangerous. High dosages of cortisol should be reserved for emergency cases or to treat an acute disease.

Principal metabolites of Cortisol are 17-hydroxy-steroids, also called 17-hydroxy-corticoids

185

I. Cortisol Deficiency: DIAGNOSIS How to detect Cortisol Deficiency Next to lab tests, an evaluation of past health history, signs, complaints, concurrent diseases and medicai imaging, if needed, will offer the best picture of the deficiency and assist in choosing the best treatment.

1. Onset of Cortisol Deficiency When did the cortisol deficiency start (past medicai history)? How can you recognize persons with untreated cortisol deficiency in childhood? By interviewing and examining the face and body shape of many patients with cortisol deficiency, it is possible to determine whether their deficiency started in childhood or if it began in adulthood. Patients with early childhood deficiency are generally more severely afflicted. As their childhood deficiency has worsened with time, they often complain more, and their face and body often looks thinner. The thinness is the result of a poor food intake favored by a lack of appetite and nausea, and poor food absorption in the gut, a gut that is too inflamed to absorb food well. The main differences are summarized in the following table:

Determining the Onset of (Untreated) Cortisol Deficiency Onset

Childhood

Severity Face

Adult

Greater severity •

More moderate •

Thinner, narrower face

•

Larger face, may have become more hollow · Thin body , if the lack of appetite and/or intestinal

Body

•

inflammation

Thinner, narrower body

predominates •

Possibly obese, if sweet cravings predominate:

Health in childhood

•

Ear, nose and throat infections, vira! infections

•

Allergies incl. skin rashes, food-rel., asthma

•

Gastrointestinal troubles (liver, colitis)

•

Excessive emotions: anger/irritability outbursts

•

Anorexia, difficult to make him/her eat, except

•

No such medicai problems in childhood

sweets; sweet cravings Note: *but notas thinas patients with severe cortiso/ deficiency in childhood

After this quick check, it is important to inquire about the timing and location of the complaints.

186

2. Timing and Location When and where do cortisol physical signs and complaints occur? When? Typically, they occur more often and with greater intensity during stressful situations and when standing up. Where? Physical signs have a tendency to be unequally localized to certain areas of the

body Ooint inflammation or skin rashes, for example, may be more localized on one hand than the other).

3. Complaints of Cortisol Deficiency The patient may intensely suffer from the deficiency in thoughts and emotions, and deep into the body, in particular in stressful situations. What does the cortisol-deficient patient complain of? The principal mental and emotional complaints of cortisol deficiency are summarized in the table below. MENTAL and EMOTIONAL COMPLAINTS of Cortisol Deficiency

(hypocorticism, adrenal deficiency, Addison's disease) • •

Mood

•

Anxiety in stressful situations1

· Depression in stressful situations, possibly resulting in suicide attempts1 2 Extreme moodiness

Memory

•

Memory loss in stressful situations2

Attention

•

Confusion, absentmindedness, especially in stressful situations2

•

Stress

• • • •

Character •

Excessiva compassion for the pain of others

o/·3

I rritabili

Negativism (experiencing reality as being more negative than it really is for others)2'3 Feeling of being a victim2•3 Paranoid-like reactions: accusatory behavior, quarrelsome2·3

•

Excessiva emotions: outbursts of anger or anxiety, panic attacks1 Frequent screaming or yelling1

•

Note: due to

Excessiva sensitivity to human suffering1·3

•

•

Behavior

Poor resistance to stress, great difficulty to function well in stressful situations or even react to them, paralyzed in stressful situations2, experiencing stress as being toa much, as an unfair event1•2

Sharp verbal retorts, use of strong, dramatized words1

1

adrenaline and other catecholamine discharges low blood sugar (hypoglycemia) 3 inflammation

2

187

The principal physical complaints of cortisol deficiency are summarized in the table below. PHYSICAL COMPLAINTS of Cortisol Deficiency • •

Physical appearance

•

•

Excessive thinness

•

Tends to be underweight, difficulty gaining weight Sometimes obesity because of bulimia due to sweet and salty food cravings Acute hair loss

•

Head

•

Headaches at stress2•3

•

lnflamed skin lesions: skin rashes (nettle rash, eczema, psoriasis)3

Skin

•

• • • •

Muscles and

•

tendons

Joints

•

•

Energy/ Vitality

Hair

•

•

Alopecia areata (hair loss in plaques)

•

Vitiligo (depigmented skin areas)3 Cheloids (thick scars)3

Sleep

•

Tempe-

•

rature

Iregular brown spots6

•

Suntans easily6 Myalgia {localized muscle pains)3 Tendonitis (recurrent tendon inflammation), especially as positive tender points)3 Arthritis {localized pain, deformities of joints)3

lnflammations •

Food

•

•

•

Digestiva

Predisposition to ali kinds of inflammatory diseases3, e.g:

•

•

Acute allergies: ENT (EarNose-Throat) allergies, conjunctivitis, otitis, rhinitis, pharyngitis, asthma, food allergies Chronic inflammatory diseases: rheumatoid arthritis, connective tissue diseases (e.g. lupus)

•

Nerves Medi-

Fatigue, low energy, especially during stressful conditions2 Burned out syndrome, sometimes transient, but great difficulties to function after emotional discharge3 In upright position: drowsiness, emptyheadedness, distraction, absentmindedness, daydreaming, vertigo2.4 Longer sleep Slight fever from time to time4 lntense hunger attacks2 Sweet, sugar cravings2 Nausea, anorexia, esp. for meat5 Salty food craving4 Gastroenteritis, colitis with abdominal pain, bloating, diarrhea3 Nausea, vomiting5

•

Excessive sensitivity to pain3

•

lntolerance to medications3

cations

Prone to infections3:

•

lnfections

•

Viral: mononucleosis infection, flu, etc. Bacterial: rhinitis, otitis, sinusitis, pharyngitis, bronchitis, pneumonia, ...

Cortíso/ defícíency symptoms due to: 1 adrenalíne and other catecho/amíne díscharges; 2/ow b/ood sugar (hypog/ycemía)/ínflammatíon;4hyponatremía wíth hyp_ernatríuresís 5míneral or nítrogen dísturbances in b/ood (e/ectrolyte) ímba/ances, azotemía ; ACTH overproductíon

Note:

With this basic knowledge we can now examine the details of the body of patients suspected of having a cortisol deficiency.

188

4. Physical Signs of Cortisol Deficiency What are the physical signs of cortisol deficiency? These physical signs are summarized in the following table. Physical Signs of Cortisol Deficiency: Table 1 Physical appearance

• • •

Ha ir

• •

Face

• • •

Eyes

and

• •

eyelids

•

No se

•

Ears Pharynx Neck

• • • • • •

Abdomen

Armpit Elbow Hands Feet

• • • • • • • • •

Temperature

Thin body1 (Obese if sugar cravings)2 Acute hair loss (the hair that fell out usually has elongated hair roots)3 Rarely: alopecia areata3 4 Yellow-brownish face Hollow cheeks1 4 Brown (hyper pigmented) spots on face 3 Painful sinus points 2 Tired look 3 Conjunctivitis (with inflamed eye globe) 4 Dark circles under the eyes Rhinitis3 (colds)

Erythematous (red) inflamed tympanic membrane3 lnflammation (otitis)3 Pharyngitis (inflamed red throat)3 Tonsillitis (Swollen, erythematous tonsils)3 Tender, swollen lymphatic nodes3 Bloated abdomen 3 Pain upon abdominal palpation 3 Colitis 4 Brownish armpit fold Heavy sweating in armpits5

4 Brown elbow fold Wet palms5

Palms: brown skin folds Wet soles5

4

Episodes of above normal temperatures or > 36.6'C (in women not taking the pill:

>98.6°F

during the first- follicular- phase of the menstrual cycle) Note: Physica/ signs due to the following mechanisms typica/ to cortiso/ deficiency: 1 inadequate food absorption 2 /ow b/ood sugar (hypog/ycemia) 3 excessive inflammation 4 overproduction of ACTH (adrenocorticotropin); pigmentation occurs only when adrenals are weak and the pituitary is healthy enough to secrete high amounts of ACTH 5 higher adrena/ine leveis

189

Physical Signs of Cortisol Deficiency: Behavior

•

Nervous, irritable behavior

•

Accusatory or "being the victim" language 1 Sharp verbal retorts with often melodramatic words that have negative and/or aggressive connotation ("terrible", "horrible", "impossible", etc.) 1 Wheezing (if asthmatic)

Language

•

Lungs

•

Heart

• •

Blood pressure Muscles Tendons

and

• • • • •

Joints

• •

Spleen

• • •

Skin

Table 2

• •

Tachycardia5 Hypotension Orthostatic hypotension Possible hypertension in stressful situation5 Painful muscles with pressure3 Painful tendons with pressure (positive tender points)3 lnflamed joints3 Rheumatoid arthritis Painful joints upon mobilization Painful spleen upon palpation3 Plaques of skin rashes (e.g. eczema, psoriasis, nettle rash)3 Vitiligo (white depigmented spots) Cheloid (excessiva) scar formation3 Irregular brown spots, melanoderma, nevi (darker brown birth spots) and scars, darker brown skin (in Caucasians ), brown spots in buccal mucosa, brown skin folds4

Note: Physical signs due to the fol/owing mechanisms typica/ to cortiso/ deficiency: 3 excessive inflammation; 4 overproduction of ACTH that next to stimulate greater cortisol production by the weak adrenals stimulates melanine production by the melanocytes, resulting in increased pigmentation when the pituitary is healthy enough to secrete high amounts of ACTH; 5 higher adrenaline leveis

After checking for complaints and for typical body signs of cortisol deficiency, it is important to look for other diseases that may develop more easily with a cortisol deficiency.

5. Susceptibility to Diseases Cortisol deficiency increases the susceptibility to many types of diseases: lnflammatory diseases such as acute allergies (such as ENT (Ear-Nose-throat) and food allergies, asthma), infections (flu, mononucleosis, etc.), chronic inflammatory diseases (rheumatoid arthritis), connective tissue diseases (lupus, etc.) Patients with low cortisol leveis or adrenal fatigue have an increased risk of dying under life­ threatening conditions such as severe infections or multiple traumatic injuries because these patients are unable to secrete adequate amounts of supplementary cortisol when needed. There is empirical data to support a correlation between cortisol deficiency and psychiatric diseases such as paranoia and autism. After this check it is essential to require lab tests.

190

6. Lab Tests for Cortisol IMPORTANT NOTICE: Do lab tests for cortisol in sedentary conditions! Avoid stress and intense activity such as hurrying, being in a traffic jam, and vigorous exercise 24 hours before and during testing because they abnormally increase cortisol levels that may mislead the MO.

What are the main laboratory tests for confirmation of cortisol deficiency?

Type

Lab tests for dia nosis of cortisol deficiency 1 1 Time Optimal Pr. Deficient References

Test

Total cortisol Free cortisol

Blood

3

550

0-360

276-690 nmoi!L

20

0-13

10-30 ng/ml

55

0-36

28-83 nmol/1

> 45

0-45

Free cortisd

(late afternoon)

10-12

0-7

30

15-60'

lncrease

0-20

Total cortisol"·5

after ACTHCRF-

ACTH

stimulation

ACTH

7-9AM

Transcortin (CBG)

Saliva

100-250 ng/ml*

4-8 PM

Free cortisol (24h)

0-130

Total cortisol4

Total cortisol

Urine

8-9AM (morning)

180

6 17-0H-steroids (gas chromatography)

Free Cortisd

>

125

0-125

lncrease

30-1 OOng/ml*

100%

increase above baseline values

45

High >70 Low < 25

2-20 ng/ml

5.5-55 nmol/1

Higher than baseline values

Med Low

20-50 mg/1

Med Med

30

> 40 0-40

13

0-10

5.8 -15.8 mg/24h

36

0-28

16-44 JJmol/24h

6.5-7

0-5.5

3.7-8.5 mg/24h

10-23 JJmol/24h

Morning Noon Evening Night

Med

Low

70

Women

Low

20-80 mg/1

24h

Men

Med

Low

Anytime

.c "
Low

80-275 nmol /1*

Less than

;o: 2 x

baseline cortisol

Value

10-100 119124h

18-19

0-15

20-30

0-10

5.1-40.2 nmoi/L

7-11

0-5

2.1-15.7 nmoi/L

6-9

0-4

1.8-12.1 nmoi/L

5

0-2.5

High

Med

0.9-9.2 nmoi/L

Notes: 1 "Pr. Deficient" means "probably deficient'� relates to leveis where patients are 9enerally free of 2

3

complaints and si9ns of cortisol deficiency. The test value is the estimated usefulness for use in practice. The free cortiso/ is best obtained by ca/culation of a formula based on total cortisol and CBG, rather than throu9h direct measurement. This is because of the excessive fluctuations of free cortisol, while

4

total cortisol and CBG are more stable. When it is not possible to obtain a24-hour urine col/ection, two or three blood measurements of total cortisol, transcortin and free cortiso/ in the mornin9, afternoon, and evenin9, and/or ACTH-stimulation test can be dane. However, this is less accurate than the combination of mornin9 values of serum

5

cortisol with24-hour urine cortiso/ and total corticosteroids. Based on recent studies, the amount of ACTH to inject shou/d be 1 micro9ram (119) and not 0.5 119, nor the high conventiona/250 119· To obtain 1 119 from the c/assic 1 m/ solution with250 119 of ACTH, inject

O. 04 m/ of the 1 m/ solution with a subcutaneous syringe into a sterilized 1O m/ physiolo9ic serum 6

7

solution, then extract 1 m/ of this newly formed mixture to intravenous/y inject in the patient. The urinary 17-hydroxysteroids must be measured with the gas chromato9raphy technique. The saliva test al/ow measurement of the circadian rhythm.

191

11. Cortisol Deficiency:TREATMENT

Cortisol and other Glucocorticoid Medications The drugs to treat cortisol deficiency and their indications are reviewed in the table below. Route

Oral

Oral Oral

Oral

IM

Product

Dose

Dose

Methyl-

IV Oral IV Aerosol

lridication:

Dose

(stress, Cortisol deficit with (sedentary) schedule main sign: infection) Women: Cortisol 2 to 4x 1.��-çhQJ!<�.fQr.: (Hydrocortisone) 15-40 mg/day 1.5 to 3 x per day • Fatigue (Cortef®, the (mainly • Low stress Men: Hydrocortisone®) 20-60 mg/day morning normal resistance dose and 1.25 x the Cortisone midday) 2nd choice acetate cortisol dose 3 • lnflammatory Predniso(lo)ne2' 2.5-7.5 mg/day 1x/day (Prednicort®) diseases W' choice) 1.5 to 3 x • lnflammatory dis. the Methyl1.��-Ç-�Q)!<�.fQr: normal prednisolone 2-6 mg/day 1x/day • Art. hypertension dose • (Medro1®}3 Frequent edema, • Obesity • MethylRheumatoid 40 or 100 mg 1x per prednisolone crisis, allergy /day season (Solu-medrol®) prevention prednisolone

(Solu-medrol®) Dexamethasone Dexamethasone

40 or 100 mg

-

1x/day

0.15-0.35

-

1x/day

5-10 mg/day

-

1x

50-400 119/day

-

mg/day

Buclesonide

(Pulmicort, Rhinocort®)

1-2 x/day

Value

High

Med Med

Med

Low

•

Allergy crisis

Low

•

Low

•

Hirsutism dueto adrenalandrogens Surgery

Low

•

Asthma, Hayfever

Low

•

Notes: " IM " means intramuscular, " IV » intravenous. 1 The recommended dosage for patients with a total absence of endogenous cortisol production (after surgical remova/ of the adrena/ glands for examp/e) is approximately for women 40 mglday and for men 60 mg/day. 2 Methylpredniso/one and dexamethasone are poor salt retainers (present a low risk of swelling) prednisone and prednisolone are intermediate salt retainers, while hydrocortisone has the best sa/t retaining ability; on the contrary, the synthetic derivatives such as methylprednisolone and dexamethasone have better anti-inflammatory action than bioidentical hydrocortisone. 3 Prednisone is the precursor that converts into prednisolone for activity.

192

Which Glucocorticoid Medication is the best? Which glucocorticoid medication is the best for a patient to take for the rest of his life? Hydrocortisone, the bioidentical hormone, covers most cases of cortisol deficiency and is the best for most life-long treatments. Synthetic derivatives work better as a temporary treatment for acute inflammatory diseases such as infections or allergies, or as a prolonged therapy for chronic inflammations such as rheumatoid arthritis or chronic colitis.

In cases where a synthetic derivative is indicated, the tactic is to start with a synthetic derivative during the first six months and once the inflammatory disease is well under contrai, switch over to bioidentical hydrocortisone. The usual medications for treatment of cortisol deficiency in recommended arder of use are presented in the following table. lndication: Cortisol Deficiency

Medication

with as main problem(s): •

Hydrocortisone

• •

•

Prednisone, Prednisolone1

Low energy or mood, fatigue, low resistance to stress, etc. Low blood pressure

Strong points •

Bioidentical hormone, fully adapted to the human body.

•

More efficient for energy, mood and blood pressure (high saltretaining capacity)

Most cortisol-deficient states Acute or chronic inflammatory or infectious diseases: flu, rheumatoid arthritis, allergies, etc.)

•

·

•

•

•

Methylprednisolone

• •

•

Dexamethasone

2

•

Fluid retention Hypertension Obesity

Hirsutism (excess body hair) caused by excessive leveis of androgens from adrenal gland origin

•

•

More efficient against inflammation (including infection) lntermediate salt-retainer and thus has blood pressure increasing capacity More efficient against inflammation (including infection) Does generally not retain salt and fluid at smaller (physiological) doses, nor cause weight gain (except if the diet is rich in sweets, grains and milk products: see dietary recommendations below) Provides the longest (48-hour) action ls the best drug to block the overproduction of androgens by the adrenal glands

Notes: 1

2

Prednísone must convert ínto predníso/one in the body to become fully actíve. When usíng dexamethasone, we strongly recommend to regularly check the androgen {17-ketosteroíds) and glucocortícoíd {17-hydroxysteroíds) metabolítes before and duríng treatment in the 24-hour urine. For further explanation, reler to lhe Follow-Up section that follows.

193

How to begin Cortisol Therapy In most cases, cortisol can be started at the estimated dose. The minimal efficient dose in women is usually 15-20 mg per day. In men, it is about 30 mg per day divided in at least two separate doses: one given in the morning and one at noon. The recommended dosing for cortisol is shown in the following table: How to start Glucocorticoid Medication? Patient

(sex)

Men

Women

Cortisol

Product

Deficiency

Borderline Mild Moderate Severe to total Borderline Mild Moderate Borderline Mild Moderate Borderline Mild Moderate Severe to total Borderline Mild Moderate Borderline Mild Moderate Hirsutism

When to take the medication? 7-SAM

Hydrocortisone Hydrocortisone

Hydrocortisone Predniso(lo)ne Predniso(lo)ne

Predniso(lo)ne Methylprednisolone Methylprednisolone Methylprednisolone Hydrocortisone Hydrocortisone

Hydrocortisone Predniso(lo)ne Predniso(lo)ne

Predniso(lo)ne Methylprednisolone Methylprednisolone Methylprednisolone Dexamethasone

15 mg 20 mg 25 mg 30 mg 2.5 mg 5 mg

6-7.5 mg 2 mg 4 mg 6-8 mg 10 mg 10 mg 15mg 20 mg 2.5 mg 5 mg 7.5 mg 2 mg 4 mg 6-8 mg

0.1-0.5

12 PM

4PM

5 mg 10 mg 10 mg (5 mg) 10 mg (10 mg)

Before bed -

(5 mg)

-

-

-

-

-

-

-

5 mg 10 mg 10 mg 10 mg

(5 mg) 5 mg

5 mg

-

-

-

-

-

-

-

-

-

-

-

-

-

mg

lmportant remarks: Sensitivity to hydrocortisone: Persons who tend to be sensitive to medication should start hydrocortisone at half of the estimated dose for two to three weeks. lf case no signs of intolerance such as fluid retention occurs, then the dose may be slowly increased by 20 % every two to three weeks up to the optimal dose.

Obesity, swelling:

Persons with obesity generally do better on methylprednisolone (Medro!®), which at 4 mg does edema and weight gain. However, if edema and weight gain occurs, it is wise to start at 2 mg per day and then increase slowly to 4 to possibly 6 mg per day. not usually cause

194

How to prevent adverse affects of Cortisol 11 Add anabolic hormones such as DHEA Excessive catabolism (with osteoporosis, skin thinning, etc.) is the main adverse effect to tear from cortisol treatment.

Adverse effects of cortisol treatment appear at excessive doses or

when the leveis of anabolic hormones are low. Concurrent treatment with anabolic hormones such as DHEA prevents the tissue wasting as shown in animal studies in many tissues from the brain to the heart, liver, bone and muscles.

We strongly recommend to correct any anabolic

deficiency at the same time as the cortisol treatment. Our most frequent association is DHEA with cortisol, thus mimicking the healthy body's normal reaction to stress consisting of increased secretions of both hormones in relatively equal amounts.

21 Eat protein lncreased protein intake may prevent the tissue wasting of excessive glucocorticoid treatment as shown in animal studies.

lndications The main indication for cortisol treatment is cortisol deficiency. Other indications: Cortisol and many glucocorticoids derived from cortisol are used with in various other indications from allergies, asthma, to rheumatoid arthritis, gastrointestinal tract inflammations, systemic infections, chronic sinusitis, and many other inflammatory diseases. For acute illnesses, glucocorticoids are used temporarily, but when the condition becomes chronic, it can require long-term glucocorticoid treatment. success

Contraindications to Glucocorticoid Treatment There are two fundamental contraindications to cortisol supplementation: when it is not necessary or when it could cause harm. First, cortisol treatment is not needed when lab tests are normal and the person is healthy. In that case, cortisol treatment will generally not help and may, on the contrary, cause harm. Second, cortisol treatment- even appropriate replacement doses of cortisol-may cause harm if the patient does not have sufficient leveis of anabolic hormones such as DHEA and sex hormones to counter cortisol's catabolic effects. The catabolic effects of cortisol can cause excessive breakdown of the tissues of the body which result in osteoporosis (loss of bone tissue), skin atrophy

(thinning), ecchymosis, petechia (bruising) and immunosuppression

(decrease in immune defenses). So the recommendation is to treat only when necessary and to do it safely with the smallest effective physiologic doses and with simultaneous correction of any deficit in anabolic hormones.

195

How to boost Cortisol Activity and Treatment There are many ways to naturally boost the daytime cortisol leveis and reduce the night-time cortisol levels. First of ali, improving the lifestyle, including the diet, helps to increase the cortisol leveis. The principal lifestyle changes that boost the effects of the cortisol produced by the body or supplied by treatment are summarized in the following table: How to optimize Cortisol activity and treatment What To Do •

Light

What To Avoid

lncrease exposure to sunlight or bright artificial light, esp. in

•

the morning1 • •

Diet

•

Foods to choose: Eat small frequent meals

• •

2

Follow a "Paleolithic" diet: fruits, vegetables, fish, eggs, poultry meat

Avoid living and working in semi-darkness during the day

•

Avoid alcohol, vinegar, caffeinated drinks

4

Avoid sugar, sweets, soft drinks, cookies, 5 bread, pastas and cereals Avoid cereal fiber (whole grain bread, bran flakes)

•

Avoid milk products

•

Avoid excessive chronic stress, including

Stress

strenuous physical activities, especially in 6 the evening or at night

Notes: 1

lncreased exposure to sunlight, especially in the morning, and maximized darkness at night, by s/eeping with an eye mask for example, which he/ps having optimal cortiso/ levels during the day and

2 3

4

minimal cortisol at night. At each mea/ b/ood leveis of cortiso/ temporarily triple. Dietary saturated fat is necessary for the production of cortiso/ as saturated fat cholesterol is the first building block for cortisol synthesis Beverages with caffeine (coffee, tea, and cola) and alcohol should be avoided before bedtime as caffeine can increase cortiso/ and considerably reduce night-time secretion of melatonin, a hormone

5 6

that tends to reduce any cortisol production at night. Dietary starch and especial/y sugar and sweets increase the blood sugar leve/, which in turn reduces cortisol production. Excessive prolonged stress exhausts the adrenal g/ands that finally become unable to produce adequate amounts of cortisol anymore (burn-out syndrome). Evening or night-time stress is a strong stimulator of cortiso/ secretion, but depletes the adrenal supply of cortisol, resulting in decreased cortisol leve/s for the next morning at a time when the serum leve/ of cortisol shou/d be high.

196

Second, cortisol production can be enhanced by correcting any other hormone deficiencies that influence the working of the adrenal glands. The principal hormone replacement therapies that can increase or decrease the secretion of cortisol and/or its action are listed in the following table. lnfluence of Hormone replacement therapies on Cortisol

•

Strong Stimulator

Mild

Strong inhibitor

Mild

of cortisol

stimulators

of cortisol

lnhibitors

Testosterone

•

Dihydrotestosterone

•

Anabolic (androgen) steroids

•

Vasopressin

•

Thyroid

•

Growth hormone

hormone

•

Hyperthyroidism

•

Parathyroid

•

Melatonin excess

•

•

•

hormone

Oral estrogens (including the birth contrai pill) DHEA Fludrocortisone, Aldosterone

Progress of Hydrocortisone/Giucocorticoid Treatment How much time does it take to improve? Cortisol supplementation provides one of the quickest improvements of ali the hormone therapies. The higher the dose, the quicker the short-term benefit.

Nevertheless, we

recommend using small physiological doses for most cortisol deficiencies that are not life­ threatening. Patients on cortisol therapy may improve during the first days of intake, but complete recovery from physical signs and complaints of cortisol deficiency takes more time. With patients who are less responsive, optimal results may take as much as two to three months. A lack of responsiveness most often has to do with a poor diet {high in sweets for example). Therefore, the patient should be encouraged to improve his diet as a way of accelerating progress.

Follow-Up of Hydrocortisone/Giucocorticoid Treatment What do you do next, once the treatment has started? 1. Find the optimal dose

Fine-tuning the cortisol dose means finding the optimal dose for the patient and not a dose that is slightly too low (suboptimal) or too high (supraoptimal). This process is primarily achieved by carefully checking physical signs and complaints, and much less by relying on lab tests. The optimal dose is the dose that relieves the patient completely from the complaints of cortisol deficiency without causing any signs of cortisol excess. Dosing lab tests may help to some degree to avoid severe over- or underdosing, but are less helpful for the fine-tuning.

197

The optimal dose may vary following changes in the needs for cortisol. The most frequent conditions that may require a permanent or occasional dose adjustment in a patient under treatment, are reviewed in the following table.

When to adapt the dose of Hydrocortisone or (Methyl)prednis(ol)one Dose

INCREASE the dose

LOWER the dose

{50 to 200 "'o more)

{25 to 50% less) Excessive cortisol effects (swollen moon-like face, agitation, etc.) Excessive amounts of 17-hydroxysteroids (cortisol metabolites > 40 "'o higher than upper reference value) in 24-hour urine {done in sedentary conditions) with bioidentical hydrocortisone therapy

•

lnsufficient cortisol effects

•

Low to average cortisol metabolites {17-hydroxysteroids) in 24-hour urine with bioidentical cortisol supplementation

•

Growth hormone treatment (creates often a need for more cortisol) Unstable Type 1 diabetes {that responds to insulin therapy with unpredictable and very variable serum glucose and insulin leveis, and ups and downs of effects}_ Melatonin treatment (only certain cases) or excess DHEA treatment (rarely) Fludrocortisone or aldosterone treatment (rarely) Hyperthyroidism Diarrhea lncreased physical activity lntensive stress Surgical operation lnfections (flu, mononucleosis infection, etc.) Allergies (asthma, ear-nose- throat infections, skin rashes, etc.) Crisis of rheumatoid arthritis

•

•

Chronic

conditions

•

Acute to Chronic

conditions •

• •

• • • •

Occasional

•

Conditions

•

•

•

198

•

Testosterone, dihydrotestosterone or other male hormone treatment

•

Hypothyroidism (only some cases) Adult qrowth hormone deficiency Decrease in physical activities (sedentary, bedridden)

• •

•

Unstressed conditions, vacations

2. Perform lab tests Lab tests may also assist in the proper adjustment of the cortisol dose but are secondary to clinicai observation. When is the best time to perform lab tests? Blood tests (free and total cortisol) should be done in the early morning before any intake of cortisol.

High leveis are indicativa of overdose.

Extremely low leveis are indicativa of

excessiva inhibition of the cortisol internally produced by the patient under glucocorticoid therapy. Urine tests should be collected for 24 hours during which the patient should remain calm and sedentary. What are the recommended tests for follow-up? Lab tests are not nearly as helpful for follow-up of cortisol treatment as patient signs and complaints; however, the tests presented in the following table may be of use: RECOMMENDED LAB TESTS FOR FOLLOW-UP

MEDICATION BIOIDENTICAL:

(ii

o

Blood •

Cortisol total and free

•

CBG (transcortin)

Urine (24-hour) •

Hydrocortisone

When? Take blood sample 9-24

When? Col/ect urine under

(Cortef®,

hours after hydrocortisone intake.

treatment but under strict calm,

Why? The tests help (half

sedentary conditions.

Hydrocortone®)

satisfactorily) to check for any

Why? The test helps (half

overdose or extreme suppression of

satisfactorily) to check if the dose is

endogenous cortiso/ production.

SYNTHETIC DERIV ATIVES:

"ê

o

Predniso(lo)ne (Prednicort®), ...) Methylprednisolone (Medro!®), ...

"ê

Dexamethasone

o

for hirsutism

IV,

lnjection Methyl-

IM

( 17 -hydroxysteroids)

prednisolone (Solu-medrol®)

insufficient or excessive.

•

Cortisol total and free, CBG

•

•

DHEA sulfate,

•

Cortisol and DHEA 17-ketosteroids (metabolites

of adrenal androgensf

androstenedione, androstanediol glucuronide When? Take blood sample 9-24 hours after hydrocortisone intake.

Why? The tests he/p to check for any excessive or insufficient suppression of both adrenal androgen and cortiso/ production and then to accordingly adapt the dose.

•

17 -hydroxy-steroids

(metabolites of cortisoif When? Take blood sample 9-24 hours after corticosteroid intake.

Why? The tests help we/1 to check for any excessive or insufficient suppression of both adrenal androgen and cortiso/ production.

(No valid test) Note: lab tests are of little value for injectable glucosteroids as their use is usual/v short-term and occasional.

Notes: " IM " means intramuscular, " iV » intravenous; · These urinary tests shou/d regularly be dane when dexamethasone is taken as the treatment for body hair overgrowth; they allow to evaluate the endogenous production of cortiso/ and DHEA and their metabolites under the glucocorticoid treatment in arder to avoid severe suppression (reflected by very low values of these hormones in urine). The urinary leveis of the hormones and metabolites should become borderline /ow but not drop to zero, otherwise the dose of dexamethasone shou/d be reduced by 25% at least.

199

3. Avoid over- and underdosing: Over- and underdosing can be avoided primarily by checking for signs and complaints of

cortisol over- or underdosage. The physician should inform his patient about the treatment, including on how to check for signs of cortisol excess or deficiency and what to do in case of adverse events. The patient's expertise greatly helps to avoid adverse events. The physician should regularly check the patient every two to nine months to monitor progress. Longer periods are acceptable for long term patients who are well-balanced and have know-how of the treatment. The principal signs and symptoms of cortisol excess are presented in the table below. Latency (time before first appearance)

Cortisol Overdose signs •

Several hours to several days

Severa! hours - days Severa! days to

Overly emotional, excessive agitation

•

Euphoric

•

lnsensitive to human suffering

•

Craves stress and creates it, stressing others but not oneself

•

lnsomnia

•

Cardiac erethism (heart poundinQ in chest)

•

Swollen hands and feet

more than a week

•

Swollen face High blood pressure

Severa! weeks

•

Weight gain, obesity

•

Ecchymosis (easy bruises)

•

Petechiae (tiny skin hemorrhaÇJes)

•

Atrophic skin

•

Osteoporosis

to severa! months Severa! months

Mental Emotional

Physical

(Cushing syndrome)

What do you do in the case of an urgent and stressful cortisol overdose?

Reduce the dose but do not stop completely, except for a synthetic derivative such as dexamethasone, which is longacting, remaining active for 48-hours in the body.

4. Solve problems quickly

Read the following section on problem solving for more information.

200

111. Cortisol PROBLEM SOLVER

How to solve problems during cortisol treatment? In general, only the small, safe physiological doses should be utilized. Respecting these principies will help the physician avoid problems for his patients. The most frequent problems during cortisol treatment are discussed in the following tables. Problems related to excessive doses of the glucocorticoid medication: Problems related to cortisol/glucocorticoid overdosing: Table 1 OVERDOSE SIGNS

SOLUTION

POSSIBLE CAUSES •

Excess salty food intake

=>

boosts the fluid retaining effects of cortisol •

•

Salt-retaining hydrocortisone

•

Reduce salty food intake

•

Switch over to methylprednisolone

or predniso{lo)ne treatment at physíologica/ doses in sensitive

Swollen hands and feet

persons

=>

excess salt and

(Medrol®) that retains much less fluid •

fluid retention •

Glucocorticoid treatment overdose

=>

•

Swollen face

glucocorticoid used

increased salt

and fluid retention 1.

=>

edema

Wrong food intake combined with excessive salt retentíon by

•

drinks and alcohol that combined

Full moon-like face during the

with cortisol therapy produce

day, increased in the evening

swelling. Switch over to

indicates an excessive dose of •

obesity

methylprednisolone (Medrol®)that

cortisol

Weight gain, 3.

retains much less fluid. Lower the

Puffy face in the morning

dose of cortisol by

indicates a thyroid deficíency

thyroid hormone treatment

the conversion of T4 to T3)

pressure

Glucocorticoid overdose

=>

increases salt and fluid retention

•

Lower the dose of hydrocortisone

•

Switch to methylprednisolone (Medrol®) that retains much less fluid

201

20 to - 60%

problem lncrease the dose of

intake (cortisol partially blocks

High blood

-

depending on the intensity of the

that is worsened by cortisol

•

Avoid eating sugar, sweets, and milk products, and drinking soft

the glucocorticoid 2.

Lower the dose of the hydrocortisone or any other

Problems related to excessive doses of the glucocorticoid medication: Problems related to cortisol/glucocorticoid overdosing: Table 2 OVERDOSE SIGNS •

Overly agitated

stressing others but not oneself, insensitive to human suffering

•

Difficulties to fali

Excessive doses of cortisol cause tissue wasting (atrophy) if they are not well antagonized by comparative amounts of DHEA and other anabolic hormones. These adverse events are more common with synthetic derivatives.

Easy bruising

(ecchymoses petechiae) •

Atrophic skin Overdose Signs

•

-

Cortisol increases the number of dopamine receptors, increasing the activity of this 'wakes you up' neurotransmittor.

asleep, heart pounding in chest, insomnia

•

SOLUTION POSSIBLE CAUSES Cortisol overdose => increases blood sugar=> • Lower the dose of cortisol by 2 0 to increases the sugar -60 % depending on the intensity availability and energy for of the problem the brain, nerves, muscles and heart.

Osteoporosis

• •

•

•

•

•

Lower the dose of hydrocortisone Take the last dose no later than 1 PM lf difficulties to fali asleep persist, take cortisol only once in early morning Always combine DHEA or other anabolic hormones (sex hormones, growth hormone, etc.) with any gluco-corticoid therapy and if needed, increase the dose of these anabolic hormones lncrease protein intake (meat, fish, etc.) that opposes tissue wasting Lower the dose of cortisol or its

synthetic derivative by 30% or more

Problems of inefficacy of the treatment: Problems of inefficacy of the cortisol treatment OVERDOSE SIGNS •

POSSIBLE CAUSES

Correct the diet:

effects of

.

cortisol therapy

The most likely cause for the absence of cortisol effects, but appearance of inconvenient side effects is a wrong food intake.

in a clearly cortisol deficient patient, but some side effects (swelling, weight gain, bruising) •

SOLUTION

No beneficiai

lnconsistent and

•

variable effects of cortisol therapy (including

stressful ups and downs of mood and energy)

•

Foods such as sweets cause high peaks of blood sugar, which temporarily inhibit the body's cortisol production.

.

.

•

Eat more protein such as meat, poultry, fish Choose acceptable starches such as fruits and vegetables. Avoid sugars, sweets, soft drinks, alcohol, cereais, and milk products. Avoid sugar, sweets, sott drinks, alcohol, milk products

•

Switch over to a synthetic

Short-lived effect (4-8 hours) of

derivative that has a

hydrocortisone, which's natural structure allows an easier and quicker consumption by the tissues.

stable 24-hour effect such as prednisolone or methylprednisolone

202

Problems of treatment intolerance :

Problems of intolerance of the cortisol treatment

PROBLEM

POSSIBLE CAUSES

SOLUTION •

•

Stomach burning, gastritis, worsening of digestive troubles

•

Vertigo, low blood pressure, tendency to lie down

Erosion of stomach mucosa by the catabolic and anti-inflammatory action of cortisol, and by the acidic properties of the acetate ligand with which the cortisol is usually bound. Occurs easier in individuais with recurrent gastroenteritis and colitis The lower blood pressure is caused by a decrease in healthy salt- and water retaining (mineral corticoid) activity in the body, caused by: • A drop in aldosterone production after intake of cortisol or one of its synthetic derivativas that inhibit the production of ACTH, an important stimulator of aldosterone secretion. •

•

• •

•

Partia! replacement of the body's own adequate salt-retaining cortisol by a poorly salt retaining synthetic derivativa of cortisol such as Medro!® or dexamethasone

Take hydrocortisone or (methyl)predniso(lo)ne supplement just after the meal (breakfast, lunch) Take an enteric coated preparation that protects the stomach against the acidic hydrocortisone or glucocorticoid preparation Take fludrocortisone Reduce the dose of synthetic glucocorticoids or hydrocortisone Switch over from a synthetic derivativa of cortisol to hydrocortisone -- the glucocorticoid with maximal salt- and fluid-retaining activity (in case of inflammatory disease and moderately low blood pressure problems, switch over to predniso(lo)ne)

Problems of product choice or treatment doses with lnflammatory conditions: Problems of chosing the adequate glucocorticoid medication for lnflammatory diseases

PROBLEM

•

lnflammatory disease such as rheumatism, flu, asthma, allergies, Crohn's disease, ulcerative colitis

POSSIBLE CAUSE lnflammatory diseases are continuous 24-hour processes needing a continuous glucocorticoid treatment: Natural glucocorticoids such as hydrocortisone and cortisone have a too short action so that even when they are taken in divided doses during the day, they do not have the same optimal anti-inflammatory action as synthetic derivativesNatural glucocorticoids have less antiinflammatory potency than synthetic derivativas.

203

SOLUTION Switch over to synthetic derivativas of cortisol, which have better antiinflammatory action and 24-hour action, which is more useful for inflammatory diseases. The switch may be temporary, e.g. 1-3 days, in cases of acute inflammatory diseases of short duration such as the flu or an asthma attack

Problems of product choice or treatment doses with lnflammatory conditions:

Problems of product choice, dosage or hormone balance with lnflammatory diseases PROBLEM

POSSIBLE CAUSES

SOLUTION Take guick action to treat acute infections or allergies:

Cortisol deficiency •

Flu, pharyngitis, otitis

•

weakens the immune

In the first five hours of the first signs of infection or allergy, increase

defenses and allows

the cortisol dose by 50% more up to

inflammation and

two to three times the normal daily

infections to develop.

dose for 1-7 days maximum, depending on the intensity of the inflammation. When the increase in dose is begun later than the first five hours, efficacy considerably decreases. •

•

Temporarily, for one or more days,

Cortisol deficiency

switch over to synthetic derivativas

leaves the body prone

such as prednisone and methyl-

to inflammation which

prednisone as they often work better

Allergies (ear-

may increase the

than natural hydrocortisone in these

nose-throat), skin

sensitivity to various

cases, providing a longer and more

rashes, asthma

triggers of allergic reactions and thereby

stable 24-hour beneficiai action •

lncrease the dose of DHEA

facilitate allergic

proportionately to the increase in

reactions

cortisol, this adaptation will further boost the immune defenses and block adverse effects of higher cortisol dosaqes

•

Persistent viral and bacterial infection aggravated by yeast infection although higher doses of glucocorticoids are given for more than two weeks

Taking cortisol at higher

•

Lower the intake of cortisol possibly

•

lncrease intake of DHEA and possibly

back to the routine daily dose

doses than normally necessary for longer than one week, without

of other anabolic hormones to oppose

a proportional increase

the immune suppression of high

in DHEA, depresses the immune system by

cortisol •

Eat protein (meat, poultry, fish) to

reducing weight and

provide enough amino acids to bolster

activity of the thymus.

thymus activity

204

Chapter eleven

DHEA and

Androstenedione Deficiencies

and

Treatment

A Case Study of a Patient with DHEA Deficiency Lise and her lack of axillary and pubic hair

Use, 48 years old, suffered from a rheumatic disorder, which worsened over the years.

She

took cortisone or prednisolone, a synthetic derivative of cortisone, that had given some relief. But over the years the cortisone seemed to help her less and less. Her joint pain flared up again and fingers became deformed.

A DEXA scan (Duai-Energy X-ray Absorptiometry),

osteodensitometry, showed bone loss compared to others of her age. thinning and her muscles seemed to be wasting away.

or

Her skin was also

She also had a diffuse, widespread

pattern of armpit and pubic hair loss. At the same time, Use found her sex drive considerably decreased. She noted fatigue combined with mild anxiety and depression. What was Lise suffering from? Many of Use's problems are typical of a deficiency in adrenal androgens, mainly in DHEA and androstenedione. lt is likely that the prednisolone treatment given without the addition of DHEA or another androgen greatly accelerated the normal, but unhealthy age-related decline in DHEA and androstenedione.

In order to better understand

what this deficiency means and what can be done about it, let's review some basic information about DHEA and androstenedione.

205

DHEA and Androstenedione: Basic lnformation

DHEA converts into many hormones

Most actions of DHEA are achieved after conversion into more potent hormones such as male and female sex hormones, including androstenedione.

These conversions take place mainly

inside target cells and not in the blood. As DHEA converts into testosterone inside of the cells and is almost immediately metabolized in situ (locally), it is not a very effective way to increase the blood leveis of testosterone in men which will generally not increase more than a few percent.

However,

DHEA does elevate the blood levei

of

androstanediol glucuronide

considerably more. Androstanediol glucuronide is the most abundant metabolite of the male androgen hormones. lt is the proof that DHEA has been metabolized into testosterone, which metabolized into DHT, which in turn metabolized into androstanediol glucuronide. lts presence in blood reflects the degree of male hormone activity.

A high levei of it signifies that a

significant amount of DHEA or testosterone is converted to dihydrotestosterone (DHT) inside target cells.

DHEA and androstenedione

Many of the effects of DHEA and androstenedione are similar.

In this chapter we mainly

discuss DHEA deficiency and treatment, but much of the information on DHEA is valid for androstenedione as well.

Roles of DHEA and androstenedione DHEA has two types of actions: Firstly, DHEA's main actions are through conversion into more potent hormones. Through these other hormones DHEA expresses typical male and female hormone activity, as well as enhances the immune system. One of the ways it reinforces immunity is by converting into the very immune-enhancing androstenediol and androstenetriol. Secondly, DHEA appears to have actions of its own probably through DHEA receptors in target cells, in particular endothelium cells of blood vessels and immune cells as suggested in severa! studies. lt is believed that DHEA boosts the immune system and protects blood vessels against atherosclerosis partially by binding to these receptors.

206

Production DHEA and androstenedione DHEA: Daily secretion approximates 30 mg per day in young men under sedentary conditions. Strenuous physical activities and stressful situations considerably increase DHEA secretion in young adult males. Women produce a third less, about 20 mg per day under sedentary conditions. Almost ali DHEA is produced by the adrenal glands in the zona reticularis, the inner layer of the adrenal cortex (outer part of the adrenal gland). Production is stimulated by the pituitary hormone ACTH (Adrenocorticotropin) and only mildly controlled through a feedback loop by the effect of the DHEA leveis on the pituitary. ACTH secretion is much more influenced by cortisol than by DHEA blood leveis. Androstenedione: Adrenals secrete about 1.5 mg a day in healthy young men and women.

Women produce

more as the avaries produce another 1.5 to 2 mg a day.

What factors can change DHEA production? lntense emotional stress may increase DHEA by increased secretion of ACTH (which increases secretion of ali adrenal cortex hormones). Foods high in protein or saturated fat increase DHEA production, but a diet rich in sugar and sweets, and cereais rich in fiber, such as whole grain bread, and bran flakes, reduces DHEA leveis.

DHEA sulfate in blood In the blood, two leveis of DHEA may be measured: DHEA (without sulfate) and DHEA sulfate (DHEA bound to a sulfate). The levei of DHEA sulfate is 500 times higher than that of DHEA and its leveis are much more stable in the blood; therefore, it is this levei that matters the most.

Does DHEA decrease with age? The levei of DHEA sulfate quickly declines with age: there is a 1-5% reduction per year in adults after age 30. At age 70-80, DHEA leveis have dropped to a mere 15-20% of leveis of 20 to 30 year-olds.

Principal metabolites: •

Male

hormones

(androgens)

such

as

androstenedione,

testosterone,

DHT

(dihydrotestosterone), and androstanediol glucuronide (generally checked in plasma); androsterone, etiocholanolone and 17-keto-steroids (usually measured in a 24-hour urine) •

Female hormones; estrogens, such as estradiol, estrone

•

Other metabolites: androstenediol and androstenetriol

207

I. DHEA and Androstenedione* Deficiencies: DIAGNOSIS *For the sake of brevity, most of the time the term "DHEA" is used in this chapter. lt is intended to mean "DHEA and androstenedione".

How do you detect DHEA deficiency? DHEA deficiencies are detected by the collecting of information from the past medicai history, signs, complaints, concurrent diseases, and lab tests.

1. The Onset of DHEA deficiency When did the DHEA deficiency start? lt is possible to know if a patient has puberty-onset or adult-onset DHEA deficiency by closely examining the armpit and pubic hair.

Below average

hair development in those areas is often the best sign of long-term DHEA deficiency, a deficiency existing since early puberty. In early puberty, the first hormone to increase in the blood is DHEA. At that time, axillary and pubic hair starts to grow. From age 30 onward, leveis of DHEA and those of growth hormone are the first to start declining. At that time too, axillary and pubic hair starts falling out. Moreover, individuais with low DHEA production beginning in early puberty often have some degree of life-long global adrenal cortex deficiency with typical signs and complaints such as allergies, thin body, inflammation, poor response to stress, etc. Checking for the presence or absence of symptoms of other hormone deficiencies of the adrenal cortex may help to distinguish between early and late-onset DHEA deficiency. The main differences between puberty and adulthood developed DHEA deficiencies are reviewed in the table below. Determining the Onset of DHEA Deficiency (Untreated) Onset

At Early Puberty

Axillary hair

In Adulthood

Sexually immature: •

Skin area occupied by hair:

Sexually mature: •

pattern, limited to one of the

Pubic hair

early puberty stages •

Skin area occupied by hair: large, adult grown hair

small or non- existent hair

pattern •

Density: diffuse thinning and loss

Often normal hair density

Signs & complaints

Other signs and complaints are often

No particular signs nor

of deficiencies in

found

complaints

other adrenal

•

hormones (cortisol, aldosterone, etc.)

•

Thin face and body, low weight,

•

Normal weight

etc.

•

Normal physical

Asthma, allergies, anorexia, low

appearance

blood pressure, etc. To fully understand how DHEA deficiency affects the body, it is important to know more about when and where complaints and signs of DHEA deficiency are observed.

208

2. Timing and Location When and where do DHEA signs and complaints occur? Typically, they occur more or less permanently through lhe day. In women, lhe signs may mildly increase with physical activity (when muscles are used) and can concern most body tissues, although with some predominance in axillary and pubic areas. With this basic knowledge, we can now further interview to check if s/he presents complaints and physical signs that may be related to DHEA deficiency.

3. Physical Signs and Complaints of DHEA deficiency What are lhe physical signs and complaints of DHEA deficiency? The intensity of signs and complaints of DHEA deficiency are moderate compared to those found in deficiencies of sex hormones (estrogen, testosterone), but they can impair health enough to justify DHEA treatment. These signs and complaints have been collected by reviewing scientific studies and interviewing physicians working with DHEA and androstenedione. DHEA (and Androstenedione) Deficiency Complaints Energy Mood Stress Sex (men) Sex (women)

•

Moderate fatigue

•

Depression

•

Moderate anxiety

Physical Signs

•

Low resistance to noise, stress

•

Low sexual desire

•

Decreased erections

•

Low sexual desire

•

Lack of sexual satisfaction

Eyes

•

Dry eyes

Skin

•

Dry skin

Muscles

•

Poor muscle development

Axilla

•

Reduced or loss of axillary hair

Pu bis

•

Reduced or loss of pubic hair

•

Reduced pubic fat (women)

After this check, it is important to look now for other diseases that may develop more easily with a DHEA deficiency.

4. Disease Susceptibility What disease conditions may develop as long-term consequences of DHEA deficiency? Scientific data based on animais and human studies support lhe possibility that DHEA deficiency may increase lhe frequency and severity of lhe following diseases or that DHEA treatment could reverse their development at least partially: cardiovascular diseases, hypertension, high cholesterol, osteoporosis, diabetes, Alzheimer's disease, depression, etc. After this check it is essential to require laboratory tests.

209

5. Laboratory Tests for DHEA and Androstenedione What are the best lab tests to dia9nose DHEA deficiency? The best blood test to evaluate daily DHEA production is DHEA sulfate which is by far the most important form of DHEA found in the blood. To evaluate DHEA's metabolic activity the measurement in the blood of androstanediol glucuronide, DHEA's major metabolite in the blood (it is also the main metabolic byproduct of the male hormones), and in the urine of the 17ketosteroids, the major urinary metabolites of DHEA, are the best tests. In women, the evaluation of the urinary 17-ketosteroids is particularly helpful as women derive almost ali of their 17-ketosteroids from DHEA. In men, 50% of the 17-ketosteroids are not derived from DHEA but from testosterone. The leveis of other metabolites such as male and female hormones may be tested for, but are less helpful in detectin9 DHEA deficiency. The blood, 24-urine and saliva tests directly or indirectly related to DHEA and the adrenal andro9ens are listed in the tables below.

Blood (serum) Lab tests for DHEA and other Adrenal Androgens (at 8 a.m.) Test

Optimal Men

DHEA

Women Men

DHEA sulfate (DHEAs) Women

9 7

Pr. Deficient

Reference Range (17-30 y)

0-6

1.8-12.5 n9/ml

0-4

1.3-9.8 n9/ml

400

0-300

200- 61o 119/dl

4000

0-3000

2000-6100 ng/ml

14

0-10

O. 7-21.2 J1moi/L

280

0-200

80-480 119/dl

2800

0-2000

800-6100 nQ/ml)

9.7

0-6.9

2.8-16.6 Jlmoi/L

Test Value

Comments ± 500 x lower levei

Low

Hi9h

than DHEAs; lar9e fluctuations Main blood test; - informs on DHEA production - this levei is stable, varies very little in the blood

Hormone metabolites derived from DHEA Androstenedione

Men

1.3

0-0.9

0.5-1.5 n9/ml

Low

Women

2.5

0-2.0

1.0- 3.5 n9/ml

Low Women

Testosterone Total

See correspondin9 chapters for more information

Estradiol Estrone

Med Low Low

Men Androstanediol glucuronide

15-18

0-13

3.4- 22 n9/ml

50-59

0-43

11-73 nmoi/L

3-3.9

0-2

0.1-6.0 n9/ml

10-23

0-7

0.3-20 nmoi/L

Hi9h Women

210

lntermediate metabolite between DHEA & testo.; may cause hirsutism DHEA intake clearly increases testosterone only in women Major metabolite of dihydrotestosterone - DHEA provides in women >90% and in men 30-50% of the androstanediol 9lucuronide levei

24-hour Urine and Saliva Lab tests for DHEA and other Adrenal Androgens Optimal

Test

Value

Men DHEA

Women

Pr. Deficient

Reference

Test

Range (17-30 y) Value 0-1.0 mg/24h

0.7

0-0.55

2.4

0-1.9

0.45

0-0.35

0-0.65 mg/24h

1.6

0-1.2

0-2.3 J,lmol/24h

0-3.47 J,lmol/24h

Med Med

Comments

Reflects the 24-h

DHEA production

Hormone and metabolítes deríved from DHEA

Men

>: 17..c o.

ketosteroids

� (Total sum)

Ol o

Women Men

êií E

e Androsterone

..c (.)

Women

(/) (I)

.9

0-9

4.7-13.3 mg/24h

38-41

0-30

16 -46J,lmol/24h

7.0

0-5.5

2.9-8.9 mg/24h

23.5

0-19.0

10-30 J,lmol/24h

3.5

0-2.5

0-4.5 mg/24h

12

0-8.5

3.8- 14.1J.imOI/24 h

2.2

0-1.7

O. 7-2.8 mg/24h

7.5

0-5.8

2.4-9.6J,lmol/24h

140

w z

<

120

15-17 Women

0.050.06

17-keto-17hydroxysteroids:

DHEA

2

250 200

<( Hormone deríved from DHEA > :i 250 Men <( Androstenecn dione Women 200

Free

0.40

Men Women

Low1 Med1

0-12

0-180 0-150

of DHEA

(& in men

testosterone)

A potent androgen urinary 17-keto metabolite of

DHEA

testosterone production is more interesting to do in women as more than

3-23 llQ/24h

0-0.042 0.01-0.08 !lmol/24h

Reflects 24h

metabolic activity

This 24h picture of

O. 17-0.70 pmol/24h

on cortisol deficiency and treatment

Women

Testosterone

<

See for more information the section 'Lab tests for cortisol deficiency' in the chapter

Men

High1

Low1 0.5

Free

Med1

50-200 llQ/24h

Men

ã: Testosterone :::::1 ..c o:t N

11-12

90 % of testosterone

Med1

in women comes from DHEA, in men only a small fraction

Low (for

DHEA

check)

Only a small fraction of

DHEA metabolizes to 17-keto -17-hydroxysteroids, which are also metabolites of cortisol

Highly variable

137-336 pg/ml

leveis, less useful than blood and

106-300 pg/ml

urinary leveis highlighted in yellow; salivary DHEA

0-180

151-350 pg/ml

0-150

125-274 pg/ml

sulfated DHEA

0-60

100

30-145 pg/ml

be useful as an

40

0-30

5-50 pg/ml

Low

reflects the free fraction of nonin blood; DHEA may indicator of the DHEA/cortisol ratio

Notes:

1 The difference in appreciation of the value of laboratory tests (''test values") related to DHEA between men and women are explained by the fact that most androgens and androgen metabolites derive from

2

DHEA in women, whereas it is different for men who get them from testosterone. The urinary 17-ketosteroids must imperatively be measured through the much better gas chromatography technique, and not through the outdated and unreliable co/orimetric technique.

211

11. DHEA and Androstenedione Deficiencies: TREATMENT DHEA and Androstenedione Medications The most convenient way to take DHEA is orally as this route provides satisfactory blood leveis of DHEA sulfate for 22 to 24 hours. Theoretically, the transdermal route would be better as it avoids any accumulation of DHEA in the liver which occurs when DHEA is taken orally. However, due to poor skin absorption, very high and expensive doses of DHEA are necessary to match the efficacy of oral DHEA. DHEA and Androstenedione Medications Route

Dose

Product

(sedentary) 1

Women: 5-30mg/day

Oral

Men: 20-55 mglday

DHEA

(physioloÇJic doses) 3-10 mg/day (physiologic doses) Men: 50-300 mg/day (supraphysiologic doses)

Oral

(compounding pharmacies)

deficiency with

timing

predominant...

1XI day

Most DHEA deficiencies •

1x I day

•

•

Sublingual

DHEA

Men:

Women:

DHEA liposomal gel

Transmg/g dermal (compounding pharmacies) lntramusc. l nject.

5-30 mg/day 20-55 mg/day

Women:

2-3 x/ day

Men: 4-8 g/day

1x I day

•

200mg DHEA

with 4 mg estradiol valerate (Gynodian depot®)

200 mg every 3 weeks or per month

ue

Med

1x/ month

Androstenedione

(women) Testosterone (male)

Low

(only excessive doses> 150 mg/day of androstenedione may help)

Quick need for some more DHEA (stress, Med . ); liver disease (subi. .

•

3-6 g/day

150

Vai

Deficiencies of:

Women:

Androstenedione

lndication: DHEA

Dose

partially spares the liver)

Patients with liver disease: Note: poor DHEA absorption through skin => higher doses > 250 mg/day (which are more expensive) may help

Med

For treatment of menopause, if Med necessary associated with a progestogen

Note: 1 Higher doses of +50% to + 100% of the normal dose may be temporarily needed to meet higher needs: intensive sports, sex, diarrhea, cortiso/ intake, etc.

212

How do you begin DHEA treatment? DHEA treatment may be started at the dose that should correct the deficiency. Some caution should be taken with women who have a tendency toward body hair and acne, and persons with severe (untreated) cortisol deficiency as unbalanced DHEA intake may worsen these conditions.

lndications The major indication is DHEA deficiency. Other indications: •

Autoimmune diseases such as lupus and rheumatoid arthritis

•

Cortisol or other glucocorticoid therapy

Most patients on glucocorticoid therapy should, in our experience, add DHEA to their treatment as glucocorticoid treatment creates a DHEA deficiency by reducing ACTH secretion and thereby DHEA production.

In this way, side-effects such as osteoporosis and other tissue

wasting effects of the glucocorticoids may be avoided.

Contraindications: In patients with genital cancers such as breast, prostate and uterine cancers that have disseminated with metastases to other organs, the current recommendation is to avoid giving DHEA because DHEA may convert into sex hormones that in some studies have been shown to accelerate the development of certain genital cancers. In reality, further studies are needed to substantiate this recommendation, as the grounds for it are quite small and tenuous. lt is possible and likely that DHEA may act as an anti-cancer agent of moderate potency in various human cancers by stimulating the immune system as shown in many animal experiments and as suggested in observational studies where patients with certain cancers were found to have significantly lower DHEA leveis (premenopausal women with breast cancer for example). Caution is recommended for subjects with hirsutism or acne as DHEA treatment may cause body hair growth and acne. Avoidance or trials with lower doses of DHEA and androstenedione may be the best approach.

213

Progress Progress with DHEA treatment is slow to come, very slow.

Most patients report the first

improvements after 3 to 4 months of therapy. Others only after six months! Six months are necessary to obtain the full effects from DHEA therapy.

An estimated 30-50% of the patients taking DHEA at small physiological doses do not feel much change with the therapy.

Explanations for this may be that the dose is too low or the

deficiency is so mild that DHEA treatment does not make any noticeable difference.

How to boost DHEA and Androstenedione treatment? The first way to boost DHEA is by optimizing the lifestyle, including eating a better diet.

The principal lifestyle changes that boost the effects of the endogenous DHEA (and androstenedione) and of DHEA supplements are summarized in the following table. For an explanation of these lifestyle suggestions, please read the footnotes under the corresponding table in the chapters on adult growth hormone and testosterone treatment. How to optimize DHEA (and Androstenedione) activity and treatment What?

What to Eat •

Eat enough calories

•

Follow a "Paleolithic"

Diet

What to Avoid • •

Avoid sugar, sweets, soft drinks, cookies, bread, pastas and other cereais

diet: fruits, vegetables, meat, poultry, eggs, fish •

Avoid alcohol, vinegar, caffeinated drinks

Eat organic foods

•

•

Medications

Avoid cereal fiber (whole grain bread, bran flakes) Avoid milk products Avoid usinq birth contrai pills

Secondly, DHEA can be increased by correcting other hormone deficiencies of a patient.

Several hormones can boost DHEA (and androstenedione) production and its effects in the body. Their absence or deficiency will adversely affect DHEA (and androstenedione) activity. The principal hormone replacement therapies that increase or decrease the secretion and/or action of DHEA, are outlined in the following table. Effect of Hormone Replacement Therapies on DHEA (and Androstenedione) Moderate to strong Stimulator

Moderate to strong lnhibitor

of DHEA •

Testosterone

•

DHT

• •

of DHEA •

Anabolic steroids (Androgens) Thvroid hormones

214

Glucocorticoids at high doses

•

Cortisol at low doses

•

Oral estrogens

Follow-up How do you maintain good control over the DHEA and androstenedione treatment? 1. Find the optimal dose:

Monitoring and dose adjustment should be done through both lab tests and clinicai which means a decrease or disappearance of signs of DHEA deficiency without the appearance of signs of excess. The patient should become symptom-free.

observation,

The optimal dose may vary in special circumstances that require a permanent or occasional dose adjustment. The most frequent conditions necessitating an adjustment are outlined in the next table. When to adapt the dose of DHEA and Androstenedione Dose

•

Conditions

• • •

• •

lncrease the dose

Lower the dose

(50 to 100% more)

(25 to 75% less)

lnsufficient DHEA blood leveis and effects lncreased physical activity lntensive stress Cortisol or other glucocorticoid treatment

•

•

• •

Excessive DHEA blood leveis and male hormone effects (acne, body hair, etc.) Decrease in physical activities (Sedentary, bedridden) Unstressed, holidays Testosterone or other male hormone treatment in women

Diarrhea lnfections

2. Avoid overdosing:

Check for physical signs of overdosing Physical Signs of DHEA

Appearance First weeks After one month 1-2 months

6-18 months

Hair

Excessive adrenal Body DHEA production*

Men

Women

Site

Hair Skin Skin Blood Skin

(and Androstenedione) Overdose

• • •

Oily hair Oily skin Acne

• •

• •

•

Acne (rare) lncreased estradiol (rare)

lncreased body hair (rare) Upper scalp hair loss (male pattern baldness:rare) Virilism, menstrual cycle disturbances, android body shape, muscle hypertrophy

Note: *Overactive adrena/ glands may produce chronically elevated DHEA leveis for years, resulting in a virilisation that is not seen with normal DHEA supplementation.

215

The patient should be able to recognize the physical signs of DHEA overdose so that when they appear, s/he can reduce the dose by taking one capsule of DHEA every two days for example instead of one per day, or even temporarily stop DHEA therapy if annoying side­ effects emerge such as hirsutism or hair loss on upper part of the scalp. However, these side­ effects are rarely encountered with DHEA overdose and if they do occur, it is almost exclusively in women as androgen activity in women depends largely upon DHEA while this is not the case for men. One of the reasons for the rarity of these signs is that the excess signs of oily hair/skin and acne appear much earlier and are the signal for the patient to decrease his dose long before the more serious side-effects develop. 3. Perform lab tests:

How do you follow-up with lab tests? lf DHEA is normally taken as an oral medication in the morning, three days before the scheduled blood test have the patient switch to taking the DHEA between 8 and 11 PM. The blood levei of DHEA sulfate that is obtained 9 to 14 hours after DHEA intake corresponds to the mean 24-hour DHEA levei. The following tests are recommended: Recommended Lab Tests For Follow-Up

Medication Oral androstenedione

DHEA sulfate

Oral DHEA Transdermal DHEA

24-Hour Urine

Blood Androstenedione (Do b/ood test 9-12 h after androstenedione intake)

(Do blood test 9-12 hours after DHEA intake) DHEA sulphate

(Do blood test 9-12 h after DHEA app/ication)

lnjectable DHEA

DHEA sulphate

(Do blood test 3 weeks after DHEA injection)

(-)' (-) '

DHEA and 17-ketosteroids DHEA and 17-ketosteroids

·

Note: To correctly evaluate an oral DHEA treatment, no urine test is satisfactory, because during such a treatment abnormally high leveis of DHEA and its 17-ketosteroid metabolites are excreted in the urine that do not reflect an overdose in oral DHEA. The high urinary leveis of 17-ketosteroids are due to a disproportionate breakdown by the liver of the intestinally ingested DHEA into metabolites - the 17-ketosteroids - before passage into the blood. These excessive urinary leveis do not most of the time reflect an overdosage. Furthermore, the high urinary leve/ of DHEA that occurs with an oral DHEA preparation is most of the time due to a loss of DHEA in the urine, not an overdose. How? Once some of the DHEA that is ingested in the intestines has escaped breakdown by the liver and reaches the blood, a transient peak levei of DHEA appears in the blood that overwhelms with DHEA the albumine, the protein that transports DHEA in the blood, exceeding its binding capacity.

Consequently, excessive amounts of 'free'

unbound DHEA appear in the b/ood during severa/ hours. During that time the DHEA-rich blood passes through the kidneys. The kidneys excrete then important amounts of the free DHEA in the urine, a DHEA that is /ost in the urine.

4. Conduct regular cancer screenings: PSA, CEA, CA15.3, mammography (controversial) in women, ultrasound prostate examination in men, etc. Recommend genetic typing for women after menopause to see if they have increased risk of breast cancer. 5. Solve problems quickly and efficiently

For a review of the most frequent problems that may occur during DHEA replacement, please reter to the next section titled "Problem Solver''.

216

111. DHEA PROBLEM SOLVER DHEA is in general well tolerated and presents a high degree of safety. Occasionally, however, there may be problems due to DHEA overdose or an increase in androgens stimulated by DHEA. Problems due to DHEA and Androstenedione Overdose: Table 1 SIGN OF OVERDOSE

SOLUTION

POSSIBLE CAUSES Possible causes in arder of frequency: 1.

•

Normal doses of DHEA in a patient who eats

Oily hair

a lot of carbohydrates (grains, sugar, sweets

(often the first sign

and milk products) that increase insulin and

to appear in case

thereby fat production in lhe sebum glands of

of excess)

lhe skin 2.

Excessive doses of DHEA that provide an overabundance of testosterone, which in

1.

carbohydrates

2.

especially in

Normal doses of DHEA in a woman who

women with

excessively converts DHEA into

smaller breasts

testosterone. Such excessive conversion

and hirsutism

usually is found in women who had severa! •

(signs of

physical signs of higher male hormones

Acne, oily skin

androgen

(more masculine traits such as a more

excess)

muscular appearance, hirsutism) before therapy 4.

Cortisol deficiency that inflames the skin and in particular the sebum Qlands

& 3. Reduce the

dose of DHEA,

excess overstimulates the sebum glands 3.

Avoid excess

4.

Correct any cortisol deficiency

Loss of the estrogen domination of the skin, •

Hirsutism (body hair overgrowth in women)

being replaced by domination of DHT, the potent DHEA metabolite that not only assures sexual sensitivity, but also body hair growth and may cause male pattern baldness. This change happens in women with:

•

Male pattern hair

•

loss (in women)

Low estrogen leveis who receive normal doses of DHEA

•

Normal estrogen leveis who receive excessive doses of DHEA

•

Excessive leveis of DHTand androstanediol glucuronide (women)

•

Normal estrogen leveis and who receive normal doses of DHEA, but have high leveis of the 5-alpha-reductase enzyme, which converts DHEA and other androgens into DHT, and low leveis of aromatase, which converts testosterone to estrogen, the hormone that counters body hair Qrowth

217

1. Correct any

estrogen deficiency in women 2. Provide lower

doses of DHEA, especially in women with hirsutism and smaller breasts

Problems due to DHEA and Androstenedione Overdose: Table 2 SIGN OF OVERDOSE

POSSIBLE CAUSES

SOLUTION

lntake of DHEA by oral route:

Stop DHEA for 4

•

Very high doses of DHEA are taken, •

months

Liver disease with

at least 200-400 mg per day in

yellow eyes,

normal patients or 100 mg per day in

weakness

persons with active liver disease

mg/day for men, 10-20

such as cirrhosis due to a high intake

mg/day in women)

•

of alcohol, hepatitis antecedents, etc.

Take sublingual DHEA at low doses (max. 30

•

Use transdermal DHEA

Problems of not tolerating DHEA: Problems related to DHEA therapy intolerance PROBLEM •

Vertigo, headache, low blood pressure, stress sensitivity, etc.

POSSIBLE CAUSES

SOLUTION

Lowering of cortisol levels by DHEA

treatment in a patient who has

1. Confirm the cortisol deficiency with

borderline low leveis of cortisol. DHEA can do this by mildly decreasing

labs and treat it. 2. Gradually reduce the dose of the

the production of ACTH by a negative

DHEA preparation

feedback mechanism.* •

•

High leveis of estradiol in men

High leveis of aromatase, the enzyme

that converts DHEA and other

benign prostate hyperplasia,

androgens to estrogens which causes

abdominal obesity and poor body

breast development and that may

hair development (they generally

cause the fibrous tissue of the prostate to increase.

have high leveis of aromatase) •

Gynecomastia

•

low-calorie diet. Losing fat tissue by eating a higher protein and a

Obesity: Fat tissue is rich in

moderately low-calorie diet will help

aromatase and it may reduce DHEA

preserve lean tissue mass while

and testosterone by increasing their

increasing the testosterone

conversion to estradiol. • •

Benign

Lose weight in case of overweight by consuming a high protein, mildly

This occurs in men with: •

Rarely: Administer lower doses of DHEA to men with gynecomastia,

conversion to DHT that counters

High caffeine and alcohol intake

the negative effects of estradiol on

which increases estrogens in men.

prostate

One glass of alcohol or more a day or

hyper-

two cups of coffee or more per day

piasia

increases the levei of estradiol by 60% on average.

the prostate. However, a diet too low in calories may decrease DHEA and testosterone production. •

Avoid food that may increase

estradiol (caffeine, alcohol etc.)

Note: * ACTH is the pituitary hormone that stimulates DHEA and cortiso/ production, but the mild decrease of ACTH in a patient with borderline /ow cortiso/ /eve/s is sufficient to make the patient collapse from an apparent mild deficiency into a fu/1-b/own cortiso/ deficiency and cause the typical signs and complaints.

218

Problems related to therapy inefficacy or lab test abnormalities PROBLEM

POSSIBLE CAUSES .

SOLUTION

Eating foods rich in cereal fiber causes a considerable

•

loss of hormones in the stools, causing or aggravating a

Avoid eating foods rich in cereal fiber

DHEA deficiency.

such as whole

How? Non-absorbable fiber such as the fiber found in

grain bread

whole grain bread or bran flakes (cellulose) will bind to the hormones that are excreted with the bile in the intestinal lumen. The complex fiber-DHEA metabolites formed in the intestinal lumen cannot be absorbed and will be evacuated in the stools, while normally the DHEA •

metabolites should be reabsorbed further down in the

lnsufficient

intestines and used again as hormones. Some 40-60%

effects of

of the hormones such as DHEA and estrogens normally

DHEA

undergo such recycling through the enterohepatic cycle. Eating cereal fiber interrupts this cycle.

.

Eating a lot of sugar such as sweets, chocolate,

•

candies, biscuits and milk products (that contain the sugar lactose) reduces production of DHEA and its

.

.

•

The DHEA dosage is too low

•

The DHEA preparation is of poor quality

lncrease the dose of DHEA

metabolites that are able to improve the blood sugar

levei.

Avoid sugar intake

Change DHEA preparation.

.

lf low blood DHEA is the sole anomaly:

•

lf insufficient DHEA sulfate leveis is the sole

a. Check blood DHEA sulfate leveis 9-14

anomaly: •

•

lnsufficient blood leveis of DHEA

hours after intake,

Blood leveis of DHEA sulfate were checked toa

when leveis

late, namely 24 hours after last intake when leveis

correspond to the

have dropped back to the initial untreated leveis •

average DHEA

Blood leveis of OHEA (non-sulfated), which fluctuate

sulfate levei over 24 h

quickly and do not stabilize, were checked and not

•

DHEA sulfate, whose levei is 500 times higher in

b. Check blood

leveis of DHEA

blood and much more stable

sulfate, not simple

DHEA 1.

Blood leveis of DHEA sulfate were checked too early, namely in the first five hours after the last

•

Excessively

the last intake for

levei

accurate DHEA 24h leveis

3.

Excessive doses of DHEA have recently been

instead of DHEA sulfate •

taken, but signs of excess have not yet appeared.

DHEA excess

9-14 hours after

do not represent the average 24-hour DHEA sulfate Blood leveis of DHEA (unreliable) were measured

without any signs of

Check blood leveis

2.

high leveis of DHEA

•

intake when leveis are peaking after absorption and

4.

Measure DHEA sulfate

Long lasting intake of high doses of DHEA, but the patient lacks the adequate enzymes to make him have any clearly visible overdose effects on the body.

219

•

Reduce the DHEA dose

Chapter Twelve

Pregnenolone Deficiency and Treatment

Case Study of Pregnenolone Deficiency Martha and her failing memory Martha, 47 years old, was well-known for her excellent memory.

Remembering names and

events was always easy for her. Whenever her kids would lose something, they would always ask their mom to help them find it, because Martha never failed to remember where she saw the object last. She could also go grocery shopping from a list entirely in her head and not ever forget a single item she needed. Sadly, for the last severa! years, Martha's memory seemed to fade away. She has unexpected memory gaps. For example, she may go upstairs to get something, only to forget what she is looking for and return confused and empty-handed. For the last severa! years she had to rely on shopping lists for ali her shopping needs, otherwise she would forget to buy severa! essential items. This forgetfulness is particularly distressing for her because she previously considered shopping lists to be the exclusive domain of old !adies. What is Martha suffering from? Her memory problems are typical of pregnenolone deficiency. To better understand what this deficiency means and how it can be treated, let's review some basic information on pregnenolone.

221

Pregnenolone: lmportant lnformation Pregnenolone is a precursor to many hormones Pregnenolone is the forerunner of many major hormones. lt is formed from cholesterol through one metabolic reaction.

lts formation is the first step to an impressive cascade of metabolic

reactions that produce ali other "steroid" hormones. Steroid hormones are chemicals made out of cholesterol such as the sex and adrenal hormones.

Roles of Pregnenolone In addition to its role in hormone production, pregnenolone functions as a neurotransmitter in the nervous system, particularly in the area of the brain responsible for memory. Pregnenolone has been shown to improve memory in animal experiments, and there is anecdotal evidence of this in humans. About

50% of patients, who take more than 50 mg per day of pregnenolone,

report satisfying improvement in memory. In fact, among anti-aging experts, memory loss has become the most frequent indication for pregnenolone treatment. Moreover, pregnenolone helps repair traumatic nerve lesions as reported in animal experiments, even in some cases improving paralysis. In humans, anti-rheumatic effects of pregnenolone were observed at high doses in a study done more than

(500 mg a day) 50 years ago. The effect of pregnenolone was stronger in rheumatic

patients who were young, had mild joint pain and only moderate disability.

Production of Pregnenolone Normal daily secretion of pregnenolone has not - to our knowledge - been documented in the scientific literature.

In our estimation, based on pregenenolone blood leveis and adrenal

hormone production, it probably averages between 1 O to by lhe adrenal glands and the brain.

50 mg/day. Pregnenolone is produced

In the brain tissues, concentrations of pregnenolone are

very high, severa! times greater than in blood. Pregnenolone secretion may be increased by eating meat, poultry, butter, and other sources of protein and saturated fat.

Pregnenolone leveis decrease with age lt is likely that the production of pregnenolone progressively declines with age, as is true for most steroid hormones.

The deficiency of pregnenolone is probably one of the important

causes of the generalized decline of the steroid hormones.

Principal hormones and metabolites that are derived from pregnenolone include: •

Androgens such as DHEA, androstenedione, testosterone, dihydrotestosterone, 17hydroxy-progesterone,

•

17-ketosteroids

(responsible for

the

male

(virilizing) effects);

Estrogens such as estradiol, estrone and estriol (responsible for the typical female effects) Progestogens such as progesterone (play a large role in pregnancy and balancing the effects of estrogen)

•

Glucocorticoids such as cortisol, 17-hydroxy-steroids (responsible for the maintenance of

•

Mineral corticoids such as aldosterone (responsible for salt and water retention)

a sufficient blood sugar levei)

222

I. Pregnenolone Deficiency: DIAGNOSIS How do you detect pregnenolone deficiency? The patient's past medicai history, complaints, signs, physical exam and laboratory tests provide clues to detect pregnenolone deficiency.

1. Onset of Pregnenolone Deficiency When did the pregnenolone deficiency start? Children with pregnenolone deficiency throughout childhood will be deficient in ali steroid hormones; consequently, they will become short and thin adults, and have underdeveloped muscles and underdeveloped sexual characteristics. The following table compares the principal differences between childhood- and adult-onset pregnenolone deficiencies.

Determining the Onset of Pregnenolone Deficiency Onset

Started in childhood

Started in adulthood

Height

•

Short

•

Body

•

Thin, small build

•

Medium build

•

Sexually mature body

Sexual

•

lmpaired sexual development

Normal height

(normal but faster aging sexual characteristics)

After this quick check, it is important to inquire about the timing and location of the patient's complaints and signs.

2. Timing and Location When do pregnenolone complaints occur? Memory troubles of pregnenolone deficiency can turn up at any time of the day, but apparently more so in stressful situations.

This may be explained by the fact that an important part of

pregnenolone is produced by the adrenal glands, glands that when they are weak, cause problems mainly under stressful conditions. With this basic knowledge, we can now verify a patient's complaints and check if they may be due to pregnenolone deficiency.

223

3. Complaints of Pregnenolone Deficiency What does a person with pregnenolone deficiency complain of? Two groups of complaints appear simultaneously: •

•

Direct consequences of pregnenolone deficiency (as suggested by some physicians) with complaints mainly consisting of central nervous system effects. lndirect consequences due to secondary hormone deficiencies.

The main complaints of pregnenolone deficiency are listed in the following table. Complaints directly suggestive of Pregnenolone Deficiency Mental Memory Vision

Senses

•

•

•

Physical Energy

Poor memorv Reduced color vision

Skin

Reduced artistic awareness

Joints & Muscles

Moderate fatique

•

Dry skin (poor sebum production)

•

•

Moderate joint pains

•

Moderate muscle pains

•

Reduced mobility

COMPLAINTS due to Deficiencies in Hormones that derive from Pregnenolone Deficiency Male

Type

Mental Complaints

Attitude/

•

Body

Lack of mental firmness and aggressiveness

hormone

Physical Complaints •

Deficient muscle, bone mass

•

Poor muscle strenqth

•

Below average sexual potency (erectile dysfunction, deficient ejaculation volume)

deficiency

Sexual

•

Low libido

Female

Psychic

•

Low mood

•

Chronic fatiQue

Sexual

•

Low libido

•

Vaginal dryness

•

Sugar cravings

•

Unclear thinking

•

Excess

•

Anger and anxiety peaks

•

adrenaline

•

Low stress resistance

hormone deficiencv Glucocorticoid deficiency

Mineral

Hypoglycemia

Low blood

•

Drowsiness, feeling faint

pressure

•

LiQht-headedness

corticoid

Poor salt

deficiency

and water

Sweating hands and armpits during stress

•

Orthostatic hypotension

•

Polyuria (excessive urination)

•

retention

Hypoglycemia attacks (with nervousness, hunQer, ... )

•

Polydipsia (excessive thirst and drinking) Salty food cravinQs

After detecting several complaints possibly due to pregnenolone deficiency, you can further gather more data to confirm the suspected diagnosis of pregnenolone deficiency by physically examining the patient.

224

4. Physical Signs of Pregnenolone Deficiency What does a person with pregnenolone deficiency look like? Pathognomonic signs of pregnenolone deficiency are unknown at the present time. Most signs are also found in other deficiencies and presented in the underlying tables. Direct signs are the direct consequence of pregnenolone deficiency as suggested by some physicians and may include complaints of dry skin and reduced joint mobility. lndirect signs result from other deficiencies of hormones that depend upon pregnenolone for their production. •

•

Physical Signs possibly due to Pregnenolone Deficiency Skin Joints

• • •

Dry skin Reduced mobility Pain with mobilization

Physical Signs due to Deficiencies in Hormones derived from Pregnenolone

Pale skin Below average pubic and armpit hair Androgen Below average Below average musculature masculine deficiency: Below average bane mass (Men and women) traits Below average testicle size Gynecomastia (breast develo_Q_ment in menl Pale skin Female hormone Deficient deficiency Small or droopy breasts feminine traits (Women) Small wrinkles around the eyes and mouth Visual or palpable signs of inflammation including but not limited to: Conjunctivitis lnflammatory Glucocorticoid deficiency diseases Eczema and rashes Arthritis with eventual joint deformations Gastroenteritis and colitis Sharp wrinkles Mineral Corticoid Dehydration lndented tongue deficiency signs Soft eye ball (with pressure) Orthostatic hypotension (low BP if standing) •

•

•

•

•

•

•

• •

•

•

•

•

• •

•

•

The next step is to look for diseases that may easier develop with a pregnenolone deficiency.

5. Disease Susceptibility Which diseases develop more easily in patients with pregnenolone deficiency? The same diseases that develop in patients with sex or adrenal hormone deficiencies may also find a favorable ground for their development with pregnenolone deficiency: cardiovascular diseases, dehydration, Alzheimer's disease, depression, burn-out syndrome, etc. After this check it is essential to require lab tests.

225

6. Lab tests for Pregnenolone To measure baseline leveis of pregnenolone and its metabolites, the patient should not engage in intense physical or emotionally stressful activities for 24 hours prior to the lab testing, otherwise the adrenals may produce excessive hormones, including pregnenolone.

In most instances the only necessary test for pregnenolone deficiency is pregnenolone sulfate

in serum (highlighted with a yellow background).

Laboratory tests for Pregnenolone Route

Timing

Blood

8A.M.

Pregnenolone

Blood

8A.M.

Pregnenolone sulfate

Test

Optimal 1 3 15

Probably

References

Deficient 0

-

4

8

40-47

o - 25

90-100

o-70

285-315

0-220

-17

pg/ml

12- 53 pmoi/L

40

-10 2

ng/ml

125-380 nmoi/L

Value

Med High

A more extensive assessment is obtained by checking the leveis of hormones and metabolites

that originate from pregnenolone.

INDIRECT MEASUREMENT by measuring the leveis of the hormones and metabolites derived from pregnenolone: see specific chapters for more details Route

Timing 8AM &4 -8 PM 8AM(activity)

Test •

Glucosteroids

•

Mineral steroids

•

Blood tests

8AM

•

Androgens

• •

8AM (Women: days 7 and 21 of menstrual cycle)'

Urine

4 2 -hour

collection

Progesterone

•

Cortisol

Androgens

Progesterone At different moments

of the day

DHEA sulfate

Progesterone 1

Estrogens

Saliva

Free testosterone DHT or Androstan. gl. Estradiol

Glucosteroids

• • • • • •

17 -OH-Steroids Aldosterone

overviews

at the end

of the book

17-ketosteroids E1-E2 E2 3 Pregnandiol Cortisol

•

Testosterone, DHEA

Estrogens

•

Estradiol

•

See lab test

Testosterone

Androgens Progesterone

Probably Deficient

Aldosterone

•

Mineral steroids

I

Testosterone

Estrogens*

•

mal

Total,free Cortisol

•

Glucosteroids

Opti-

Proqesterone

Notes: 1 In women, day 7 of the menstrual cycle allows to measure adrenal production of

rrogesterone, whi/e day 21 helps to measure the much higher ovarian production of progesterone; E1 stands for estrone, E2 for estradio/ and E3 for esfrio/, the three main estrogens

226

11/ Pregnenolone Deficiency: TREATMENT Pregnenolone Medications The principal pregnenolone treatments are presented in the table below: Pregnenolone Medications Major complaint =

Route

Product

Adrenal deficit symptoms in

young adults 1

=

=

Memory loss

Product Value

such as arthritis High

Physiologic

doses

doses

Major physical dysfunctions

Supraphysiologic doses

Pregnenolone Sublingual

(compounding pharmacy, health food stores)

5-40 mg/day

Pregnenolone Oral

(compounding pharmacy, health food stores)

10-50 mg/day

40-100 mg

Sublingual not

twice a day

recommended

50-150 mg/day in AM (or 2x/day: AM and

before bedtime)

Low

200-500 mg/day

(but only for

Medi um

limited time)

Note: 1 A minority of young adults are ab/e to readily convert pregnenolone to other hormones. In the majority of adults, however, experience teaches us that pregnenolone therapy afane is not sufficient for the treatment of "global" adrenal cortex deficiency (deficiency of cortisol, DHEA, aldosterone and other hormones derived from these hormones).

How do you start Pregnenolone Treatment? For memory loss, it is best to start pregnenolone at a higher dose of 100 mg per day during the first 4 months and then, once improvement is sufficient, decrease the dose to 50 mg per day. As indicated in the above chart, the dose will depend on the severity of the deficiency and the concomitant disease conditions such as adrenal insufficiency, memory loss, or arthritis. We recommend taking pregnenolone in the morning to improve memory during the day. Possibly, taking pregnenolone both morning and evening may be indicated for some patients as it helps to keep blood leveis of pregnenolone high enough for 24 hours.

Progress during Pregnenolone How long must the pregnenolone treatment be continued before the patients improve? Usually, it takes 3 to 4 months before the first improvements in memory appear.

227

How long should patients take Pregnenolone 11 patients want to keep the effects, they should continue the treatment for the rest oi their life. Otherwise, they will regress to the initial situation after stopping the treatment.

Pregnenolone Overdose: Risks Taking orally doses of pregnenolone of 200 to 300 mg or higher per day for prolonged periods could overload the liver and cause signs of pregnenolone excess.

lndications for Pregnenolone Treatment Chronic, long-term indication: • •

•

Pregnenolone deficiency as demonstrated by laboratory tests Overt clinicai steroid hormone deficiency syndrome (e.g., memory loss with various signs and complaints of adrenal and sex hormone deficiency) Global adrenal deficiency (for which it rarely works as a sole treatment, but if it does, it is usually in young adults).

Acute, occasional, short-term indication: •

Memory enhancement before important mental tasks in a person with memory troubles

Contraindications to Pregnenolone Treatment No known contraindication. We recommend caution with the use of higher doses of oral pregnenolone in patients with liver disease as steroid hormones may accumulate in the liver and disturb liver function.

How to boost the Pregnenolone leveis? The best way to boost pregnenolone leveis and its effects is by eating more foods that stimulate brain and adrenal gland production of pregnenolone such as foods that are rich in cholesterol (animal foods). Sleeping better may possibly help to keep pregnenolone leveis high by preventing any overconsumption of pregnenolone during the night as would be the case during sleep-disturbed nights. How to optimize Pregnenolone Leveis WhatTo Do Diet

•

•

Sleep

•

Eat cholesterol containing foods such as eggs, liver, butter, meat, fish and poultry. Follow a "Paleolithic" diet: fruits, vegetables, meat, poultry, eggs , fish Get adequate sleep

228

Follow-up of Pregnenolone Treatment How do you follow-up once treatment has started? 1. Find the optimal dose.

Check with the patient to see his progress and if there is amelioration of complaints. lf there is important improvement then keep the dose the same during a while. After severa! months the improvement is usually maintained at half the dose that brought improvement. lf improvement is marginal then consider increasing the dose by 50 mg per day more. The optimal dose may vary in special conditions. The main tasks that require adjustment of the dose are summarized in the table below. When to adapt the dose of Pregnenolone lncrease the dose 1 (50 -100 mg /day more)*

Dose Condition

• •

Lower the dose

(20 to 100 mg/day less)

Tasks that demand better memorv lntensive stress

• •

Sedentary Unstressed, holidays

Note: We advise not to remain on doses of 200 mg/day for /onger than 2 months for safety reasons. ·

2. Perform lab tests. The following tests are recommended:

Recommended Lab Tests for Follow-Up Medication

Pregnenolone

Urine (24-hour)

Blood Pregnenolone (sulfate)

(8-14 hours after intake)

1 In young adults only : 17-hvdroxv- and 17-keto-steroids

Note: 1 At 8 to 14 hours after intake there is a stabilization of the leve/ of pregnenolone sulfate. 3. Avoid under- and overdosing.

The greatest concern should be to watch for clinicai signs and elevated lab values showing excessive leveis of pregnenolone and its metabolites. However, at doses lower than 100 mg per day, they rarely occur. Type of Excess Pregnenolone Excess

Signs of Excess •

Possibly oily skin (?)

Excess of Hormones derived from pregnenolone1:

- Glucocorticoid excess

•

- Mineralocorticoid excess

•

- Androgen excess

•

- Female hormone excess

•

Swollen moon-like face, hiqh blood pressure, etc . Swollen hands and feet, etc. Acne, hirsutism, etc . Swollen tender breasts, etc.

Notes: 1 Signs of hormonal excess derived from pregnenolone rarely appear, and when they do, it is usually in young adults as they are often the only ones to efficiently convert pregneno/one to other hormones. This is a/so the reason why we advise doing a 24-hour urine test for metabolites of pregnenolone in young adults.

4. Solve problems quickly and efficiently: Please read the next section "Problem solver".

229

111/ Pregnenolone Problem Solver How do you solve problems that occur during treatment? Reter to the table below: Problems related to Pregnenolone Overdosing: PROBLEM

POSSIBLE CAUSE

SOLUTION

Pregnenolone overdose expressed •

Oily skin

•

Oily hair

by signs of androgen excess: is probably due to the conversion of pregnenolone to DHEA and androstenedione and from these hormones to testosterone.

Reduce the dose by 30-70% depending on the severity of the signs of overdose, if necessary stop for a few days or weeks.

Problems related to inefficacy of Pregnenolone Treatlment PROBLEM

SOLUTION

POSSIBLE CAUSES

The treatment period is too short.

Wait four months to assess treatment

efficacy. In general, a minimum of 50 mg per day are necessary to improve memory. • Moreover, we advise during the first 4 months to take 100 mg per day, then if a clear improvement appears, lower the dose down to a maintenance dose of 50 mg per day. Pregnenolone should be taken either: •

The dose of pregnenolone treatment is too low •

Lack of symptom improvement

such as continued memory impairment

The pregnenolone has been taken before bedtime and the effect is already gone upon awaking.

•

• •

The treatment has not been taken. The memory loss is not due to pregnenolone deficiency

230

•

Only in the morning so that it may exert its memory-enhancing effects during the day. Twice a day (morning and evening). Try to motivate the patient by reinforming him/her on the beneficiai of and effects importance pregnenolone and its safety. Search for other causes

Chapter Thirteen

Aldosterone Deficiency and Treatment

Case Study of a Patient with Aldosterone Deficiency Tom, with his head in the clouds Tom is a thin man with a hollow face. He regularly complains of symptoms of having low blood pressure: He tends to feel as if he is going to faint, and complains of getting drowsy when he stands up. Some people have the impression that he lives in two different worlds, here in this world and somewhere else, in a world of thoughts and daydreaming. In fact, this only happens when he sits or stands up in the same position for a long time. Tom himself feels that the word "absent-mindedness" better describes his condition. Tom feels better when he moves or lies down flat on a bed or takes medication to elevate his blood pressure. When lying flat on a bed, his mind works better and he gets a clear look on life and feels life as being more enjoyable. lf he goes on vacation, ali Tom wants to do is lie on the beach as then his body and mind are in harmony. At dinnertime, Tom feels attracted to salty food.

His family finds he adds excessive amounts of salt to his food.

even when drinking a lot.

Tom often feels thirsty

But he is embarrassed when he drinks, because as soon as he

drinks, he almost immediately afterwards has to hurry to the bathroom and urinate ali the fluid he just drank. For this reason Tom restrains himself from drinking when he goes out to work or see friends. What is he suffering from?

Most of the Tom's problems are typical of aldosterone deficiency.

To better understand what this deficiency means and what can you do about it, let us review some basic information on aldosterone.

231

ALDOSTERONE: Basic lnformation

Role of Aldosterone Aldosterone's major role is to keep water in the body and the blood pressure up during the day. To achieve this, aldosterone makes the kidneys retain sodium, and thus water by osmosis, thereby filling the blood vessels and tissues up with more fluid. At the same time, aldosterone makes the kidneys secrete a supplementary amount of potassium, the antagonistic ion to sodium, to increase further sodium's water-retaining action.

Production of Aldosterone Daily secretion of aldosterone in young healthy adults averages the 150 J.l9 a day. Aldosterone is produced by the the cortex of the adrenal glands. Higher daytime aldosterone leveis are found because individuais stand up during the day. The upright position strongly stimulates aldosterone secretion in order to maintain normal blood pressure.

What increases the production of Aldosterone Aldosterone production is increased with physical activity, by standing up, stress, low salt intake, increased salt losses (caused by sweating or a diuretic), high protein and saturated fat diets.

Aldosterone production or leveis decline with age The excretion of aldosterone in the 24-hour urines during a normally salted diet declines by about 20% in elderly persons, aged 70-80, compared to young adults. When the diet is low in salt, the difference between young and old is more pronounced.

To compensate for the low

intake of salt, aldosterone leveis increase both in young and old, but the compensatory increase is about 50% less in elderly persons than in young subjects, showing that with increasing age, individuais Jose part of the ability to increase aldosterone production to respond to increased salt and fluid needs.

232

1/ ALDOSTERONE DEFICIENCY: DIAGNOSIS

How do you recognize Aldosterone Deficiency? To detect aldosterone deficiency, it is important to recognize the typical signs and complaints of the deficiency, as well as to do some lab tests.

1. Onset of Aldosterone Deficiency When did the aldosterone deficiency start? Older aldosterone deficiencies are often more severe.

Finding out when the deficiency began

helps the physician in evaluating the impact of the deficiency and to get clues on the dose of the medication he will later prescribe. The way to discern the onset is to interview the patient and search for typical aldosterone deficiency signs and complaints that may have appeared long ago in his childhood. The differences between childhood and adulthood-onset aldosterone deficiency are reviewed in the following table.

Determining the Onset of Aldosterone Deficiency Onset

Adulthood

Childhood Children with aldosterone deficiency often have other deficiencies in cholesterol containing hormones

Physical Signs

(steroids) such as cortisol deficiencies, global steroid hormone deficiency manifesting with signs such as:

•

Fuller face

•

Thin face, trunk and limbs

•

Fuller body

•

A certain degree of physical sexual immaturity

•

Normal sexual development

Complaints of aldosterone deficiency during Complaints

childhood: exaggerated thirst, need to quickly run to the bathroom after drinking, dizziness, absentmindedness, distraction at school, low blood pressure

No such complaints in childhood

After this quick check, it is important to inquire about the timing and location of the patient's complaints and signs.

233

2. Timing and Location When during the day do aldosterone complaints manifest themselves? Aldosterone deficiency complaints appear the most frequently when a person stands up or sits down for a prolonged period of time. With this knowledge it is important to check the patient's complaints and signs.

3. Complaints of Aldosterone Deficiency How does a person with aldosterone deficiency feel? Typically, individuais with aldosterone deficiency have low blood pressure. The lack of aldosterone, the principal salt-and water-retaining hormone, makes the patient lose a great deal of fluid in the urine. Because of the low blood pressure, the blood and thus nutrient and oxygen supply does not reach well the brain of a person with low blood pressure, particularly when the person stands up, making the patient feel drowsy and absent-minded. The principie complaints suggestive of aldosterone deficiency are listed in the table below.

When

Complaints of Aldosterone Deficiency •

Behavior

•

• •

Standing

Concentration

•

up or

sitting

•

Vision Hearing

•

•

Tendency to lie down Tendency to move ali the time when standing up to increase blood pressure Drowsiness, zombie-like feeling Easily distracted, absent-minded; daydreaming Difficulty focusing on tasks Feels better in head when lying flat on a bed or moving ali the time Troubled vision with difficulties in focusing on objects and tasks when standing up Reduced hearing, age-related hearinq loss

Food

•

Salt and salty food cravings Thirsty often, strong tendency to drink a lot of water and other liquids

Urine

•

Polyuria especially during the day

•

234

4. Physical signs of Aldosterone Deficiency What is the appearance of a person with aldosterone deficiency? S/he looks dehydrated. Cause

Physical Signs of Aldosterone Deficiency

Face Expression

Low

•

Pale face

•

A drowsy, absent-minded look

•

blood pressure

(arterial hypotension)

Blood pressure

Face

•

•

Hollow face Sharp wrinkles

•

Dehydration

Tongue Skin

Orthostatic hypotension: check for it by taking the blood pressure while lying down and immediately after standing up. A difference of more than 1 Omm/Hg is labeled as orthostatic hypotension.

• •

Eyes

Low blood pressure (arterial hypotension): below 110/60 mm Hg

•

•

Eyes deep in orbit Soft eyes (eye ball feels soft to pressure because of low eyeball pressure) Tongue with teeth marks visible at tongue borders (tongue indentations) Skin 'tenting' - prolonged stiff skin fold after pinching the skin of the back of the hand

5. Disease Susceptibility Does aldosterone deficiency cause any other health conditions? Several diseases may be aggravated or possibly caused by the dehydration that accompanies aldosterone deficiency, in particular cardiovascular diseases (thromboses, coronary heart disease), rheumatoid and digestive diseases, and possibly Alzheimer's dementia. After this check it is essential to require lab tests.

6. Lab tests for Aldosterone Test conditions IMPORTANT NOTE: in order to avoid excessive stimulation of aldosterone secretion during the tests the patient should be: 5. 6. 7. 8.

Calm, sedentary, avoiding any heavy physical activities Consuming a normal amount of salt for the average population Sweating normally (not excessively) Not standing up for prolonged times during or just before the tests

235

To check aldosterone leveis with lab tests, measure the baseline aldosterone leveis, obtained in conditions free of important stress or physical activity and during a normally salted diet. Average salt intake: Check lab tests for aldosterone during a normally salted diet. Lab Tests for Aldosterone Deficiency with an Average Salt lntake Tissue

Blood

Average Salt lntake

Lab Test

(serum)

Optimal

Sodium

141

Potassium

4.3

>1 5 > 150 > 415

Aldosterone

(after activity)

Aldosterone

(bedridden, lying down )

Sodium

24 h Urine

Prob. Deficient* LOW<138 Hlgh >4.8 0-10

> 100

0-100 0-277 0-70

<277

0-193

160

0-120

Potassium

65

0-45

Phosphorus

65 13 3.6

0-45

Aldosterone

0-9

0-2.2

References

136-146 mmoi/L 3.5-5.1 mmoi/L

4-30 ng/dl 40-300 pg/ml 111-831 pmol/mL 30-160pg/ml 83-443 pmoi/L 100-220 mmol/24h 35-80 mmol/24h 22-125 mmol/24h 5-20 jlg/24h 1.4- 5.5 pmol/24h

Test Value

Med Low Med Low Med Low Low HiQh

Note: "Prob. Deficient" means probably deficient

Low and high salt diets:

Optimal and deficient values for aldosterone in laboratory tests differ according to salt intake. When salt intake is low, aldosterone secretion, blood and urine leveis increase in order to increase salt retention and assure that the body gets enough sodium for its needs. When salt intake is high, the aldosterone leveis are lower. In one study of healthy young adults on salt restricted diets, the mean urinary aldosterone excretion (in 24-hour urine) reached 28 Jl9 per 24 hours, while the upper reference value is 20. Thus, in healthy adults on low-salt diets, the optimal value for aldosterone should exceed the upper reference value to compensate for the lack of sodium. In contrast, with diets high in salt, optimal values should be lower than the mean value, but not necessarily under the lower reference value. Lab Tests for Aldosterone Deficiency with Low and High Salt lntake Tissue Blood

24-hr Urine

Test Aldosterone Sodium Aldosterone

Low-Salt Diet Optimal

> 3o >20 >5.5

I P. Deficient I <250

< 100

I

I

o- 20

o- 5.5

High-Salt Diet Optimal

> 80

I Pr. Deficient I <80

7 - 12 I 2-3.4 I

>220

0 -6

o- 1.7

References

50-300 pÇJ/ml 100-220 mmol/24h

5-20 JlQ/24h

1.4- 5.5 pmol/24h

Sodium and potassium: When you check for aldosterone in blood and urine, simultaneously

check for sodium, the dominant electrolyte found in the extracellular fluid, and potassium, the dominant electrolyte inside the cells, as they are closely interrelated to one another.

Urinary cortisol and 17-0H-corticoids: are useful tests when evaluating aldosterone, because high leveis of glucocorticoids may decrease ACTH and thereby aldosterone production, the reverse being true for low glucocorticoid leveis.

236

11/ Aldosterone Deficiency: TREATMENT

Aldosterone Medications The basic 9uideline for treatment of aldosterone deficiency, other than takin9 a medication, is to drink sufficient quantities of water and ingest enough (sodium) salt. Generally, fludrocortisone, a synthetic derivativa of aldosterone, is considered the dru9 of choice because it has a 24-hour action; whereas bioidentical aldosterone is quickly metabolized and thus needs to be 9iven in three to four divided doses. Moreover, bioidentical aldosterone is not readily available in most pharmacies.

Medications for Aldosterone Deficiency •

Route

Product

Doses (sedentary)

9-alpha-fluoroOral

hydrocortisone (fludrocortisone

50-200 119/day (most common startin9

such as Florinef®)

dose

=

1 00 119/day)

Prolon9ed standin9 up

•

Stress

•

Jet la9

Aldosterone

125-500 119/day

Time

Take 50-100 119/day more Take

Oral

Dosing

50-250 119/day more

Value

1x/day

Hi9h

(mornin9) 2- 3x/day (mornin9

Med

& late

Hl9h

-

afternoon)

How do you begin Aldosterone Treatment? For most patients, the startin9 dose is 100 119 per day of fludrocortisone. There are two exceptions to the rule: •

Patients with a tendency to swell or who suffer from arterial hypertension (hi9h blood pressure) should not receive aldosterone or should start at lower doses (see para9raph above for more information).

•

Patients with severe low blood pressure (90 mmH9 of systolic blood pressure) may start at 125-150 119 per day.

237

When

should

the

routine

dose

be

increased

or

decreased? Doses should be increased in conditions where more aldosterone is needed (low salt diet, etc.), used up (prolon9ed standin9 up or sittin9 position, heavy sweatin9, severe stress, etc.), or less is produced Uet la9).

Progress How lon9 does it take before the patient notices improvement? Sometimes, the increase in blood pressure, which is usually the first improvement noticed, may occur quickly, even the first day of therapy. noticeable improvement.

In some subjects it takes several weeks before

The slow pro9ress is often due to low water or salt intake or an

insufficient dose of fludrocortisone.

lndications: Aldosterone deficiency Low blood pressure •

Jet la9 Hearin9 loss in people with low blood pressure

Contraindications to treatment Caution is recommended with individuais whose feet, ankles and/or hands easily swell, or who have hi9h blood pressure, as these are ali si9ns and symptoms that may exacerbate with aldosterone replacement without si9nificant benefit from the therapy. Patients who tend to swell or have hi9h blood pressure should not take fludrocortisone nor aldosterone, of if they do, should start on doses as low as 25 to 50 119 per day and then after 1 O days cautiously increase the daily dose by 25 119 every 1 O days up to 100 119 unless the patient shows si9ns of excess.

238

How to naturally boost Aldosterone Firstly, lifestyle changes can have a very positive effect on this condition.

The principal lifestyle factors for boosting the effects of fludrocortisone treatment or of the body's own (endogenous) aldosterone are summarized in the following table. How to optimize Aldosterone Activity and Ttreatment What

What to Do

What to Avoid

1. Eat sufficient salt

2. Drink sufficient water" •

Eat adequate calories

•

Eat sufficient protein and (unburned) cholesterol-containing red meat, poultry, eggs

•

Eat organic foods (pesticides damage the adrenal glands and thereby reduce aldosterone secretion)

•

Take breaks throughout the day lying down. 4

•

Move regularly, do not stand or sit in the same position for a lonq time.

Diet

Position Movement

•

Avoid low salt diets

•

Avoid drinks that make the kidneys excrete more fluid: coffee, tea, soft drinks, alcohol, etc.

•

Avoid standing up or sitting for prolonged periods.

•

Avoid exposure to prolonged stress, including intensive sports4

Stress

Notes: 1

Diets high in salt reduce a/dosterone secretion, but at the same time they greatly increase its efficacy.

2

Next to salt, water is the important chemica/ for a/dosterone action. An insufficient water intake decreases

3

Dietary proteins and cholestero/ can increase aldosterone production (cholesterol is the first building block for

4

Standing up and stress stimulate the production of a/dosterone. However, in patients with aldosterone deficiency,

a/dosterone's ability to further retain water. aldosterone synthesis). these conditions put an extra strain on the body. They deplete the already /ow supply of aldosterone, exhaust the a/dosterone production, and push the patient into fu/1-b/own a/dosterone deficiency. Even if f/udrocortisone is taken, these conditions decrease the efficacy of the treatment and make a higher dose necessary.

Secondly, correct other hormone dysfunctions that impair aldsterone production or effects. lnfluence of Hormone Replacement Therapies on Aldosterone activity &for production Strong

Mild

Stimulators

Stimulators

Strong

of Aldosterone •

Growth hormone

•

Estradiol and other estrogens, esp. oral estroQens

Mild

lnhibitors of

lnhibitors

Aldosterone •

Anabolic (androgen) steroids

•

Progesterone

•

Cortisol at low doses

•

Glucocorticoids at high doses

•

(Melatonin)

•

(Thyroid hormones)*

Note: • Thyroid hormones increases urination, an effect that is opposite to the fluid-retaining effects of a/dosterone.

239

Follow-up:

How do you follow up once the treatment has started?

1. Find the optimal dose.

Monitoring and dose adjustment should be based on signs and complaints of improvement or aldosterone excess. The following conditions may also necessitate dose adjustments: When to Adapt the dose of Fludrocortisone lncrease the dose

Lower the dose

(50 to 100 119/day more) • Prolonged standing • lntensive stress • Jet lag • Low-salt diet • Low fluid intake

(25 to 75 119/day less) Sedentary, bedridden Unstressed, vacations (holidays) High-salt diet Excessive fluid intake

• • • •

2. Avoid overdosing.

The patient should be educated on the signs and complaints of aldosterone overdose so he can notify the physician and also lower his dose. The main signs and complaints of aldosterone excess are reviewed in the table below. Aldosterone - Fludrocortisone Excess Cause

High blood pressure Water retention

Complaints •

• •

Signs

A feeling of being under pressure Headaches Oliguria (reduced urination during the day)

3. Perform lab tests:

• • • • •

Reddish face Hard feeling when pressing the eyeballs Hypertension > 140/90 mm Hg PittinÇJ edema; Swollen face, hands Swollen ankles and feet (#1 sign of excess)

What lab tests are recommended for follow-up?

Most tests are of little use for fludrocortisone treatment follow-up. Sodium, potassium and aldosterone leveis are used in monitoring aldosterone treatment efficacy. Aldosterone and fludrocortisone retain sodium and water, while increasing the loss of potassium in the urine Recommended Lab Tests For Follow-up of Fludrocortisone treatment Product used

Blood

Urine (24-hour)

Fludrocortisone

sodium, (potassium, aldosterone) sodium, (potassium, aldosterone)

(sodium, aldosterone) sodium, potassium, aldosterone

Aldosterone

Note: Potassium leveis are more difficult to interpret as they often change with the amount of potassium-rich fruits and vegetables ingested in addition to changes in aldosterone leveis and sodium intake. There is no way to measure fludrocortisone leveis in the body in normal laboratories but measuring aldosterone may give an idea of the degree of inhibition of aldosterone by fludrocortisone (which should be moderate in most cases). Sodium leveis wi/1 be high in the blood and low in the urine when the dose of f/udrocortisone is excessive and the contrary when the dose is too low.

4. Solve problems during follow-up quickly and efficiently:

Refer to the next section titled "Aidosterone Problem Solver'' for more information.

240

111/ Aldosterone PROBLEM SOLVER How do you solve problems that may occur during treatment? Problems related to Aldosterone Overdosage Problems related to Aldosterone Overdosage POSSIBLE CAUSES

PROBLEM?

•

(in order of frequency)

Swollen

1. lnadequate potassium intake (Average diet contains 5g/day but the optimal Paleolithic diet contains 12-15 g/day.

feet and

2. Excessive salt intake (salt's

ankles,

water retaining effect is amplified by fludrocortisone)

and less often swollen hands

3. Fludrocortisone overdose 4. Being on one's feet ali day

long. 5. Many other causes exist that may cause swelling 1. Excessive fludrocortisone.

•

High blood pressure

2. lnsufficient potassium intake 3. Excessive salt intake with

the fludrocortisone treatment

• •

Red face Swollen face

•

•

A large overdose of fludrocortisone can stimulate blood flow to lhe skin, reddening lhe face, and increasing water retention, making lhe face swell

Headaches

A feeling of

•

being under pressure •

A tensed look

•

SOLUTION

Correct the diet: •

lncrease fruit and vegetables (rich in potassium) intake

Take potassium supplements (acts as a diuretic) : 1 to 3 grams per day Avoid adding too much salt to the diet (salt is often hidden in soup, cheese, ham, etc.) Stop or lower the dose of fludrocortisone Lie flat on a bed while elevating the legs and feet severa! times a day for 1O to 15' Check for other hormone deficiencies and excesses that may cause swelling and •

correct !hem ( see end of chapter on female hormones for more information)

Stop or lower the dose of fludrocortisone lncrease fruit and vegetable intake in the diet, take potassium supplements. Reduce salt intake 1. Stop or reduce dose of fludrocortisone 2. lmprove ali the other conditions of swelling cited above. 3. Read also the "Problem Solver'' section in the chapters on female hormone deficiencies

Aldosterone excess causes high blood pressure which can cause headaches.

Reduce the dose of fludrocortisone or aldosterone.

Cortisol deficiency causes low blood pressure which can cause headaches (esp. in people takinQ a low-salt diet)

1.Test for cortisol 2. Supplement with hydrocortisone (or on rare occasion with methyl-prednisolone if high bloodQressure)

Fluid retention that puts tissues under pressure

Reduce the dose of fludrocortisone or aldosterone

High blood pressure caused by an excessive dose of fludrocortisone

Reduce the dose of fludrocortisone or aldosterone

241

Other problems due to the existence or appearance during fludrocortisone treatment of cortisol deficiency, or simply due to a poor diet, may occur and their solution discussed in the table below. Problems due Cortisol Deficiency or a Poor Diet PROBLEM

POSSIBLE CAUSES

SOLUTION

These complaints are typical

•

of cortisol deficiency. The •

Any of the following complaints: increased anxiety and stress, sugar cravings, confusion, tachycardia (rapid heartbeat), muscle tension, outbursts of anger, irritability

After confirming the low cortisol leveis in blood and urine,

most likely cause is that the

correct the cortisol deficiency

fludrocortisone or aldosterone

by prescribing cortisol in the

treatment by mildly inhibiting

form of hydrocortisone (15-30

the release of the pituitary

mg/day in women, 25-40

hormone ACTH, the hormone

mg/day in men) or by

that stimulates the adrenals

increasing the dose with 5-1 O

to produce cortisol and

mg/day of hydrocortisone if a

aldosterone, reduces

cortisol supplement is already

cortisol secretion, thereby

taken.

pushing a person with

•

borderline low cortisol production into an overt

lf complaints remain, lower the dose of fludrocortisone or aldosterone

deficiency.

Correct the diet: 1. Wrong food intake:

•

insufficient salt and/or water intake are the most usual causes.

Follow the dietary recommendations listed previously in this chapter.

•

lncrease salt, water and fludrocortiosone intake, eat sufficient amounts of protein

•

No improvement from the treatment.

2. A preexisting cortisol

deficiency that exceeds in

lf symptoms and lab tests confirm a

severity the aldosterone

cortisol deficiency, then prescribe

deficiency (see above). A

± 25-40 mg hydrocortisone/day for

cortisol deficiency with low

men, 15-30 mg for women, or a

blood pressure negates or

synthetic derivativa if specifically

masks the elevation of blood

indicated (see chapter on cortisol

pressure obtained with

for more information).

aldosterone.

242

Chapter Fourteen

lnsulin deficiency (with or without diabetes)

and treatment A patient with lnsulin Deficiency without diabetes Fanny and her severe chronic fatigue syndrome:

Fanny, a 32-year old lonely mother of a boy of seven, had seemed to come to an end of her life. She had lost her husband several years before and had developed a severe chronic fatigue syndrome for which no treatment helped. She had lost her job and spent almost ali of her time in bed, unable to stand up for a long time. She managed to come to the physician's office five kilometers from her home, brought in a car by a friend. Her body was extremely thin (BMI under 16) and looked pale and fragile. Whatever and however much she ate, she remained thin and meager. Her face was emaciated. Many hormone deficiencies were diagnosed in her such as sex hormone, adrenal and mild thyroid hormone deficiencies. Providing her with the adequate supplements improved her a little. She could spend half of her day out of bed and walk outdoors for 600 metres, a big change compared to before. Some hope carne to her, but she still had to stay the whole morning and noon in bed, strength less. She presented a growth hormone deficiency, but did not have the money to pay for the treatment. One other deficiency had been overlooked. As she was abnormally thin, the physician suspected that a certain degree of insulin deficiency was present. A blood analysis revealed fasting insulin leveis in the serum that were undetectable (under 2 units per ml). As insulin can increase the production of IGF-1, the hormone that exerts many, if not most of the effects of growth hormone, the idea was to correct with small doses of 1 to 2 lU of rapid acting insulin before each meal both her insulin and IGF-1 leveis at a much cheaper price than growth hormone. The results of those small doses were beyond expectations. Fanny regained six kilos of weight (probably three kilos of fat and three of lean tissue, which consists mainly of muscles). She was not in bed during the day anymore and went on daily walks of up to six kilometres. Her energy with the insulin was so much better that she took on a more than full-time stressful job as a tax expert and accountant, and could cope with this as well if not better than most other accountants. Most of Fanny's problems are typical of insulin deficiency. To better understand what this deficiency means and what can be done about it, let us review some basic information.

243

Basic lnformation on lnsulin

lnsulin's roles lnsulin has three major roles: 1.

Energy supply to the body's cells. lnsulin makes glucose, the major energy nutrient for the cells, penetrate inside of the cells. Glucose cannot penetrate into the cells without insulin. Deprived of insulin, a patient's cells lack glucose, the potent energy nutrient, and the levei of glucose in the blood or glycemia increases to very high leveis, forming a sticky glue that slows down the passage of nutrients and oxygen to the cells, causing the disease diabetes mellitus type 1 or insulin-dependent diabetes. When cells are totally deprived of sugar, the patient falls into a coma and dies after several days with a blood full of sugar. By bringing the sugar inside of the cells, insulin quickly reduces the leveis of glucose in the serum in the first minutes after its secretion.

2.

Maintenance and development of muscles and other lean tissue. lnsulin is one of the most powerful anabolic hormones, equal in efficacy to growth hormone. One of the major mechanisms of its anabolic action is an increase in intestinal absorption of amino acids and other nutrients necessary for muscle development.

3.

Maintenance and development of fat. lnsulin

tends to increase fat mass, contrary to

growth hormone, which reduces the fat. Depending on a person's body weight, insulin will favour muscle development upon fat mass development or the opposite. In thin, lean and athletic people, insulin works more as an anabolic hormone than as a fat-producing hormone People with excessive thinness may particularly benefit from insulin with muscle development and an increase in fat that shapes their body better, whilst in overweight people excessive leveis of insulin only increase of fat mass, not muscle mass.

lnsulin production: lnsulin is produced in the pancreas by specialized cells called the beta-cells of the islets of Langerhans. About 50 to 100 IU/day of insulin are produced in normal healthy adults depending on the size of a person and the type of meal he consumes.

lnsulin Leveis: lnsulin leveis increase in the serum with meals and in particular after the ingestion of carbohydrate-rich foods such as sweets, bread and pastas. The half-life of insulin in the serum is approximately ten minutes, a time which is longer than the time necessary to transport glucose inside the cells. As explained in the paragraph below, the persistence of higher insulin leveis in the blood after ingestion of sugar-rich foods due to insulin's longer half-life in blood than that of glucose produces hypoglycemia.

244

Regular consumption of sweet foods imbalances the insulin production and produces: •

Hypoglycemia and sweet cravings: When people eat sugar-rich foods, the sugar or

glucose levei peaks in the blood, triggering the release of high amounts of insulin, which job is to quickly transport the sugar into the cells. When the sugar levei normalizes again, insulin leveis still remain high for many minutes, further lowering the blood glucose leveis to lower leveis, causing hypoglycemia. The hypoglycemia generates a craving for sugar that will persuade a person to eat sweet food again. A vicious circle of sweet craving sweet food consumption develops- sugar craving is thus created with ups and downs of sugar and insulin leveis - hyperglycemia and hypQglycemia with hyperinsulinemia and hypQinsulinemia - that may exhaust the pancreas, unable in the long run to adapt the insulin secretion to the abnormal changes in glucose leveis. •

Obesity and diabetes: After years of high consumption of sugar-rich foods people may

become obese and develop type 2 diabetes due to excessive calorie intake and high leveis of the fat-producing hormone insulin. On the long run, the excessive demands put on the pancreas to produce insulin may exhaust it and lead to a deficiency in insulin production and the development of type 1 diabetes.

Avoid the wrong foods: Therefore, we should avoid eating sugar and other sweet foods that

cause an imbalance of glucose and insulin leveis.

Age-dependent reduction in efficacy of insulin

With advancing age, insulin becomes less efficient by two main mechanisms. On one hand, the pancreas of elderly adults responds with greater delay to any increase of glucose in the blood. The delay in adaptation of the insulin production results in higher leveis of serum glucose after food ingestion, especially consumption of carbohydrate-rich foods. On the other hand, target organs for insulin such as neurons and muscle fibers become with age less sensitive to insulin's action. This target cell resistance prolongs the higher leveis of glucose that appear after meals. Thus, aging tends to produce higher serum leveis of glucose and (a not very active) insulin, a state that is designated by the terms 'insulin resistance' or 'glucose intolerance' or 'pre­ diabetes'. The prediabetic state slowly progresses into 'type 2 diabetes', and after exhaustion of the insulin secretion into 'type 1' or 'insulin-dependent' diabetes. The age-related insulin deficiency may be the reason why very old people tend to Jose weight and look pale and emaciated.

245

I. lnsulin Deficiency: DIAGNOSIS How do you detect insulin deficiency? lndications from a patient's past health, his physical signs, complaints, concurring diseases, and laboratory tests will help detect insulin deficiency and evaluate its severity.

1. Types of lnsulin Deficiency When did the insulin deficiency start? Two major forms of insulin deficiency exist: with or without diabetes. •

In insulin deficiency without diabetes, serum leveis of insulin are low, but glucose leveis remain normal. The patient shows signs of deficiency in insulin such as a poor intestinal nutrient absorption even in the presence of a high calorie intake, a poor muscle development, an abnormally low fat mass, thin body, fatigue, very low fasting insulin leveis, etc. This kind of insulin deficiency is generally not recognized as a disorder, but may nevertheless have far-reaching adverse health consequences such as explained in the case study at the beginning of this chapter. With age, very old people tend to have some degree of insulin deficiency without diabetes that contributes to the loss of muscle (sarcopenia), fat and weight.

People who have always been very thin

often suffer from this form of insulin deficiency that contributes to their extreme thinness. •

In insulin deficiency with diabetes, also called type 1 or insulin-dependent diabetes, the serum insulin levei is low, while the glucose levei is excessive. This is the traditional well-recognized insulin deficiency disease. The patients suffering from type 1 diabetes do not produce sufficient amounts of insulin to put the glucose in the target cells.

Note: Type 2 diabetes is not an insulin-deficient, but insulin-resistant disorder. High leveis of insulin are found in the serum, but the insulin is poorly active on the cells of the brain, heart and muscles, the main targets such for insulin. lnsulin remains nevertheless efficient on fat mass, favoring weight gain and the development of obesity.

246

The main differences between insulin deficiency with and without diabetes are summarized in the following table: Determining the type of untreated lnsulin Deficiency Disease Onset

•

•

Patient's age

Blood leveis

Start

lnsulin deficiency_without diabetes

Type 1 diabetes

Childhood

Syncopal

Athero-

Mortality

Babies, children, adults who were thin ali their life

•

•

High glucose

•

•

Low insulin

•

•

High glycosylated hemoglobin

•

Often acute, developing over several weeks, months

•

From birth on, or

•

Slow, progressive

•

Elderly men, postmenopausal women who became thinner with age Normal to low glucose Low insulin Low-normal glycosylated hemoglobin

Major signs: Thin body, low weight

•

Dehydration: poly/dipsia/uria

•

Thin(ning of the) body

•

Greater fatigue, sleepiness

•

Weight loss

•

Suqar cravinqs

•

Sweets and sugar are less well tolerated

•

Syncopal signs caused by

•

hyperglycemia and cellular depletion in glucose •

Signs of dehydration: sunken

•

eyes, prolonged skin fold, etc. •

sclerosis Prognosis

Slowly progressive in old age

Adults who became thin at a certain period of life

•

signs Dehydration

Birth, or

• •

Children

Major signs: Diabetic signs Major signs

•

•

•

Often present: gangrene and poor wound healing

•

•

Poor if left untreated High, if left untreated

•

Less frequent syncopal signs caused by hypoglycemia and cellular depletion in glucose Absent or less frequently found signs of dehydration Less or no gangrene, but possible poor wound healing Remains acceptable, if no major trauma or disease occurs Normal, if no major trauma or disease occurs

After this quick check, inquire about the timing and location of the patients' complaints.

2. Timing and Location When and where do insulin deficiency signs and complaints occur? When? In most cases, insulin deficiency produces symptoms throughout the day, but may be aggravated if no food is taken at regular times. Where? Muscle, fat and nervous (brain, nerves) tissues will show signs, but also the abdomen

as the digestive system may suffer from pains and present abdominal bloating that regresses and may disappear with insulin supplementation. The next step is to check for the complaints of insulin deficiency.

247

3. Complaints of lnsulin Deficiency A patient afflicted with insulin deficiency may suffer from two types of complaints: complaints caused by diabetes, if there is diabetes, and complaints from non-diabetic origin. The principal symptoms suggestive of insulin deficiency are listed in the following table: Complaints suggestive of lnsulin Deficiency PHYSICAL Diabetes tvoe 1

No diabetes

Head

•

Face

•

Hollow, emaciated face

•

Emaciated face

•

Thinning

•

Major thinness

Body

Normal (no or rare headaches)

Headache

•

Weight loss

•

Low body weight

•

Premature aqinq

•

Muscle hypotrophy

•

Underdeveloped muscles, hypotrophy

•

Volume loss, hypotrophy

Muscles

•

Strength loss

•

Greater weakness

Nervous

•

Sleepiness

system

•

Polvneuropathv

•

Sugar cravings

•

Sugar cravings

•

Feels transientlv better with sweets

•

Sugar intolerance

•

Excessive thirst

•

Excessive water drinkinq (polydipsia)

•

Excessive urination

•

Dry skin

Appetite Thirst Urine Skin

•

Episodes

•

+

Poor strength Normal (no or low sleepiness; no polyneuropathy)

Normal

(i)olvuria)

episodes Sexual

•

of sweating (hyperglycemia intracellular sugar depletion)

Normal •

Less dry skin

•

Episodes of sweating (hvpoolvcaemia) Normal or

Sexual impotence

mildly attenuated

PSYCHIC Energy Alertness Behavior Character Sexual

•

Greater fatigue, general weakness

•

Fatigue, weakness

•

Greater lack of endurance

•

Lack of endurance

•

Moments of low alertness, inattention

•

Coma possible

•

Apathetic

Normal or mildly attenuated

•

Difficulties in receiving and giving love

•

Low libido

•

Men: low sexual potency

•

Relatively normal

•

Fragile personality

•

Vulnerable character Normal or mildly attenuated

Knowing more about the patient's complaints, we can now search for physical signs suggestive of insulin deficiency

248

4. Physical Signs of lnsulin Deficiency Most physical signs of insulin deficiency without diabetes are caused by body weight loss and difficulties to accumulate weight, develop muscles and store fat. In the case of real diabetes, most signs are due to the inadequate glucose supply to the tissues. Physical signs suggestive of lnsulin Deficiency lnsulin deficiency with (type 1)_diabetes

Type Face

• •

•

Body

•

•

Muscles

•

•

Nervous system

•

•

Fat • •

Thirst Genitais (men) Skin

•

Thin, hollow, emaciated face Loss of facial fat

• • •

lnsulin deficiency (without diabetes)_ Emaciated face Lack of facial fat Prominent jugular bones

Thinning • Extreme thinness, 'skin on bone' Low body weight, weight loss (BMI person (BMI < 18 kg/m2) < 22 kg/m2} • Low body weight Premature aging body Droopy muscles (with volume loss, • Underdeveloped muscles (hypotrophy) hypotrophy) Loss of nervous reflexes Abnormal Babinski reflex (slow Normal extension of foot when foot sole is run over with the point of a reflex hammer) Often severe lack of fat mass Loss of fat: loss of subcutaneous, • facial, breast, subscapular, Loss of fat: loss of subcutaneous, abdominal, buttock, hip and thigh facial, breast, subscapular, abdominal, buttock, hip and thigh fat fat • Thin feet, lacking fat Thin feet, lacking fat Excessive thirst Normal Excessive water drinking (polydipsia)

•

Peyronie's disease

•

Dry skin

Normal •

Less dry skin

After checking for complaints and physical signs of insulin deficiency, it is important to look for any disease that may be facilitated by insulin deficiency

5. Disease Susceptibility Which diseases are likely to develop in people with insulin deficiency? Diabetes mellitus, vascular diseases (gangrene, necrotic dermatitis, leg ulcers, proneness to thrombosis, stroke, etc.), cardiac diseases including coronary heart disease, dementia (vascular type or Alzheimer's disease) and sexual impotence, cataract, etc.

249

6. Lab Tests for lnsulin Deficiency What are the laboratory tests to check for insulin deficiency? The laboratory tests for detection of an insulin deficiency are presented in the table below: Blood must be taken in the fasting state after a food fast of preferably 14 hours. Water may be drunk during that period of time. Laboratory tests for detection of lnsulin Deficiency Type

Tissue

Ali types

Serum

Test lnsulin

(fasting}

Glucose Serum

4.4-5.0

1.5-2.4

C-peptide

0.5-0.8

Hemoglobin A1 c Urine •

•

PreDiabetes Serum Type 1 Diabetes Urine

lnsulin treated Serum • Type 1 Diabetes • Severe Type2 Diabetes Urine Note: *

'>'

Glucose

4-7 80-90

(fasting) No diabetes

Optimal value *

(fasting}

4-5 o

Glucose

80-90

(fasting)

4.4-5.0

1.5-2.4

C-peptide

0.5-0.8

Hemoglobin A1 c Glucose (fasting)

4-5

Probable lnsulin Deficiency

References

0-2

3-25 U/ml High 70-105 mg/dl Normal (3.9-5.8 mmoVI) 3.9-5.8 mmoi!J 1.0-3.0 ng/ml Normal (1.0-3.0) Low Normal (0.33-1.0) 0.33-1.00 nmo//1 Normal (4-5.9) 4-5.9% Normal (?o. tos mgtdl)

Normal (no glucose)

High >105* High > 5.8 Low <1.35** <0.45 2: 5.5***

o

Traces of glucose

90-130

No urine glucose

70-105 mg/dl 3.9-5.8 mmoi!J 1.0-3.0 ng/ml High 0.33-1.00 nmo//1 4-6% No urine glucose

70-105 mg/dl 3.9-5.8 mmoi!J 70-180 mg/dl 3.9-8.25 mmol!l High 4-5.9%

Hemoglobin A1 c

4-6.5

High >130/150 High > 7.15/8.25 High > 180 High > 9.9 2: 6.5**

Glucose (fasting]

o

Traces of glucose

No urine glucose

Microalbumine

o

Microalbuminuria

o

Glucose

(fasting)

Glucose (nonfasting)

means 'higher than'; **

'<'

4.95-7.15

90- 180 4.95-9.9

Test Value

means 'lower than'; *** '2:' means 'equal to or higher than'

At what leveis of the glycosylated hemoglobin assay should a patient with type 2 diabetes be treated with insulin injections?

At persistent serum leveis of glycosylated hemoglobin (HbA1C) over the 7 or 8% after failure of dietary changes and oral antidiabetic agents. Each oral agent can decrease the HbA1 C by 12%. A switch to a Paleolithic diet can decrease the HbA1C by 1 to 1.5%, while the typical diabetic diet that includes milk products and complex carbohydrates such as pasta's and whole grain bread, which are absent in the Paleolithic diet, only by O to 0.5%.

250

11. lnsulin Deficiency: TREATMENT lnsulin Medications Treatment of diabetes with insulin injections, an insulin pump or other Subcutaneous insulin injections are the most popular treatment for severe insulin deficiency. The table below presents frequently available insulin preparations for patients with diabetes:

Treatment of Diabetes with lnsulin lnjections Route

Action

Products (ali are human biosynthetic insulin)

Peak

Start

Ultrashort (rapid) acting insulin

5'

-

Subcutaneous (IM oriV in emergencies)

o Novorapid®

lnsulin aspart: 1oo U/ml in

5'to 15'

lnsulin lispro: 1oo U/ml in

afterthe afterthe afterthe injection injection

5x 3m I cartridge or 1O ml vial

oHumalog®

1to 2 h 2to 5h

5x 3m I cartridge or 1O ml vial injection lnsulin glulisin: 100 U/ml in 5x 3ml cartridge

oApidra®

Short-acting insulin

o Actrapid® o Humulin

Biosynthetic insulin: 100 U/ml 20' to 40'

1 to 3 h 2to 6 h

5x 3m I cartridge or 1O ml viaI

regular®

lntermediate-acting insulin •

o

lnsulin isophane:100 U/ml:

lnsulatard®

5x 3ml cartridge or 1O ml vial 1 to2h

Humulin NPH®

When

Duration

4to7h

10to 18h

fcN611eS�re

eac h meal or just before an afternoon snack (or just after) 20 to 30' before a meal or afternoon snack

lonQer action than insulin detenmir)

o Lantus® Subcutaneous (not

lnsulin determir:100 U/ml:

5x 3ml cartridge

•

1h30

to4h

No peak

20 to24h

Before bed

•

resistant to oral antidiabetics

Occasional use: •

during

5x 3ml cartridge

infections, stress,

lnsulin aspart soluble 30 U/ml

trauma

2 peaks:

lnsulin aspart protamine 70 U/ml:

5x 3ml cartridqe

10'

IV!) o Humalog Mix® lnsulin lispro protamine 70 U/ml: 5x 3ml cartridge

1to 2h & 4to7h

10to 18h

5to 10' before a meal

Mixtard 30®

o Humulin® 30{70

o Mixtard 50®

Biosynthetic insulin: 30 U/ml

lnsulin isophane: 70 U/ml:

5x 3m I cartridge or 1O ml vial

Pregnancy diabetes

the serum leveis of:

5x 3ml cartridge

- Short-& intermediate-acting insulin associations o

•

=>to reduce

nsulin lispro soluble 50 U/ml o Humalog Mix® lnsulin lispro protamine 50 U/ml:

50/50

Type 2 diabetes

lnsulin glargine: 100 U/ml

lnsulin lispro soluble 30 U/ml

25{75

Type 2 diabetes

Ultrashort-& intermediate-acting insulin associations

o Novomix 30®

Type 1 diabetes

&for bed

lnsulin protamine:100 U/ml 5x 3m I cartridge or 1O ml viaI

=>

Permanent use:

Before breakfast

Long-acting insulin

I(lnsulin QlarQine o Levemir®

lndication

- glucose

� peaks: 20' to 30' 1 to 3h

Biosynthetic insulin: 50 U/ml

lnsulin isophane: 50 U/ml: 5x 3ml cartridge or 1O ml vial

251

& 4to7h

- insulin 10to 16h

20to 30' before a meal

- glycosylated

hemoglobin

Treatment of lnsulin Deficiency with an insulin pump Route

(with human biosynthetic insulin)

lnsulin

Sub-

ultra-

cutaneous

short (rapid)-

injectable

Frequency

Bolus insulin

dose

doses

dose

Diabecare®

0.01

Ping®

0.025 u

12x/day

a fixed or

0.05 u

48x/day

basal

Best life®

0.05 u

48x/day

Paradigm®

0.05 u

48x/day

automatically

48x/day

12 to 48

pumps Cozmo®

with

Basal insulin

Smallest

Devices

acting Omnipod® insulin

to 0.1 U 24x/day

0.05 u

(up to 30 U/h) 0.1 u

Spirit®

(up to 25 U/h)

variable insulin doseis

Additional 'bolus' doses are injected

Permanent 5' to 10' before each use: meal or

injected times

per day

24x/day

lndication

Type 1

•

diabetes

just after an afternoon snack (or just after)

Note: The pattern for delivering basal insulin throughout the day can be adapted to suit the pump user, e. g.:

•

Programming a pre-dawn insulin increase to prevent the increase in blood sugar due to the 'dawn effect' in adults and teenagers.

•

Programming an increase of the basal insulin delivery before regularly scheduled exercise times such as morning gymnastics or after work o r school swimming and jogging.

•

Programming a reduction of lhe basal insulin delivery at night to prevent a drop in the blood sugar often observed in infants and toddlers, while in teenagers the opposite may be necessary, namely to program an increase of the basal insulin delivery at night to counteract increases in blood sugar leveis due to the nighttime peak leveis of growth hormone.

Treatment of lnsulin Deficiency with other devices than subcutaneous administration Route

Action

Products (al i

with human biosynthetic insulin)

S tart

Peak

Duration

When to inject Split the dose:

Ultrashort

2to

Oral spray:

(rapid)-acting 2canisters with 80 S'to 15' 30 to 50' Buccal insulin puffs => 1 puff 1 after after u thepuff thepuff (Orai-Lyn, =

of insulin

Orai-Recosulin®)

Oral lntranasal

2h30

after the puff

In development

Tablets

•

half the dose

before the meal

just •

half the dose

after the meal

just

•

Pu Imonary

lnhalable insulin ( E xubera®)

use: •

Type 1

•

Type2

diabetes diabetes

resistant to

insulin reach the

oral

blood stream

antidiabetics

Occasional use:

90 or 180 blisters

•

of 1 mg insulin dose 5' to 15' 30 to 90' •

Permanent

About 30% of the

In development

Nose spray

lndication

90 blisters

of 3 mg insulin dose after after thepuff thepuff =>1mg=3U

6h

Type2 diabetes

Before each meal

during infections, stress,

of subcut. insulin

trauma

Withdrawn from the market by its producer due to a lack of acceptance and concerns on possible bronchial tissue

damage; An USA firm works on a new inhalable insulin.

252

•

Pregnancy diabetes

Note: •

•

In patients with type 1 diabetes, buccal and inhalable insulin medications should be used in regimens that include a long-acting injectable insulin. For patients with type 2 diabetes, buccal and inhalable insulin may be used as monotherapy or in combination with oral agents or longer-acting insulin. lnhalable insulin is contraindicated in patients who smoke or who have discontinued smoking less than 6 months prior to starting the therapy. lf a patient starts or resumes smoking, the inhalable insulin must be discontinued immediately due to the increased risk of hypoglycemia, and an alternative treatment must be utilized. The safety and efficacy of inhalable insulin in patients who smoke have not been established.

Target serum glucose leveis for a diabetic patient treated with subcutaneous insulin For most diabetic patients the following target blood leveis are recommended:

TARGET serum glucose

Diabetic patients •

not at higher risk of hypoglycemia

•

at risk of hypoglycemia (previous

in mQ/dL

Fasting

90 to 130 mg/dl

Meals Fasting

<

180 mg/dl

90 to 150 mg/dl

in mmoi/L 5 to 7.2 mmoi/L <

10 mmoi/L

5 to 8.3 mmoi/L

hypoglycemic episodes, tapering off a glucocorticoid therapy, liver/kidney

Meals

<

disease, etc.) Note:

"<"

180 mg/dl

<

10 mmoi/L

means "below"

Frequently used insulin regimens The following insulin therapy regimens are the most popular:

FREQUENT REGIMENS

When to administer? 20 to 30' before Breakfast ++

3 injections

4 injections

Frequent checks of the blood glucose levei For diabetic patients, none of the above-mentioned regimens can be optimized without frequent assessment by blood glucose monitoring.

253

Determining the total amount of insulin to supply each day to a patient without any endogenous insulin production In diabetic patients who cannot produce any insulin anymore the total amount that they need to live and feel good can be calculated by knowing the body weight as shown in the table below:

Determining the total daily insulin dose Multiplication

Body weight

coefficient

In pounds

x0.25

In kilograms

X 0.55

Body

Body

Total insulin

weight

weight

dose per day

(lb)

Formula=>

lb X 0.025

240 lb X 0.25

2401b

109 kg

2001b

91 kg

200 lb X 0.25

1601b

73 kg

160 lb X 0.25

=

60 U

of ínsulin!day

=

units/day

kg X 0.55

(kg)

Total daily insulin dose

=

units/day

1201b

54 kg

120 lb X 0.25

801b

36 kg

80 lb X 0.25

401b

18 kg

40 lb X 0.25

=

50 U

=

40 U

=

30 U

=

20 U

=

10 U

Adapting the insulin dose to the body size and age

As we can see, lean people (body mass index (BMI) below the 25) need a lower dose (often around the 0.4 units per kg per day), while a higher dose is necessary for overweight persons (BMI 25-30, the dosage should be 25 % higher, often around the 0.5 units/kg/day) and obese subjects (BMI

>

30, the dosage should be 50 % higher, usually around the 0.6 units/kg/day).

Furthermore, •

Patients with important insulin resistance usually require a higher dose, while patients with a high sensitivity to insulin may require a lower dose.

•

Diabetic patients on high dose steroids also have higher insulin requirements (about 0.6 units/kg/day).

•

Patients on dialysis need lower doses (0.3 units/kg/day) regardless of their body mass index.

•

Prepubertal children (outside the partia! remission phase) usually require 0.7-1.0 U/kg per

day. During puberty, requirements may rise substantially above the 1 U/kg per day Determining the amount of insulin necessary to supply to ensure adequate basal insulin leveis outside of meals?

In most patients this basal or background insulin dose is 40 to 50 % of the total daily insulin dose. lf the total daily insulin dose is 40 units per day for example, then 50 % of 40 units (thus 20 units per day) should be used as basal insulin dose and supplied as subcutaneous injections of intermediate or long-acting insulin or through an insulin pump, which delivers ultrashort (rapid)­ insulin.

acting

254

Determining the amount of insulin necessary to supply before meals to ensure adequate insulin activity at meals?

The additional amount of insulin to provide at meals or in case of extra needs is called a 'bolus'. The bolus to provide may vary following the total daily insulin dose and in particular the amount of carbohydrate consumed in the next meal.

The rule of 500 To calculate how much grams of carbohydrate one unit of insulin can cover, the rule of "500" is often applied as shown in the table below:

Determining the additional insulin dose for a meal Grams of Total insulin dose per day

Body

Body

weight

weight

(lb)

(kg)

Rule of "500"

Additional insulin dose

carbohydrate

to correct a dietary

covered by

carboh drate load of ...

1 unit of insulin

(Carbohydrate

50g

100 g

200 g

coverage ratio) 500 60 u

2401b

109 kg

divided by the 'total

50 u 40 u

2001b 1601b

91 kg

insulin dose per day'

73 kg =

30 u 20 u 10 u

1201b 801b 401b

54 kg 36 kg 18 kg

number

500 :60 =

8 g of carbs covered

500:50 =

1O g carbs for 1 U

500:40 =

12.5 g carbs for 1U

of grams

500:30

of carbo-

=

hydrate that 1 unit of insulin will cover

6U

12.5 u

25 u

5U

10 u

20 u

4U

8U

16 u

3U

6U

12 u

2U

4U

8U

1 u

2U

4U

by 1 U of insulin

17 g carbs for 1U

500:20 =

25 Q carbs for 1 U

500: 10 =

50 g carbs for 1U

The example above assumes that the patient has a constant response to insulin throughout the day. In reality, the individual insulin sensitivity varies during the day, being often lower in the morning and in the evening than at lunch. For this reason patients may need to adjust their insulin dose to the difference in carbohydrate content of each meal. lf for example, the total daily insulin is the 40 units per day, the insulin-to-carbohydrate ratio at breakfast may be 1 to 8 (meaning that 1 unit of insulin is necessary to cover 8 grams), at lunch the ratio may be 1 unit of insulin to 15 grams and at supper 1 to 12 grams.

255

Please keep the following in mind: o

The estimated insulin regimen is an initial "best guess". The dose may need to be modified to keep the blood sugar on target.

o

There are many variations of insulin therapy. The patient will need to work out his/her specific insulin requirements and dose regimen with the medicai provider.

Determining the amount of insulin necessary to correct excessive blood sugar leveis (hyperglycemia) The additional insulin dose necessary to correct an excessive blood glucose leveis can be found by applying the rule of "1800" as shown in lhe table below The following table provides advice on how to correct an excessive blood sugar following the extent of excess in the blood:

Determining the insulin dose necessary to correct hyperglycemia Total insulin dose per day

Body

Body

weight

weight

(lb)

(kg)

60 u

2401b

109 kg

50 u

2001b

91 kg

40 u

160 lb

73 kg

30U

120 lb

54 kg

20U

801b

36 kg

10 u

40 lb

18 kg

Drop in serum Rule of

glucose levei

"1800"

(mg/dl) with 1 uni! of insulin

1800: 60 1800 divided = -30 mg/dl by the 'total 1800: 50 insulin dose = -36 mQ/dL per day'= 1800:40 reduction in = -45 mg/dl serum 1800:30 glucose levei = -60 mg/dl (mg per dl) 1800: 20 obtained

lower lower lower lower

with 1 uni! of = -90 mg/dl lower 1800: 10 insulin = -180 mg/dL lower

Additional insulin dose to correct an excess in serum ! lucose of ... +50 mg/dl

+ 100 mg/dl

+ 200 mg/dl

2U

3U

7U

1.5 u

3U

5.5 u

1 u

2U

4U

1u

1.5 u

3U

0.5 u

1u

2U

o

0.5 u

1 u

Distributing the insulin doses over the day Patients on twice-daily regimens often require more (perhaps two-thirds) of their total daily insulin in lhe morning, and less (perhaps one-third) in lhe evening. For example, a patient on 70/30 whose total insulin dose per day is 60units may have to take 40 units in the morning and 20 units at dinner.

256

Conditions that may increase the glycemia (blood sugar) above recommended leveis A temporary high blood sugar levei from time to time is impossible to avoid in everyday life. The following conditions may increase the blood sugar levei above recommended leveis: infection, high-sugar-containing foods (cakes, ice cream, candies, chocolate, etc.), stress, high­ dose glucocorticoid therapy, missed insulin injections, problems with the injection technique or sites {lipodystrophy, lumpy areas under injection sites) The following table provides advice on how to correct an excessive blood sugar levei following the time of the day the hyperglycemia appears:

Determining the best time of the day and type of insulin to additionally inject to correct hyperglycemia PROBLEM: H__\'Q_erglycemia When? Blood ÇJiucose Before breakfast After breakfast

>

>

130 or 150 mg/dl 180 mg/dl

SOLUTION: increase the insulin dose When? Before supper or bed Before breakfast Before

Before supper (evening) After supper

>

130 or 150

mg/dl

>

180 mg/dl

breakfast

Type of insulin to increase lnsulin dose to add lntermediate or long-acting

Short- or ultrashort-acting •

lntermediate-acting insulin

(or)

Short or ultrashort-acting

Before lunch

insulin if the patient takesboluses before meals

Before supper

•

(increase basal insulin)

Short- or ultrashort-acting

lf only one glucose check is > 180 mg/dl => increase with 2 to 4 units of insulin lf severa! glucose measurements were > 180 mg/dl and none < 80 mg/dl => use 11 O % of yesterday's total as new total and then re-divide as 50% basal and 50% bolus

Conditions that may reduce the glycemia (blood sugar) below recommended leveis A temporary low blood sugar levei from time to time is impossible to avoid in everyday life. The following conditions may lower the blood sugar levei below recommended leveis: Reasons for low blood sugar leveis include: missed or delayed meals, too much insulin, increased exercise, unexpected exercise, alcohol, problems with the injection technique or sites {lipodystrophy, lumpy areas under injection sites).

Determining the best time of the day and type of insulin to additionally inject to correct hypoglycemia PROBLEM: H..YQ..oglycemia When?

Serum glucose

Before teatime (afternoon snack) Before supper

After supper

When? Before supper or bed

Before breakfast Before lunch

SOLUTION: reduce the insulin dose

<

80

or <

Before breakfast

Short or ultrashort-acting

Before lunch

Short or ultrashort-acting

Before lunch

Short or ultrashort-acting insulin if the patient takesboluses before mea/s

Before supper or bed

lntermediate or longactinq (basal insu/in delivery)

90

mg/dl

Type of insulin to reduce lntermediate or longacting (to reduce the basa/ insulin delivery)

257

lnsulin dose to reduce •

lf only one glucose analysis is < 80mg/dl=> reduce with 2 to

4 units of insulin .

lf severa! glucose measurements were < 80 mg/dl =>use 80% of yesterday's total insulin given as new total

lnsulin Treatment of Non-lnsulin Deficient States

Several non-diabetic states of insulin deficiency exist in states of cancer or AIDS cachexia, and in extreme thinness or malabsorption syndromes. In these cases the preference is given to use shortacting insulin injections before each meal to optimize intestinal nutrient absorption. In the non-therapeutic (ab)use of insulin in body building, body builders prefer injecting daily the long-acting insulin once per day. We recommend the use of insulin for therapeutic reasons only. Very low doses of insulin are in nondiabetic states recommended and generally safe and sufficient for the treatment of conditions without diabetes. Higher doses may cause dangerous hypoglycemia. The table below presents frequently used insulin preparations for patients without diabetes:

lnsulin Treatment of Non-lnsulin Deficient States Route Product Subcutaneous

Short-acting insulin

Beneficiai effects •

lncreases muscle mass

•

lncreases fat

When to inject

Before each meal

mass, without

Doses 1 to 3

lndication

U of

•

short-acting insulin

excess, in people

Subcuta- lntermediate neous or long-acting (possibly insulin

IM)

with lean body who practice regular sports and follow a diet

•

Before breakfast or

rich in protein-rich before foods and poor in bed refined

5 to 10

U of

intermediateor long-acting insulin

Muscle gain in

thin persons with low muscle and fat mass Weight (fat & muscle) gain in very thin people, patients with cancer/AIDS cachexia, malabsorption syndromes

carbohydrates

Note: Candies, chocolate, unsprouted bread, pasta's, muesli, rice, etc. are refined carbohydrates.

258

lndications for lnsulin Treatment General indication: lnsulin deficiency with diabetes. Specific indications: •

Medicai conditions with low fasting serum insulin levei (but without diabetes) such as extreme thinness, cancer or AIDS cachexia, malabsorption syndromes

•

Rarely: insulin-resistant diabetes with glucose leveis that remain high despite the intake of oral anti-diabetic medications.

Contraindications to lnsulin Treatment: Absolute contraindications: •

Low fasting blood sugar leveis

•

lnsulinoma

Relative contraindications: •

Cortisol deficiency - as patients with low cortisol fali into hypoglycaemia more easily with insulin treatment than other people. Many patients with diabetes who frequently fali with insulin treatment from hyperglycaemia into hypoglycaemia (a condition called labile diabetes) have in fact cortisol deficiency. The best way to treat patients with combined cortisol and moderate insulin deficiencies is to correct first the cortisol deficiency with hydrocortisone or a synthetic glucocorticoid derivativa, then add insulin a week or two !ater. When the insulin deficiency is severe, both treatments should be provided from the beginning.

•

Contradindications for ultrashort-acting insulin: persons with gastroparesia's

259

How to start lnsulin Therapy In cases of type 1 diabetes mellitus, treatment should be fine-tuned under the supervision of diabetologists during a stay in hospital. We recommend beginning with low doses of insulin to 1 O units) slowly titrated to the optimal levei.

(5

Check by frequent blood analyses the se rum

glucose levei. For low insulin conditions without diabetes, treatment with short-acting insulin should start at low doses of 1 U before each meal and then after a week possibly increase to 2 U before each meal and possibly a week later to a maximum of 3 U before each meal. lf the patient presents with side-effects of nausea or dizziness, reduce the dose by 1 to 2 U before each meal. In cachexia, higher doses may be necessary and well-tolerated. In the case that long-acting (slow releasing) insulin is used to treat non-diabetic conditions with low insulin, the dose to administer is around

5

to 1 O U per day, preferably taken in the

morning. Some patients need or tolerate only 1 to 2 U of a short-acting insulin before each meal. These oversensitive people may be deficient in cortisol, a condition which facilitates intolerance to many medications. In this case, it works better to correct the cortisol deficiency first and then to simultaneously or afterwards correct the insulin deficiency.

How to Start lnsulin Treatment Route

Product

lndication

Starting Dose

Type 1 diabetes

5 to

1 O IU/day

Qptimal dose Depends on the patient: 20-1 00 U/day

Depends on the severity of

lnsulin, Subcu1 IU/day for shortshort & taneous Low insulin acting insulin longinjection without acting (®) diabetes 3 IU/day for longacting insulin

the insulin deficiency and the patient's sensitivity to insulin: 2 to 15 U /day •

2 to 3x/day of a shortacting insulin before meals, or:

•

1 to 2x/ day of a long-

acting insulin in morning

Progress with lnsulin Treatment How quick can improvement be noticed with insulin treatment? •

•

For diabetes: lnsulin starts improving the glycemia in the first ten to thirty minutes after injection. For non-diabetic conditions: o

Energy leveis increase within the first week of treatment.

o

Weight gain with muscle mass increase appears within the first three to four weeks of insulin treatment and climaxes about two to four months after the start of the treatment.

260

How to Optimize lnsulin leveis and avoid lnsulin Spilling Firstly, you can boost insulin production and/or its effects by improving the lifestyle, including eating a better diet.

What to do and what not to do to obtain optimal insulin leveis and avoid unnecessarily wasting insulin is summarized in the following table. Optimal Lifestyle for lnsulin WhatTo Avoid

WhatTo Do

(conditions that reduce insulin production or effects, or induce insulin spilling)

(conditions that increase insulin production or effects) Eat foods that are rich in proteins (meat, poultry, fish, eggs, etc.)

•

Eat foods that are rich in magnesium (green leafy vegetables such as spinach and lettuce, etc.)

•

Diet

Eat foods that are rich in trace elements such as zinc (seafood, soaked nuts, etc.), chromium (oysters, liver, sprouted whole grains) and manganese (chard, raspberries, pineapple, romaine lettuce, kale)

•

Physical

lncrease moderate physical activity such as walking and leisure- jogging

•

activity

•

•

•

•

•

Avoid malnutrition, avoid eating too little protein- and magnesium-rich foods Avoid sugar, sweets, cakes, soft drinks, not sprouted grains (bread, rice, pasta, pizzas, muesli) as they cause spillage of insulin Avoid milk products as they increase the risk of insulin-deficient type 1 diabetes, esp. in children Avoid caffeinated beverages (coffee, tea, cola) and alcohol as they cause spillage of insulin Avoid a sedentary lifestyle

Secondly, insulin leveis can be increased by correcting other hormone dysfunctions that adversely affect insulin production and/or its effects.

The hormone replacement therapies that can influence insulin production and its effects on the body are summarized in the following table: lnfluence of Hormone ReplacementTherapies on lnsulin Potent lnsulin

•

• •

Transdermal estradiol DHEA

•

Testosterone

•

Melatonin

•

Vasopressin

•

1 ,25-(0H)2-Vitamin D

•

inhibitors/ blockers

blockers

IGF-1 Thyroid treatment

Potent lnsulin

inhibitors/

Stimulators

Optimizers •

Weaker lnsulin

Weaker lnsulin

Stimulators/

• • •

Progesterone

261

• •

Oral estrogens Growth hormone Hydrocortisone Parathormone MSH

• •

Glucagon Excessiva doses of glucosteroids

Follow-up of ln s ulin Treatment

1.

Find the adequate dose:

After starting insulin at a low dose - 1 or 5 U per meal - depending on the absence or presence of diabetes, doses should be slowly increased and titrated to the optimal dose that provides maximal effects without side effects. The most frequent conditions that require a change and adjustment in dose are reviewed in the following table: When to adapt the dose of insulin Dose •

Diet • •

Hormone treatment

•

• •

Disease

2.

•

lncrease the dose {25 to 200% more) Carbohydrate-rich diet:

sugar, sweets, bread, pasta, soft drinks, etc.

Alcohol drinkinQ Oral synthetic glucorticoids Cortisol (glucocorticoid) treatment of adrenal deficiency Growth hormone treatment Diabetes mellitus Hyperparathyroidism (excessive parathormone)

Lower the dose {25 to 75 % less) • •

• • • • • •

Fasting, empty stomach Protein-rich diets IG F-1 treatment Transdermal estradiol Testosterone treatment Thyroid treatment Cortisol deficiency Tendency to hypoglycaemia

Avoid overdosing and underdosing:

Control of the treatment occurs primarily by checking for the presence of any signs and complaints of insulin over- or underdose. When to check? The patient should monitor himself every day for improper dosing and the physician should follow-up with the patient every two to nine months.

262

lnsulin overdoses: The following table summarizes the main complaints of insulin excess/overdosing:

lnsulin Overdosage Frequencv

Overdose Si!:ms • •

Fatigue

•

Being unwell, dizziness

Most

•

Somnolence

frequent

•

Nausea

•

Headaches

•

Cold sweating

•

Coldness access

•

Coma

•

Multiple hormone

Rare

MECHANISM

HiQh risk patients

Hunger, sugar craving

deficiencies (thyroid, testosterone, growth hormone, etc.) Less

•

Thin (BMI < 18.5 2 kg/m ) and lean 2 (BMI: < 25 kg/m )

•

Cortisol-deficient

Hypoglycemia

persons persons

Severe

•

hypoglycemia An important increase in muscle volume by body building requires higher amounts of ali hormones

frequent

•

Athletes practicing body building

•

and solely

Overweight (BMI : 2 25-29.9 kg/m ) and obese people

with longterm use

Type 1 diabetic patients

• •

Excessive weight gain Fat increase on belly, hips, thighs

Excess increase in fat mass in overweight persons

(BMI: 30 or higher) •

A diet high in foods rich in carbohydrate such as sugar, sweets, cookies, chocolate, soft drinks, etc.

3. Correct any problems during follow-up quickly and efficiently

4. Solve problems quickly and efficiently: See next section to know how to do it.

263

111. lnsulin PROBLEM SOLVER How to solve problems that occur during insulin treatment? The most frequent problems that may occur during treatment and their solutions are described in the following table: Problems due to insulin overdose or underdose

Problems due to lnsulin Overdose or Underdose

Sugar craving

•

Fatigue

•

Feeling of

•

SOLUTION

POSSIBLE CAUSE

PROBLEM •

•

Provide a piece of sugar in the mouth to Reduce the insulin dose by 1 O to 70 % Correct the cortisol deficiency at low

quickly restore normal glucose leveis

being unwell,

Hypoglycaemia

•

dizziness

due to

•

doses with hydrocortisone or a synthetic and is at less risk of

Somnolence of various

derivative

an excessive

•

aggravating any existing osteoporosis.

dose of insulin

degrees •

Nausea

or

•

Headaches

•

•

Cold sweating

•

Coldness

Add DHEA to the glucocorticoid treatment and/or any other anabolic hormone in

cortisol deficiency

which the patient may be deficient, to maintain

outburst •

•

Severe

anabolic-

cases:

intravenous glucose

infusion

dose of insulin •

Provide a piece of sugar in the mouth to extreme

to an excessive

Coma

well-balanced

quickly restore normal glucose leveis; in

hypoglycaemia due

•

a

catabolic ratio.

•

Reduce the insulin dose by 1 O to 90 %

Major hyperglycaemia due to an

•

insufficient dose

Provide subcutaneous or

intravenous

insulin quickly

of insulin in patients with diabetes •

Excessive thirst (polydipsia)

•

Excess urine (polyuria)

•

Fatigue

•

Somnolence

Hyperglycaemia due to an insufficient

•

dose of insulin in

lncrease the dose of subcutaneous insulin

patients with diabetes

264

Problems due to long-term inadequate use of insulin

Problems due to long-term lnadequate use of lnsulin PROBLEM

POSSIBLE

HIGH RISK

CAUSE

PATIENTS

SOLUTION

Excessive development of lean mass (organomegaly) and muscle mass •

Multiple

in body builders

deficiencies in

who use insulin to

hormones

increase their

other than

muscle mass

insulin (thyroid,

(insulin's anabolic

testosterone,

actions)

growth hormone,

supplementary

etc.)

amounts of

•

Reduce the insulin dose or stop the

•

Athletes

treatment if

practicing body building

=>

unnecessary .

Treat the other hormone deficiencies

hormones are necessary to supply the extra cell and tissue mass • •

Excessive fat •

•

(BMI:

Excessiva

overweight

obese persons

weight increase

persons due to:

(BMI:

Fat

•

on belly, hips, thighs

lncreased fat

•

production •

treatment (in

25-29.9

2 kg/m ) and

accumulation

dose or stop the

Overweight

mass in

�

30)

borderline insulin deficiencies only) •

(GH, thyroid, hormone

rich food

Reduced fat

intake: sugar, sweets,

with insulin

cookies,

treatment

chocolate, soft drinks, etc.

Treat the other testosterone)

Carbohydrate-

breakdown

Reduce the insulin

deficiencies that allow the person to easily increase in fat mass •

Eat a better diet: low in carbohydrates and rich in protein

265

Chapter Fifteen

Estrogen and

Progesterone Deficiency and Treatment in Women Case Study of a Patient with Female Hormone Deficiency Marjorie, age 46, is a strong businesswoman who is well-known for her stable and dependable character but lately her stable routine has been interrupted by her highly irregular menstrual periods. One month they come early, the next month late. She is also experiencing other new symptoms that change from month to month. One month, her breasts are tender, painfully swollen, and her periods are heavy with blood clots. The next month, her breasts may be fine and her period flow is rather light. Marjorie's mood has also changed; her stable character has been replaced by mood swings. She may be depressed or anxious for no reason. Moreover, her high amounts of energy have disappeared and now she often feels fatigued. Her looks are changing too.

Her face has

become pale. Her hair is thinning at the top of the skull. Small vertical wrinkles have appeared just above her lips and crow's feet at the corner of her eyes. At her annual mammogram, cysts were found in her breasts, but luckily they were found to be benign. She feels that her body is aging much too quickly. What is Marjorie suffering from? Marjorie's problems are typical of female hormone deficiency. To better understand what this deficiency means and how it can be treated, we will review some basic information on female hormones.

267

Female Hormones: Basic lnformation

Estrogen potency Estradiol is the most potent estrogen. lt is ten times more potent than estrone. lt converts into estrone and then to estriol.

Functions of Estrogens and Progesterone There is a delicate balance between the female hormones estrogens and progesterone. These hormones have both antagonistic and complementary effects to keep the body in homeostasis. Antagonistic effects of Estrogens and Progesterone While estrogens make the body retain fluid and cause swelling (especially of the breasts and abdomen), progesterone acts as a diuretic. lt blocks excessive swelling in two ways: firstly, by reducing the number of estrogen receptors in the body (especially in the breasts and uterus), and secondly, by blocking the receptors for a major water­ retaining hormone, namely aldosterone.

The diuretic property of progesterone is not

shared by most synthetic progestogens, which are derived from androgens and are structurally different from progesterone. As androgens make the body retain fluid (especially in the feet and ankles), so do synthetic progestogens that are generally derived from androgens.

Nevertheless they may decrease breast swelling by reducing

the number of estrogen receptors in the breast. While estrogens may increase menstrual blood loss by stimulating the proliferation of uterine endometrium, progesterone stops endometrial proliferation, limiting menstrual blood loss. Estrogens also stimulate the sympathetic nervous system and in this way increase alertness, but if uncontrolled and unopposed by progesterone they can make a woman very nervous. On the other hand, progesterone calms down the emotions and mood by stimulating the parasympathetic nervous system. Complementary effects of Estrogens and Progesterone Estrogens, estradiol in particular, "feminize" the body. They shape the female body, enlarge breasts and pelvis, redden the skin (by increasing blood supply to the skin), cause proliferation of the endometrium in the uterus and thus make menstruation possible.

The quick drop of the levei of estrogens at the end of the menstrual cycle

causes the period to start. Also, estradiol is responsible for vaginal lubrication, a healthy libido, the female voice, and initiating ovulation.

Estriol's effects are more limited; its

main known role is to thicken and humidify the mucous membranes of vagina, bladder and eyes, making them resistant to infection, but it has very little effect on the endometrium of the uterus.

268

Progesterone's role is to prepare the uterus for implantation of a fertilized egg cell. lt plays an essential role in pregnancy. One of the most important roles is the transformation of the proliferative endometrium of the first (follicular) phase of the menstrual cycle into a secretory one during the second (luteal) phase where the serum progesterone levei is high. The changing of the phases prepares the uterus for implantation of a fertilized egg cell. Progesterone also closes the uterine cervix during the luteal phase and pregnancy, so that the fertilized egg cell and later fetus remain inside of the uterus for the time of the pregnancy.

Production of Estrogens and Progesterone Daily secretion of estradiol in young (18-30 years old), healthy women is 60-200 119 a day depending on the phase of the menstrual cycle (with greater production in the second half of the cycle). Progesterone secretion is 1 to 2 mg a day in the first half of the menstrual cycle (follicular phase) where it is almost entirely produced by the adrenal glands and 20-40 milligrams per day in the second half (luteal phase) of the menstrual cycle due to ovarian production.

Factors that influence Estrogen and Progesterone production lntensive prolonged physical activity, such as sexual intercourse and long-distance running, use up the sex hormones and may thereby reduce the leveis of female hormone. lntense emotional stress can inhibit the secretion of estrogens and progesterone by inhibiting the release of the pituitary hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH) which stimulate the production of estrogen and progesterone. Eating foods high in protein or saturated fat increases estrogen and progesterone production, but eating sugar, and fiber (e.g., cereais rich in fiber, whole grain breads, bran flakes) can reduce female sex hormone leveis.

Female hormones and the aging process Women are born with one to two million undeveloped eggs in her ovaries. When women reach puberty and start menstruating, only about 300,000 immature egg cells, or follicles remain, of which an average of 600 egg cells die per month and are not replaced. No good eggs remain at the time of menopause and since the eggs are the principal producers of female hormones, this explains why ali women become hormone deficient over time.

Principal metabolites of Estrogens and Progesterone: For estradiol: Estrone, estriol, 2-0H-estrone, 4-0H-estrone and alpha-16-0H-estrone, 2methoxy- estrone and 4- methoxy -estrone For progesterone: Pregnandiol

269

1/ Female Hormone Deficiency: DIAGNOSIS How can you detect Female Hormone Deficiency?

The patient's past medicai history, signs, symptoms and lab tests are ali important factors in the female hormone deficiency diagnosis.

1. Onset of Female Hormone deficiency When did the female hormone deficiency start? lt is important to determine when the deficiency began as the longer the hormone deficiency exists, the greater it generally is. In rare instances a woman may have had the female hormone deficiency since puberty. The main way to determine this possibility in a woman is by evaluating the degree of sexual maturity of her body. An overview of the main differences between the two types of the major female hormone deficiencies is presented in the following tables: Women who have estrogen deficiency from early puberty remain relatively sexually immature; whereas women who began to suffer from estrogen deficiency later in adulthood, have developed a sexually mature body but they develop symptoms of menopause. Determining the Onset of ESTROGEN DEFICIENCY Onset

Before or at puberty

Physical appearance Body

Breasts Pelvis Genitais

History

Later in adulthood

Eunuchoid ("neutra!"), or • Android ("boy-like") • Sexually immature body • Micromastia (small breasts) • Android (narrow) • Underdeveloped: Smaller vagina and uterus • Late menarche (age 15 and up) Early appearance of menstruation problems, namely at puberty • Irregular menstrual cycles, esp. spano-menorrhea (long cycles of more than 32 days) • Hypo-or amenorrhoea (scanty or no menstruation) • Lowered fertility, necessity of invitro fertilizations to become pregnant • Spasmodic dysmenorrhea •

270

•

• • • •

Gynoid (female) Sexually mature body Breast ptosis (droopy breasts) Gynoid (wide) Normal size, but atrophying

Normal menarche (ages 12-14) Menstruation problems appeared later, namely in adulthood • Irregular menstrual cycles, esp. spano-menorrhea (long cycles of more than 32 days) • Hypo- or amenorrhoea (scanty or no menstruation) • Lowered fertility, necessity of in-vitro fertilizations to become pregnant • Spasmodic dysmenorrhea •

Progesterone deficiency alone, even if it begins in puberty, will not lead to a sexually immature body. Since a progesterone deficiency results in the inability to keep estrogen in check, the body will have magnified estrogen-related sexual characteristics such as an enlargement of genital areas, especially the breasts. A progesterone deficiency that originated later in adulthood, when organs are already developed, will lead less to an increase in size of organs but more frequently will cause benign tumor formation in genital areas (because of local edema problems) such as breast fibrocysts, ovarian cysts, uterine fibroids.

Determining the Onset of PROGESTERONE DEFICIENCY

(in the presence of a relative estrogen excess)

Breasts Body

Later in adulthood

Before or at puberty

Onset

•

Macromastia (enlarged breasts-greater than Tanner stage 4)

Ovaries Uterus

Breast cysts

Ovarian cysts Normal sized uterus • Uterine fibroids Problems have appeared later: in adulthood: •

•

Often enlarged, overdeveloped uterus

Problems since puberty: Premenstrual syndrome with • Swelling, especially breast swelling • Breast tenderness • Menorrhagia (heavy menstrual bleeding) • Constant dysmenorrhea (painful menstruation) •

History

•

•

Possibly resulting in surgical operations for: • • •

Breast cysts Ovarian cysts Fibroids

After this quick check it is important to inquire about the timing and location of the patient's complaints and signs.

2. Timing and Location When and where do female hormone deficiency signs and complaints manifest themselves? Signs and complaints of female hormone deficiencies tend to be present the whole day, in a more or less chronic way, although certain symptoms are temporary and recurrent such as hot flushes that arise more frequently at night and vaginal dryness with a pain that, in general, is felt during sexual intercourse. Problems from these deficiencies often concern different body tissues, although they sometimes clearly predominate in areas related to female sexuality such as the breasts, vagina and other genital areas.

271

3. Complaints of Female Hormone Deficiency Estrogens

stimulate the sympathetic nervous system in women which may cause anxiety and irritability, while progesterone stimulates the parasympathetic nervous system, which has a calming effect. Complaints of Female Hormone Deficiency Type

PROGESTERONE DEFICIENCY

ESTROGEN DEFICIENCY

(=

Estrogen excess)

PSYCHIC complaints Vitality

•

Fatigue (persistent)

• •

Mood

•

Sex

•

Memory

•

Depression (persistent)

•

Muscle and nervous tenseness lrritability, aggressiveness (esp. as premenstrual syndrome (PMS)) Anxiety and anger, climaxing in outbursts of panic or rage

Poor libido (sex drive) Poor memory •

Pain

•

Sleep

lncreased sensitivity to pain, increased expression of pain lnsomnia with excessive nervous tension and anxiety

PHYSICAL complaints Face,

•

chest Breasts

•

Hot flushes with excessive night sweats (esp. at niÇJht) •

Breast ptosis

Abdomen Menstrual

• •

cycle •

Menstruation

•

Uterus

•

Vagina

•

•

•

Sexual intercourse

•

caused by poor lubrication or vaginal atrophy) •

Urological

•

• •

•

Premenstrual abdominal bloating Menorrhagia (excessive menstruation)

Endometriosis-caused complaints (deep pain during intercourse)

Recurrent cystitis (bladder infections)

• •

Joints

Menstrual cycle irregularities with polymenorrhea and/or spanomenorrhea Hypo- or amenorrhea Vaginal dryness Vaginal itchinÇJ Uterine prolapse Vaginal prolapse Decreased vaginallubrication during sexual intercourse Dyspareunia (painful intercourse

Premenstrual tension with breast tenderness and swollen breasts Swollen belly, bloating

•

Urinary stress incontinence Bladder prolapse ArthraiÇJias ((osteo)arthritis, .. )

After this check we can now examine the body of a female patients with these deficiencies.

272

4. Physical Signs of Female Hormone Deficiency Physical signs of estrogen and progesterone deficiencies are often opposite signs, a consequence of the antagonistic actions of the two hormones. The signs of female hormone deficiencies are summarized in the following table: Physical Signs of Female Hormone Deficiency Where?

PROGESTERONE DEFICIENCY

ESTROGEN DEFICIENCY

( Estrogen excess)* =

Face

•

Pale face

•

Hollow face

•

•

Breasts

• •

Dry (mucous membranas of the) eyes, mouth

Micromastia (small breasts) Breast ptosis (droopy breasts)

Hands

•

Hand palms: small, sharp folds

•

Pale skin

Skin

•

Dry, dehydrated skin

•

Vagina

Uterus

•

Reddish face

•

Swollen face

•

Macromastia (enlarged breasts)

•

Mammary edema (swollen breasts

•

Mastalgia (painful breasts)

•

Breast cysts

Small, sharp wrinkles (above upper lip, corner of the eyes)

Abdomen

•

•

Small, sharp wrinkles

•

Distended abdomen

•

Painful abdomen upon palpation

•

lncreased abdominal fat

•

Reddish skin

•

Swollen skin

Vaginal dryness (atrophied, thin vaginal mucous membranas resulting in a dry vagina) Atrophied endometrium (uterine lining)

• •

Feet

•

Endometrial hyperplasia (glandulocystic) Fibroids Swollen feet, ankles

Note: *A minimum leve/ of estrogen (in the range of what is necessary to maintain bone density: 70-90 pglml) is required for signs of progesterone deficiency to show up. At lower estrogen leveis, there is not enough estrogen to produce water retention, nervousness, and other actions of estrogen. Therefore, a deficiency in progesterone does not automatical/y cause visible physical signs. Progesterone's major role is to b/ock excessive estrogen activity. When progesterone is /acking, the brake on estrogens is missing and the opposite happens: excessive enhancement of estrogen activity! Most signs of progesterone deficiency are in fact signs of estrogen excess.

The next step is to check for other diseases that may develop more easily in presence of a female hormone deficiency.

273

5. Disease Susceptibility Does female hormone deficiency cause any other health conditions? There is a great deal of scientific literature with reports that female hormone deficiencies can cause or facilitate the development of other diseases. Estrogen deficiency: lnfertility, premature aging, osteopenia, osteoporosis due to the reduced bone mineral density, cardiovascular disease, Alzheimer's disease. Progesterone deficiency: Breasts cysts,

breast cancer,

ovarian

cysts,

endometriosis,

endometrial hyperplasia,

endometrial cancer, uterine fibroids, enlarged uterus, infertility, pregnancy problems i.e., preeclampsia and increased risk of miscarriage or premature delivery.

6. Medicai lmaging for detection of Pathologies related to Ovarian Dysfunction The following tests are recommended to detect cysts, fibroids and other abnormalities: 1. Mammography:

Every two years (every six months for women with a high risk of breast cancer) Note: Recently, its usefulness has been serious/y challenged by data from scientific research. Moreover, suspicion has arisen that the amount of x-ray exposure used may be harmful. Be sure to provide patients with information on both the risks and the benefits of mammography.

2. Ultrasound imaging of breast, ovaries and uterus: once a year 3. Pap smear: once a year

274

7. Lab tests for Female Hormones Measuring the leveis of FSH, estradiol, progesterone and SHBG are the most recommended

tests for diagnosis of female hormone deficiency.

BLOOD tests for Female Hormones Test to check

Which Day of Pr.E2 or P4 the Menstrual Optimal Deficient cycle to check?

Reference

Test Value

lU/L (miU/mL)

Low

lnterpretation

PREMENOPAUSAL WOMEN

13-14th day LH

FSH

70

0-35

i" or 21st day

2-4

0-1 or > 12

Any day

3-5

(ovulation)

> 20

24-105 0.2-12

IU/L-(miU/mL) Low

2-13

lU/L (miU/mL) Med

Stimulates ovulation

and progesterone 5 production FSH stim. =

ih day Estradiol

(E2)1,2

13th day 21st day

Estrone(E1) Progesterone (P4)

21st day 21st day

Any day

FSH

Anyday

Estrone Progesterone (P4)

0-40

20-100 pg/mL

240-330

0-147

73-367 pmoi!L

650

0-300

2400

0-1100

150

0-100

550

0-370

130

0-60

480

0-220

13-23

0-10

41-73

0-32

Low

peri-menopause Follicular phase 1

200-800 pg/mL E2 peak precedes 6 730-2930 pmo/L Low LH ovulation peak 100-210

pg/mL

370-770 pmo/L 40-200

pg/mL

150-740 pmo/L 3-27

Med Low

ng/mL Med

10-86nmo/L -Low

Luteal phase

E1

>

2

E2 => sign of

PCO or menopausa Luteal phase

POSTMENOPAUSAL WOMEN with female hormone replacement therapy (HRT) LH > FSH > 40 in 15-62 lU/L (miU/mL) > 35 15-30 Low

LH

Estradiol

65-90

E2 produc-

tion; a higher FSH

Any day Any day Any day

20-50 80-150

> 60 0-70

295-550

0-255

80-130

0-60

295-480

0-220

menopausa

28-138

lU/L (miU/mL) Low FSH > 28 menopause 0-35 pg/mL High=

0-130 pmo/L Med 10-60

pg/mL

37-220pmo/L

pg/ml

1.5-8

0-1.2

0-1.0

4.8-25

0-3.8

0-3.2nmo/L

Low

E1

>

E2 => sign of

PCO or menopausa

Low

PRE- and POSTMENOPAUSAL WOMEN with female hormone replacement therapy Prolactin SHBG (TeBG)3 CBG4 or Transcortin

Any day Any day Any day

5-19

>30

1-24

ng/mL Low mg/L

6.1

0-5.2 or � 8.5

3.9-7.7

65

0-55 ar ;?90

41-79 pmo//L

30

> 40

20-50

lnhibits production of sex hormones

E2 Med or T3 deficit, high an-

mg/L Low

Low SHBG due to

drogens, malnutrition7

CBG in blood = main 8 P4 transport protein

'·2The fol/icular phase is lhe first half of lhe menstrual cyc/e, whi/e the /utea/ phase is the second half; 3A high serum SHBG (sex hormone binding globulin; TeBG is a synonym and abbreviation of testosterone binding globulin) greatly increases lhe binding of estrogens

Notes:

to SHBG in blood, resulting in lower estrogen and androgen leveis in the target cells, and possibly a deficiency; 4 CBG is cortisol binding

globulin; 5 When the LH leve/ is higher than that of FSH and the E1 leve/ highe than that of E2 on day 21 of a normal menstrual cycle =>probable po/ycystic ovary syndrome (PCO); 6 Serum tests of estradiol dane on the 13" day of a menstrual cycle are usefu/ when checking for fertility (high peak estradio/ levels precede a high peak of LH in adequate fertily and ovulation); 7 A high SHBG levei can be due to estradiol or thyroid hormone deficiency; or androgen or GH excess; 8 CBG weakly binds so that during progesterone intake more than h after almost no detectable leveis of progesterone are found, while progesterone does remain aclive enough inside of lhe target cells.

275

10

When in the menstrual cycle is the best time to test in blood? •

Premenopausal women: The best time to measure the hormones of a premenopausal woman is on the 2151 day of a 28-day menstrual cycle (one or two days before or after are also acceptable). When menstrual cycles are longer or shorter than 28 days, leveis should be checked approximately seven days before the period. (Note: Each menstrual cycle starts on the first day of menstruation.)

•

Postmenopausal women: HRT: When the daily dose of estrogen and progesterone is fixed, wait a week of treatment o before checking blood leveis, afterwards any day during treatment is OK (don't do them in the usual 3 to 7 days per month of therapy stop); if a menstrual cycle is mimicked, the blood check should take place in the second part of the cycle. o No HRT: Any day is OK.

Urine or saliva tests may also be helpful. URINE and SALIVA tests for Female Hormones Test to check

When to

checkin

the cycle?

Estradiol (E2) ......_ '

1ií

E

Estrone (E1)

e

.c. o (J) co

� w z

ii: ::;)

.c.

....

..;. C\1

Estriol (E3) 2-0H-estrone Alpha16-0H-estrone Pregnandiol

Premenop.: �day of cycle of the menstrual cycle

Postmen. + HRT: any day of intake HRT

Same as above

:i

c:( cn

0-9

7-73 J1moV24h

185

0-130

22-260 j1g/24h

50

0-35

10-75 JlQ/24h

175

0-120

>5

0-5

0-1.3

>1.9

40

0-30

0-12

Premenop. yth

10

0-7

13-141 day

20-25

?'h day

" 211 day Postmen. + HRT3

2-20 JlQ/24h

0-33

55

16-22

Premenop.

'2 Progesterone1

15

0-4

2151 day

Reference

Deficient

5-7

Postmen. + HRT3

c:( >

mal

Probably E2 or P4

21st day of cycle day

Estradiol1'2

Opti-

5-70 JlQ/24h

Test Value

Low Low

E1, E2 and E3

A high urinary ratio E3 vs. E2 and E1

Low

=

2.2-10.9Jlg/24h

Low

increased breast

1.5-1.9 Jlg/24h

Med

increased breast

35-260 Jlmol/24h

2-7 mg/24h 6-22 JlffiOI/24h

Low

Low

0-15

10-30 pg/ml

Med

15

0-10

7-20 pg/ml

Med

7-10

0-5

1 .5-10.0 pg/ml

Med

70

0-30

20-100 pg/ml

Low

300

0-200

65-500 pg/ml

Med

0-400

500-3000 pg/ml

Low

1500

24-hour picture of productions;

5-13 pg/ml

400-

lnterpretation

lowbreast

cancer risk? Low2-0H-E1

=

cancer risk? High 16-0H-E1 cancer risk Major metabolite of progesterone

May provide an interesting picture of menstrual cycle, but less reliable, because of the large variations in hormone leveis attested by the (very) broad reference ranges

Notes: 1 Salivary tests al/ow measurement of the changes in hormone leveis during the menstrual cycle. 2 The optimal va/ues for progesterone and estradiol during the fol/ow-up for b/ood and saliva test are va/ues measured 9 to 14 hours after administration of the medications. Va/ues are much higher if the blood sample is taken the first seven hours after taking the medications. 3 HRT means (tema/e) hormone rep/acement therapy

276

=

11/ Female Hormone Deficiency: TREATMENT Treatments for Female Hormone Deficiency In our experience, transdermal estradiol (E2) gel and micronized oral or vaginal progesterone (P4) are the best female hormone replacements for most patients. This

treatment is not contraceptiva when used in premenopausal women who have a healthy uterus. The treatments for female hormone deficiency are compared in the tables below. We advise to use a combination of estrogens and progesterone, even if the uterus has been removed. Ali estrogen therapies should be combined with progesterone therapy for safety reasons. Corrective Female Hormone Therapies: 1. ESTROGENS

Route

Dose for Product

sedentary women

Conjugated Estrogens

(Premarin®) Estradiol valerate

Oral

Estradiol micronized

(Zumenon®) Biest 0 . 1 mg capsules I (often 80% E3, 20% E2)* Triest 0.1 mg capsules;often 80% E3, 10% E2, 10% E1

quency

Estradiol gel 0.6 mg/g

Trans((O)Estrogei,Gynokadin, derm. Oestrodose®) iii E ...

Gl "C 111 c 111 ...

1-

Vagi-

naI

Estradiol gel1 mg/g

lm-

Oays

1-2 mg 1-4 mg

1x/day

in the morning

2-8 mg 0.5-2 mg/day 1-4 pump/day 0.75-3mg/d 1-5 pump/day

lndication: ESTROGEN

2 x/day

Rarely indicated unless patient is unable or unwilling to take s'h·251hday transdermal of the estrogen menstrual Occasional use cycle

PREmenopaus. women:

for stress, efforts

in the POSTdeficiencies morning menopaus. (1pump=0.75mg) women:

Triest1 mg/g

Do not forget to take progesterone

Estradiol (Estradiol

implant® from Organon)

1-6 g/day

1x/day

0.1-0.6 mg E2

bedtime

25-50-100 ll9

2 x/ week

10-25-50- 100 mg

1x/3-6 months

3 on 4 wks

Women who are unwilling to Constant take daily E2

then 1 wk off

Notes: *Biest and triest mixtures can be purchased in compounding pharmacies.

277

Low Low Low Low Low Low

Most estrogen

1x/ day

May permeate less through skin => need to apply more E2

I (80% E3-10% E2-10% E1)*

Value

OEFICIENCY

(Estreva®);1 pump=O.S mg) 0.5-2.5 mg/day 1x/day 1-6 g/day Biest 1 mg/g 181-251hday 0.5-3 mg E2-E3 in the (50% E3-50 % E2)* of each morning Biest 5 mg/g 0.5-2 g/day month 0.1-1.2 mg E2 (80% E3-20% E2)*

Trans- Estradiol patch derm. '(Estraderm®, Systen®) lplant

take?

More adverse effects and risks

*

SubEstradiol micronized* ingual

When to

0.3-1.25 mg 1-2 mg

I (Progynova®)

Fre-

High Low Low Med Low Low Low

Corrective Female Hormone Therapies: 2. PROGESTOGENS Route

Daily Dose for sedentary women

Progestogens

Frequency

When to take?

lndication:

Progesterone Deficiency

Value

Progesterone

(P4; micronized; Utrogest®, or Utrogestan®, Vaginal Progestan®, Prometrium®)

1x/day

Oral*

50-200 mg/d

before bedtime

1x/day Oral

Dydrogesterone

morning or before bedtime

5-20 mg/d

(Duphaston®)

Most cases of progesterone deficiency PREmenopausa! women:

Less frequent use; useful if

•

15TH. 25th

day of menstrual cycle

High

•

Heavy period bleeding;

lntolerance to progest. (drowsiness, d epression fainting) Only if menorrhagia (severe periods) no! corrected by P4

High

,

As birth contra/ pi/1: 0.5-1mg/d.;

Noethisterone

(Primolut-Nor 10 mg) Oral

morning

POSTmenopausa! women:

1x/day

without menses (periods):

morning

1st_ 25th day

1x/day

For fibroids, menorrhagia:

10 mg/day

Synthetic such as medroxy

5-10 mg/d

-progesterone

(Provera,

Farlutal®)

of each

Low

or dydroÇJesterone

To avoid (higher breast cancer or heart disease risk)

In emergency to quickly with menses: correct a progesterone th th 13 -25 day deficiency

Avoid

month

Sublingual

Progesterone

(Compound. pharmacy)

50-200 mg/d

2x/day

100-400 mg/d

1-4 g/day

2.5-5 g/day

1x/day

Progesterone

100 mg/g (Comp. pharmacy) Transdermal

Progesterone 25 mg/g

(Progestogel® )

Note: 1

Vaginal adminislralion of progeslerone may permil 25

of each month

Some cases of progesterone deficiency. As local treatment on breasts to reduce swelling, cysts

2

The

Med

Low2

% more effecls lhan when lhe progeslerone is orally taken as % of

the vaginal route avoids the first passage through the liver (which breakdowns progesterone) undergone by 90 lhe orally ingested progeslerone.

Low

2.5% concenlration is too low for whole body use, but sufficienl for local use.

278

How to start a Female Hormone Treatment

When starting female hormone therapy, we propose the following schedules of treatment:

PREmenopausal women with solely a progesterone deficiency (women 15-40 years of age) with normal periods Premenopausal women: Treatment of Progesterone Deficiency with normal periods Hormone Deficiencies

Mild Moderate Progesterone Deficiency with normal periods

lmportant Severe Very severe Extreme

Treatment

Oral or vaginal Progesterone (100 mg micronized capsules) to take before bedtime

Menstrual Cycle Davs 5-14

Days 15-26

Days 18-26

(no treatment)

1 caps./day

(no treatment)

Alternate 1 & 2 caps./day

(no treatment) (no treatment) Alternate O & 1 capsule/day 1 caps./day

2 caps./day

Alternate 1 & 2 caps./day Alternate 1 & 2 caps./day 2 caps.s/day

PREmenopausal women with solely a progesterone deficiency (women 15-40 years of age) with heavy periods (menorrhagia) Premenopausal women: Treatment of Progesterone Deficiency alone with heavy periods Hormone Deficiencies

lmportant Severe Very severe Progesterone Deficiency with menorrhagia

Extreme lmportant Severe Very severe Extreme

Treatment

Oral or vaginal Progesterone (100 mg micronized capsules) to take before bedtime

Oral Dydrogesterone (10 mg tablets) to take in the morning or before bedtime

279

Menstrual Cycle Davs 5-14

Davs 15-26

(no treatment)

2 caps./day

Alternate O & 1 caosule/dav

Alternate 1 & 2 caps./dav Alternate 1 & 2 caps./day

1 caps./day

2 caps.s/day

(no treatment)

1Y2 to 2 tablets/dav

(no treatment) (no treatment) Y2 tablet/day 1 tablet/day

Days 18-26

1Y2

tablets/day 1Y2

tablets/day 2 tablets/day

PREmenopausal women with progesterone and estrogen deficiency (age: 15-50 yearsf: Premenopausal women: Treatment of Estrogen and Progesterone Deficiencies with periods Hormone Deficiencies Estrogen Deficiency

Mild Moderate Severe Mild Moderate

Progesterone

lmportant

Deficiency

Severe Very severe Androgen

Menstrual Cycle

Treatment

Days 10-14 Days 15-25 2.5 g /day (1.5 mg estradiol)

Days 5-9

Transdermal Estradiol

3.75 g/day (2.25 mg estradiol)

in the morning

4 g/day (3.75 mg estradiol)

(0.6 mg/g gel) Oral or vaginal Progesterone (100 mg micronized capsules) to take before bedtime

(no treatm.) (no treatment) (no treatment) (no treatment) Alternate O & 1 caps./day

Testosterone, DHEA, etc.

Deficiency

(no treatment) (no treatment) Alternate O & 1 capsule/day Alternate O & 1 capsule/day 1 capsule/day

1 caps./day Alternate 1 & 2 caps./day Alternate 1 & 2 caps./day 2 capsules/day 2 capsules/day

Testosterone (T) works as a progestogen; most women need to have androgen therapy with the E2-P4, T is taken daily without interruption

" POSTmenopausal women (women 48 years or over) wanting a treatment with periods : Postmenop. women: Treatment of Estrogen and Progesterone Deficiencies with periods Hormone Deficiencies Low Estrogen responsiveness: history of poor periods, long menstrual cycles High Estrogen Sensitivity: history of breast menorrhagia, tenderness, breast cysts, fibroids Low Estrogen

Average Average lmportant

High Estrogen

lmportant AveraQe important Severe Extreme

Androgen Deficiency

Days 1-12

I

Days 13-25

Days 26-31

(5 g or 3.75 mg E2J

Transdermal Estradiol

(Estrogel 0.6 mg/g gel) in the morning (1 pump 1.25 g= 0.75 mg) =

3 pumps/day (3.75 g or 2.25 mg E2)

2 pumps/day (2.5 g or 1.5 mg E2) 1Y2 pumps/day

(no treatment) =>

menses

(1.88 g, or 1.15 mg estradiol) Y2 to 1 pump/day (0.375 to 0.75 mg E2)

Severe Poor

The Month (January, February, March, ..)

4 pumps/day

Poor

Average

Sensitivity

Treatment

Oral or vaginal Progesterone (100 mg caps.) before bedtime

Oral Dydrogesterone (10 mg tablets) in the morning or prior bedtime

Testosterone, DHEA, ...

no treatm.) no treatm.) Y2 tab./day

1 caps./day Alternate 1 & 2 caps./day 2 caps./day 1 Y2 t./day 2 tablets/day 1 Y2 to 2t./day

1 tabl./day

2 tablets/day

(no treatm.) (no treatm.) (no treatm.)

(no treatment) =>

menses

Testosterone (T) works as a progestogen; most women need to have androgen therapy with the E2-P4, T is taken daily without interruption

Note: Women of sma/1 body build such as many women of Asian origin wi/1 do generalfy better with lower doses: about two thirds of the doses mentioned in the tables.

280

POSTmenopausal women (women 48 years or over) wishing to have no periods with the treatment. The same treatment that includes an interruption of the female hormones is valid for women who have undergone hysterectomy (remova! of the uterus). Postmenop. women: Treatment of Estrogen & Progesterone Deficiencies without periods Hormone Deficiencies Low Estrogen sensitivity: history

of poor menses, spaniomenorrhea (long cycles)

High Estrogen Sensitivity:

history of breast menorrhagia, tenderness, breast cysts, fibroids Low Estrogen sensitivity

Poor Moderate Average lmportant

Transdermal Estradiol (Estrogel 0.6 mg/g gel) in the morning (1 pump = 1.25 g= 0.75mg)

Poor

lmportant Average important

The Month (Januar11, February, ...) Days 1-25 Days 26-31 4 pumps/day

(5 g or 3.75 mg estradiol) 3 pumps/day

(3.75 g or 2.25 mg E2)

(no treatment)

2 pumps/day

(2.5 g or 1.5 mg E2)

=>no menses

1% pumps/day (1.88 g,

or 1.15 mg E2)

% to 1 pump/day

Severe

Average

High Estrogen Sensitivity

Treatment

(0.375 to 0.75 mg E2) Oral or vaginal Progesterone

(100 mg caps.) to take before bedtime

Oral Dydrogesterone

1 capsule/day

Alternate 1 & 2 caps./day 2 capsules/day 1 tablet/day 1 Y2 tablets/day

(no treatment) =>no menses

(1O mg tablets) Severe

Androgen Deficiency

in lhe morning or before bedtime

Testosterone, DHEA, etc.

2 tablets/day

Often an essential associate to the estroprogestogen therapy, works as a progestogen; to take daily without interruption

Note: Women of sma/1 body bui/d such as many women of Asian origin wi/1 do generally better wilh lower doses: aboul two lhirds of lhe doses menlioned in lhe lables.

Cyclical or continuous Female hormone replacement therapy (HRT)? Stopping each month for severa! days the female hormone treatment ("cycling" the treatment) has been found to be associated with a 50% decrease in risk of breast cancer compared to continuous treatment. Therefore, it is best to interrupt the estrogen-progesterone treatment 5 days at the end of the month. The periodic stop of the estrogen and progesterone stimulation puts possible cancer cells into apoptosis (death).

Estrogens alone or estrogen-progesterone treatment for women with hysterectomy? For women who have undergone hysterectomy, we propose to maintain progesterone intake in order to adequately balance the estradiol treatment. Progesterone neutralizes the swelling, nervousness and possibly cancer-promoting effects of estrogens. One recent large-scale French prospectiva study showed a significant decrease in breast cancer risk with the use of bioidentical progesterone. Moreover, most women to our experience just feel better with progesterone added to estradiol.

281

How to apply the estradiol gel on the skin Tips on how to apply estradiol gel on the skin

Spread the gel preferably on the following locations: the outer and inner sides of the arms and shoulders (1.25 g pump per arm and shoulder), inner side of the thighs, abdomen (in thin persons), and possibly on the face (to reduce facial hair and wrinkles or when absorption on other places is poor).

•

Location

Use always the same skin surfaces, so the absorption is stable and constant.

•

Spread a thin layer of the estradiol gel on a large skin surface. Putting a thin layer on the skin avoids spilling any excess estradiol gel. When layers are too thick only the part close to the skin can diffuse in, the most outer layer rubs off.

•

Note: Applying the gel on large skin surfaces (i.e. the inner and outer side ,

of the fui/ arms and shou/ders and inner sides of the thighs) produces a

longer action that will last a full 24 hours. The reason is that once the estradiol has penetrated the skin, it accumulates in the fat just beneath the skin. The subcutaneous fat under the skin forms a reservoir of estrogen that s/owly and progressively gets released into the bloodstream over a 24-hour period. In contrast, when ali the estradiol gel is applied on a sma/1 skin surface (for example on the inner part of the forearms only), then most of the aborbed estrogen wi/1 not accumulate in a fat reservoir, but directly go to the bloodstream. This surplus of estradiol wi/1 quickly reach a peak leve/ in the b/ood and quick/y dísappear from it, resulting in a /oss of estrogen effects /ater on in the day.

Estradiol layer: Thickness and Size

Rub the estradiol gel not twice but ten times back and forth on the skin surface. The repeated rubbing improves deep penetration and absorption of the estrogen into the skin.

•

Rubbing

An application once a day is generally enough. lf despite correct application the estradiol gel still does not give persistent 24-hour effects, then apply it twice a day, morning and evening.

•

Frequency

Review: Tips to improve the efficacy of transdermal estradiol Tips for Patients on Transdermal Estradiol: Review For stronger effects

(greater potency) For prolonged

Make the gel diffuse better through the skin: •

e

Rub ten times hence and forth over the skin surface.

•

Always apply the gel on a large skin area (half of an arm is not sufficient!)

•

24-hour effects with a once-a-day treatment

Avoid putting creams and lotions on skin surfaces where estradiol is applied. Do not put oils in bath. They may block the absorption of estradiol.

•

Apply estradiol on large skin surfaces (not only on forearms for example, but also on the whole arm and shoulder, inner and outer sides) Avoid eating high amounts of cereal fiber (whole grain bread, bran flakes, etc.)

lf still no 24-hour effects: •

Apply the gel twice daily (morning and evening)

282

What to avoid when using transdermal estradiol gel Avoid putting creams, lotions and oils (including bath oils) on the skin surfaces where estradiol gel is applied, otherwise these products may block the absorption of estradiol. Avoid eating large amounts of cereal fiber (whole grain bread, bran flakes, etc.) Eating foods rich in cereal fiber considerably increases the loss of estrogens and other hormones in the stools, creating or aggravating estrogen deficiency. How? Fiber that is not digestible such as the fiber in cereais (cellulose) will capture estrogens that come into the gut from the liver (but normally are reabsorbed further down in the digestive tract), and excrete them in the stools.

How do you harmoniously balance estrogens with progesterone? Firstly, check the patient's medicai history for complaints and signs of either estrogen or progesterone deficiency. Often the patient will need to take a higher dose of the hormone, estradiol or progesterone, that she was most deficient in, in the past. Women who frequently have been plagued by breast tenderness, bloating before menstruation, heavy periods, uterine fibroids and breast cysts, predominantly suffered from progesterone deficiency and are likely to need proportionately more progesterone than estrogen. In contrast, women who have suffered in the past from irregular menstruation with hypo- or amenorrhea, droopy or small breasts, vaginal dryness, predominantly suffered from estrogen deficiency.

lt is likely that they will need proportionately more estrogen than progesterone in

their treatment. Secondly, know by heart the typical complaints and body signs related to deficiency and excess in estrogens and progesterone. This knowledge is fundamental if you want to be able to correctly balance the two hormones during the follow-up. When a female patient is more deficient in one of the female hormones, she will suffer more from the most deficient one and need proportionately a higher dose of that hormone and a lower dose of the other.

lndications for Estrogen and Progesterone Treatment Chronic, long-term indication: treatment of ali degrees of chronic estrogen and progesterone deficiency, including premenopausal deficiencies next to the classical postmenopausal deficits. Acute, occasional, short-term indications for use of testosterone in higher doses: women who have temporarily menstrual cycle problems due to acute conditions of stress, periods of intensive sports, severe hypocaloric diets, cachectism (exceptional).

Contraindications to Female Hormone Treatment The following conditions contraindicate the use of ali estrogens: Active untreated breast cancer, uterine cancer (not surgically removed). The following conditions contraindicate the use of oral estrogens (including bioidentical) and synthetically modified progestogens: increased tendency to blood clot formation (phlebitis, thromboses), and liver disease. For patients with these diseases, use relatively low doses of a transdermal estradiol gel and vaginal progesterone capsules.

283

Progress with Estrogen and Progesterone Treatment How soon will the patient notice improvements?

Usually, the first improvements appear quickly during the first month of treatment, even in the first few days. However, for full stabilization of treatment, two or three months of treatment may be necessary.

How to naturally Boost Estradiol and Progesterone Treatment? First of ali, by improving the lifestyle, including choosing better foods.

The principal lifestyle changes to increase the body's own hormone production and effects, and those of an estroprogestative treatment are summarized in the following table. Many of these factors also influence growth hormone and other hormones that build up the body similarly (please read the Growth Hormone chapter for details.) How to optimize Female Hormone Activity andTreatment WhatTo Do

Diet

Follow the principies below: • Eat enough calories • Follow a "Paleolithic" diet: fruits, vegetables, meat, poultry, eggs, fish1 • Possibly add amino acid supplements • Eat organic foods2

WhatTo Avoid

Avoid the intake of the following foods: • Caffeinated drinks3 • Sugar, sweets, soft drinks, cookies, bread, pastas and other cereais • Cereal fiber (whole grain bread, bran flakes) • Milk products

•

Weight

•

Stress

•

Abuse

•

Avoid beinQ overweiQht, obese4 Avoid excessiva chronic stress5, including strenuous physical activity Avoid tobacco smoking Avoid Marijuana, other drugs

Notes: 1

2

3 4

5

Foods rich in protein and saturated fat increase the production and effects of estradiol and progesterone. Many pesticides in the food mimic the effects of estrogen, others are just toa toxic for the avaries. Caffeine may increase breast cancer risk by increasing epithelial proliferation in the breast, causing precancerous lesions. Obesity may decrease ovulation and thus production of tema/e hormones. Chronic stress makes a woman overconsume tema/e hormones whi/e partia/ly inhibiting its production through a decrease in secretion of FSH and LH, the stimulating pituitary hormones.

284

Secondly, the leveis of female hormones can be increased in younger women by correcting other hormonal abnormalities that influence the production and/or function of female hormones.

The principal hormone replacement therapies that affect the secretion of estrogens and progesterone and/or their action, are summarized in the following table: lnfluence of other Corrective Hormone Therapies on Estrogens and Progesterone Strong stimulators of estrogen/progesterone • •

•

(activity or production) Growth hormone Cortisol and other glucocorticoids at low doses (for cortisol-deficiency) Thyroid hormone treatment at low doses (for thyroid deficiency)

Strong inhibitors of estrogen/progesterone

Mild stimulators •

• •

DHEA • •

(activity or production) Cortisol and other glucocorticoids at high doses Birth-control pills (blocks ovarian estrogen production by negative feedback) Excess thyroid hormones Melatonin at very high doses (> 1 O mg/day)

lnfluence of other Corrective Hormone Therapies on Estrogens Strong estrogen stimulator

Mild stimulators

Strong estrogen inhibitors •

•

Estradiol and other estrogens

•

Thyroid hormones

•

•

Testosterone and other androgens Anabolic steroids (synthetic derivativas of testosterone) Progesterone and progestogens (synthetic derivativas of progesterone)

lnfluence of other Corrective Hormone Thera�ies on Progesterone Strong progesterone stimulator •

•

•

Testosterone and other androgens Anabolic steroids (synthetic derivativas of testosterone) Progesterone and progestogens (synthetic derivativas of progesterone)

Mild stimulators

•

Thyroid hormones

285

Strong progesterone inhibitors

•

Estradiol and other estrogens

Follow-up of Female Hormone Treatment What do you do to follow-up once treatment has begun? 1. Find the optimal dose.

When to change the dose of Female Hormones? lncrease the dose of estrogens

Lower the dose of estrogens

(25 to 200% more), or

Dose

(25 to 75% less), or

Reduce the dose of progesterone

lncrease the progesterone dose

(25 to 75% less) Chronic

Occasional

Conditions

(25 to 200% more)

•

lnsufficient estroaen effects

•

Low-protein diet

•

High-protein diet

•

High-fiber diet

•

High-fat diet

•

Low-protein diet

•

High caloria diet

•

Diarrhea

•

Yeast infection Unstressed, vacations, holidays

Excessiva estrogen effects

•

•

Intensiva and/or chronic stress

•

•

lncreased physical activity, sports

•

Decrease in physical activity

(sedentary, bedridden, prolonged rest) • •

Occasional

Summertime

Testosterone, dihydrotestosterone or other male hormone treatment

to permanent

•

Adult growth hormone deficiency

conditions

•

Melatonin treatment (rarely)

•

Hyperthvroidism

•

Growth hormone treatment (rarely)

2. Avoid under- and overdosing.

lt is highly recommended for the patient to know the signs and symptoms of female hormone deficiency and overdose so that she can help her physician to adjust the treatment. In particular, attention should be paid to the signs and complaints of estrogen overdose listed in the table below. See the next section "Problem Solver'' for how to correct signs of an overdose. ESTROGEN OVERDOSE (or Progesterone deficiency) Breasts

Mood

Sleep Body

Menstruation

Swollen, painful, tender breasts •

Nervousness, tension

•

Anxiety

•

lrritability, outbursts of anger, especially before menstruation

•

Anxious oremenstrual svndrome

•

Sleep difficulties, especially before menstruation

•

Swollen reddish face

•

Abdominal bloating, hands or feet edema swelling

•

WeiQht Qain esoeciallv before the oeriods (oremenstrual tension)

•

Heavy menstrual bleeding (menorrhagia)

•

Constant painful periods (dysmenorrhea),

•

MiQraines before periods (premenstrual miqraine)

286

3. Perform lab tests:

lt may be useful to perform lab tests to adjust the dose, although they are generally less helpful than the signs and symptoms collected by interview and physical examination. The following tests are recommended:

Recommended Tests For Follow-Up

Medication

Urine (24-hour)

Blood

Transdermal estradiol Oral estradiol, conjugated estrogens Synthetic ethinylestradiol

(birth control pill)

Oral synthetic progestogen (birth control pills &

postmenopausal HRT)

Oral progesterone Vaginal progesterone Transdermal progesterone

FSH, estradiol,SHBG FSH, estradiol, estrone, SHBG

(estradiol,estrone,estriol); 2-0H-estrone,4-0H-

estrone, 16-alpha-estrone -

FSH,SHBG (LH),SHBG (Note: LH is suppressed in younger women if the progestogen is potent enouqh) (LH), progesterone, (CBG)

Pregnandiol1

Note: 1 Pregnandiol is /ess va/uab/e to eva/uate progesterone taken by mouth, because most of the oral progesterone is broken down by the /iver before it enters the b/ood stream. During oral intake of micronized progesterone, the urinary test shows abnormally high leveis of progesterone that are use/ess to eva/uate progesterone activity as they do not reflect the real metabolic activíty of the progesterone that enters the b/ood stream.

4. Do cancer screening: Advise the patient to have cancer screenings and genetic typing. Mammography with ultrasound investigation (once every two years, every year if fibrocystic breast disease), every

six

months

breast

examination

by

the

physician

(but

monthly

self-examination

is

recommended), every six months to a year a vaginal PAP smear, blood CEA and CA 15.3

check, etc. Genetic typing allows the physician to identify those patients with certain genes

associated with increased cancer risks and thus to adapt the screening and treatment

accordingly. In case of genetic predisposition to genital cancers (including breast cancer), the

physician should prescribe lower doses of estrogen, and order more frequent and extensive

cancer screenings.

5. Solve problems quickly and efficiently as explained in the following section.

287

111. Female Hormone PROBLEM SOLVER How do you solve problems during treatment?

Problems related to a short-term estrogen deficiency: Problems probably due to LOW ESTROGEN: Table 1 PROBLEM

•

CAUSE

SOLUTION

Estrogens are lacking because of 1. Underdosage Estrogen 2. Lower production of deficiency estrogens (due to complaints and chronic stress, infection, signs remain: aging...) pale face, flabby 3. Higher consumption of breasts, vaginal estrogens (due to dryness, hot excessive physical flushes, fatigue, activity, hard work ... ) depression ... 4. lncorrect application of the estradiol gel 5. Low calorie/ protein diet

Short menstrual cycles of 26

days or less: 18, 21,24 days (polymenorrhea)

•

30 to

+

2. (see 1.) 3. (see 1.) 4. Carefully follow the application guidelines

for the estradiol gel (larger skin surface, rubbing more often on the same skin surface, apply on more penetrable skin areas, etc.) 5. lncrease protein intake

Eat a sufficient amount of food/calories (in particular proteins of animal origin) to boost droopy breasts in the hormone production by the ovaries second phase of the 2. Check for other deficiencies that cause the cycle then the most ovaries to malfunction (thyroid, cortisol, frequent cause is etc.) and correct them estrogen deficiency 3. Droopy breasts: supply or increase estradiol (almost always in case of short 2. lf patient has painful and long menstrual cycle): Transdermal swollen breasts in the estradiol-gel (Estrogel, Oestrogel, second phase of the Gynokadin®) 3.75 g/day from Day 5 to 25 cycle, the cause is combined with oral micronized progesterone deficiency progesterone 1OQ-150 mg/day from the Ih

Ih

15 to the 25 day of the menstrual cycle.

Long 4.

menstrual cycles of 32

A patient usually also

days or more:

has droopy breasts estrogen deficiency

35- 40 -60

+

100%; Reduce the dose of progesterone

1.

1. lf the patient has

•

1. lncrease the dose of estradiol by

=>

days, etc. (Spanomenorrhea)

288

lf menses come too early: start later with Ih

Ih

progesterone from the 18 to the 25 day of the cycle 5. Painful swollen breasts: increase micronized progesterone by 100 mg per day or every two days up to 200 mg/day

Problems probably due to LOW ESTROGEN: Table 2 PROBLEM

CAUSE

SOLUTION

Low estradiol leveis

with relatively normal

or low progesterone •

Depressiva constant fatigue

=>

cause a lack of

catecholamines and catecholestrogens,

1. lncrease estradiol gel (0.6 mg alcoholic

resulting in

solution (Estrogel, Oestrogel, Gynokadin®))

depression and low

with 1.25 to 2.5 g/day more from the 5th to

energy

the 25th day of the menstrual cycle.

Rare form of estrogen 2.

Reduce progesterone: lower the dose to

other signs and

the 15th or 18 th to the 25th day of the cycle

deficiency, generally

•

Premenstrual depression

complaints of

100 mg/day (or 150 mg/day maximum) from

estrogen deficiency

are found: droopy

breasts, fatigue, joint

pains, poor menstrual

blood loss

•

/f estrogen deficiency signs and complaints are found during the entire menstrual cyc/e: lncrease estradiol by 1.25 to 2.5 g/day of the transdermal 0.6 mg/g gel from the 5

th

the 25th day of the menstrual cycle. /f this is not sufficient:

Generally caused by

Reduce progesterone:

a chronic estrogen

Decrease the dose of progesterone by

deficiency that causes

50 to 150 mg/day less from the 15 or 18 th th

other signs and

•

Menstrual hot flushes

to

th

to the 25

complaints of

day of the menstrual cycle (the

mean dose of progesterone may not go

estrogen deficiency during the cycle:

lower than 50 mg/day)

fatigue, depression,

prolonged estrogenic dominating effects by

droopy breasts,

=>

lf this still does not suffice, ensure more

decreasing the days of progesterone intake:

hypomenorrhea

e.g. from 18th to the 25th day of the cycle

rather than starting on the 15th day. •

/f estrogen deficiency signs and complaints

are found only at menstruation:

lncrease estradiol by taking 1.25 to 2.5

g/day from the 1st to the 4th day of the cvcle

289

Problems related to long-term estrogen and progesterone deficiency Problems due to Long-Term Estrogen Deficiency: Table PROBLEM

•

•

Most frequent cause: Estrogen deficiency. o Small breasts is a sign, which suggests that the female patient has been estrogen deficient since puberty (as she never had enough estrogens to fully develop her breasts to the average adult size). Droopy breasts with o normal adult size mean that the deficiency appeared later during adulthood.

•

Deficiencies in other hormones necessary for breast development: DHEA, GH, insulin and progesterone.

•

Rarely: androgen excess

Droopy, flabby breasts

•

Small breasts

3

SOLUTION

CAUSES

1. lncrease animal protein intake 2. Reduce progesterone dose 3. Use natural progesterone--which can convert into estradiol in very small amounts, while synthetic derivatives cannot 4. lncrease the leveis of estradiol with estrogen treatment 5. lf androgen deficiencies are found, consider correcting these deficiencies with androgens that can convert into estradiol by aromatase such as testosterone, DHEA, androstenedione, etc. 6. Avoid giving high doses of androgens (may reduce breast volume), esp. those that cannot convert into estradiol (dihydrotestosterone, synthetic derivatives) 7. Correct other hormone deficiencies

Example of how to adapt the transdermal estradiol gel treatment of women before menopause with predominant estrogen deficiency as is the case when menstrual cycles are too short o r too long (poly -or spanomenorrhea) Treatment

Dose

Day ofthe menstrual cvcle

Start with a sufficiently high Administer transdermal estradiol gel at a sufficiently high dose

Administer (oral micronized) progesterone at a low dose

dose of the gel (Estrogel,

Oestrogel, Oestrodose, Gynokadin®, 0.6 mg/g) lf dose is still too low (estrogen deficiency signs remain such as irregular menses, hot flushes, flabby breasts, etc.) the estradiol gel should always be taken in combination with Progesterone (Prometrium, Utrogestan, Utrogest, Progestan ®, 100 mg capsules)

290

Start with 3. 75 g/day From the 5 th to (3 pumps/day)

=>

=>

lncrease by 1.25 to 2.5 g/day (1 to 2 pumps/day)

the 25 th day of the menstrual cycle

Start with a low dose of 100mg/day

1h From the 15 to the 25 th dav

Possibly reduce the number of days of progesterone intake

=> reduce the dosing days to days 18 to 25.

How to solve the problems related to estrogen overdose or progesterone deficiency? Problems related to Estrogen Overdose (or progesterone deficiency): Table 1 PROBLEM •

POSSIBLE CAUSES PREmeno�ausal woman:

tension, anxiety,

•

irritability,

menstrual cycle

sleep difficulties, especially before menstruation (premenstrual syndrome)

(dysmenorrhea),

menstrual migraine) •

•

half of the menstrual progesterone deficiency

cause

=

POSTmeno�ausal woman

Anxious

Possible causes are

•

First, increase the dose of progesterone by + 30 to + 1 00%

•

lf not sufficient, reduce the dose of estradiol

or estrogen excess relatively high estradiol 1. Brain edema

syndrome with

2. estrogens increase

=>

1. Progesterone 2. Check for other deficiencies that

may weaken ovulation and lead to poor hormone production by the ovaries

catecholamines & convert into catecholestrogens •

lncrease the dose of progesterone by + 30 to + 1 00%

•

Change from bioidentical micronized progesterone to a synthetic derivative, preferably one structurally close to the natural progesterone such as dydrogesterone (Duphaston®)

•

Reduce the dose of estrogen (estradiol), esp. when other signs of

Estradiol excess (possibly •

Heavy menstrual bleeding

(menorrhagia)

When symptoms and signs are found only in the second half of the menstrual cycle: SOLUTION: lncrease the dose of progesterone by + 30 to + 1 00%

SOLUTION:

progesterone deficiency

premenstrual major irritability

estrogen (estradiol) by ± 30% •

on HRT treatment:

Low progesterone with •

=>

SOLUTION: Reduce the dose of

For POSTmeno�ausal women:

cycle

breasts, swollen

=>

When symptoms and signs are found in the first (and second) half(s) of the menstrual cycle

lf the symptoms are found only in the second

Swollen, painful

reddish face, swollen hands and/or feet abdominal bloating, weight gain esp. before periods (premenstrual tension).

•

=>

=

menstruation

periods (pre-

For PREmeno�ausal women:

cause estradiol excess that causes some degree of brain edema (more water retention), and overstimulates the sympathetic nervous system

Constant painful

migraines before

lf the symptoms

predominate the whole

outbursts of anger,

•

SOLUTION

Nervousness,

caused by progesterone deficiency) that causes excessive proliferation of the endometrium of the uterus

estrogen excess are reported in the first half of the cycle Premenop. woman: lncrease the

number of days on progesterone (start earlier in the cycle taking it)

291

Problems related to long-term progesterone deficiency

Problems due to long-term progesterone deficiency PROBLEM

CAUSES

SOLUTION: Reduce the estradiol-progesterone ratio by

giving higher doses of progesterone for

more prolonged times and using a synthetic derivative of progesterone (that remains

longer in blood): •

Before menopause: Administer a lower dose of maximally 2.5 g per day of Estradiol gel from the 5th to the

25th menstrual cycle day, and a relatively

A long-term progesterone

higher dose of progesterone very early in

deficiency (possibly also

•

Uterine fibroids

the menstrual cycle, e.g.:

androgen deficiency) is

•

present since many years

5 to 1O mg/day Duphaston® from the

5th or the 10th to the 14th day, or15 to 20

associated with relatively high

mg/day of Duphaston® from 5th to the

estradiol leveis

25th day After menopause:

Administer a lower dose of a maximum of

2.5 g per day of Estradiol gel from the 1st to

the 25th day of the month, associated with

a relatively higher dose of progesterone from the 1st to the 25th day of the month as

either: •

200 mg/day of oral micronized

progesterone, or •

CAUSE: Breast cysts develop

1O to 25 ma/dav dvdroaesterone

because the estradiol levels are relatively high, while

•

Apply local progesterone cream or gel on

edema of the breasts, creating

•

Provida or increase the dose of

and stimulating epithelial cell

•

progesterone leveis are low,

=> •

Breast cysts

the breast

the imbalance causes

differential areas of pressure proliferation in the breasts

progesterone

the combination of both

the conversion of estradiol to the much

phenomena makes cyst

less active estrone), or by reducing the

formation possible

CAUSE: The breasts tend to

excessively develop in the •

Large breasts

Reduce leveis of estradiol by supplying

progesterone and androgens (that increase

=>

dose of estradiol •

Supply and increase the dose of

androgens that can not convert into

long-term presence and

estrogens such as the synthetic derivativa

stimulation of high leveis of

estrogens, while at the same

time progesterone and/or androaens are deficient

292

mesterolon (Proviron®)

Irregular or paradoxal effects of the female hormone treatment that may occur:

Paradoxal effects of the female hormone treatment PROBLEM

CAUSE

SOLUTION 1. Stop putting another

cream or lotion on

PARADOXICAL EFFECT: •

The MORE estradiol gel and progesterone is taken, the more complaints and signs appear of estrogen deficiency, such as hot flushes, vaginal dryness, breast ptosis, fatigue, depression,

the skin areas where The patient's applies a skin lotion or

the estradiol gel is

cream on the same skin surfaces as

applied.

the estradiol gel. The lotion or cream

2. lmprove the

makes the skin impenetrable for the

application of the

estradiol gel.

estradiol gel that

On the other hand, the oral or vaginal

may have been put

progesterone is well absorbed and

on too small skin

reduces further the baseline estradiol

surfaces; possibly increase the dose of

leveis to very low values.

estradiol gel

etc.

3. Possibly, lower the dose of proqesterone The patient's estrone levei is probably much higher than that of estradiol. This imbalance is found

PARADOXICAL

typically after intake of oral estrogens

EFFECT:

(mainly with the use of conjugated

•

The MORE

estrogens, but also even bioidentical

progesterone is

estradiol, taken with micronized

taken, the more

progesterone), because after intestinal

complaints and

absorption of the estrogens, the liver

signs appear of

converts the ingested estradiol to high

progesterone

amounts of estrone. While normally

deficiency, or

progesterone decreases estrogen

estrogen excess:

effects by stimulating estradiol

swelling, weight gain,

conversion to estrone, in the presence

redness of face,

of such an abnormally high serum

breast enlargement,

estrone and low to normal serum

weight gain

estradiol, progesterone treatment accelerates the conversion of weak estrone to potent estradiol, thus increasing the effects of estrogen.

293

•

Switch over from an oral to transdermal estrogen treatment.

•

Switch over from bioidentical progesterone to dydrogesterone or possibly another synthetic derivative of progesterone that almost never presents such paradoxal effect.

Unexpected problems PROBLEM

CAUSE

IRREGULAR beneficiai effects of progesterone therapy in a woman with clear progesterone

•

Wrong food intake (sugar, sweets, soft

Change the diet.

drinks, milk products, bread, pastas)

To quickly correct the

causing: •

deficiency:

SOLUTION

"ups and downs" of progesterone deficiency complaints and signs (breast swelling and tenderness, swollen belly, redness of face, enlarged breasts, weig_ht gain,

situation: eat during

Yeast infection in intestinas. Yeast

the next two to four

has a protein (steroid binding globulin)

days only boiled or

that preferably inactivates

steamed foods (no

progesterone rather than estradiol.

fruits, but only boiled

With yeast infections, the

chicken, fish, meat,

progesterone treatment will work

vegetables, rice)

irregularly despite regular dosing,

Thereafter, base the

because a yeast infection typically

diet on fresh fruits,

neutralizes in an "up and down"

vegetables, and

intermittent way, causing intermittent

animal protein cooked

symptoms.

at low temperaturas.

Example of progesterone intake to treat menorrhagia (heavy menstrual bleeding) without estradiol treatment: Example of Progesterone intake to treat menorrhagia Progesterone Deficiency MIL O MODERATE

Progestogen treatment Take progesterone th

th

(100-150 mg/day)

18 to 26 day of the menstrual cvcle Take dydrogesterone (Duphaston®; 10-20 mg/d) from the

from the

th

th

15 to the 26 day of the menstrual cycle

Take dydrogesterone at a small dose of 5-10 mg/day from 5 th to the SEVERE

day of the menstrual cycle, then increase the dose to th

th

15 to the 26 day of the menstrual cycle

294

th

14

10-20 mg/d from the

Problems related to low or imbalanced doses of female hormones in birth-control pills:

Problems due to Birth-control Pills PROBLEM?

POSSIBLE

SOLUTION:

CAUSES

1. Take a birth control pill with high progestogen activity (which increases less the serum leveis of the plasma binding proteins that transport hormones and •

thus less disturb the endocrine system) such as

Young women

Microgynon 30, LO-Ovral, Minidril® (but possiblly acne

on the contraceptive

Too low

pill with signs

dose of the

of estrogen

estrogen

deficiency: dry eyes, vaginal

21 days (which correspond to 1st to the 21st day of the pill intake")

as a side-effect) during the

and ADD bioidentical hormones:

2. Transdermal estradiol gel (0.6 mg/g) component 1.25 to 2.5 g per day: of the pill, from the 1st to the 21st day of the pill to substantially ethinyl-

dryness,

estradiol,

droopy breasts,

(this is

permanent

actually the

fatigue, pallor,

case for

sometimes

most pills).

even hot

increase the estrogen doses

(100 mg capsules): 100 mg per day at bedtime: from the 11th to the 21st day to protect against excess

3. Oral micronized progesterone

estrogenicity Possibly add an androgen that can convert into estradiol by the aromatase enzyme (and thus increase

flushes, etc.

estradiol levels) such as:

5 mg/day 5. DHEA: O to 25 mg per day 6. Androstenedione: 1 O rl!9_per day 1. Take a birth control pill with high progestogen activity such as: Microgynon 30® (which contains 150 119 of 4. Testosterone, transdermal liposomal: 3 to

•

Young women on the

levonorgestrel as potent progestogen; may cause

contraceptive

acne) during

pill with signs of

lnsufficient

progesterone

dose or

deficiency:

potency of

premenstrual

the

syndrome,

progestin of

breast

the pill

tenderness, heavy menstrual bleeding, etc.

21 day every 28 days

lf still insufficient effects, add:

2. Dydrogesterone (Duphaston®, 1O mg tablets): 1o mg per day from the 1 1th to the 21st day lf still not sufficient: 3. lncrease up to 20 mg per day

4. Start earlier (esp. if heavy menstrual bleed1ng): 7th , 9th .

or

1oth day of the pill intake up to the 21st day

Possibly add: •

Androgens that are not convertible into estradiol (and thus have a progestogen effect) such as mesterolone (Proviron®):

295

12.5 to 25 mq per day

Cyclical headaches (migraines and other forms) during the menstrual cycle: Cyclical migraines (migraines occurring during the menstrual cycle) When? •

CAUSE

SOLUTION

At menstruation

(with droopy breasts, fatigue, depression, hypomenorrhea) •

In the first half of

Estrogen deficiency

menstrual cycle

(with droopy breasts) •

In the second half of menstrual

cycle (with droopy breasts)

lncrease the estradiol levels by supplying extra estradiol during 3 of the 4 weeks of the cycle (and combine with a low dose of progesterone in the second half of the cycle) e.g. • transdermal estradiol gel from (0.6 mg/g) 3.75 g per day from the 5th to the 25th day • oral micronized progesterone: 100 mg per day at bedtime from the 15th to the 25th day of the menstrual cycle

Reduce the estradiol levels by •

Just before or at

ovulation (with breast edema and tenderness)

•

In the second half of the cycle (with

breast edema and tenderness)

•

Just before menstruation

1. reducing the dose of estradiol if an estradiol treatment is administered 2. taking progesterone (which reduces serum estradiol by increasing the conversion of estradiol into the poorly active estrone) early in the menstrual cycle from the 1oth day on at a low dose 50 to100 mg/day Estrogen lncrease the progesterone leveis by supplying excess or Progesterone extra progesterone during the second half of the cycle, e.g. deficiency oral micronized progesterone 150 to 200 mg per day at bedtime: • from the 15th to the 25th day of the menstrual cycle if estradiol treatment is taken from the 5th to the 25th day • from the 18th to the 26th day of the menstrual cycle if no estradiol treatment is followed

How to take 150 mg per day of progesterone: How to take 150 mg of Micronized Progesterone per day PROBLEM Micronized Progesterone is

SOLUTION •

sold by pharmaceutical firms in capsules of at least 100 mg (Utrogest®,

Utrogestan®, Progestan®, Prometrium®)

•

lf the capsules of progesterone only contain 100 mg of micronized progesterone, you can obtain a mean intake of 150 mg per day by alternatively taking one day 100 mg (one capsule), the other day 200 mg (two capsules) Let a com_Q_ounding_pharmacy make 150 mg capsules

296

How to solve problems related to swelling? Women may suffer from various kinds of swelling. The most frequent causes and solutions to swelling are summarized in the following table: Differentiating the swelling (edema) caused by female hormone imbalance from the swelling due to other causes CAUSE: DEFICIENCIES

SWELLING •

•

Breast swelling and tenderness especially before menstruation

Low progesterone

Face swelling (puffy face) with swollen calves, hands and feet, especially in the morning

Low thyroid

•

•

Feet and ankle swelling

•

•

•

Feet and ankle swelling, with malnutrition signs

Very low protein diet

With muscle cramps during the day

Low magnesium

With muscle weakness (legs)

Low potassium

In the evening especially with higher blood pressure

Low cortisol with compensating high aldosterone

SWELLING •

•

• •

•

•

Feet, ankle and hand swelling

CAUSE:EXCESSES •

Especially in the evening with higher blood pressure

•

Higher blood pressure

•

HiQh salt diet

SOLUTION

Correct the cause. The cause can usually be found by detecting other more typical complaints and physical signs of imbalance and by lab tests

SOLUTION

High aldosterone High sodium

Breast swelling with painful breast tenderness during the whole menstrual cycle (starting in the first half)

High estrogens: high ratio estradiol/progesterone

Feet swelling

High testosterone

Feet swelling, hands and feet during the entire day

High growth hormone

Face swelling (moon face), possibly hands and feet, especially in the morning

High cortisol

Abdominal bloating with intestinal gas, especially after meals

Excess food intake Wrong foods: cereais (bread), milk products, etc.

297

Correct the cause.

Chapter Sixteen

Testosterone Deficiency and Treatment in Women

Case Study of a Woman with Testosterone Deficiency Michelle, with her failing sex drive, excessive emotions and eternal doubting Michelle is an attractive young lady of 30 years. sought after by men.

Because of her pretty, feminine body, she is

But Michelle has one big problem. Although she desperately needs and

seeks affection, she doesn't really feel sexually attracted to men of any type even though she is not gay. Her libido is near zero and having sex with a man is just such a boring, tiresome activity. She has had very few orgasms. The few times it occurred, it took such a long time and effort to achieve it that her partner stopped trying to make her have an orgasm again. Physically, she looks pale and has thin muscles. Sports are not her field of interest, as physical activity tires her easily. Emotionally, she is known for her anxiety, hesitancy and lack of assertiveness. Michelle is rather short tempered. From time to time, she explodes in outbursts of anger or anxiety that sometimes approach hysteria. She has taken birth control pills from puberty onward, not for contraception, but to get rid of her painful menstrual cramps.

In her late teens as she started to have acne, she took a pill that

contained a medication that blocked androgen activity, which only seemed to have aggravated her problems. What is the source of Michelle's problems?

Most of Michelle's problems are typical of

testosterone deficiency. To better understand the impact of this deficiency in women and what can be done about it, let us review the basic information on testosterone.

299

Testosterone in Women: Basic lnformation Roles of Testosterone in women

Testosterone performs the following important roles in women: 1.

lmprovement of mood and assertiveness, reduction of depression and anxiety.

2.

lmprovement of bone density, muscle size and strength, and skin sebum secretion.

3.

Enhancement of sex drive and sexual sensitivity, including orgasm.

4.

Maintenance of the female genital system: nipples, labia majora (vulva lips) and in particular the clitoris (size, sensitivity), female body hair pattern.

5.

Possible protection against atherosclerosis. In two studies higher leveis of testosterone in women (DHEA and androstenedione also) were found to be significantly associated with thinner intima media of the carotid arteries, which lowers the risk of atherosclerosis.

Testosterone production

The daily production of testosterone in young healthy women approximates 250 micrograms, an amount that is 20 to 30 times lower than what is produced in men. Despite the difference, it is our experience that testosterone is nearly as important to women as it is to men. Half of the testosterone in women comes from the conversion of DHEA and androstenedione in fat and skin tissues, one-fourth is made by the ovaries and one-fourth by the adrenals. The pituitary hormone LH is the hormone that stimulates testosterone production from the ovaries; the pituitary ACTH stimulates testosterone production by the adrenals. Progressiva decline of Testosterone leveis with age

The decrease occurs earlier and initially at a greater rate for women than for men. A study reported that the average testosterone blood levei in women of age 40 is low, less than half of that in women of 21 years of age. What factors can influence Testosterone production?

Intensa physical activity such as long-distance running and other vigorous sports make the body consume high amounts of testosterone, thereby depleting androgen leveis. Moreover, intensa emotional stress inhibits the release of LH, and thus testosterone secretion. Foods high in protein or saturated fat increase testosterone production. On the other hand, many foods can reduce leveis of testosterone and of DHEA, the main provider of testosterone in women. Sugar and sweets do this by decreasing androgen production. Cereais rich in fiber (whole grain bread, bran flakes) reduce testosterone by increasing the loss of testosterone in the stools (much of the testosterone is secreted in the bile and thereafter reabsorbed in the gut and used again, cereal fiber sticks to the testosterone and inhibits its enterohepatic cycle). Principal metabolites of Testosterone:

Dihydrotestosterone and particularly androstanediol glucuronide. Dihydrotestosterone (DHT) is the main metabolite of testosterone and its androgen potency is three times greater. After having expressed its activity, DHT converts into the metabolite androstanediol glucuronide. Measuring the leveis of this major androgen metabolite best reflects male hormone metabolic activity.

300

I. Female Testosterone Deficiency: DIAGNOSIS How do you detect testosterone deficiency in women?

Testosterone deficiency is best detected with physical examination, medicai history, complaints and laboratory tests.

1. Onset of Female Testosterone Deficiency When did the testosterone deficiency start? Women with (untreated) testosterone deficiency, which started at puberty, show signs of sexual immaturity. The most characteristic sign of it is a lack of body hair. The basic differences between puberty- and adult-onset testosterone deficiencies are summarized in the following table. The patient should be asked if any of the signs and symptoms listed below have been present since puberty to determine the onset. Determining the Onset of Testosterone Deficiency in Women Onset Hair

Puberty •

Face

•

Voice

•

Muscles Skin

•

•

Body h air Pubic h air

•

•

Clitoris

•

Libido

•

Clitoris

•

Orgasm

•

• •

Behavior

• • •

Medicai history

•

Adulthood

Horizontal hair line (no hair recession at sides of the forehead) Smooth, thin childlike face Higher, childish voice Thin, poorly developed muscles Dry skin (absent sebum) with little to no body scent

•

Hair recession at sides of the forehead Female face, but older looking Mature female (adult) voice Larger, better developed, but atrophying muscles

•

Normal skin and body scent

•

• • •

•

Little to no body hair The pubic hair is limited to a small zone around the vulva Smaller clitoris Underdeveloped sex drive Underdeveloped sexual sensitivity lnfrequent or absent orgasms (frigidity) Submissive, lacks authority Rigid Often lacking initiative Anxious; little self-assurance Avoids sport and physical activity Presents the above mentioned mental, physical and sexless characteristics since puberty

301

•

• • • •

•

•

•

Normal female pattern of body hair, but thinning The pubic is normal (has grown up to the upper horizontal border of the pubis in a inverse pyramid shape) Normal-sized clitoris Developed sex drive but reduced Developed but reduced sensitivity Able to achieve orgasm, but increasingly difficult Normal behavior and attitudes but becoming more passive since the onset of the deficiency Likes physical activity and sports, but the interest has been fading recently Problems started much later in adulthood

2. Timing and Location When and where do testosterone deficiency signs and complaints occur? When? Typically, testosterone deficiency signs and symptoms are chronic throughout the day. They increase with physical activity such as sports that put strain on the muscles. Where? The parts of the body most affected by testosterone deficiency are the brain, muscles, bones and areas related to sexual maturity.

3. Complaints of Testosterone Deficiency in Women What do women with testosterone deficiency complain about? The main complaints of testosterone deficiency a female patient may express are summarized in the following table. COMPLAINTS of Testosterone Deficiency in Women MENTAL •

Behavior

• • • •

Character

•

•

Memory

•

Nervous lrritable 111 at ease Lack of mental firmness Undecided, hesitating Lack of self confidence, lack of assertiveness Lack of authority, submissiveness Poor memory

Mood

• •

• •

Stress • •

Depression the whole day long Excessiva anxiety, fears Excessiva emotions Excessiva sensitivity to difficulties, low resistance to stress Unnecessary worry Hysterical reactions

PHYSICAL Health Physical appearance

•

• • • •

Temperature

•

Hypochondriac (frequent complaints of being sick) Aging appearance Abdominal obesity Muscle laxity Hot flushes Day and night sweat outbursts (especially head and upper chest)

Permanent fatigue that increases with physical activity • Low energy, tires easily Exercise • Lack of interest • Lack of endurance

Muscles Bones Joints Skin Bladder

•

Energy/ vitality

Sports

302

Sex

Vagina

Reduced muscle strength, volume, (rare) muscle pains • Back pain up to lumbago and sciatica • Jointpain • Dry skin • Easily sun-burned skin (Caucasian women) • Urinary incontinence Decreased or absent: • libido • clitoris and nipple sensitivity • orgasm •

• •

Vaginal pruritus (itching) Painful intercourse

4. Physical Signs of Testosterone Deficiency (Women) The principal physical signs of testosterone deficiency that can be seen at physical examination of a female patient are summarized in the following table.

PHYSICAL SIGNS of Testosterone Deficiency in Women

Physical

•

Pai e

•

Nervous

•

Slumped, fragile

•

lrritable

•

Older looking (adulthood-onset

•

Hesitant

appearance

deficiency); younger looking (uncorrected early puberty-onset deficiency)

Back Fat

Mood

•

Depressiva,

•

Neqative attitude

•

Kyphosis, lordosis

Mental

•

Poor concentration

•

Often overweight, even obese

Memory

•

Poor memory

•

Fat accumulation on the breasts, abdomen and hips

o

•

Voice

Loss of height (adulthood-onset deficiency);

Height

Behavior

Sometimes taller than average (some forms of uncorrected early

•

•

Lack of body hair:

•

Puberty type: small patches of dense body

Body hair

Higher, more anxious tone

hair •

puberty-onset deficiency)

Adult type: less dense but larger patches of bodv hair

• •

Face

•

•

Pale face Poorly muscled (hypotonic) face Small wrinkles at the corner of eyes

Eyes

•

Dry eyes

•

Decreased armoit and oubic hair

•

Poor muscle volume

belly, legs

Scent Muscle

•

Flabby belly

•

lncreased abdominal fat

Thighs

•

Cellulite

Leas

•

Varicose veins

Abdomen

•

Pale skin

•

Atrophic skin, dry, thin

•

Bruises easily

Small vertical wrinkles above lios

Armpits/Pubis Arms, back,

Skin

Clitoris Vagina

•

Lack of sexual body scent

•

Poor or reduced muscle volume, tone, strength

•

•

Smaller clitoris Vaginal atrophy, dryness, pruritus

5. Disease Susceptibility Which diseases develop easier in patients with testosterone deficiency? Based on the known effects of androgens, it is likely that long-term testosterone deficiency predisposes women to depression, anxiety disorders, joint disorders (osteoarthritis, rheumatoid arthritis), osteoporosis and atherosclerosis.

303

6. Lab Tests for Testosterone in Women Which lab tests help to confirm the diagnosis of testosterone deficiency in women? The best tests to evaluate daily testosterone production in blood is total testosterone and also DHEA sulfate, as in women more than 90% of the testosterone comes from DHEA. But knowing the production is not sufficient, for we also need to know how much of the testosterone that is produced is available to the target cells? The best tests to evaluate the availability of testosterone to the target cells are free testosterone and the ratio total testosterone/SHBG (the higher the ratio, the greater the androgen effects). Even more important is to know how much of the testosterone is effectively used to exert androgen action after being converted into dihydrotestosterone? The best marker to measure this androgen metabolic activity is obtained by measuring in the blood the major metabolite androstanediol glucuronide. 24-hour urinary testosterone 1s both a good marker for testosterone production and availability. BLOOD Lab Tests (at 8 a.m.) for Testosterone in Women Opti-

TEST

mal1

LH Total testosterone

(T)

Free testosterone*

P. Defi-

�alue4

2-12 miU/mL

Low Med3

3

� 8 0-25

350

0-250

100-500 pg/ml

1.2

0-0.9

0.3-1. 7 nmoi/L

8

0-5

28

0-17

90

0-60

4

150

testosterone (DHT)

250

860

0-120

0-619 0-2 0-7

DHEA sulfate Androstenedione

100-250 pg/ml

80-350 pg/ml

3-3.9

65

30-120 pg/ml (follicular phase)

0-180

10-23

(TeBG)

2-15 pÇJ/ml

7-52 pmoi/L

(luteal phase)

glucuronide (AG)

6.1

10-50 ng/ml

or>220

Androstanediol

SHBG

0-5.2 or � 8.5 0-55 or

� 90

275-1204 pmoi/L 0.1-6.0 nÇJ/mL 0.3-20 nmoi/L

3.9-7.7 mg/L

80 - 480 IJÇJ/dl

0-200

2800

0-2000

800-4800 ng/ml

9. 7

0-6.9

2.8-16.6 J1moi/L

0-2.0

Low Low

1.0 -3.5

nglml)

lnformation

lncreases T production Serum total T is more stable in blood than serum free T Fluctuates Low E2 may be a sign of low T (the precursor of E2), or of excess

T (because of the progestative

Med

activity of

T); Hiqh E2 leveis may

reduce testosterone effects Less valuable than androstanediol

Med

(as DHT does not reflect androgen activity and the test kit quality is poor), 10x lower levei than T

High

Major DHT metabolite ; reflects androgen metabolic activity A hiqh SHBG excessively binds

Med

41-79 pmoi/L

280

2.5

Test

(young adults)

35

Estradiol (E2) '5

Dihydro-

References3

cienf

androgens in the blood, reducing the uptake of T by target cells, thus reducing its cellular effects

Med

Main substrate for the production of T in women

Low

Substrate for T production

Notes: Symbol'�" means more or equal to; "p. deficienf' means "probably deficient" 1

The optimal value is presented for a woman with a height of 5'4 and 125 pounds (1 meter 70 and 55-60

kg). Ta/ler women with an athletic build may need higher optimal testosterone leveis; whereas in shorter women with minimal muscle development lower leveis may suffice;

2

Ranges of deficient values in

testosterone and related hormones; 3 References of adult women age 20-30 years; 4

Test value: estimated usefulness for use in practice.

304

URINE & SALIVA Lab Tests for Testosterone in Women

TEST

Optimal1

15-17

Testosterone --

E

(free)

o

... .c u

UI 111 Cl

0.05-0.06 2.2

Androsterone

w z

ã: ::J

Etiocholanolone

... :I

o .c I

..,. N

Defi-

3 References

cienf

(young adults)

0-12

3-23 J..LQ/24h

0-0.04

0.01-0.08 f.1mOI/24h

0-1.7



0-5.8

2.4-9.6 f.1mOI/24h

2

0-1.6

0.7-2.7 mg/24h

6.8

0-5.5

2.4-9.3 f.1mol/24h

6.5-7

0-5.5

2.9-8.9 mg/24h

17-ketosteroids

:i


Testosterone

0-30

40

Low

O. 7-2.8 mg/24h

7.5

22.5-24.5 0-19.0

Test Value4

10-30 f.1mol/24h

Med

Med

Med

5-50 pg/ml Low

(free)

104

139

17-174 pmoi/L

lnformation Provides a 24-hour picture oi testosterone (T) production Provides a 24-hour picture of DHT's and testosterone 's metabolic activity Provides a 24-hour picture of testosterone's metabolic impact Total sum reflects the 24-hour adrenal androgen metabolic impact on target cells Less valuable than blood and urinary tests because of excessive fluctuations and broadness of reference ranQe

When do you do Lab Tests for Follow-Up of Testosterone Treatment? The blood test for follow-up of testosterone replacement should be obtained: •

•

8 to 14 hours after applying the testosterone gel on the skin. Ask the patient to apply the

testosterone gel before bedtime during the 3 nights before the blood test instead of in the morning. 21 days after a 30 to 50 mg (intramuscular) injection of testosterone (enanthate or cyprionate)

At those times tests related to testosterone reach stable values that correspond more or less

to the 24-hour average values.

305

11. Female Testosterone Deficiency: TREATMENT Medications for Testosterone Treatment in Women How do you correct testosterone deficiency in women? Various treatments for testosterone deficiency in women are on the market and are listed in the following table. The treatments that work better in our experience are highlighted with a yellow background. Treatments of Testosterone Deficiency in Women Route

Product Testosterone undecanoate (Andriol®, Testocaps®)

Oral

Mesterolone

Oral

(Proviron®)

Sublingual Transdermal Transdermal

Transdermal

lnjection

Dose

(sedentary)' 40 mg every 2-4 days

12.5-25 mg

Testosterone

5-10 mg/day

Testosterone gel

10 mg/day or per 2 days

(Androgel®: 1O mg/g) Testosterone liposomal gel

10 mg/g (compounding pharmacies)

Dihydrotestosterone gel

25mg/g (Andractim®)

Testosterone enanthate or cyprionate (Testoviron

depot, Androtardyl®)

(intramuseu.) Nandrolone 25 mg (Decadurabolin®)

lmplant Testosterone 5-30 mg

3 mg/day (2.5-10 mg/day)

1-5 mg/day

25-50 mg every month (or 3 weeks)

lndication: Female

Testosterone deficiency For occasional needs: low libido, specific stress, etc. Mild to moderate deficiency in young and middle-aged female adults; Not for patients with liver disease Acute need for more testosterone: take it Y2 to 2 hours before sex, giving a lecture, stress, etc. Mild testosterone deficiency Ali degrees and at ali ages of testosterone deficiency; also for women with low libido For local application of very small doses on the vulva against: lichen sclerosis, on the clitoris against a lack of orgasm and sexual sensitivity, and on burn skin wounds ; Not for systemic use in women For women with low libido and no or poor orgasms who do not respond to the abovementioned treatments

25 mg/month Osteoporosis 1x/ 3-6 wks Every For women unwilling or unable to 2-6 months take a daily testosterone treatment

Note: Strenuous physical activity requires higher doses. ·

306

Value

Low

Med

Low

Low High

Med

Med

Med Med

Change Testosterone Medication or its Dosage? Various conditions may necessitate to change product or to adjust the dose of testosterone. The most frequent of these conditions are summarized in the following table. When to adjust the dose or to change medication Severe deficiencies Strenuous physical activity, sports

Testosterone liposomal gel and injectable testosterone are the best delivery

Heavy diarrhea

Require higher doses of testosterone: increase (temporarily) daily doses up to to + 75% the normal dose

Wounds (induced by trauma or burns)

The transdermal dihydrotestosterone gel works well to accelerate the healing of the wounds

Liver disease

Transdermal forms are indicated. Avoid the use of mesterolone, a synthetic derivative of testosterone

Frequent sexual activity

+

25%

What is the best form of treatment for most women with Testosterone Deficiency? Transdermal testosterone gel is the best, because it offers a higher efficacy for building up libido, sexual sensitivity, muscle and bone. The second best route, in our experience, is sublingual testosterone divided in morning and evening doses and mesterolone (Proviron®; taken once in the morning). lnjectable testosterone treatments are used when a female patient seems not to do well enough with transdermal or oral treatments, or has a major problem of low libido and lack of orgasm, or severe depression. Where should the patient apply transdermal testosterone gel? The inner side of the arm is a good place to start the treatment. The penetration through the skin of the arm is low compared to facial skin but safe enough to avoid unwanted hair growth locally and in most cases sufficient, as women do not need high doses of testosterone. Rarely, when the results are unsatisfying because of a poor absorption, it is better to apply the gel on the skin with higher absorption, namely the areas that redden when blushing such as the upper part of the chest above the collarbone, and possibly forehead, and sides of the neck. The application of a transdermal gel of estradiol at the same site as testosterone possibly during the same session does not seem to impair its absorption or create any problem.

How do you start testosterone treatment? In most patients, testosterone can initially be started at the dose that is thought to bring complete relief. lf a woman suffers from male pattern hair loss or body hair overgrowth, it may be prudent to start with a dose that is 25 to 75% lower than the optimal dose and then after 2 months, if no adverse side effects occur, increase the dose by 25% of what seems to be the optimal dose every two months until the optimal dose has been reached. Continually monitor the patient for progress and side-effects and adjust the dose accordingly.

307

Balancing Testosterone with Female Hormones Supplementing a woman with testosterone may disturb the female hormone balance and cause virilism signs unless it is associated with a female hormone treatment. Moreover, the vast majority of women who are deficient in testosterone have a deficiency in female hormones, too. For these reasons it is safer to nearly always add female hormones to the androgen treatment.

How to Avoid Body Hair Overgrowth Body hair overgrowth in women taking testosterone is uncommon if below-mentioned recommendations are respected. lf it does show up nevertheless, the problem can usually be corrected in six weeks to six months. Observing the following recommendations helps avoiding body hair problems: •

Combine female hormone replacement with testosterone.

The skin and hair follicles

must have a sufficient amount of estrogens and progesterone to avoid body hair overgrowth.

Female hormone treatment blocks the action of DHT, which forms out of

testosterone and powerfully stimulates body hair growth, and thus blocks body hair growth. •

Whenever signs of testosterone overdose show up such as oily hair, oily skin and acne, reduce the dose of testosterone.

These signs usually appear long before any body hair

overgrowth starts. •

Whenever a woman already has excessive body hair or if you want to be extra cautious: •

Start at half the dose of testosterone.

lf after months of treatment no excess body

hair or any other sign of androgen excess develops, gradually increase the dose up to a more efficacious dose. •

Advise the patient to apply daily a thin layer of estradiol gel on the face during the first months of treatment to block any hair growth in this highly sensitive area. The estradiol will protect the face during therapy.

•

In women who have a high tendency to grow body hair:

Add finasteride (Proscar,

Propecia®) at 2 to 2.5 mg per day or another 5-alpha-reductase inhibitor, a substance that inhibits the conversion of testosterone to DHT--the hormone that grows body hair. Finasteride, for most female patients, protects against body hair growth. Some care should be taken with women sensitive to the 5-alpha reductase inhibitor. About one out of six women experiences side-effects such as anxiety, decreased sexual sensitivity and libido, or swelling of the feet with doses of 2.5 mg per day.

Simply lowering the

dose to 1.5 mg per day or less of finasteride is usually enough to solve the problem. •

/f excess body hair is observed and in particular (slight) facial hair, do the following: •

Stop or drastically reduce by -50% the dose of testosterone for two to six months.

•

Stop or reduce in the same manner any other androgen (DHEA, etc.)

•

Continue (and if necessary increase) the dose of the female hormones, especially estradiol, and apply a thin layer of estradiol gel on the face every day.

•

lf the woman is extremely distressed about the hair growth, supply a 5-alpha-reductase inhibitor and even perhaps an androgen receptor blocker such as cyproterone acetate (Androcur, Cyprostat® 1O to maximum 20 mg per day). These measures may quickly and considerably reverse most cases of excess body and facial hair recently caused by a testosterone treatment, in six weeks to six months.

308

Progress with Testosterone Treatment in Women How soon are the first improvements noted? Testosterone replacement works slowly.

The first improvements are usually emotional and

sexual and appear during the second, third and fourth month of treatment.

lmprovements in

muscle mass and bone density take more time, four to eight months, before any clear signs are seen.

Women who eat more foods that increase testosterone leveis and efficacy such as

animal protein (meat, poultry, etc.) and avoid eating foods which lower the testosterone leveis such as grains, sugars and alcohol, usually obtain quicker effects.

lndications for Testosterone Treatment in Women Permanent indication: Ali degrees of testosterone deficiency in women. Short-term indications for transdermal testosterone locally applied: The patient can apply the testosterone locally to burns, to traumatic or atherosclerotic injuries to improve healing, to the clitoris to increase its sensitivity and arousal, to the opening of the urethra to reduce stress incontinence (the testosterone strengthens the musculature of urethra and bladder sphincter--use small amounts), varicose veins (mixed efficacy). lndications for injectable testosterone: Osteoporosis, severe degree of frigidity, severe depression, cellulite.

Contraindications to Testosterone Treatment in Women Absoluta contraindications: Absence of testosterone deficiency, extremely severe hirsutism, male pattern hair loss in women, breast cancer (at least for bioidentical testosterone as it can convert into estradiol)

309

How to Boost Testosterone Treatment in Women First of ali, improve the diet. The dietary principies to follow are summarized in the following table:

Optimal Diet for Testosterone in Women What to Avoid

What to Eat •

Follow a "Paleolithic"

diet: fruits, vegetables,

•

fish1'2

•

Eat organic foods3

•

meat, poultry, eggs,

Diet •

•

Avoid alcohol, vinegar, caffeinated drinks4·5 Avoid sugar, sweets, soft drinks, cookies, bread, pastas and other cereais

Avoid cereal fiber (whole grain bread, bran flakes) Avoid milk products

Notes: 1

A high intake of protein-rich foods such as meat and poultry may actual/y /ower total testosterone leveis in blood, but at lhe same time amplify testosterone activity by increasing lhe leveis of free testosterone, lhe most

2

bioavailable form of testosterone for lhe target cells. Foods rich in saturated fat such as eggs, bacon and (clarified) butter increase lhe production and lhe leve/ of testosterone (clarified butter is also called ghee and is butter without lhe 'al/ergenic' milk proteins; lhe separation can be obtained by warming up at a very low temperature lhe butter: lhe upper whiter layer contains lhe proteins

3 4

5

that you can extract). Certain pesticides may a/ter testosterone secretion and effects. Alcohol may increase lhe conversion of testosterone to estradiol depleting a woman of her testosterone, while at lhe same time adverse/y affecting lhe essential, but fragile estradio/- progesterone balance Caffeine intake may increase the breast cancer risk by increasing epithelial proliferation in lhe breast, causing precancerous /esions. Decaffeinated drinks (where lhe caffeine has been extracted by the safe method based on water and carbonic acid) may be an acceptable alternative.

Second, correct any other hormone abnormality that influences testosterone's efficacy. The principal hormone replacement therapies therapies, which influence the secretion of testosterone and/or its action, are summarized in the following table:

lnfluences of Hormone Replacement Therapies on Testosterone/Dihydrotestosterone in Women Strong

Strong Mild

Stimulator of

lnhibitors of and DHT

and DHT • •

Other

Mild lnhibitor

Testosterone

Stimulators

Testosterone

•

Growth hormone Thyroid hormone (as therapy of

androgens •

hypothyroidism) DHEA

•

•

Oral estradiol and

other estrogens

Glucosteroids at high doses

310

• •

Progesterone Cortisol at low doses

•

Thyroid hormones

•

Transdermal estradiol

in excess

Follow-Up of Testosterone Treatment in Women What do you do next, once the treatment has started? 1. Find the optimal dose:

lt may vary depending upon factors outlined in the table below. When to adapt the dose of Testosterone Lower the dose:

lncrease the dose Treatment

• • •

Dietary, digestive

•

or lifestyle

•

conditions

• • •

Hormone

•

dysfunctions

•

or treatments

•

(25% to 150% more) lnsufficient testosterone effects Low-protein diet High-cereal fiber diet (whole grain bread, ali bran flakes) Low-calorie diet Diarrhea lncreased physical activity lntensive and/or chronic stress Adult growth hormone deficit Excess thyroid h. (hyperthyroidism) Oral estrogen treatment (Birth control pill, conjugated estrogens oral estradiol,}

• • • • • • • • • • •

(25 to 50% less) Excessive testosterone effects High-protein diet High-fat diet High-calorie diet Decrease in physical activities Sedentary, bedridden, Prolonged rest Unstressed, vacations Growth hormone treatment Excessive body hair (hirsutism) Women with male pattern baldness (androgenic alopecia)

2. Avoid under- or overdosing:

Particular attention should be paid to avoiding any overdose of testosterone. This is easier to do when the female patient knows the signs and symptoms of testosterone hormone deficiency and excess. The patient can then assist the physician in adjusting the dose. The typical signs of testosterone excess are presented in the table below. The typical signs of Testosterone Excess Latency

Hair 1 month Face Skin Feet 1-2 months Sex 1-3 months Clitoris 2-3 months Behavior Muscles 4-6 months Hair 4-12 months Body hair 3. Perform Lab tests:

Cause

Sign

Type • • • • • • • • • •

Oily hair Acne Oily skin Feet edema (rare: only with injections) Excessive sex drive (libido), sensitivity Excessive clitoris swelling - sensitivity Excessively aggressive, authoritarian attitudes Excessive muscle development Male pattern hair loss Hirsutism (excess body hair)

Excess Testosterone

(T)

Excess DHT

formed from T

see section on Follow-up of Testosterone Treatment in Men

4. Solve problems quickly and efficiently during follow-up.

311

111. Testosterone PROBLEM SOLVER How do you solve problems that may occur during treatment? Problems related to Overdose: Testosterone Excess WHERE

Face

PROBLEM

•

Acne

POSSIBLE CAUSES

SOLUTION

Excessiva stimulation of

1.

that may cause acne during an

testosterone (T) and

androgen treatment

such as sweets, chocolate and milk products

DHEA (but not by dihydrotestosterone

2.

Muscles

Excessiva muscle

development Feet

Behavior

•

Feet edema

•

Reduce the dose of androgens (T, DHEA)

(DHT)) •

Diet adjustment: avoid foods

sebum production by

Excessive muscle development, primarily caused by excessive leveis of T (and DHT)

Reduce the dose of androgens

Excessiva salt and thus

•

fluid retention due to

/f the edema persists:

androgens

.

Androgen overdose may cause aggressiveness by strongly stimulating brain Very excitatory neurotransmitters aggressive* and possibly also by causing water retention in the head and thus brain edema Excessive conversion of T into E2 in the brain Excessive stimulation of the parasympathetic Excessiva system by androgens libido Excessive increase in

(testosterone, DHEA, DHT) Take potassium

(1-3 g/day)

Reduce the androgen dose

Reduce the dose of androgens (testosterone, DHEA, DHT) Correct the GH deficiency with GH

•

1.

Reduce the dose of androgens

2.

Reduce the conversion of T to

(testosterone, DHEA, DHT)

•

•

•

androgen receptors in the clitoris & other highly

sensitivegenital areas •

Excessiva conversion of testosterone into

Sex

DHT •

Painful clitoral swelling and sensitivity

•

Excessiva increase in androgen DHT receptors in the clitoris and other highly sensitive genital areas

E2 with an androgen derivativa (mesterolone or rarely methyltestosterone) that cannot convert into E2 1. Reduce the dose of androgens

(T, DHEA, DHT) 2. Reduce the conversion of T to

DHT with a 5-a-reductase blocker

such as finasteride (Proscar®, Propecia® at a daily dose of 1.5-2 mg ) or with an androgen receptor blocker such as cyproterone acetate (Androcur®, Cyprostat ®) at 5-1 O mg/day) ,

Engorgement of the clitoris by Stop for ten days, and then start local application of a DHT gel again with much less of the DHT gel (to increase clitoris sensitivity) Notes: *Excessive aggressiveness with testosterone treatment seems to occur more Jikely in women with GH deficiency, which is associated with a low-deficient parasympathetic nervous system activity.

312

Problems related to excessive conversion of testosterone to the virilizing dihydrotestoterone. Problems related to Excessive Transformation of Testosterone into DHT Dihydrotestosterone H air

Body

•

Hair loss

(male pattern)

•

h air

Hirsutism

(Excessive body hair)

(DHT) is the hormone responsible for body hair growth and male pattern baldness in men and women. An excess in DHT is thus the culprit due to: High testosterone dose DHT treatment and/or Excessive conversion of testosterone into DHT

•

•

•

•

• •

•

Reduce the dose

of testosterone Take finasteride 2.5 (1.5 to 5) mg/day with testost. treatment {don't give it without testosterone supplementation) Avoid taking DHT Eat less meat (meat increases conversion of testosterone to DHT)

Problems of high leveis of sex hormones in the blood. Problems due to Excessive Blood Leveis of Sex Hormones TOO HIGH TESTOSTERONE LEVELS •

The most likely cause is that the blood test is done too soon after taking testosterone

•

Excessive se rum testosterone

•

although the female patient shows no sign of overdose •

1.

Check blood from 9 to 14 hours after

the last transdermal The needle of the syringe for blood testosterone gel application (take withdrawal has gone through a testosterone in the evening for 3 zone of testosterone storage in the days before the test and then skin because the transdermal take blood in the morning after testosterone is applied on the the 3'd night), or wait for blood (inner) elbow fold at the same place tests 21 days after testosterone where blood is taken inj ection Patient has mistakenly and 2. Avoid applying testosterone in occasionally taken more the elbow fold 3 to 5 days before testosterone than prescribed (by the blood draw distraction, or because of difficulty 3. Review dosage and correct in correct dosing with difficult tube application techniques with or bottle). patient Patient has received an extra 4. Advise the male partner to apply amount of testosterone through: the transdermal testosterone on - body contact with her male "safer'' {for his female partner) partner who uses a transdermal areas: skin above the collar testosterone therapy that he rubs bone, forehead, sides of the on his chest, abdomen or penis neck, sides of the trunk - through the sperm because of frequent intercourse

TOO HIGH ESTRADIOL LEVELS

Breast tenderness

Breast edema caused by excess estradiol (E2) through excessive conversion of testosterone into estradiol.

313

•

Reduce

the dose of estradiol

if no estradiol treatment is given: •

Reduce

the dose of T, DHEA and other hormones that can convert into estradiol (E2)

Problems related to the inefficacy of testosterone or excessive activity of other hormones that are stimulated by testosterone treatment Testosterone can influence the activity of other hormones.

Problems may occur during

testosterone treatment caused by the overstimulation of other hormones. Testosterone increases thyroid, growth hormone, estradiol and dihydrotestosterone; therefore, whenever a patient takes these hormones in conjunction with testosterone and overdose symptoms of these other hormones appear, the first thing to do is to reduce the dose of the other hormone of which overdose signs are found and not the testosterone.

Problems of lnefficacy of Testosterone Treatment: Table 1 PROBLEM

POSSIBLE CAUSES •

SOLUTION

lf signs and complaints of testosterone deficiency are sufficiently improved by the testosterone treatment, -

The most likely cause of low testosterone leveis is a late blood draw, done 24 hours or more after the last testosterone intake.

•

Testosterone leveis are then back

lnsufficient

down to the low leveis found before

increase of

any treatment.

blood leveis

-

of testosterone

hours before the blood tests that

(leveis remain

have depleted the testosterone

low and do not differ from initial levels)

Other causes include strenuous physical activity in the 24-48

stores. •

lf signs and symptoms are not sufficiently corrected by the testosterone treatment, one should suspect that the cause is -

an insufficient dose

-

an inefficient absorption

-

-

-

a wrong product a wrong diet, or diarrhea (with testosterone loss in the stools).

314

1. lf signs and complaints of

testosterone deficiency are corrected, check blood 9 to 14 hours after last

applying the transdermal testosterone gel (take testosterone at bedtime 3 days before the morning blood draw); check the blood test 12 days after testosterone injection of 250 mg. Avoid strenuous activity 18 hours before the blood

test. 2. lf signs and complaints

are not sufficiently corrected, correct the cause (see below).

Problems of lnefficacy of Testosterone Treatment: PROBLEM

POSSIBLE CAUSES •

•

SOLUTION •

lnsufficient dose lnefficient absorption

of the

•

produd

lnsufficient beneficiai

•

Wrong product

•

Wrong diet

effects of testosterone therapy in a clearly testosterone deficient female,

with no side effects

•

improvement with testosterone therapy in a clearly testosterone deficient woman,

but

side effects:

•

•

•

Swelling Acne, oily skin and hair body hair overgrowth

especially some oral synthetic derivativas may have poor efficacy -

•

•

insufficient protein intake (meat, poultry) -

or frequent the enterohepatic cycle of testosterone and related androgens: the testosterone that should be reabsorbed, is carried out in the stools2 High-cereal fiber diet

•

diarrhea interrupts

•

Minor

•

•

Table 2

(most likely cause): Too much sugar, sweets, chocolate, soft drinks, milk products, caffeine, alcohol. They Wrong food intake

• •

lncrease the dose

lmprove absorption (avoid putting other creams or lotions on the same skin surfaces as the testosterone gel, improve digestion, etc.) Change product: use a natural testosterone instead of a synthetic derivativa Change the route of administration, switch to transdermal preferably to oral, or use injection Correct the diet:

increase protein intake Avoid dietary cereal fiber Stop the diarrhea (eat only boiled foods for 2-3 days, add supplements of lactobacillus acidophilus and other good bacterial flora, etc.)

1 . 1mprove the diet: •

reduce the beneficiai effects of testosterone, while increasing its adverse effects on the skin, especially oil formation and inflammation of sebum glands, and thus acne.

The swelling may result from eating a high salt diet, combined to the testosterone treatment that increases salt and water retention. Obese women: Fat tissue may absorb and inactivate too much of the testosterone

of

testosterone

•

•

Avoid sugar, sweets, chocolate, soft drinks, milk products, caffeine, alcohol Avoid excess salt (if there is swelling) Eat more meat and other protein-rich foods

2.

(improves production of testosterone and DHT) Eat less to lose fat and excess weight, exercise moderately to increase muscle mass

Note: 1 A transdermal testosterone gel can be poorly absorbed: because the patient applies the gel too quick/y without rubbing enough on the skin or because before application of the gel she puts another cream or /otion on her arm that blocks 2

the absorption of the testosterone gel. Digestive disturbances decrease the absorption of oral testosterone.

315

Chapter Seventeen

Testosterone Deficiency and Treatment in Men

Case Study of a Man with Testosterone Deficiency Brad and his failing sexual potency and depressed mood Brad, a 56 year old white male, used to be a strong macho man. However, during the last two to three years something has changed.

His muscles are not as firm and strong as before,

although he continues working out. His belly and breasts have become fatty. He even had two or three prostate infections that were difficult to cure even with antibiotics. Brad feels increasing fatigue when he participates in sports. Brad, who always was a bit of a jolly lad, has lost much of his smile and joy. Brad is concerned about his depressed moods.

But what makes him really lose his self-assurance is that his

sexual potency is failing. Not only can he lose his erection in the middle of intercourse, but also there are times when he can not even get an erection. Even his sex drive is declining; looking at women doesn't arouse him as much as it used to. What is Brad suffering from?

Most of Brad's problems are typical of testosterone deficiency.

To better understand what this deficiency means and what can be done about it, let us review some basic information on testosterone.

317

TESTOSTERONE: lmportant lnformation Testosterone converts into dihydrotestosterone and estradiol Testosterone, the predominant male hormone, can convert into dihydrotestosterone (DHT), the most potent male hormone, thanks to the enzyme 5-alpha-reductase. DHT produces the male sexual characteristics: the virile body with moustache, beard, body hair, pubic and armpit hair, penis, erections, deep voice, etc. lf testosterone does not convert into DHT, it converts into estradiol, the female hormone, thanks to the enzyme aromatase.

Estradiol generates the female body appearance, enlarging the

breasts, widening the pelvis, reducing body hair, increasing the sex drive, producing the female voice, etc. Once produced, estradiol and dihydrotestosterone cannot convert back into testosterone. Synthetic androgens are often derivatives of dihydrotestosterone that cannot convert into estradiol or other estrogens.

Roles of Testosterone in men Testosterone performs many roles, some of which are listed below: 6.

lt safeguards the cardiovascular system: testosterone makes the heart beat stronger, widens the lumen of the coronary arteries, increasing the blood supply to the heart; it reduces serum cholesterol and minimizes atherosclerosis; testosterone reduces high blood pressure by vasodilatation and makes blood more fluid by increasing the fibrinolytic activity of the blood, the capacity to oppose blood clot formation and dissolve blood clots.

7.

lt protects against obesity and diabetes and decreases the severity and incidence of these diseases by reducing fat mass and increasing lean muscle mass, and by increasing the efficacy of insulin to make glucose penetrate into the brain, the muscles, the heart and other lean tissue targets.

8.

lt develops and maintains reproductive health: penis (size, sexual potency), prostate, body hair, testicles (blood supply, sperm count, fertility - however, high doses of testosterone that suppress LH and FSH may adversely affect sperm).

9.

lt supports the brain and nerves by increasing the blood supply and the number of connections between neurons.

1 O. lt sustains the bones (density and strength), the muscles (mass and strength) and skin

(blood supply, sebum secretion). 11. lt improves the mood and memory, and reduces anxiety.

Testosterone Production The daily production of testosterone in young healthy men is seven mg a day an amount 20 to 30 times higher than in women.

In young men, a circadian rhythm of serum testosterone has

been documented with a 20% higher levei of testosterone in the morning than in the evening. Testosterone production is greatly stimulated by the pituitary hormone luteinizing hormone (LH). In individuais who don't produce LH, testosterone leveis are very low (less than 20% of normal).

The testicles mainly produce testosterone; however, a small amount is produced by

the adrenal glands and in other tissues such as the fat cells by conversion from adrenal androgens such as DHEA and androstenedione into testosterone.

318

Factors that affect Testosterone production lntense physical activity such as frequent sexual intercourse, long-distance running, and other strenuous activities, "burns" greater amounts of testosterone and can thereby deeply deplete androgen leveis.

lntense emotional stress blocks the release of LH, and thus testosterone

secretion as LH is the main endogenous stimulator of this production. Positive emotions such as happiness and sexual pleasure may temporarily increase testosterone in young individuais. Foods high in protein or saturated fat, increase testosterone production, but sweets (sugars, chocolate, etc.) and a high-cereal fiber diet can reduce testosterone leveis.

Testosterone leveis decrease with aging Approximately every four seconds, one testosterone-producing Leydig cell dies in the testicles without being replaced. Of the 700 million healthy Leydig cells at age 18, only about one-third will remain at age 70-80 and the free testosterone leveis will decrease by more than 50% in the urine and blood.

Consequently, over time men will experience the mental and physical

symptoms of testosterone deficiency, while their height and size remains comparable to what it was in their twenties. An aging body still needs as much testosterone and other hormones as young adult bodies of the same size and height. Sadly, with aging, the body can no longer produce the amount of testosterone that he needs to stay young and healthy and consequently, his health goes downhill.

Principal metabolites of testosterone: Androstanediol glucuronide (generally checked in plasma) Androsterone and etiocholanolone (both checked in 24-hour urine)

319

I. Testosterone Deficiency in Men: DIAGNOSIS Testosterone deficiency is diagnosed based on the patient's medicai history and complaints, through physical examination and lab tests.

1. Onset of Male Testosterone Deficiency When did the testosterone deficiency start? To get an answer to the question, the first step is to look at lhe patient, which will give clues if there is a testosterone deficiency and if the onset was at puberty or later in adulthood. Men who have been testosterone deficient since childhood or early puberty tend to look less masculine as they have not developed ali the typical signs of virilization. Their body is not fully sexually mature. In the extreme case, they look like "eunuchs," castrated men with very poor masculine development which makes this type easy to diagnose. Conversely, men with an adult-onset deficiency look clearly masculine, but the traits are regressing, with signs of aging such as hair loss, decreased muscle mass etc. The basic differences between the two types are summarized in the following table. How to Determine the onset of Testosterone Deficiency in Men Onset

Puberty-onset

Adult-onset

Signs of

Prepubescent man:

Aging man: Fully developed,

virilization Hair

but regressing signs of virilization

Few signs of virilization •

No hair recession

•

Hair recession at forehead and sides

•

No male pattern baldness

•

Some degree of male pattern baldness*

Face

•

Young looking, boyish face

•

Aging male face

Beard

•

Absent or sparse beard

•

Fully developed beard

Voice

•

High tone, immature, boyish voice (No voice maturation)

•

Deep, adult male voice (Voice maturation at puberty)

Body

•

Feminine, eunuch-type body

•

More masculine body but regressing

Muscles

•

Poorly developed muscles

•

Developed, but atrophying muscles

Skin Body hair Pubic hair Genitais

•

•

• •

Nearly absent sebum and sexual body scent Poorly developed or absent body hair Horizontal pubic hair line

•

Reduced sebum production

•

Some sexual body scent

•

•

Sexual infantilism : Underdeveloped genitais

•

Clearly developed body hair, but diffuse regression Pubic hair up to the navel Sexual maturity: Fully developed genitais

Penis

•

Small penis

•

Average adult-sized penis

Testicles

•

Small or undescended testes

•

Average adult-sized testicles

Prostate

•

Underdeveloped prostate

•

Normal to prostatic hypertrophy

Sex drive

•

Poor or not developed

•

Developed sex drive but declining

Sex potency

•

Poor or not developed

•

Developed but potency problems

•

Has never been very masculine

•

Was masculine in the past

History

Note: *80% of aging Caucasian males and 50 % of Asian males develop ma/e pattern baldness.

320

2. Timing and Location: When do testosterone signs and complaints of testosterone deficiency manifest themselves in

men? They are present throughout the day, but increase with physical activity when muscles, a primary target for testosterone, are put under strain. Where? Most tissues can be affected by testosterone deficiency, but predominantly those related to male sexual maturity, including the urogenital system, the muscles, bones and

brain.

3. Complaints of Male Testosterone Deficiency The most common complaints of men with testosterone deficiency are listed in the table below. Physical complaints of Testosterone Deficiency in Men Physical

•

Aging appearance

appearance

•

Abdominal obesity

Head

•

Headache

Ear

•

Ear buzzing (tinnitus)

•

Aging face

•

Small wrinkles

Face

•

Heart

•

•

Muscles

•

Vitality

Decreased muscle mass and strength Muscle pains (probably due to muscle and nerve ischemia)

•

Joint pains

Skin

•

Easily sunburned

Digestiva

Energy/

Tachycardia, palpitations Quickly out of breath with physical activity

Joints Nerves

Health

Sports, Exercise Sleep Temperature

•

•

•

• •

Hypochondria (complains frequently of being sick) Persistent fatigue that increases with physical activity Fatigability and lassitude Lack of interest in sports Lack of endurance when exercising

•

Disturbed sleep

•

Hot flushes

•

•

Prostate

Sweating spells (mostly head and upper chest) Prostatism: dysuria, mictalgia, nocturia (prostate hypertrophy)

Prostate infections Decrease or absence of:

•

Sex drive

•

Numbness and tingling

•

Slow bowel movements

•

(low smooth muscle funct.)

•

Constipation

•

Nervous, irritable

Attention

•

•

111 at ease

Memory

•

Poor memory

•

Lack of mental firmness

•

Excessive emotions

•

Sex

•

•

Erections: reductions in volume, frequency, firmness & persistence Ejaculation volume

Mental complaints of Testosterone Deficiency in Men Behavior

Character

•

lndecisive, hesitating

•

Loss of self confidence

Excessive sensitivity to difficulties

•

Lack of authority

•

Unnecessary, futile worry

•

Submissiveness

•

Excessive anxiety, tear

•

Loss of initiative

•

Mood

•

Stress

Poor concentration

Depression the whole day long (may include crying, suicida! tendencies)

321

lnterest Social

•

Loss of interest in life

•

Few social contacts, withdrawn

4. Physical Signs of Testosterone Deficiency in Men What are the physical signs of testosterone deficiency? The principal physical signs of testosterone deficiency that can be seen at physical examination of a man are summarized in the following table. Physical Signs of Testosterone Deficiency in Men • •

Physical

•

appearance •

Back

• •

Fat

Scalp hair

•

•

• •

Face

• • •

Eyes

•

Underarms

•

Pubis

•

Chest

•

Abdomen Body hair Body scent

• • • •

Anus

•

Thighs

• •

Legs •

Pai e Slumped, fragile Older-looking (adulthood-onset deficiency); or Younger-looking (uncorrected early puberty-onset deficiency) Kyphosis, lordosis Often overweight, even obese Fat accumulation on the breasts, abdomen and hips Male pattern baldness {androgenic alopecia)

(Male Hypogonadism) •

Behavior

• •

Mental

•

Memory

•

Mood

•

Voice

•

•

Clothes

Pai e

•

Lacks muscle tone Small wrinkles at the corner of eyes Small vertical wrinkles above lips Poorly or undeveloped beard and moustache (puberty-onset defic.) Dry eyes (conjunctiva sicca) Decreased axillary hair Decreased pubic hair Gynecomastia Flabby belly lncreased abdominal fat Lack or loss of (sexual) body hair Lack or loss of body scent (pheromones) Hemorrhoids Cellulite Hair loss on legs, esp. externai sides Varicose veins

Height

Skin

•

• •

Heart

•

Blood

•

vessels

• •

Prostate • •

Penis

• • •

•

Testicles

•

Nervous lrritable Hesitant Poor concentration Poor memory Depressed attitude Higher, anxious tone Messy clothing (due to the depressive tendency and lack of the desire to be sexually attractive) May have been originally taller (prepuber onset def.) Becoming shorter (adult onset deficiency) Pale skin Drv, thin (atrophic) skin Weak heartbeat Bruises easily Gangrene Prostate hypertrophy or atrophy Prostatitis Pale, dry glans penis Loose prepuce Small, flaccid, atrophied, Peyronie's disease Hypotonic, lax testicles Testicles are reduced in size (normal: 46 x 26 mm)

After these checks it may be important to see if the patient has diseases that may have developed easier with a testosterone deficiency. Which are these diseases?

322

5. Disease Susceptibility Which diseases would a testosterone deficient man easier develop? Long-term testosterone deficiency may increase susceptibility to the following diseases: cardiovascular diseases (myocardial infarction, coronary insufficiency, high blood pressure, high cholesterol, thrombosis, hemorrhagia), infertility, obesity, type 2 diabetes, depression, memory loss, Alzheimer's disease, osteoporosis and its consequences (bone fractures), poor wound healing.

6. Medicai lmaging Tests Which medicai imaging tests should you do to check for complications of long-term testosterone deficiency? The following imaging tests may reveal complications of chronic long-term testosterone deficiency: 1.

Doppler of carotid arteries: increased thickness of the inner wall (intima-media), a sign of

2.

Electrocardiogram: weaker electric amplitudes of cardiac contractions

prematura atherosclerosis 3.

Osteodensitometry or Dual-energy X-ray Absorptiometry (DEXA):

Decreased bone

density 4.

Ultrasound imaging of the prostate:

to check for benign or malignant prostate

hypertrophy 5.

Dynamic uroflow by radiography: decreased urine flow, compression of urethra by

6.

lntravenous urography: urine retention in the bladder, signs of irritable or overfilled

prostatic tissue bladder and urethra compression (better visualized by dynamic RX uroflow testing)

7. Lab Tests for Testosterone in Men What are the best lab tests to confirm the diagnosis of testosterone deficiency in men? The best are to my experience blood tests, such as total testosterone, androstanediol glucoronide, enriched with the SHBG and estradiol, and pituitary hormones such as LH and in particular FSH (that is more often than LH abnormal), and possibly 24-hour urine testosterone and its testosterone metabolites androsterone and etiocholanolone. The optimal conditions for testing are to perform blood and 24-hour urine tests under sedentary conditions to obtain baseline leveis. Patients should avoid intense physical activities such as sexual intercourse, vigorous exercise or emotional stress 24 to 72 hours before or during tests as these states may temporarily reduce testosterone leveis.

323

The following blood lab tests are helpful to confirm the diagnosis of testosterone deficiency in men.

Opti1 mal

Test

Blood Lab Tests for Testosterone (Men) 3 P. DefiReferences Valnformation 2 4 (young men) cient lue

10

>20

1-19 pg/ml

Low

inhibits testosterone production

LH

3

2: 8

2-12 miU/ml

Low

FSH

2

2:7

1-8 miU/ml

Low

lncreases testosterone production FSH stimulates E2 secretion and spermatogenesis; A high FSH is a sign of poor spermatogenesis,

Prolactin

Total testosterone

700

0-550

300-1000 ng/dl

7000

0-5500

3000-1 OOOOpg/mL

24

0-19

10-35 nmoi/L

25-35

0-18

5-25 ng/dl

Free

250-

testosterone

350

(FT)

0.81.2

0-180

50-250 pg/ml

0-0.6

0.2-0.9 nmoi/L

Med

Total testosterone is more stable in blood than free testosterone

Low

The FT fluctuates and the reference range is too wide to be useful; often aberrant lab references are given (5-28 vs. 50280, while in healthy young adults often > 300 pg/ml)

25

2:32

10-45 pg/ml

Med

30-60

2:45

20-60 pg/ml

Low

70

0-50

testosterone

700

0-500

(DHT)

2.4

0-1.7

15-18

0-13

50-59

0-43

Estradiol

(E2)

Estrone ( E1 ) Dihydro-

Androstanediol glucuronide

(AG)

2.3-

SHBG

{TeBG)5

2.8 25-30

2:3.7

�40

High estrogens may reduce testosterone effects

Less valuable than androstanediol Low because of the poor quality of 300-1000 pg/ml - Med most DHT test kits; the test reflects 1.0-3.4 nmoi/L only DHT production, not activity AG is a good marker of androgen 3.4-22 ng/ml metabolic activity as it is the major High metabolite of DHT, produced from DHT only after DHT has exerted 11-73 nmoi/L its activity A high SHBG levei reduces the 1.9-5.1 mg/L effects of testosterone by binding Med greater amounts of testosterone in the blood, slowing down 20-55 pmoi/L testosterone's uptake by the cells 30-1 00 ng/dl

Notes: "P. Deficient" means "probably detieient". 1

The optimal /evel is the levei where the patient is generally tree of eomplaints and signs ot testosterone

deficiency. The optimal va/ue is presented for a man with a height ot 5'8" and 155 pounds (1 meter 75 em to 1 meter 80 em and 70-75 kg of weight). Tal/ men with an athletie build may need higher optimal testosterone leveis; whereas short men with mínima/ musele deve/opment may have enough with lower leveis. 1t is based on the author's subjeetive experienee in treating patients.

2

Ranges of defieient va/ues in not only testosterone but a/so related hormones.

4

The test va/ue is the estimated usefulness in praetiee. Also based on the experienee ot the author.

3 5

Referenees ot adult men age 20-49 years. SHBG is the abbreviation of sex hormone binding globulin, whi/e the synonym TeBG is the abbreviation of testosterone binding globulin.

324

Additionally urine and, more rarely, saliva lab tests may be helpful to confirm the diagnosis of testosterone deficiency in men. These tests are summarized in the table below. Urine and Saliva Lab Tests for Testosterone (Men) Opti-

TEST

mal1

Testosterone Free

< <

120

0.40

P. Defi-

ciene

References

140

50-200 llQ/24h

0.5

0.17-0.71lmol/24h

Test lnformation Value4 24-hour picture Med

of testosterone production Total sum oi

0-9 w 17-keto-steroids (Total) z (gas chromat.) a: � a: � o ::t -=t C'll Androsterone

11-12

urinary androgen

4.7-13.3 mg/24h

metabolites;

Low

0-30

38-41

reflects partially testosterone's metabolic activity

16-46 f.imol/24h

in men, partially DHEA's

3.5

0-2.5

1.10-4.09 mg/24h

12

0-8.5

3.8-14.1 llmol/24h

3.5

0-2.5

0.09-4.6 mg/24h

Etiocholanolone 12

0-8.5

0.3-15. 71lmol/24h

121

0-90

84-150 pg/ml

420

0-300

86

0-70

300

0-240

58

0-50

200

0-170

24-hour picture Med

of DHT's metabolic activity; androsterone is more

Low

androgenic than etiocholanolone

Morning :i Free
Midday Afternoon Evening

86

0-30

130

0-100

lmportant

290-520 pmoi/L

fluctuations of

55-100 pg/ml

190-350 pmoi/L 40-63 pg/ml

140-220 pmoi/L 14-46 pg/ml

50-160 pmoi/L

this levei and Low

the broadness of the reference range make it less valuable

When to do Lab Tests for Follow-up The blood tests for follow-up of male testosterone replacement should be obtained at the following times: •

Testosterone gel: wait 8 to 14 hours after applying the gel on the skin. Ask the patient to apply the testosterone gel before bedtime during the 3 nights before the blood test instead of putting it on in the morning.

•

Testosterone injections: wait 12 days after a 250 mg (intramuscular) injection of testosterone (enanthate or cyprionate)

At those times tests related to testosterone reach stable values that correspond more or less to the 24-hour average values.

325

11/ Male Testosterone Deficiency: TREATMENT Medications for Testosterone Treatment in Men In the following table various treatments for testosterone deficiency in men are listed. The treatments that, in our experience, work better are highlighted with a yellow background. Treatments for Male Testosterone Deficiency: Table 1 Route

Drug Testosterone

(micronized) Oral

Testosterone undecanoate (Andriol®, Testocaps®) Mesterolone

Sublingual

(Proviron®) Testosterone Testosterone patches (Testoderm® Androderm®

Dose

(sedentary)1 300-600 mg per day

Transdermal

Value lndication

in divided doses of 2-3x/day_

Low

Rarely indicated

40-160 mg per day

1 to 2x/day

Med

Mild testosterone deficit in middle-aged men

25-100 mg

1-3x/day

Med

Mild deficit in young men2

2-3x/day

Low

Acute need for more testosterone (T)3

Low

Patches on the nonscrotal skin for mildaverage deficits; Rarely high blood testo. leveis;

50-200 mg Testoderm: 4-5-6 mg/day patches Androderm: 2.5- 5 mg/day

1x/day, (often: 2x/day)

50 -150 mg

1x/day, (rarely: 2x/day)

Low

For mild deficiencies; doses are insufficient to attain optimal T leveis in severe T deficiency

50 - 300 mg

1x/day, (rarely: 2x/day)

High

Ali degrees and at ali ages of testosterone deficiencl

Testosterone gel10 mg/g (Androgel®: 1020-50 mg)

Frequency

Testosterone liposomal gel

100mg/g (comp. pharm.) Dihydrotestosterone gel

25mg/g (Andractim®)

50-250 mg

1x/day

Med

For local use: gyneco mastia, Peyronie's dis.

-

For S)lstemic use:

rarely used except for men with a high E2 5

2 Notes: 1 Strenuous physica/ activity requires higher doses; Mesterolone: at higher dosages 75-150 mg 3 per day may from time to time cause e/evated /iver enzymes; Take sublingua/ testosterone Y2 to 2 hours 4 before sex, giving a lecture, stress, etc; For more severe deficiencies, testosterone /iposomal gel and

injectab/e testosterone work best ; 5 For local use most of the times; For general use only in men who

tend to make too much estradio/ when given testosterone and are not prone to ma/e pattern baldness.

326

Treatments for Male Testosterone Deficiency: Table 2 Route

Dose

Drug

Frequency

Value

10 mg

1x/day, or 1x/2days

Low

100 mg

1x/week

250 mg

1x/2 weeks (more rarely: 1x per 7, 10 or 21 days)

250 mg

1x every 2 or 3weeks

1000 mg

1x/month or 2-3 months

Med

25 or 50 mg

1x every 1-3 weeks

Med

50-100-200-300 mg

Every 2-6 months

Med

(sedentary

Testosterone Lproprionate Testosterone enanthate or cyprionate (Testoviron depot, Androtardyl®) Testosterone lnjection mixing (intra(Sustanon®) muscular) Testosterone undecanoate (Nebido® 1OOOmg)

Nandrolone (Decadurabolin®)

lmplant

Note:

'

Testosterone

High

Med

lndication

Rarely indicated For severe testosterone (T) deficiency in me� above 55-60 yrs ; The T mix (of several esters of T) is less satisfacory than lhe T enanthate or cyprionate, which are equivalent in action

Expensive, but good alternative for non compliant men Severe testost. deficiency with high estrogen leveis in men above 55 yrs Mean to severe testosterone deficiency

For more severe deficiencies, testosterone liposomal gel and injectable testosterone work best.

Change Medication or the Dosage? Various conditions may cause the need to change product or to adjust the dose of testosterone. The most frequent of these conditions are summarized in the following table. When to adapt the dose or to change medication More severe deficiencies Strenuous physical activity, sports Freguent sexual activity Heavy diarrhea Wounds (induced by trauma or burns) Liver disease

Testosterone liposomal gel and injectable testosterone obtain better results than other forms Require higher doses of testosterone: increase (temporarily) daily doses up to + 25% to + 75% the normal dose The transdermal dihydrotestosterone gel works well to accelerate the healing of the wounds Transdermal forms are indicated. Avoid the use of mesterolone, a synthetic derivative of testosterone

327

What is the best route for Testosterone Treatment? Controversy exists on the best route of administration. The principal routes for administration of testosterone and their advantages or inconveniences are discussed in the underlying table. Routes for Testosterone administration Route

Transdermal

Explanation The transdermal route is the number one choice because it completely bypasses the first passage through the liver (where normally it would be broken down) and may provide a longer action.

High doses are needed for efficacy as the liver breaks down most of absorbed testosterone. The intestinal absorption of oral testosterone varies according to gastrointestinal health. In general, the action of an oral form of Oral

testosterone is weaker than that of transdermal liposomal testosterone. CAUTION! At vety high doses the oral route is not recommended for longterm use due to the increased risk of liver damage.

The sublingual route permits a quick absorption. However, the effects also tend to quickly die off. Therefore, its use is limited to treatment of acute conditions or of mild testosterone deficiency. Sublingual testosterone is not recommended for severe testosterone deficiency. Sub-

With the sublingual route, a small part of the testosterone is absorbed

lingual

through the buccal mucosa, another part is swallowed and absorbed in the intestinas. The testosterone that permeates through the sublingual route goes directly into the bloodstream. The sublingual mode of adminstration is superior to the oral route where testosterone is after ingestion mostly broken down in the liver before entering the bloodstream.

lnjectable testosterone treatments are used when a male patient has a lnjectable

severe deficiency and is above 60 years of age, or has important sexual potency problems.

Subcu-

Some patients and physicians find this route to be the best. Leveis can be

taneous

quite stable, although it does not permit to adapt the dose when a

lmplant

momentary increase in acitivity requires more testosterone. In that case, the patient can occasionally take a supplement of transdermal testosterone.

328

1m prove the efficacy of Transdermal Testosterone lt is not sufficient to apply testosterone on the skin to obtain ideal blood leveis. Among the factors that matter for optimal testosterone effects is the kind of transdermal testosterone used. Liposomal gels of testosterone enter the skin better than traditional gels based on carbopol. The way testosterone is applied also highly matters and is discussed in the following table. Tips To lmprove Efficacy of Transdermal Testosterone TIP

GOAL •

•

To improve testosterone efficacy

•

•

• •

To obtain a 24-hour testosterone effect with

the once-a-day testosterone application

•

To avoid high leveis of

•

estradiol (estrogen) and

Rub ten times back and forth over the skin surface for maximal absorption Use always a large skin area1 Use a highly concentrated testosterone liposomal gel for superior penetration: 100 mg/g. Avoid putting creams and lotions on skin surfaces or using bath oil where testosterone is to be applied. They may prevent the absorption of testosterone {T) Apply to hairless areas of the skin Apply testosterone on large1 skin surfaces with high penetration such as the forehead, the non-hairy neck, the non-hairy upper chest, and possibly sides of the abdomen (if more than one gram has to be applied) Avoid eating large amounts of fibe� as they cause a significant loss of androÇJens in the stools Avoid applying testosterone on skin surfaces high in fat tissue, such as the skin of an obese abdomen as fat tissue is rich in aromatase (the enzyme that converts T to E2)

the resulting gynecomastia and benign prostate hyperplasia

•

Avoid other causes of high estradiol {E2) (caffeine, alcohol intake, wearing tight underwear3, varicocele3)

To avoid excessive

•

Avoid putting T on hairy skin. Skin surfaces rich in body hair such as the cheeks, the hairy chest or abdomen, are rich in 5alpha-reductase, the enzyme that converts T to DHT

leveis of DHT (responsible

for baldness, body hair) To avoid contaminating

•

the partner with undesired testosterone (and promoting hair growth on her face and body)

•

Avoid applying the testosterone on skin surfaces with a large area of body contact during intercourse such as the penis, abdomen, lower arms. lnstead apply it to the forehead, the sides of the neck, and the regions above the collarbone (clavicle) on the chest

Notes: 1

On/y part of the transdermal testosterone passes through the skin and accumulates in the subcutaneous fat under the skin where it is s/ow/y re/eased into the blood stream.

/f the testosterone is applied to a

sma/1 skin surface, the entering testosterone wi/1 overload the underlying fat and most of it wi/1 go directly into the b/ood stream, creating a quick b/ood peak of testosterone that wi/1 also quick/y 2

disappear from the blood stream requiring more frequent dosing. Eating foods rich in fiber considerably increases the loss of estrogens and other hormones in the stoo/s, creating or aggravating an androgen deficiency. Cereal fiber in the intestines tends to strongly fix the important amounts of testosterone found in the bife and bring it in the stoo/s, instead of /etting the

3

testosterone be reabsorbed further in the intestines as is the case under normal conditions. Tight underwear and varicoce/es (varicose veins above a testic/e) impair the b/ood supply in testicles causing hypoxia and an imbalanced high estradio/- low testosterone production.

329

lndications for Testosterone Treatment in Men Chronic, long-term lndication: treatment of ali degrees of testosterone deficiency Acute, occasional, short-term indications

for use of testosterone in higher doses: for

gangrene, thrombosis, myocardial infarct, severe weight loss (cachexia, anorexia) and other conditions where testosterone's beneficiai effects on blood vessels (such as vasodilatation and fibrinolysis) and lean body mass (muscles, bones and inner organs) are needed.

Contraindications to Testosterone Treatment in Men There are two fundamental contraindications: Absolute contraindication: absence of testosterone deficiency, and, possibly, prostate cancer

that may be aggravated by testosterone (a major controversy exists whether testosterone treatment promotes or protects against prostate cancer. The rare studies of testosterone treatment in terminal prostate cancer showed beneficiai effects of androgens on quality of life and survival). Relative contraindication:

acute active prostate infection or obstruction of urinary flow by

enlarged prostate (although testosterone could also improve the resistance to prostate infection and decrease prostate obstruction of urination).

How do you begin Testosterone Treatment In most patients, testosterone can directly be started at the dose that is thought to bring complete relief of the deficiency. lf risks of male pattern hair loss (presence of an already started form of male pattern baldness and/or a familial tendency to male pattern baldness) or acne exist, it may be prudent to start with testosterone at a dose that is 25-50% lower than the optimal dose and after two months, if there are no adverse side effects, increase the dose by 25% and follow up with the patient in two months. Two to four months later, if no hair loss or acne has occurred but the dose still seems to be too low, increase the dose by an additional 25%, and schedule regular follow-ups to monitor progress.

Progress with Testosterone Treatment How much time is needed to obtain the first improvements? Testosterone replacement works slowly. Generally, the first improvements are felt after one to three months of treatment. For improvement of sexual potency, it often takes more time, three to six months.

Faster and greater improvement is seen in men whose diet is near perfect for

testosterone treatment: high in animal protein, devoid of sweets and starches (carbohydrates), and extremely low in alcohol.

330

How do you enhance Testosterone Treatment The most important way to enhance the treatment is to improve the lifestyle and in particular the diet. The principal lifestyle factors to do so are outlined in the following table. How to optimize Testosterone activity and treatment To Avoid

To Eat • •

Diet

•

•

•

Eat enough calories Follow a "Paleolithic" diet: fruits, vegetables, meat, 1 ·2 poultry, eggs, fish Add a well-balanced, mixed amino acid supplement Eat organic foods3

Weight Clothing

•

•

Avoid cereal fiber (whole grain bread, bran flakes) Avoid milk products

•

Avoid overweight, obesitl

•

Avoid tiqht underwear and trousers7

•

Avoid excessive chronic stress (especially prolonged), including strenuous physical activities

•

Avoid tobacco smoking

• •

Abuse

Avoid sugar, sweets, soft drinks, cookies, bread, pastas and other cereais

•

Stress

Drug

Avoid alcohol, vinegar, caffeinated drinks4•5

Avoid marijuana, other drugs8 Avoid or reduce the dose of beta-blockers9

Notes: 1 A high intake of protein-rich foods such as meat and poultry may actually Jower total testosterone leveis in blood, but at lhe same time increase testosterone activity by increasing the leveis of free testosterone, lhe most 2

3

4

5

6 7

8

9

bioavai/able form of testosterone for lhe target cel/s. Foods rich in saturated fat such as eggs, bacon and (clarified) butter increase lhe production and the levei of testosterone (clarified butter is cal/ed a/so ghee and is butter without lhe 'allergenic' milk proteins; extracted after warming up lhe butter at a very Jow tempera fure abd taking out lhe upper white layer of proteins). Certain pesticides may a/ter testosterone secretion and effects. Alcohol may increase lhe conversion of testosterone to estradiol depleting a man of his testosterone, while at the same time excessively increasing estradiol leveis, imbalancing lhe essential, but fragile low estradiol-high testosterone equilibrium. Regular drinking of caffeinated beverages has been reported to increase lhe risk of prostate hypertrophy. Decaffeinated drinks (where the caffeine has been extracted by lhe safe method based on water and carbonic acid) may be an acceptable alternative. Fat tissue is rich in lhe enzyme aromatase that inactivates ma/e hormones by converting testosterone to estradiol. Tight underwear and trousers may increase estradiol by squeezing the testicles against lhe body, which impairs blood supply and causes hypoxia of lhe Leydig cells that produce testosterone, while lhe stronger Sertoli cells, which produce estradiol, are not as affected and compensa/e by increasing their production of estradiol. Furthermore, tight e/olhes keep the testicles too close to lhe body increasing the local temperature which impairs their function. To work we/1, testicles have to be 2 em under the pelvis and at a 2'C Jower t emperature. Marijuana and many other drugs, which increase the body's opioids or have morphine-like activity, reduce LH secretion and consequently lower lhe testosterone production (which is stimulated by LH). The pale skin of drug-addicts may partially be caused by lhe reduced blood flow in lhe skin due to lhe testosterone deficiency. Beta-blockers reduce the human body's production of testosterone.

331

The second step is to correct any other hormone abnormalities that influence testosterone. Many hormones can boost or reduce testosterone production and its effects in the body.

The principal hormone replacement therapies, which influence the secretion of testosterone

and/or its action, are listed in the following table.

lnfluence of hormone replacement therapies on testosterone/DHT Strong Stimulator of testosterone/DHT • •

Growth hormone1 Androgen

Strong testosterone/DHT inhibitors

Mild stimulators •

• •

•

Thyroid

hormone2 DHEA

3 Progesterone

Glucocorticoids

Mild inhibitor •

at high doses;

•

other estrogens4

•

Estradiol and

•

Cortisol at low doses Melatonin

3 Progesterone

Thyroid hormone2

Notes: 1

Growth hormone Jowers serum SHBG, the predominant plasma binding protein for testosterone and OHT, thus increasing the bioavai/ability of these androgens for the target cells.

2

Thyroid hormones increase testosterone leveis by stimulating testosterone production by the testicles. On the other hand, thyroid hormones, especially in excess, can reduce testosterone leveis and subsequent effects by s/owing down the conversion of testosterone to OHT and increasing the conversion of testosterone to estradiol.

3

Progesterone can increase ma/e hormone leveis (testosterone and OHT) by converting to 17-a­ progesterone to androstenedione to testosterone to DHT. In contrast, progesterone can a/so decrease

4

ma/e hormone leveis by blocking the conversion of testosterone to OHT (competitiva inhibition). Estrogens, particularly the powerful estradiol, block the effects of testosterone and its conversion to OHT. Maximal inhibition is obtained with the use of oral estrogen treatment in men with prostate cancer, etc.

Testosterone and Prostate Cancer Reports show that 14-46% of men over age 40 at autopsy have prostate cancer cells. Based on

these findings, the standard of medicai care is to avoid giving androgens to any man as they may accelerate prostate cancer development.

This longstanding view is being challenged. Two studies where androgen treatment was given

to

terminal

prostate

cancer

patients

showed

that

the

men

who

received

androgen

supplementation survived longer and enjoyed a better quality of life than the cancer patients who did not take male hormones.

Some data exists to support the view that it is not the presence of testosterone or

dihydrotestosterone (DHT) that prometes prostate cancer, but its decline through the years that

allows precancerous transformation of prostate glandular cells, in particular when estrogen leveis are high. Even more important is that severa! studies with testosterone treatment of

prostate cancer patients show a decrease in recurrence rate and mortality (see further the section opn 'testosterone and prostate cancer' at the end of the testosterone references). Furthermore, prostate cancer patients who do not receive androgen treatment but instead take

androgen blockers, undergo a severe testosterone deficiency. This androgen depletion may considerably accelerate cardiovascular aging and impair the quality of life and overall health,

thereby shortening the life expectancy. This issue is controversial and it is incumbent upon the physician to explain the pros and cons of testosterone therapy to their testosterone-deficient male patients and let them decide for themselves.

332

Treatment for Men with Prostate Cancer Some experienced physicians propose to patients who have had prostate cancer and suffer considerably from testosterone deficiency to take small doses of synthetic androgens that cannot convert into estrogens. Let us enumerate the exceptional cases where the use of androgen treatment in prostate cancer patients may be justifiable: •

Men with testosterone deficiency who have survived 5 to 1 O years following the treatment of prostate cancer, have had total removal of the prostate (undetectable PSA in blood) and there is no indication of recurrence of prostate cancer

•

Men with testosterone deficiency who have survived less than 5 years having the same features as above, but are intensely suffering from signs of low testosterone deficiency (cardiovascular problems, severe lowering of quality of life, premature aging, etc.)

•

Terminal prostate cancer patients who have to combat severe weight and energy loss (cachexia) being at the end stage of their life.

Caution: These circumstances require very close monitoring and discontinuation of therapy if any acceleration of prostate cancer occurs.

How to correct excessive Estradiol Leveis A high blood levei of estradiol is a problem in testosterone treatments. This is because high estradiol leveis stimulate the proliferation of fibrous tissue (stroma) in the prostate, causing the prostate to enlarge. The prostate enlargement possibly aggravates with time forming a benign prostate hypertrophy and causes increasing difficulties to urinate. leveis have been associated with myocardial infarction.

Moreover, high estrogen

A testosterone treatment can increase the leveis of estradiol by conversion of some of the supplemented testosterone into estradiol. Several factors stimulate this conversion. The most frequent in our experience are caffeinated drinks, alcohol, wearing tight underwear and obesity. Correcting those four factors often reduces the estradiol levei and optimizes testosterone treatment without estradiol excess. In most cases the estradiol leveis do not adversely increase in men given supplemental testosterone, but sometimes they do.

333

The different causes of increased estradiol and proposed solutions are listed in the table below. How to Lower High Estradiol (and SHBG) Leveis in Men: Table 1 POSSIBLE CAUSES • • •

Diet

•

•

•

Diseases

•

Clothes

SOLUTION

Alcohol � 1 glass/day: increases estradiol levels

•

Stop daily alcohol

Coffee � 2 cups/day: increases estradiol leveis

•

Stop daily coffee

Low intake of animal protein, esp. meat: reduces 5-alpha-reductase activity, and in compensation may let the unopposed aromatase activity predominate, with increased estradiol production as a consequence High calorie intake: leads to obesity and increased fat mass, a tissue rich in aromatase, increasing thereby the estradiol production Obesity: the increased fat mass, a tissue rich in aromatase, increases the estradiol production A varicocele reduces the blood flow, causing a certain degree of blood stagnation and lack of oxygen supply in the testicle, resulting in a decreased testosterone production by the weak Leydig cells and a compensatory increased estradiol secretion by the stronger Sertoli cells Tight underwear: squeezes the testes against the body, disturbing their blood flow and increasing their temperature by 2 degrees Celsius, resulting in increased estradiol and reduced testosterone production

•

•

•

latrogenic: an excessive amount of the

•

Lose weight

lncrease muscle mass

•

•

Hormone excess

large boxer shorts

•

Stop caffeine, alcohol

•

Stop tight underwear

•

•

estrogen deficiency or against prostate cancer)

Drugs that reduce androgen

•

Antifungal drugs Antibiotics, isoniazid?

•

•

Cardiovascular drugs: coumadin, betablockers; calcium channel-blockers, amiodarone, quinidine Psychiatric drugs: Thorazine

334

Surgical remova! of varicocele

large trousers

Excessive estrogen treatment in men (for

•

Apply testosterone or DHT locally or (on the scrotum in front of the varicocele)

•

• •

Exercise

•

•

Hyperthyroidism: excessively stimulates the conversion of testosterone to. estradiol

•

Wear

supplemented testosterone converts into estradiol

•

Eat less, but with sufficient protein

•

•

Testosterone treatment

lncrease meat and other animal protein intake

•

Lose weight Use aromatase blockers: Chrysin, Arimidex®, DIM (diindolyl-methane), etc. Replace testosterone with DHT or synthetic androgens Normalize thyroid function Avoid estrogen treatment, and if essential, take the lowest dose possible

lf necessary, take at lowest dose possible

How to Lower High Estradiol (and SHBG) Leveis in Men: Table 2 POSSIBLE CAUSES •

SOLUTION

Testosterone and DHT deficiencies: set off the 5-alpha-reductase activity, letting the unopposed

•

and DHT

aromatase activity predominate, which leads to

treatment:

increased estradiol production •

Testosterone

Growth hormone deficiency: reduces androgenicity (GH is necessary to stimulate androgen effects, in its absence the serum SHBG

•

Growth

remains high, consequently inactivating androgens

hormone

in blood by excessively binding them), letting the

treatment

unopposed aromatase activity predominate and increase the estradiol production Hormone

•

deficits

Cortisol deficiency: may facilitate testicular insufficiency and tends to increase the serum SHBG

•

Hydrocortisone or other

(which increases the sequestration of remaining androgens in blood). 8oth factors permit a higher

glucocorticoid

expression of aromatase and thus an increased

treatment

estradiol production •

Progesterone deficiency: results in a lazy conversion of estradiol to estrone permitting an

•

accumulation of estradiol •

Progesterone treatment

Hypothyroidism: is associated with male hypogonadism with lack of virilization, obesity. 8oth factors increase estradiol production through

•

Normalize thyroid function

unopposed aromatase activity

Additionally, other measures may help lowering the blood estradiol leveis as shown in the following table: Avoid medications, which compete

Foods or nutrients to take

for testosterone receptors

Foods •

Meat

•

Soy products

•

Cruciferous vegetables

• •

•

Shellfish

•

Resveratrol (supplement from grape skins)

Nutrients •

Vitamin C & K

•

Zinc

•

Niacin

335

Spironolactone (Aidactone®), Cyproterone acetate (Androcur, Cyprostat®),

•

Chemotherapy agents

•

Thiazides

Follow-up of Testosterone Treatment in Men 1. Find the optimal dose. When a male patient under testosterone treatment receives additonnally in a later stage a growth hormone (GH) treatment for growth hormone deficiency, the doses of testosterone usually will have to be lowered by 1 O to 30%, because growth hormone increases the penetration of testosterone into target cells (by lowering SHBG, testosterone's major plasma binding protein), an effect that results in a considerable increase in testosterone activity.

When to adapt the dose of testosterone and related androgens Dose

Lower the dose of testosterone

lncrease the dose of testosterone

(-25 to -50%)

(+25% to +150%) Testo.Therapy

• • •

Diet, Lifestyle factors

• •

• •

Hormone dysfunctions or treatments

• • •

lnsufficient testosterone effects Low-protein diet High-cereal fiber diet Low-calorie diet lncreased physical activity, participation in intensiva sports Intensiva and/or chronic stress Diarrhea Adult growth horm. deficiency Hyperthyroidism (excess thyroid) Progesterone treatment

• • • • •

• •

Excessiva testosterone effects High-protein diet High-fat diet High-calorie diet Decrease in physical activities (sedentary, prolonged rest, bedridden) Unstressed, vacation Growth hormone treatment

2. Avoid under- and overdosing:

lt is highly recommended that the patient knows the signs and symptoms of male hormone so that he can help his physician adjust the treatment and can reduce by himself the dose if side-effects are severe. In particular, attention should be given to the signs and symptoms of testosterone overdose listed in the following table: deficiency and overdose

The Typical Signs of Testosterone Excess Latency

1 month

1-2

months

1-3 months

Sign

Type

Hair Face Skin Feet Sex Penis

• • • • • • •

2-3 months Behavior 4-6 months Muscles Hair 4-12 months Body hair

• • • •

Cause

Oily hair Acne Oily skin Feet edema (rare: only with injections) Excess Testosterone Excessiva sex drive (libido), sensitivity (T) Excessiva reddening of the glans penis Too quick erections, sexual overstimulation Excessively aggressive, authoritarian attitudes Excessiva muscle development Excess DHT Male pattern hair loss Hirsutism (excess body hair: on the back e.Q.) formed from T

336

3. Perform lab tests: The tests should be done about 9 to 14 hours after the last application

of transdermal testosterone, or if depot testosterone is given, two days before the next injection. The most useful tests are serum total testosterone and in particular androstanediol glucuronide (which should increase) and serum SHBG (which should decrease). Serum estradiol should also be tested as it must remain low normal, otherwise estrogen-related pathologies may develop in men (gynecomastia, prostate hyperplasia, etc.) Undergo regular cancer screenings and genetic typing. Most important is a prostate exam along with blood total and free PSA once every year or every six months for men at high risk for prostate cancer. lf any abnormalities of the prostate are found upon digital examination or if a significant change in PSA leveis occurs, obtain an ultrasound of the prostate. Genetic typing can help determine cancer risk and help the physician determine a screening and prevention plan to minimize risk. Plasma total PSA with age Age

Optimal

Reference values

0.5-1

O --1.8 ng/ml

40-49 years old

1

O-2.5 ng/ml

50-59 years old

1.5

O- 3.5 ng/ml

60- 69 years old

2

O-4.5 ng/ml

Under40 years old

Over 70 years old

3.5

O- 6.5 ng/ml

Prostate infection

<3

3-45 ng/ml

<3.5

Prostate cancer

>

70 ng/ml

Check free PSA and the ratio of free PSA!total PSA Plasma ratio of free PSA/ total PSA Blood ratio free PSA/ total PSA

Prostate

What to do

cancer risk •

�10%

High

•

Thorough urological exam with biopsies No androgen treatment until reassurance of beniQn tissue

•

Rectal examination every 6 months followed by more extensive urological exam if clinicai signs suggestive of prostate cancer are found

10%-25%

lntermediate

•

Eliminate factors promoting prostate hypertrophy, irritation or infection (high plasma estradiol, obesity, alcohol and coffee consumption, spices, well-done meat, not urinating after sexual intercourse, etc.)

;:::25%

Very Low (PC risk< 10%)

Good hygiene and minimize factors that promote prostate hypertrophy and infection

4. Solve problems at follow-up examination quickly and efficiently:

See Problem Solver for tables with reviews of the most frequent problems that may occur during testosterone replacement and their solutions.

337

11/ Testosterone PROBLEM SOLVER How to solve problems that may occur during testosterone treatment?

Physical problems due to testosterone excess or other factors: Physical Problems due to Testosterone Excess or other factors PROBLEM

SOLUTION

CAUSES

•

•

Red face

Excessive stimulation of blood flow in the skin by the administered testosterone and in particular by its metabolite estradiol

•

•

•

Excessiva stimulation of •

Acne

sebum production by

androgens

•

Excessive muscle

development

•

Excessiva muscle development caused by excessive leveis of testosterone (and accessory dihydrotestosterone)

Diet adjustment: avoid foods that may cause acne during an androgen treatment: milk products, esp. yoghurt, and sweets such as sugar and chocolate Reduce the dose of androgens (testosterone, DHEA)

Reduce the dose of androgens (testosterone, DHEA, dihydrotestosterone)

Excessive body hair:

above the collar bone, on the back, etc. •

•

Reduce the dose of testosterone lf excessive conversion from testosterone to estradiol occurs, correct the cause (alcohol or caffeine, obesity, tight underwear, progesterone deficiency). Consider substituting a synthetic derivativa of testosterone that cannot convert to estradiol.

Feet edema

Excessiva stimulation of body hair follicles by androgens

Excessive salt and fluid retention from androgens

338

•

•

Reduce the dose of androgens (testosterone, DHEA) Avoid using dihydrotestosterone

1. Take potassium (1-3 g per day) /f edema persists despite potassium intake: 2. Reduce the dose of androgens

Behavioral and sexual problems due to testosterone excess or other factors: Behavioral and Sexual Problems due to Testosterone Excess or other factors PROBLEM

CAUSES •

•

Excessively aggressive •

•

•

Excessive libido

•

SOLUTION

An androgen overdose can make a patient aggressive by excessive stimulation of the excitatory neurotransmitters in the brain and rarely by brain edema More common in men with GH deficiency Excessive conversion of testosterone into estradiol, the most potent libido enhancer of the male brain Excessive increase in androgen receptors in glans penis and other highly sensitive genital areas such as scrotum and nipple areas

Excessive increase or stimulation of the following factors that stimulate erectile function: •

•

Excessive erections

•

•

The conversion of testosterone into dihydrotestosterone The parasympathetic neNous system peripherally The number of androgen receptors in the glans penis and other highly sensitive genital areas such as penis and scrotum

1. Reduce the dose of

androgens (testosterone, DHEA, dihydrotestosterone) 2. Correct the GH deficiency with the appropriate dose of GH 1. Reduce the dose of

androgens (testosterone, DHEA, dihydrotestosterone.) 2. Reduce the conversion to estradiol

Reduce the dose of androgens (testosterone, DHEA, dihydrotestosterone) 2. Reduce the conversion to DHT 1.

Problems due to an excessive transformation of testosterone into dihydrotestosterone Problems due to excessive conversion of testosterone into dihydrotestosterone •

Hair loss

(male pattern) •

Excessive body hair

(hirsutism): above the collar bone, on the back, etc.

•

Excessive conversion of testosterone into dihydrotestosterone (DHT)

339

•

Finasteride 1 to 2.5 mg/day (do not give without testosterone supplementation, otherwise sexual performance may be at risk!) Eat less meat (consumption of red meat increases the conversion of testosterone to dihydrotestosterone)

Problems related to inefficacy or excessiva increase of other hormones Testosterone can influence the activity of other hormones. From time to time problems occur during testosterone treatment caused by overstimulation of these other endocrine systems. Testosterone increases thyroid and growth hormones or may also excessively convert to potent hormones such as estradiol and dihydrotestosterone.

Problems due to test error or treatment inefficacy: Table 1 P ROBLEM •

•

•

lnsufficient increase of blood leveis of testosterone (leveis remain low and do not differ from initial levels)

lnsufficient beneficiai effects of testosterone therapy in a clearly testosterone deficient male, with side-effects (swelling, weight gain, redness of face, acne, gynecomastia, swollen prostate)

SOLUTION

CAUSE

•

•

lf signs and complaints of testosterone deficiency are sufficiently improved by the testosterone treatment, the most likely cause of low testosterone leveis is a late blood draw, done 24 hours or more after the last testosterone intake. Testosterone leveis are then back down to the low leveis found before any treatment. Other causes include strenuous physical activity in the 24-48 hours before the blood tests that have depleted the testosterone stores. lf signs and symptoms are not sufficiently corrected by the testosterone treatment, one should suspect that the cause is an insufficient dose, an inefficient absorption, a wrong product, a wrong diet, or diarrhea (with loss of testosterone in the stools)

•

•

Wrong food intake (most likely cause):

•

Too much sugar, sweets, chocolate,

•

soft drinks, milk products, caffeine, alcohol. They reduce the beneficiai effects of testosterone, while increasing its adverse effects on the

•

skin, esp. oil formation and inflammation of sebum glands, and

•

Most of the testosterone is converted to estradiol because of caffeine or alcohol intake, obesity, tight underwear

•

The swelling may result from eating a

•

high salt diet, combined with the testosterone treatment, which increases salt- and water retention •

Obese men: Fat tissue absorbs and inactivates too much testosterone

340

lf signs and complaints are not sufficiently corrected, correct the cause (see below). 1mprove the diet: Avoid sugar, sweets, chocolate, soft drinks, milk products, caffeine, alcohol Avoid excess salt (if there is swelling)

thus acne. •

lf signs and complaints of testosterone deficiency are corrected, check blood 9 to 14 hours after last applying the transdermal testosterone gel (take testosterone at bedtime 3 days before the morning blood draw); check the blood test 12 days after testosterone injection of 250 mg. Avoid strenuous activity 18 hours before the blood test.

•

Eat more meat and other protein-rich foods (improves production of T and dihydrotestosterone) Wear wide boxer shorts in large trousers Eat less to lose fat and excess weight, exercise moderately to increase muscle mass

Problems due to Treatment lnefficacy: table 2 PROBLEM

•

lnsufficient dose

•

lnefficient absorption of the product,

•

a transdermal gel of testosterone that is too quickly and superficially applied on the skin of the arm or whose penetration is blocked by other skin lotions or creams applied on the same skin areas before application of testosterone gel, digestive disturbances that decrease the absorption of oral testosterone.

lnsufficient beneficiai etfects of testosterone therapy in a

clearly testosterone deficient male, with no side effects

SOLUTION

CAUSES

•

•

•

Wrong product - especially some

oral synthetic derivatives may have poor efficacy •

Wrong diet - insufficient protein

•

(meat, poultry) •

High-cereal fiber diet or diarrhea interrupt the enterohepatic cycle of testosterone and related androgens: the testosterone that should be reabsorbed is carried out in the stools

341

•

lncrease the dose of testosterone lmprove absorption (avoid putting other creams or lotions on the same skin surfaces as the testosterone gel, improve digestion, etc.) Change product: use a natural testosterone instead of a synthetic derivative Change the route of administration, switch to transdermal preferably to oral, or use injections Correct the diet: increase protein intake. Avoid a high-cereal fiber diet.

Stop the diarrhea (eat only boiled foods for 2-3 days, add supplements of lactobacillus acidophilus and other good bacterial flora, etc.)

Genital Problems during Testosterone Treatment PROBLEM

CAUSES

SOLUTION •

Fat accumulation in the breast •

caused by insufficient

Pseudo-

DHT •

testosterone (T) and

gynacomastia

Diet: lose overweight, eat more meat which increases conversion of T to Apply DHT locally (that, unlike testosterone, cannot convert back

dihydrotestosterone

into estradiol by adipose aromatase)

supplementation

and take testosterone gel for svstemic effects. • •

Check for low estradiol levels lncrease the dose of androgens especially testosterone, secondarily

•

DHEA, that may convert into

Excessively low leveis of

Libido

estradiol (which is derived from

decrease

testosterone) in the brain

estradiol)

in rare cases if the serum leveis of estradiol remain too /ow (<12 pg/ml) whatever dose of androgen treatment •

Small doses of oxytocin (10 IU/day) or transdermal estradiol mav be tried

•

Excessively low leveis of DHT

•

or even better of androstanediol

in the genital organs •

glucuronide

lnsufficient stimulation of the parasympathetic nervous

•

Sexual impotence

Check for a low serum levei of DHT,

system (necessary for

lncrease the dose of androgens (as well as testosterone, DHEA and

erections) because of the low

DHT)

•

androqens (especially low DHT) •

Appearance of high leveis of E2 stemming from an excessiva conversion of T to E2 (E2 may block the effect of DHT

•

Reduce excessiva estradiol leveis by following lifestyle guidelines mentioned above

on erections) 1. Testosterone enanthate IM injection 250 mg every 7 to 1 O days for the first two months, then every 14 days thereafter Fibrosis of the penis caused by a lack of androgens, testosterone •

Peyronie's

and principally DHT, possibly

disease

combined to low cortisol (which permits unopposed proliferation of fibrous tissue)

2. Apply DHT gel daily to the penis (use condom with intercourse) 3. Take GH in sufficient doses (from

0.25 mg/day or higher, often 0.4 mg) 4. Small physiologic doses of oral cortisol may be helpful (in case of cortisol deficiency) as they reduce the fibrosis 5. Vitamin E topically and orally at 2,000 mg a day during 6-12 months 6. DHEA 20 to 60 mq a day

342

Problems associated with Excessive Blood Testosterone Leveis: 1. Too High T3 PROBLEM •

CAUSE

SOLUTION

Signs of Generally occurs in persons being

excess thyroid:

treated with thyroid therapy. By

anxiety,

various mechanisms (testosterone

tachycardia,

lowers TBG, increases the

poor sleep,

conversion of T4 to active thyroid

excessive

hormone T3), the testosterone

thirst, hunger,

treatment increases thyroid activity

weight loss,

in the cells.

Lower the dose of the thyroid hormone treatment

(-10

to -3 0% )

tremblinÇJ, etc. 2. Excess testosterone

PROBLEM

CAUSE

SOLUTION •

Check blood from 9 to 14 hours after the last

•

•

•

Excessive

transdermal testosterone

blood test is done too soon

gel application (take

after taking the testosterone

testosterone in the

dose

evening for 3 days before

The needle of the syringe for

the test and then take

blood withdrawal has gone

blood in the morning after ct the 3' night), or wait for

through a zone of testosterone

serum testosterone although male patient shows no sign of overdose

The most likely cause is that the

storage in the skin because the

blood tests 6 days after

transdermal testosterone is

testosterone enanthate or

applied on the (inner) elbow fold

cyprionate

at the same place where blood is

injection, or

a 250 mg injection

taken •

100 mg 12 days after

Patient has mistakenly and

•

Avoid applying

occasionally taken more

testosterone in the elbow

testosterone than prescribed

fold 3 to

(by distraction, or because of

the blood draw

difficulty in correct dosing with difficult tube or bottle).

•

5

days before

Review dosage and correct application techniques with patient

343

Problems due to Excessive Blood Hormone Leveis: 3. Excess Estradiol

PROBLEM

•

SOLUTION

POSSIBLE CAUSES

1. Locally and systemically increase the dose

Breast edema caused by excess estradiol (through excessive conversion of testosterone into estradiol)

Breast tenderness

2.

of dihydrotestosterone (transdermal DHT) which has better anti-glandular action than testosterone and progesterone Reduce estradiol levels or effects: •

•

1. Breast development is

•

gynecomastia

the testosterone administered 2.

Breast edema caused by the excess estradiol

increases the conversion of estradiol to the less potent estrone (100 mg per day before bedtime) and/or administer estradiol receptor blockers such as Tamoxifen (Nolvadex®) 3. Reduce the dose of androgens (testosterone, DHEA, androstenedione), which can convert into estrogens 4. Replace them partially or totally by androgens that can't be converted to estradiol such as mesterolone, stanozolol, dihydrotestosterone etc. •

•

•

A substantial portion of testosterone converts into estradiol, thereby excessively increasing the estradiol levels and stimulating stromal hyperplasia of the prostate.

Benign prostate hypertrophy aggravation

(with increased urination problems)

•

•

Testicle shrinkage

(atrophy) •

and/or administer an estradiol converter such as progesterone, which

caused by excessive stimulation of the proliferation of canaliculi by high leveis of estradiol derived from

Real

Administer an aromatase inhibitor such as Arimidex® (0.1 to 0.5 mg per day)

•

Treat the cause that favors the conversion of androgens into estrogens: reduce or stop alcohol and caffeine consumption, reduce fat mass by a weight reduction diet, etc. Stop the administration of androgens that can convert to estradiol by aromatase. Replace them partially or totally by androgens that can't be converted to estradiol such as mesterolone, stanozolol, dihydrotestosterone etc.

Main cause: lncreased • Reduce the conversion of testosterone to leveis of E2 that block estradiol (see subchapter "How do you lower FSH secretion, which is excessive estradiol levels in men? in chapter responsible for stimulation of 14 "Particular problems" sperm formation (spermatogenesis that occupies 80/f sti/1 no ímprovement after 3 months: 90% of the volume of testicles). The low FSH causes testicle shrinkage. • Reduce the dose of androgens

Excessive leveis of T mildly block the FSH secretion and thereby reduce sperm formation and testicular volume.

•

344

lnject subcutaneously with HCG (human chorionic gonadotropin) 150 lU daily or 2 to 3 times intramuscularly 1500 (or 5000) lU per week.

Problems due to cancer The appearance of prostate cancer: the appearance of cancer, especially prostate cancer, in an androgen deficient man, always confronts the physician with a dilemma: to treat or not to treat with testosterone.

Problems due to Cancer PROBLEM

SOLUTION

POSSIBLE CAUSES 1.

Testosterone or

•

DHT deficiency

2. High estrogen 3.

•

•

•

leveis

take melatonin at physiological doses, possibly even higher (sublingually at

treatment in

0.2 mg/day up to 5 mg/day before

presence of

bedtime)Add phytoestrogens at doses of

250 mg daily (the dose generally necessary for symptom relief). Notes:

(unproven hypothesis)

Other cancer

0.1 to

prostate cancer

(PC)

in men

Q-1 O (200 to 400

mg/day). In case of melatonin deficiency,

Testosterone

Prostate cancer

Breast cancer

Stop testosterone administration. Take high doses of coenzyme

•

Note: To date no serious studies have proven that testosterone treatment increases the risk of prostate cancer (see prostate cancer and testosterone treatment in the references for the testosterone chaoter)

DHEA treatment after PC: Some physicians are giving DHEA to

PC patients

who have undergone surgery for it, and report having no signs of reactivation of •

to

1 O years of survival after surgery without

recurrence of prostate cancer and heavy symptoms of androgen deficiency, some physicians treat with low doses of testosterone after having the patient sign an informed consent.

Generally no relation

To date, only genital cancer seems to be a

with androoen leveis

contraindication for testosterone treatment

345

PC. 5

Testosterone treatment after PC: After

Chapter Eighteen

Progesterone Deficiency and Treatment in Men

Case Study of a Man with Progesterone Deficiency Gunther and his prostate problems Gunther had been a well-built man: tall, moderately muscled and handsome. Now at the age of 55, his body had changed. Gradually fat was building up in his breasts, a progressiva process which embarrassed him; he did not like the idea of having women's breasts. His abdomen was getting a bit flabbier every year. But what worried him the most was his prostate. Previously, Gunther had not even been aware he had a prostate, but now day-by-day he felt irritation when he went to the bathroom. lt took him more time; it seemed to him an unreasonable amount of time for the urine to come. He had to relax deeply. When the urine carne, the urine flow was scant and he experienced some difficulty in emptying the last drop. He wondered, "What was going on?" His diet hadn't changed and h e thought he ate healthy food. H e did eat some sweets but not in excess.

He took moderate amounts of coffee, about three cups per day. Every evening he

drank a glass or two of wine, a habit he had for more than 20 years. Not so long ago, this never caused him any problems, so why should it now? What is Gunther's problem? Most of Gunther's difficulties are indicativa of high estradiol leveis, a phenomenon possibly supported by progesterone deficiency.

To better understand this

deficiency in men and what can be done about it, let's review some basic information on progesterone.

347

PROGESTERONE: Basic lnformation Progesterone: Progesterone is third in the steroid hormone cascade starting from cholesterol. Does progesterone play a role in men? In men, progesterone has not been as thoroughly studied as in women.

Possible roles are:

1 ) Progesterone holds the serum levei of estradiol low and may thereby minimize the risk or severity of myocardial infarction, benign prostate hyperplasia, and possibly prostate cancer favored by estradiol excess.

Progesterone also keeps dihydrotestosterone

(DHT) at a lower levei, possibly preventing or attenuating male pattern baldness, favored by DHT excess. How does progesterone in men reduce the leveis of the most potent female and male hormones? •

Reducing estradiol leveis: Progesterone keeps estradiol leveis low in the blood and prostate by increasing the speed of the conversion of estradiol into estrone, an estrogen that is ten times less active. In my clinicai experience 100 milligrams of micronized progesterone supplementation reduces estradiol levels by approximately 30%.

Why keep the estradiol levels low in men? To minimize the risk of prostate and heart diseases that appear to be facilitated by high leveis of estradiol. In men, a high levei of estradiol causes enlargement of the prostate by stimulating the proliferation of the inactive stroma (fibrous tissue).

Stroma is hard. This

explains why the prostate of a man with long-term high serum estradiol generally feels hard during digital rectal examination. More concerning is that mice studies have shown that high leveis of estrogen may cause mutagenic changes of prostate glandular cells. Thus,

estrogens have the

potential to harm the prostate

and promote prostate

degeneration and possibly cancer growth. In one of these studies, progesterone treatment of

the

mice

receiving

high

estrogen

therapy

counteracted

the

estradiol-induced

mutagenesis. Another disturbing observation is that oral estrogens given to prostate cancer patients seem to increase the cardiovascular risk.

This is in agreement with the findings that

patients with myocardial infarction (MI) have significantly higher blood estradiol levels and that the severity of the Ml seems to be directly proportional to the amount of estradiol in the bloodstream. •

Reducing dihydrotestosterone (DHT) leveis Progesterone maintains DHT in the blood and prostate at a low levei by competing for the 5-alpha reductase enzyme and preventing in this manner some of the testosterone from being converted to the more potent male hormone DHT (partia! blockage of the conversion). The progesterone is then converted into 5-alpha-dihydro-progesterone, and testosterone remains testosterone.

Why avoid excessiva dihydrotestosterone leveis in men? Because excessive dihydrotestosterone generates male pattern baldness. To counter the typical male hair loss, there have been many products on the market containing

348

progesterone in a solution applied to the scalp or with oral capsules. Thus far, results have been disappointing.

2'

Progesterone is important for the production of aldosterone, cortisol and severa! androgens

Progesterone serves as substrate for the production of important hormones: adrenal hormones such as cortisol and cortisone, and androgens such as androstenedione and testosterone (but not DHEA). Therefore, progesterone deficiency is often accompanied by deficiencies in cortisol and androgens. Progesterone's possible conversion to cortisol explains why high doses of progesterone can keep animais alive after removal of the adrenal glands, a role normally devoted to cortisol. Progesterone's possible conversion to testosterone explains why acne and oily skin may appear in some women while taking micronized progesterone, a side-effect normally attributed to excess testosterone (and not dihydrotestosterone). 3'

Progesterone keeps aldosterone in balance.

Progesterone partially blocks aldosterone receptors and therefore may prevent excessive fluid retention and possible high blood pressure caused by high leveis of aldosterone production. 4'

Progesterone has a calming effect on the body.

Progesterone calms down nerves and muscles thanks to its conversion in the body to the sleep-inducing and relaxing metabolites, pregnanolone and allo-pregnanolone. This is especially helpful for men who are tense or anxious. 5 ' Progesterone stimulates spermatozoid motility a nd may be important for male fertility.

Production of Progesterone

Progesterone production apparently amounts to 1.5 to 3 milligrams per day* in healthy men and is almost entirely produced by the adrenal glands. One key way to increase progesterone production is to eat a diet rich in protein and cholesterol which is a precursor to progesterone synthesis.

Do leveis of progesterone decline with age in men?

As for practically ali major steroids from the adrenal glands, progesterone production and leveis decline with age in men. Older men show lower lab test values compared to the leveis of younger men. Luckily, the production of progesterone does not decrease as quickly as DHEA and pregnenolone.

Progesterone metabolites Principal metabolite:

Pregnandiol

Principal hormones and metabolites derived from progesterone: 17-hydroxy-progesterone,

androstenedione, aldosterone.

testosterone

and

androsterone,

349

cortisol

and

17-hydroxy-steroids,

I. Male Progesterone Deficiency: DIAGNOSIS More data is needed to fully understand the importance of progesterone deficiency in men. Nevertheless, there is enough data to consider that many signs of excess of estrogen and probably of dihydrotestosterone in men are caused or aggravated by progesterone deficiency.

1. Timing and Location When during the day and where on the body do progesterone signs and complaints manifest themselves? When? Most of them are apparent continuously throughout the day. Where? Except for the muscle tension that may be diffusely spread over the body, although some men say it is concentrated in the shoulders and neck, most complaints and signs are often located in specific regions such as the breasts and prostate for men with high estrogen leveis and on the scalp and regions of body hair for men with high dihydrotestosterone.

2. Complaints of Progesterone Deficiency in Men Complaints suggestive of Progesterone Deficiency Complaints

Cause Behavior Low Tone of the Parasympathetic Nervous System

•

Tense, nervous behavior

Emotional

•

Anxiety, lack of inner peace

Sleep

•

Superficial, nervous sleep

•

Reduced urine flow

Urine Abdomen

•

Need more time to urinate (dysuria)

•

Constipation

3. Physical signs of Progesterone Deficiency The signs in the table below may be caused or aggravated by progesterone deficiency: Signs suggestive of Progesterone Deficiency Physical Signs

Cause Dihydrotestosterone Scalp hair

•

excess

Body hair

•

Excess body hair

Behavior

•

Nervous, tense

Breasts

•

Enlarged breasts (gynecomastia)

Abdomen

•

Swollen abdomen

Muscles

•

Tense muscles

Prostate

•

Estrogen excess

Male pattern baldness

" Hard and enlarged prostate (benign prostate hypertrophy)

Note: High leveis of estrogens in the prostate stimulate lhe fibrous tissue in it to proliferate - enlargening and hardening it, a process calles 'stromal hyperplasia'.

350

4. Disease Susceptibility Progesterone deficiency is a favorable soil for the development of diseases in men that are associated with estrogen excess, such as breast development (gynecomastia), ischemic heart disease, benign prostate hypertrophy and possibly prostate cancer. Similarly, progesterone deficiency may facilitate the effects of a prolonged high levei of dihydrotestosterone such as body hair overgrowth (hirsutism) on the back for example and male pattern baldness.

5. Lab Tests for Progesterone in Men lt is important for patients who have their progesterone tested to remain calm and sedentary for 24 hours before the blood or the 24-hour urine tests as vigorous activity and stress can falsely increase the leveis through a global activation of the adrenal glands. Lab tests for Detection of Progesterone Deficiency

Probably TYPE

Optimal

Test

Progesterone

References

deficient Progesterone

(P4) at 8 a.m.2

Transcortin

1.2

0-0.9

0.1-1.3 ng/ml

3.8

0-2.9

0.3-4.1 nmoi/L

30

(CBG)3

20-25 Estradiol (E2) BLOOD Estrone (E1)

75- 90

High,? 120 Low: 0-0.13

(2:0.9)

40 0.15

URINE SALIVA

(gas chromat.) Progesterone

Low: 0-130 90

>

700

3.1

Low : 0-550

High DHTIT ratio

24

Low: 0- 19

(2:0.2)

High

High

Med Med

0.04-0.17 nmoi!L

Med

40-170 pmoi/L

15-65 pÇJ/mL 0.05-0.24 nmoi/L

Low

55-240 pmoi/L

>

70

Testosterone Pregnandiol

Low: 0-35

1

10-45 pg/ml

HiÇJh 2:32 High E2/E1 ratio

2.4

4

20-50 mg/L

40

High ,?0.12

sterone (DHT)

(T)

>

0.07-0.09

150

Dihydrotesto-

High

Test Value

30-100 ng/ml

1.0-3.4 nmoi!L

300-1000 nÇJ/dl

10-35 nmoi/L

Med Low

2

0-1.2

0-2.5 mg/24h

High

50

0-35

0-65 pg/ml

Low

Notes: ':?:" means "more than or equal to" 1

2 3

Estimated usefulness of the test We advise the physician to measure the morning leveis of progesterone as other adrenal cortex hormones peak in early morning. Transcortin (or CBG cortiso/ binding protein) is the major plasma binding protein of progesterone used to transport progesterone; 4 Pregnandio/ is a major metabolite of progesterone and reflects the metabolic activity of progesterone over a period of 24 hours. lt can be better measured by the gas chromatography technique, and not through the outdated, unreliable co/orimetric technique.

351

11. Male Progesterone Deficiency: TREATMENT Progesterone Medications The most efficient form of bioidentical progesterone for men is oral progesterone before bedtime. Other forms (including transdermal) have been shown to be insufficient in reducing estradiol levels. Progesterone treatment options are listed in the following table:

Progesterone treatments Route

Oral

Product

Doses

Progesterone (micronized)

50-100 mg/day (Prometrium®, Utrogest®) Utrogestan®, Progestan®)

Progesterone Sub(compounding lingual pharmacy) Progesterone gel Trans25 mg/g dermal (Progestogel®) Progesterone Trans- liposomal gel 100 mg/g dermal (compounding pharmacy) Progesterone Suppo (compounding -sitory pharmacy)

50-100

mg/day

2 . 5-5g/day

1-4

g/day

Time

lndication Progesterone deficit dominated by:

Value

1x/day (before bedtime)

High blood estradiol, nervousness, poor sleep at night1

Hlgh

Sleep problems, nervous tension at night1

Med

1x/day (before bedtime)

1x/day (before bedtime) every days (4--6 months)

1x 100-150

mg

2-3

Milder forms of hard and enlarged prostate2 Milder forms of hard and enlarged prostate2 Aldosterone-induced arterial hypertension3 (some cases) Milder forms of hard and enlarged prostate4

Low or Med? Med

High

Note: 1

Progesterone has sleep-inducing and relaxing proprieties after conversion into pregnanolone and

2

In our experience, progesterone reduces the excessive size and/or hardness of the benign prostate

allopregnanolone. hypertrophy due to a high serum estradiol in about one-third of the men, particulary those with the highest estradio/ leveis and whose prostate en/argement has recently appeared are good candidates for this treatment.

3

Progesterone should not be considered as the sole treatment for a/dosterone induced hypertension. lt

4

In our experience, progesterone suppositories combined with oral progesterone 100 mglday moderately

lowers blood pressure by competitively blocking the aldosterone receptors in the kidneys. reduce the size andlor hardness of the prostate in near/y half of men with prostate en/argement caused

by stromal hyperplasia (see footnote 2 for explanation).

352

lndications for Progesterone Treatment in Men Main

indication:

Progesterone

deficiency

with

excess

in

estradiol

(benign

prostate

hypertrophy, cardiovascular diseases) Secondary indication: Dihydrotestosterone (male pattern baldness, hirsutism). Progesterone treatment lowers estradiol excess better than it reduces DHT excess.

Contraindications to Progesterone Treatment in Men The following conditions may be considered as relative contraindications: 11 Contraindications for ali forms of progesterone : 1.

Healthy

men without

any degree

of

progesterone

deficiency,

estradiol excess or

dihydrotestosterone surplus. 2.

Men with low sex drive and potency as progesterone may further decrease the sex drive and potency in some of these patients. Progesterone reduces the secretion of LH which is a stimulus for testosterone secretion.

21 Contraindications for oral progesterone only: 3.

Severe liver disease, since even doses as little as 100 mg per day of progesterone, which are a safe dose for most men, may increase the damage to the liver in highly sensitive men.

How to start Progesterone Treatment Most patients start at 100 mg of oral progesterone a day. lf the patient complains of low libido and impotence, we advise the physician to prudently start on a dose 50% lower than the optimal dose (one capsule of 100 mg every two days for instance) and then after 2 months, if no adverse side effects occur, to increase the dose by 25% and monitor closely. The best time to take the progesterone is before bedtime because progesterone, in particular the oral form, may make the patient sleepy and even a little dizzy, a side effect that is not a major problem when it is time for the patient to go sleep. Some men have to urinate more half an hour after taking the progesterone.

This increased

urination is due to progesterone's diuretic effects by blocking the aldosterone receptors and by lowering the salt- and water retaining estradiol leveis.

lntake of progesterone half an hour to

one hour before bedtime may give time to the patient to urinate the extra urine before sleeping.

353

Progress during Progesterone Treatment in Men How much time is necessary before improvements are felt? The sedative effect on muscle tension and nervousness may occur with the first dose, but it usually takes four to six weeks before maximal effects are felt. Evaluate the beneficiai effects on prostate enlargement and hardness, and serum PSA after 6 months of progesterone treatment. Shorter times usually do not give clear results, except for a decrease in dysuria that may show up after a month of treatment.

How to naturally Boost Progesterone Treatment Above ali, improve the diet.

An overview of the principal dietary factors of importance to augment both progesterone production and effects is shown in the following table. How to Optimize Progesterone Activity and Treatment Foods to Eat •

Diet

•

•

Foods to Avoid

Eat sufficiently (a minimum amount of food is necessary to make progesterone)

• •

Follow a "Paleolithic" diet: fruits, vegetables, meat, poultry, eggs, fish Eat organic foods

•

•

Avoid alcohol, vinegar, caffeinated drinks Avoid sugar, sweets, soft drinks, cookies, bread, pastas and other cereais Avoid cereal fiber (whole grain bread, bran flakes) Avoid milk products

Follow-up of Progesterone Treatment in Men The following principies may help the physician optimize the treatment: 1. Find the optimal dose:

The main conditions necessitating a change in dosing are summarized in the following table. When to adapt the dose of Progesterone in men

• •

lncrease the dose

Lower the dose

(50 mg/day more)

(25 to 75 mg/day less)

lnsufficient dose Male patient with very high estradiol leveis (and normal aldosterone leveis)

•

Excess dose (patient has signs of overdose)

•

Male patient with libido and impotency problems

•

Male patient with low aldosterone leveis

354

2. Avoid side effects:

A patient taking progesterone may occasionally experience side-effects such as dizziness, fogginess, fatigue (signs of an aldosterone deficiency) and impotence (androgen deficiency). These secondary effects are caused by an aggravation of the corresponding deficiencies through progesterone. Progesterone blocks aldosterone receptors and reduces the conversion of testosterone to DHT. The physician should either reduce the dose of progesterone or treat the other deficiencies. The goal is to free the patient from ali symptoms.

3. Check with lab tests:

Lab tests are a great help to see if the dose of progesterone is adequate or needs adjustment. An adequate dose lowers serum estradiol sufficiently. lf the estradiol levei remains high, then other medications should be considered such as anastrozole (Arimidex®) to lower estradiol. Thus, the most important lab test is not serum progesterone, but serum estradiol and perhaps serum estrone. The blood progesterone levei is only useful to show gross excesses. Measuring the urinary 24hour excretion of pregnandiol, progesterone's major metabolite (whose urinary excretion in untreated conditions reflects progesterone's metabolic activity) is only useful for transdermal progesterone use. Treatments with oral progesterone cause an unusually high pregnandiol excretion that does not reflect progesterone activity, as most of the pregnandiol found in the urine in this case comes from an intense breakdown of ingested progesterone by the liver immediately after its intestinal absorption, without any significant effect on the body. Tests for follow-up during progesterone treatment

Type

Ser um

24-hour urine

Test Value for

Test

Progesterone Treatment Oral

Transdermal

Progesterone CBG (transcortin)

Medium Low

Medium Low

Estradiol

High

High

Estrone

High

High

Testosterone Dihyrotestosterone/ Androstanediol Qlucuronide

Low

Low

Low to Medium

Low to Medium

Low: not useful

Hlgh

Pregnandiol

In men with high estradiol, an efficient progesterone treatment reduces the serum levei of estradiol and increases that of estrone, lowering the overall estradiol/estrone ratio. In case of excess dihydrotestosterone/androstanediol glucuronide, theoretically the progesterone should block the 5-alpha-reductase, increase testosterone and decrease dihdyrotestosterone and androstanediol glucuronide, increasing the overall testosterone/DHT-androstandiol glucuronide ratio.

355

4. Avoid overdosing.

Checking the patient for clinicai signs of overdose (see corresponding table) often helps to better spot progesterone excess than through lab tests. Progesterone Overdose Latency*

Overdose Sign

Severa! days to

•

Fatigue

severa! weeks

•

Depression

30 to 90 minutes

•

Sleepiness

30 minutes

to 10 hours

Severa! weeks

•

Cause Too strong drop in estradiol, which results in a decrease in activity of the sympathetic nervous system Excess conversion of progesterone to sleep-inducing metabolites

Drowsiness, vertigo, faint feelings, fogginess

•

Low blood oressure

•

Partial loss of sex drive

•

Partia! or total sexual imootence

Note:

•

Decreased blood pressure by blockage of aldosterone receptors Blockage of the LH secretion and therefore of testosterone (production)

Duration of treatment before the first appearance of the unwanted overdose side effect.

5. Correct any problem as quickly as possible.

See section "Problem solver'' for more information.

356

111. Progesterone PROBLEM SOLVER in Men How to solve problems that may occur during treatment? At present no dangerous side effects have been reported, but some unpleasant ones may occur: In the following tables the most frequent problems that may occur are described with their solution:

Problems due to Progesterone Conversion into Metabolites PROBLEM

POSSIBLE CAUSE

SOLUTION

Progesterone calms nerves and

1.

•

Feeling sleepy, yawning, heavy head

relaxation after conversion into

Take progesterone before bedtime when sleep is welcome

muscles and induces sleep and 2.

Use another route such as

pregnenolone and alio-

transdermal that avoids the first

pregnenolone. Sleepiness occurs

pass through the liver. Second

more easily after oral intake of

choice is the sublingual route that

progesterone (production of sleep-

partially avoids the passage through the liver.

inducing progesterone metabolites by the liver )

3.

Reduce the dose of oroaesterone

Problems related to deficiency of other hormone activities Problems related to Androgen Deficiency or Blockage POSSIBLE CAUSES

PROBLEM

SOLUTION

DECREASED ANDROGENS (MALE HOMONES) •

Progesterone decreases the leveis of

Avoid using progesterone in men

Decrease in

male hormones (testosterone,

with potency problems.

sex drive

dihydrotestosterone) by two

lf serum estradiol in these men

mechanisms.

is high, the use of a synthetic

•

•

Decrease in sexual potency:

•

Firstly progesterone partially inhibits

blocker of aromatase, the

the secretion of LH, the pituitary

enzyme that converts

hormone that stimulates the

testosterone to estradiol, is

secretion of the male hormone

preferable.

testosterone. Consequently, serum

IMPORTANT NOTE: Most men

testosterone and DHT decrease

on progesterone treatment do

(which lowers sexual potency).

not experience potency

Secondly, progesterone inhibits the

problems.

reduced

conversion of testosterone to DHT,

Some even improve their

erections

the hormone of erections.

potency with progesterone by

Consequently serum DHT drops

having an increase in male

which lowers sexual potency.

hormones through the conversion of progesterone into

Potency problems generally only appear in patients who already had low potency

17-0H-progesterone, and then to

before the treatment started.

androstenedione and testost.

357

Problems related to Aldosterone Deficiency anc:l/or Blockage PROBLEM

POSSIBLE CAUSES

•

Nocturia (excessive need to frequently urinate large volumes of urine at night), causing frequent waking

SOLUTION

Excessive blockage of the receptors for the salt- and water retaining aldosterone in the kidneys by progesterone, which leads to an excessive excretion of urine

•

•

its salt- and water-retaining effect •

•

•

some degree of pre-

Correct a possible aldosterone deficiency by (50 �g of fludrocortisone before sleep for example) before bedtime Take progesterone earlier in the day half an

hour to three hours before sleep, for example

existing aldosterone

(watch out for side effects due to aldosterone

deficiency

deficiency caused by progesterone such as

Progesterone overdose

•

Drink less water or other liquids (in particular caffeinated and soft dinks) in the hours before going to bed; avoid eating fruits in the evening to avoid increased urination taking a small dose

Possibly favored by

•

lncrease the intake of dietary salt at supper so that the endogenous aldosterone may exert

dizziness or sleepiness when taken earlier) •

Reduce or stop the dose of progesterone

Problems related to Deficiency or Blockage of Aldosterone and/or Testosterone PROBLEM

POSSIBLE CAUSES

SOLUTION

Decrease of the effects of aldosterone by progesterone. Aldosterone is the hormone that •

•

Dizziness, drowsiness when standing,

increases blood pressure. Progesterone binds to the aldosterone receptors and thereby reduces the number of receptors available for aldosterone so that blood pressure may sometimes significantly decrease with

Low blood pressure

progesterone therapy. Such a problem generally only happens in men

Take progesterone before bedtime 2. Correct the aldosterone deficiency 3. Reduce the dose of progesterone 1.

with borderline or overt aldosterone deficiency. •

The same causes as above (i.e. excessiva blockage of aldosterone receptors, a preexisting aldosterone deficiency, a progesterone overdose) may facilitate urinary incontinence

1.

Often in the presence of: •

Urinary incontinence (rare)

•

A pre-existing testosterone deficiency

75%

because testosterone is necessary for a good tone and efficacy of the bladder sphincter. Progesterone may slow down the secretion of LH, the pituitary hormone that stimlulates the

secretion of testosterone by the testicles •

Excessiva blockage of testosterone receptors by progesterone

358

Reduce the dose of progesterone or stop the treatment by 50-

2.

Correct the testosterone deficiency

V.

TREATMENT OF PARTICULAR PROBLEMS

A. Treatment of Men's Diseases The Prostate The prostate is not one big gland but a tissue containing some sparse glands imbedded in abundant fibrous tissue and surrounded on the outside by a capsule mainly made of muscles. On the outside, a robust muscular capsule surrounds the prostate. nourished and maintained mainly by testosterone.

lts muscular fibers are

When the leveis of testosterone drop with

aging, the deficiency allows the capsule to degenerate and its muscle fibers to be slowly replaced by fibrous tissue.

The fibrosis prevents the prostate from contracting and propelling

prostate liquid from the glands into the urethra during intercourse, an essential function of the prostate. lnside the prostate, about 65% of the space is occupied by hard, fibrous tissue called stroma. The stroma increases depending on the leveis of female hormone estradiol.

When estradiol

leveis are too high, stroma overwhelms the inside of the prostate, occupying up to 95% of the space, while it should normally not exceed 65 %. The rest of the prostate is made of small glands that give the soft feeling to the healthy prostate upon digital rectal exam. These glands also depend on male hormones for their well-being, in particular on dihydrotestosterone (DHT). lf leveis of DHT decline, for example, with aging or by taking finasteride (Proscar®), which decreases dihydrostestosterone production by blocking the enzyme 5-alpha-reductase that converts testosterone to DHT, the glands atrophy and perish. A long-term use of finasteride and other 5-alpha-reductase blockers can adversely affect the prostate. Men who suffer from benign prostatic hypertrophy (BPH) have dysuria (difficulty urinating) and are often prescribed blockers of the production of DHT such as finasteride. The first few months of intake of a 5-alpha-reductase blocker, patients may feel relieved and experience urination improvement. The improvement is due to shrinkage of the small glands within the prostate, caused by the decreased levei of DHT.

Unfortunately, on a long-term basis, the coexistence of

low DHT and high estradiol leveis stimulates wild proliferation of the stroma. The expansion of stroma considerably increases the size of the prostate, but, worse, it transforms it into a hard, fibrous mass that further blocks urine outflow through the urethra. reductase blockers are never a long-term answer for BPH. The better treatment is to treat the high estradiol levels instead.

361

Therefore, 5-alpha­

1. How t o lower high e stradiollevels in me n Aging men often have elevated leveis of estrogens in the blood, especially estradiol.

One

reason for this is that older men tend to have more body fat than young men. Fat tissue is rich in aromatase that converts testosterone to estradiol. The fatter men become, the higher the estradiol leveis usualiy are. Prolonged

exposure to high leveis of estrogen is associated with various "old man" problems: gynecomastia (breast development), impotence, benign prostate hypertrophy with

urination difficulties, and myocardial infarction. The benign prostate hypertrophy usually results from an excessive proliferation of stroma (fibrous tissue) in the prostate stimulated by the high estradiol leveis. The increased stroma hardens and enlarges the prostate, and, thereby, compresses the urethra and decreases the urine flow.

Studies have shown metaplasia

(abnormal celi transformation) of the prostate glands in animais given estrogen treatment. Other studies have shown a direct correlation between estrogen leveis and myocardial infarctions. The higher the leveis, the more severe the heart attack. As

testosterone (T) can convert into estradiol (E2) with the help of the enzyme aromatase,

T treatment may increase the E2 leveis. The reverse can also be true, namely that T treatment may reduce the E2 levei through an inhibition of the aromatase enzyme and a stimulation of the 5-alpha-reductase, the enzyme that converts T into DHT.

Careful obseNation can help the

physician to predict which men will usually produce more E2 or DHT when given T therapy. Men with obesity, gynecomastia and deficient body hair are rich in aromatase, and wili generaliy make more E2 than DHT from the testosterone therapy. In contrast, the reverse is true for men with higher-than-average body hair development, who are proportionately richer in the 5-alpha-reductase enzyme that produces DHT. These men have no or a low tendency to produce high E2 leveis, are at low risk of developing breasts or obesity, but are inclined to lose hair at the top of the head, the typical form of male pattern baldness. Various

causes increase the leveis of estradiol in men. The most common causes are heavy

drinking of caffeinated beverages and alcohol, obesity (because of the richness of adipose tissue in aromatase), and wearing tight underwear and trousers. Tight underwear wili compress the testicles' blood vessels. The compression slows the blood flow, causing ischemia (a lack of fresh blood and oxygen) for the testosterone-producing Leydig celis.

The Leydig cells suffer

more from the asphyxia than the estradiol-producing Sertoli cells, which are able to compensate by overproducing E2.

The correction of ali these causes is often sufficient to normalize the

levei of E2. lf a man presents one or more of these conditions, correcting them ali together may lower the levei of E2 by 20 to 70% and thus normalize it. Medications that decrease estradiol should be given when the initial (before any treatment) E2 levei is above 55 pg per ml in the blood, a value that is double that of what is optimal, or when it is above 35 mg per ml during treatment and remains so after the correction of adverse conditions that increase it.

The first choice is 100 mg of oral micronized progesterone (P4)

before bedtime. P4 lowers blood E2 by increasing its conversion to the ten times less active estrone. Hundred miliigrams of P4 treatment in men lowers blood E2 by approximately 35 %. Some caution with oral P4 is recommended for men with sexual potency problems who may experience a decline in potency with the treatment. The lower sexual potency results from a decrease in the endogenous production of T, caused by P4's inhibition of the release of LH, the pituitary hormone that stimulates T production. concerns only a minority of men.

Fortunately, the decline of sexual potency

lf P4 does not work, the next alternative is an aromatase

blocker, a compound that blocks the conversion of T into E2 such as Arimidex® (anastrozole) or, less common, a blocker of the celiular E2 receptors such as Nolvadex® (tamoxifen).

362

How to treat high estrogen leveis in men is reviewed in the following table.

How to Lower High Estradiol (and SHBG*) Leveis in Men SOLUTION

POSSIBLE CAUSES

Diet

Alcohol � 1 glass per day*

•

Stop drinking alcohol

Coffee � 2 cups per day* Low intake of animal protein, esp. meat High calorie intake

•

Stop drinking caffeinated coffee

•

Consume more animal protein such as meat

Obesity Diseases

Eat less, lower the calorie intake •

Lose weight; Lose fat

•

Be physically more active

•

lncrease muscle mass by exercising

•

Apply locally a gel of testosterone or DHT (at the levei of the varicocele) for more than 3 months => may regress the varicocele

•

Surgical removal of varicocele

Varicocele

Clothes

Tight underwear

Wear •

Testosterone treatment (iatrogenic) Hormone treatments

OHT

Hormone deficits

Hormone excess

Growth hormone Cortisol (certain cases)

large trousers

Stop taking caffeinated beverages, alcohol, stop wearing tight underwear; lose weight

•

Use aromatase blockers: Arimidex®, DIM, .. Use an estrogen receptor blocker: Tamoxifen (Nolvadex®) Replace testosterone with DHT or a synthetic derivative that cannot convert into estradiol

•

The female partner should avoid applying the estradiol treatment on the abdomen or inner thighs where close body contact is possible with her male partner during sex

•

Mesterolone (Proviron®): 1 to 4 tablets/day

•

DHT gel (Andractim®)

•

Growth hormone treatment

•

Hydrocortisone or other glucocorticoid treatment that may lower endogenous testosterone production and leveis, and the serum SHBG levei

Progesterone

•

Progesterone treatment

Hyperthyroidism

•

Normalize the thyroid function

Estrogen treatment in men •

Drugs

large boxer shorts

•

•

•

Transdermal estradiol treatment of female hormone partner

•

• •

Antifungal drugs Antibiotics Cardiovascular drugs: �-blockers, ...

Avoid estrogen treatment, and if essential, take the lowest dose possible lf these drugs are essential, take them at the lowest dose possible (for more information refer to section on "How to correct excessive estradiol leveis" of the chapter on Testosterone in men •

Note: * Many of these interventions /ower a/so the serum levei of SHBG (Sex Hormone Binding Globulin), the blood protein that transports testosterone and DHT from the endocrine gland to the target cells. High amounts of SHBG in the blood wi/1 bind and keep too much testosterone in the blood, reducing thereby the amount of testosterone that diffuses into the cells. As estradiol stimulates the production of SHBG, interventions that reduce blood estradiol reduce the blood levei of SHBG.

363

Additionally, other interventions such as taking specific foods and nutrients, and avoiding certain medications may help to lower the blood levei of estradiol as shown in following table. Foods to Eat • • • • •

Nutrients to Take

Meat Soy products Cruciferous vegetables Shell fish Resveratrol (from Qrape skins)

• •

•

Vitamin C & K Zinc (50 to 100 mg/day) Niacin

Avoid certain medications • •

• •

Spironolactone {Aidactone®) Cyproterone acetate (Androcur, Cyprostat®) Chemotherapy agents Thiazides

2. How to treat Benign Prostate Hypertrophy? Most cases of prostate hypertrophy are caused by a large increase in stroma. The stroma overgrowth is stimulated by the coexistence of high estrogen leveis and a low DHT levei. Therefore, the first step in treating stromal hyperplasia of the prostate is to restore an adequate balance of these hormone leveis in the prostate as well as in the blood. One of the ways to do so is to insert progesterone suppositories at bedtime every two or three days as local progesterone can reduce the levei of estradiol in the prostate by increasing the conversion of estradiol to the much less active estrone. The most important measures are reviewed in the following table: Measures to reverse or minimize the development of Benign Prostate Hypertrophy

(especially stromal hyperplasia of the prostate)

HOW?

MEASURES

Remarks

Change blood leveis of sex hormones •

Reduce

•

estrogen leveis

lncrease T

•

&

•

DHT leveis

Diet and other life style measures Natural supplements: di-indolyl-methane (DIM, 75 mg/day), Chrysin Medications such as progesterone or Arimidex® (3 x 0.25 mg/week to 0.5 mg/day) Male hormones that do not convert into estrogens: e.g. mesterolone (Proviron®}, DHT gel (Andractim® )

See table just above on how to lower high estradiol leveis (and SHBG) in men

Change prostate leveis of sex hormones locally Take suppositories

Reduce

•

estrogen leveis or effects

• •

lncrease T DHT leveis

&

•

Progesterone: 100 - 150 mg every 2 or 3 days during 4 to 6 months Aromatase blocker such as anastrozole (Arimidex®) (?)* Estrogen receptor blocker such as tamoxifen (Nolvaldex®) (?)* DHT (?)*

·

Works in± 50%of men Theoretical, not yet researched

Note: rhis information is sti/1 hypothetical. Further investigations with valid studies are necessary before this information can be considered as scientific truth.

364

3. What to do with Prostate Cancer Patients Many men fear prostate cancer as it is an epidemic. lnterestingly, only a very small percentage of men die from prostate cancer. The great majority of prostate cancers discovered at autopsy were not detected during their lifetimes. Research studies have reported a prostate cancer incidence of men over age 40 at autopsy ranging from 14-46%. The severity of prostate cancer tumors is graded by the Gleason score of the two predominant zones of the suspicious prostate tissue. The score is based on a scale that increases from 2 (minimally) to 1 O (maximally malignant) following the grade of abnormality or malignancy of prostate glandular cells upon histological examination. Gleason Prostate Cancer Grading System

Histological score of zone 1 Grade

1

Histological score of zone 2

very Grade differentiated

1

very differentiated

Grade 2

lntermediate

Grade 2

lntermediate

Grade 3

lntermediate Grade 3

lntermediate

Grade4

lntermediate

Grade4

lntermediate

Grade

Very unGrade 5 differentiated

Very undifferentiated

Gleason Score

Score of zone 1 (value from 1 to 5) =

+ Score of zone 2 (value from 1 to 5)

value from 2 to 10 =

5

Tumor Score Gleason 1+ 1 :The lowest grade tumors, they grow slowly and rarely spread

In the more common intermediate grade tumors, behavior is extremely variable.

Gleason 4+5 tumors are often widely metastatic at the time of diagnosis.

The lowest grade tumors, Gleason 1+ 1, grow slowly and rarely spread. Gleason 4+5 tumors are often widely metastatic at the time of diagnosis. In the commoner intermediate grade tumors, however, behavior is extremely variable. Treating prostate cancer patients with hormone therapies is a delicate issue as there is a widespread tear that hormone therapy might aggravate the prostate cancer. No study has proven that testosterone therapies cause prostate cancer in men. There are laboratory studies in rodents where testosterone therapy stimulated prostate cancer growth. Paradoxically, studies exist that show the opposite in the same animal species: testosterone inhibits prostate cancer growth. There are not many studies to support either side of the argument. In two studies of terminal prostate cancer patients, male hormone therapy helped the patients to live longer and with a better quality of life. Nevertheless, because of the controversial fear of aggravating an existing prostate cancer with testosterone or growth hormone therapy, we recommend not to use any of these therapies in prostate cancer patients at least not during the first years after cancer diagnosis and therapy.

365

The adjuvant treatments we propose for prostate cancer patients are explained in the following table:

Which treatments may or may not be given to prostate cancer patients? •

Stop testosterone and growth hormone treatments if the patient is takinQ them

•

High doses of Coenzyme Q 10

•

Administer only acceptable and recommendable hormone treatments (because they stimulate the immunity and have anti-cancer actions): Melatonin treatment at physiologic doses o Thyroid hormone therapy in case of thyroid deficiency (hypothyroidism). o

•

Phytoestrogens in doses of 250-400 mg daily (minimum dose generally necessary for symptom relief): some controversies exist concerning their use in prostate cancer

•

(400 mg/day)

In exceptional cases such as prostate cancer patients with many signs and complaints of low male hormones and who are terminally ill or in complete remission, androgen (and growth hormone) therapy may be considered following some experienced physicians. These physicians advise their prostate cancer patients to take small doses of a synthetic derivative of testosterone that is not convertible to the female hormone estradiol. In such cases, patients need to sign an informed consent form mentioning ali the risks and benefits that have been discussed with the patient. Please, use the greatest caution in such circumstances: do optimal monitoring with PSA, free PSA, echography, bone scintigraphy, etc. Stop therapy immediately if obvious acceleration or recurrence of prostate cancer develops.

•

Certain urologists have used DHEA treatment in prostate cancer patients who had their a complete surgival remova! of their prostate cancer. They claim that DHEA caused no adverse effects, in particular no signs of recurrence. The information 1 should still be considered anecdotal at the moment.

•

Other physicians have used 7-keto-DHEA (50 mg/day) as an alternative, as this naturally occurring metabolite of DHEA has some of the beneficiai DHEA effects, while it is said not to convert into estrogens, nor in testosterone, and therefore should not be a potential risk factor for developing genital cancer. The scientific literature on 7-keto-DHEA is almost nonexistent.

Notes: 1

Various studies on the influence of DHEA blood leveis on the prostate have been carried out in

healthy men and prostate cancer patients.

No adverse effects at ali were found with high serum

DHEA. Conversely, a protective effect of DHEA treatment was reported in three out of four animal studies and in the fourth study, an adverse effect was observed but only in castrated animais where high doses of DHEA normalized the decreased prostate cancer risk of the castrated animais. Their risk did not exceed that of non-castrated animais.

366

4. How to treat Peyronie's Disease? Peyronie's disease is a stressful disease to men as it causes the penis to become fibrotic and curved especially with an erection. The curved shape of the penis hinders sexual intercourse, and may even make copulation impossible. At examination, hard cords of fibrous tissue on the back of the flaccid penis can be felt. In our experience, several hormone or vitamin deficiencies make the development of Peyronie's disease possible: testosterone (and more exactly DHT), growth hormone, cortisol, vitamin E and possibly also essential fatty acids. The standard treatment for Peyronie's disease is surgery. lt is crucial that these deficiencies be diagnosed and treated before resorting to surgery as medicai treatment may have beneficiai effects. An overview of efficient treatment approaches is represented in the following table. The improvement that is obtained in most patients with moderate Peyronie's disease by administering ali these therapies together lies, in our experience, around 40 to 85 % reduction of the disease. The "big five" treatments for

Condition

Peyronie's Disease

to correct 1.

Testosterone enanthate or cyprionate intramuscular injections:

one injection of 250 mg a week for the first 5 weeks (5 injections), then 1 every 10 days the next 50 days (5 inj.), then 1 every 12 days (5 inj.), then 1 every 14 days (and continue at this dose)

Testosterone deficiency

Growth hormone deficiency

2.

Dihydrotestosterone deficiency

3.

4.

Vitamin E deficiency

5.

Testosterone improves sex drive and erections, and widens the blood vessels of the penis (vasodilatation), which increases the blood supply and helps the reconstruction of the penis.

Growth hormone increases the volume, tone and size of penis and injections: doses of at least erections, partially reversing the 0.4 mg (1.2 I.U.) per day penis atrophy of Peyronie's disease. DHT (DHT} is essential for penis DHT gel 25 mg/g to apply locally in a development; DHT renews the thin layer on the penis twice daily (first penile tissues, reduces the fibrosis; 6 months), then once a day Use a condom for sex to avoid exposing the partner to DHT Growth hormone subcutaneous

Hydrocortisone oral treatments:

mg per day divided in morning and midday doses or synthetic derivativas ((methyl) prednis(ol)one) once a day Vitamin E 1 ,200-2,000 mg per day for 8-18 months 25-35

Cortisol deficiency

How it works

367

Cortisol decreases the inflammation and the proliferation of fibrous tissue that contribute to Peyronie's disease Vitamin

E

decreases the fibrosis

Condition to

Other treatments for

correct

Peyronie's Disease

How it works

Combine the following approaches: •

Polyunsaturated fatty acids type omega 3 and 6 deficiency

•

Omega-3 and omega-6 fatty acids •

•

Eat at least 700 grams of fish per week cooked at low temperatures (maximally 90-1 00°Celsius); o r take 2-4 grams of fish oi I capsules (omega 3 fatty acids); or take 1 to 3 tablespoons of cod liver or fish oi I. Take 500 milligrams a day of Evening Primrose oil and flaxseed oil cts Take a teaspoon of a mix of 2/3' rapeseed (or flaxseed) oil and of ct 1/3' olive oil (omeQa 3-6-9)

Zinc deficiency

Excessjunk food

Anti-androgen drugs

•

•

•

Zinc 50 mg per day

As zinc may lower estrogen leveis and protect against prostate infections, it may beneficially work on parts of the genital system other than the prostate such as the penis

Paleolithic diet

Eat fruits, vegetables and protein such as meat, fish, poultry. Avoid unhealthy foods that make the abdomen bloat or that imbalance hormone leveis: alcohol, caffeinated drinks, soft drinks, sweets, sugar, milk products, high-fiber cereais, etc.

Avoid anti-androgen drugs

368

These drugs block the conversion of testosterone to DHT (such as finasteride) or inhibit the effects of androgens (such as cyproterone acetate) or diuretics (such as spi ronolactone)

B. Treatment of Women's Diseases 1. How to correct an excess in body hair and "male pattern" hair loss in women? Women develop hirsutism and androgenic alopecia when the leveis of female hormones are low, while the levei of DHT, the most virilizing male hormone, is proportionately higher. A high DHT activity appears in serum tests as a high levei of androstanediol glucuronide. Other hormone deficiencies may generate body hair overgrowth such as thyroid and cortisol deficiencies. Thyroid deficiency: In the case of thyroid deficiency the normal conversion of testosterone to estradiol is decreased (because of a reduction in the activity of the aromatase enzyme) and the conversion to testosterone to DHT is increased (because of a proportionately higher activity of the 5-alpha-reductase enzyme). Both imbalances stimulate body hair growth. Cortisol deficiency: When adrenals can not make enough cortisol, the pituitary gland secretes massive amounts of ACTH to stimulate the adrenals to produce more cortisol.

lf the

overstimulation fails to increase the production of cortisol, the adrenal glands will produce, through other metabolic pathways that do respond to the ACTH overstimulation, greater amounts of androgens such as DHEA and androstenedione, causing virilism with excess body hair.

A treatment with exogenous cortisol calms down the excessiva adrenal androgen

production. The inhibition is better achieved by administering a glucocorticoid with prolonged action, preferably dexamethasone (36 to 48-hour action).

How to treat excessive body hair growth and male pattern hair loss The essential step is to detect and treat any underlying hormone or food deficiencies and excesses that cause or aggravate hirsutism such as illustrated in the table below. In mild hirsutism, the treatment generally consists of correcting the deficiencies in female hormones and/or thyroid hormones, and food-related factors, and not to take an anti­ androgen compound that may excessively reduce androgen activity in the human body. In severe hirsutism, a more complex approach is necessary to obtain success. lt often combines ali the treatments together, including the intake of an anti-androgen birth contrai pill.

369

The main therapies a9ainst hirsutism are outlined in the table below. The best methods are

hi9hli9hted with a yellow back9round.

Treatment of Excessive Body Hair and/or Male Pattern Hair Loss in Women: Table 1 CAUSES/TYPE

TREATMENT

LAB TESTS

DEFICIENCIES PREmenopausal women: •

Estradiol 9el: 3.75 9 per day from the 51h

to the 251h day •

Estradiol (and

pro9esterone) deficiency

Pro9esterone 100-150 m9 per day from

the 151h to the 251h day of menstrual

Low blood estradiol at the

21st day of menstrual cycle

cycle

POSTmenopausal women: •

Estradiol 9el: 3.75 9 per day from the 1st

to the 251h day of the month

•

Pro9esterone: 100 m9 per day from the

1st to the 251h day of month if periods are

9t,

not re uired or 100-50 m9 per day from

the 151 to the 251h day of cycle Progesterone deficiency Thyroid deficiency

Low blood pro9esterone at

•

the 21st day of cycle

•

Blood:

•

Low T3, T4, hi9h TSH

deficiency

and free, hi9h CBG

Desiccated thyroid: 45-180 m9 per day

Synthetic T3-T4: 3.4 to 2 tablets per day

(75 to 200 1-19 of T4 and 15 to 40 1-19 of T3

24h urine: Low T3, (T4)?

per day)

Blood: Low cortisol total

Cortisol

Pro9esterone: 100-200 m9 per day from

the 151h to the 251h day of cycle

•

24-hour urine: Low cortisol,

Provide dexamethasone at 0.15 to 0.5

m9 per day

17-hydroxysteroids

EXCESSES Adrenal androgens excess

(adreno9enital

syndrome) Ovarian

androgens excess

(polycystic

ovarian

syndrome) Growth horm. excess (rare)

Blood: normal LH & FSH (FSH

>

LH), hi9h DHEAs,

hi9h androstenedione,

•

hi9h androstanediol 9luc.

Provide dexamethasone treatment

24h urine: hi9h DHEA & other 17-ketosteroids

Blood: hi9h LH (LH

hi9h testosterone,

>

FSH),

To reduce the production of adrenal

andro9ens:

•

To reduce the production and effects of

ovarian andro9ens:

hi9h androstenedione,

Provide female hormone replacement

hi9h androstanediol 9luc.,

with estradiol and pro9esterone

low SHBG

(see chapter on 'Estrogen and progesterone deficiency and treatmentJ

24h urine: mainly hi9h androsterone

Blood: hi9h IGF-1, low IGF-

BP-3, low SHBG

370

•

lf the patient takes 9rowth hormone,

lower the dose of GH

Treatment of Excessive Body Hair and/or Male Pattern Hair Loss in Women: Table 2 CAUSE/Type

Lab tests

Treatment

FOOD Animal protein intake

24h urine: high/excessive phosphorus

Reduce the intake of animal protein such as meat, poultry (which increase the conversion of testosterone into DHT) and fish

COMPLEX

Severe hirsutism (facial

and abdominal hair) with little to no improvement from other treatments

Persistence of hirsutism, despite a normalization of ali blood leveis including androstanediol glucuronide

Administer an antiandrogen birth contrai pill (often with 2 mg of cyproterone acetate)* for 6-13 months with estradiol gel 0.6 mg/g gel: 2.5 to 5 grams per day transdermal estradiol from the 1st to the 21st day of pill intake

•

Add: Micronized progesterone 100 mg per day from the 11th to the 21st day of pill intake Use cyproterone acetate (Androcur®) in the place of progesterone (1 tablet Androcur 10 mg 100 mg progesterone 10 mg dydrogesterone) •

=

=

Use finasteride: ± 2.5 mg per day Note:

Desogen, Ortho-Cept, Ortho-Cyclen, Ortho-Tri-Cyclen, Brevicon, Modicon, Ovcon-35, Demu/en-35, Diane 35

·

Progress? In most cases, the first improvements are observed

only after 4 months of therapy.

Lab tests in the follow-up of treatment against body hair excess or hair loss in women:

lt is wise to check the patient every 4 to 6 months and order the following tests for monitoring. Laboratory tests for follow-up of treatments for body hair overgrowth and male pattern hair loss Tests

Type •

Essential

•

•

Estradiol, SHBG, testosterone,

Androstanediol glucuronide (most important; if not available: order DHT) Progesterone

Adrenal androgen excess: Blood

Optional

(depending on causes and treatment)

• • •

Androstenedione

Other dysfunctions: • •

24-hour urine

17-0H-progesterone (androgen precursor) DHEA sulfate

Free T3 & T4, TSH (IGF-1, IGF-BP-3)

Essential

•

17-ketosteroids

Optional

•

Free cortisol

• •

17-hydroxysteroids Free T3 & T4

371

2. How to Treat Women with Endometriosis? In endometriosis, pieces of endometrium, the typical mucous membranes of the inner wall of the uterus, develop in unexpected places such as the ovaries, the colon and the externai sides of the uterus. As progesterone is responsible for keeping endometrial growth at normal leveis, progesterone deficiency in the presence of normal estrogen leveis is accompanied by excessive proliferation of the endometrium, which in turn predisposes women to endometriosis. As thyroid hormone and cortisol deficiencies may cause progesterone deficiency, we recommend the physician to screen and treat these deficiencies first or simultaneously with progesterone treatment. Treatment of Endometriosis Deficiency

lndication

Treatment

Moderate Oral Progesterone: endometriosis (few From day 1 5 or 1 8 to day 26 of the menstrual cycle: 1 00 to or mild symptoms) 200 mg a day Dydrogesterone (Duphaston®): Progesterone Severe From day 5 to day 1 4 : 5- 1 O mg/day From day 1 5 to day 25: 1 0-20 mg/day endometriosis (if the effects are insufficient, stronger but potentially toxic (many severe progestogens may then be tried such as Primolut Nor® symptoms) norethisterone) Correct any thyroid and cortisol deficiencies as they Coexistent Thyroid may predispose the patient to endometriosis by their thyroid deficiency adverse effects on ovarian activity (poor ovulation and low Coexistent For products and doses, please consult hormones). Cortisol cortisol deficiency specific hormone chapters. 300-600 mg daily of elemental magnesium Coexistent magnesium (relaxes muscles including those of the uterus) Magnesium deficiency Avoid milk products, fiber-rich fruit and vegetables, cereais (bread, in particular whole grain bread), sugar, Coexistent sweets and food allergens that disturb the gut function Food digestive troubles and thereby may irritate other organs in the abdominal cavity, facilitatir19 endometriosis ÇJrowth •

=>

ifthe

above therapies are insufficient

=>

iftherapy

is still

Extensive endometriosis insufficiently improved by precedent methods

•

•

Block the estrogenic effects on the uterus: administer a gonadotropin antagonist (danazol - Danatrol®: 200 to 800 mg/day) for 6 months. lf the drug causes menopausa! symptoms, they can be relieved by Tibolone (Livial®): 1 per day (does not stimulate endometrium proliferation but relieves menopausa! symptoms) Surgery: Followed by progesterone treatment

insufficient

372

3. How to treat Uterine Cancer Patients? Two different cancers of the uterus exist: cervical and endometrial cancer. Cervical cancer: Cervical cancer does not depend on sex hormones. Once the cancer has been surgicaliy removed, hormone supplements may be given, even in the case of metastases after surgery and chemotherapy. Cervical cancer patients are often severely deficient in vitamin A, an immune-stimulating vitamin. A

vitamin A

deficiency

may

exacerbate

the

cancer;

therefore,

vitamin A

supplementation for 6 to 18 months is highly advisable, and longer if the patient tends to have the deficiency come back each time she stops taking it. Endometrial cancer: Endometrial cancer is hormone dependent as it is promoted by the presence of high leveis of estradiol with low leveis of progesterone. Treatment after uterine cancer Treatment

Cancer

Dose

50,000 I.U. (up to 300,000 I.U.) per day VitaminA

for 6 months up to - for the lower doses -

18 months Ali Uterine Cancers

Selenium

200 to 400 !19 per day 400 mg per day the first year, 100 mg per

Coenzyme 010

day onward

Eat lots of fruits, vegetables;

Avoid alcohol, caffeine

Avoid heating food at high

No griliing, barbecue, baking in oil, butter

temperature Acceptable hormone treatments: •

Cervical

Ali necessary therapies at correct doses, including sex hormone replacement

Cancer

•

In particular immune-enhancing melatonin and thyroid replacement (if necessary) are recommended

Acceptable hormone treatments: •

After complete surgical removal and absence of metastases: Ali essential hormone corrective therapies should be administered at safe physiological doses, but be cautious with the use of sex

Endometrial Cancer

hormone replacement •

In particular immune-enhancing melatonin and thyroid replacement are recommended. These treatments are safe before surgery, but as they need a certain time to have an effect, treatment can be delayed until after surgery. Melatonin may have to be avoided during certain chemotherapies, but afterwards it should be OK.

•

Locally limited

•

lnvasive, metastatic cancer

•

•

Wait one to tive years for sex hormone replacement No sex hormone replacement (at least wait for the patient to be cancer free for 5-1O years)

373

4-7. Treatment of Benign Breast Cysts, Breast Cancer, Menorrhagia, Uterine Fibroids For treatment of benign breast cysts, breast cancer, menorrhagia and uterine fibroids, reter to the "Female Hormone Problem Solver" section of the chapter on "Estrogens and Progesterone".

8. How to treat Ovarian Cysts Ovarian cysts can have various origins. Several hormone deficiencies have been associated with an increased incidence of ovarian cysts such as thyroid and cortisol deficiencies, progesterone deficiency (accompanied with a relatively low progesterone/estradiol ratio). A high prolactin levei appears also to stimulate the development of cysts in the ovaries. Thyroid hormone treatment may block the formation of such cysts by two mechanisms. Firstly, thyroid supplements may normalize excessive leveis of prolactin (a cause of ovarian cysts) in hypothyroid women. They do this by decreasing prolactin production after inhibiting the secretion of TRH (thyroid releasing hormone), which is a necessary stimulator of both the secretion of prolactin and of TSH (thyroid stimulating hormone). Secondly, thyroid therapy for hypothyroidism stimulates ovulation and the production of progesterone, thus correcting any progesterone deficiency, which is another contributor to ovarian cysts. With cortisol deficiency, there is little or no ovulation and progesterone production is low, creating an imbalance with low progesterone/high estradiol that favors the formation of ovarian cysts. Glucocorticoid correction normalizes the balance and helps prevent and reverse ovarian cysts. The syndrome of polycystic ovaries,

also called Stein-Lõwenthal syndrome,

can be

accompanied by high LH, estrone and testosterone leveis. lt may respond well to the treatments proposed below.

When there is persistent amenorrhea (no periods), as often is

seen in women with this disease, a low dose of estradiol complemented with a higher amount of progesterone may restore the menstrual cycle and help prevent the development of ovarian cysts in young women.

374

In the followin9 table we summarize the different therapy options.

Treatment of Ovarian Cysts Cause

Treatment

Dose

100 to 200 m9 a day from the 15th or 18th to the 26th day of the

Pro9esterone: (1st choice for small cysts)

Progesterone Deficiency

menstrual cycle

Or Dydro9esterone (Duphaston®) pst choice for bi99er cysts)

5-10 m9 per day from the 5th to the 14th day, then 10-20 m9 per day from the 15th to the 25th day of the menstrual cycle

Or Norethisterone (Primolut-nor®, 3'd choice for bi99er cysts that are resistant to pro9esterone and dydrogesterone)

5-1O m9/day as for dydro9esterone

•

Or a birth control pill •

Thyroid Deficiency

Cortisol Deficiency Essential Fatty acid Deficiency

Armour Thyroid (desiccated thyroid) (1st choice)

Excess

(hyperprolactinemia)

60-180 m9/day % to 2 tablets per day synthetic

T3/T4 (75-200 1-19 of T4 with 15-40 1-19 of T3 per

Synthetic T3/T4 (2"d choice)

day)

20-30 m9 per day

Hydrocortisone

divided in morning and midday doses

Predniso(lo)ne Medrol®

5 mg per day (2.5 to 7.5 mg per day) 4 m9 per day

Evenin9 Primrose Oil and Fish or Cod Liver Oil

1000 m9 per day for two months and then 500 m9; 1-3 tsp. per day

•

Prolactin

Ethinylestradiol-pro9esto9en combinations: 1 pill per day for 3 weeks, then stop 1 week, or Pro9esto9en alone medications: 1 pill per day (every day of the month}

•

Bromocriptine (Parlodel®) Avoid or minimize factors such as stress and nipple manipulation that increase prolactin secretion

1.25 to 2.5 m9 per day

lt may be necessary to combine several treatments for at least six months before obtainin9 the disappearance of ovarian cysts.

375

VI.

Quick Overviews

1. Overview of Mental and Emotional Complaints of Hormone Deficiencies The table below is a quick overview of the main complaints a hormone deficient patient can have: MENTAL and EMOTIONAL COMPLAINTS of HORMONE DEFICIENCIES Adult Melatonin Deficiency Poor sleep: •

Sleep

A superficial, anxious, agitated sleep with a lot of anxious thinking

•

Easily waking up during the night

•

Difficulties to fali asleep and fali back asleep

•

Poor dreaming

Adult Growth Hormone /IGF-1 Deficiency Quality of life Mood

Social behavior

•

Poor quality of life, feels unwell

•

Lack of inner peace

•

Chronic anxiety, without any reason

•

Tendency to be depressed

•

Lack of self-control; Excessiva emotional reactions

•

Melodramatic, histrionic

•

Outbursts of panic and anxiety

•

Sharp verbal retorts

•

Tendency to social isolation

•

lmpaired social status {lower professional position, lower income, generally living without a partner, alone or still at parents' home, poor social integration)

MSH deficiency Sexuality

I

Women

•

Lower sexual arousal and frequency of erotic fantasies

Men

•

Many doubts on sexual potency

Oxvtocin deficiency Character

•

Social behavior

•

lntrovert, lntellectual, not emotional Few social contacts, withdrawn

Vasopressin deficiency Memory

•

Difficulty in memorizing and learning

Hypothyroidism Behavior Mood

Memory

•

Slowness

•

Apathyflack of interest and initiative)

•

Morning depression

•

Slow thinking and reaction

•

Easily distracted

• • •

Poor concentration, poor attention Poor memory Poor school performance

379

MENTAL and EMOTIONAL COMPLAINTS of HORMONE DEFICIENCIES Pregnenolone Deficiency Possible DIRECT complaints Memory

•

Vision

•

Poor memory

Poor color vision INDIRECT complaints: resulting from deficiencies in hormones derived from pregnenolone (mainly adrenal cortex & sex hormones) DHEA (& Androstenedione) Deficiency Men Women

• • • •

Low sexual desire Erectile dysfunction Low sexual desire Low sexual satisfaction

Cortisol Deficienc� •

Stress • • • •

Character

• •

Poor resistance to stress, great difficulty to function well in stressful situations or even react to them, paralyzed in stressful situations, experiencing stress as being too much, as an unfair event Excessiva sensitivity to human suffering Excessiva compassion for the pain of others lrritability Negativism (experiencing reality as being more negativa than it really is for others) Feeling of being of a victim Paranoid-like reactions: accusatory behavior, quarrelsome

Excessiva emotions: outbursts of anger or anxiety, panic attacks • Behavior Easy screaming or yelling • Sharp verbal retorts, use of strong, dramatized words Aldosterone Deficiency When STANDING UP OR SITTING •

• •

Concentration

• • • •

Vision

•

Drowsiness, zombie-like feeling Easily distracted, absent-minded Day dreaming Difficulty focusing on tasks Feels better in head when laying flat on a bed or moving ali the time Troubled vision with difficulty to focus on objects and tasks when standing

lnsulin deficiency Alertness

•

Moments of low alertness, inattention

380

MENTAL and EMOTIONAL COMPLAINTS of HORMONE DEFICIENCIES WOMEN Estrogen Deficiency • Vitality Fatigue (persistent) • Mood Depression (persistent) Pro11esterone Deficiency (or EstroQen excess}

Vitality

• •

Mood •

Muscle and nervous tension lrritability, aggressiveness (especially during premenstrual syndrome) Anxiety and anQer, outbursts of panic or raQe

Testosterone Deficiency •

Character

• • • • •

Mood

• • • • •

Stress

• • •

Lack of mental firmness: Undecided, hesitating Loss of self-confidence, lack of assertiveness Lack of authority, submissiveness Chronic depression Excessive anxiety, fears Nervous lrritable 111 at ease Excessive emotions Excessive sensitivity to difficulties Low resistance to stress Unnecessary worry Hysterical reactions

MEN Testosterone Deficiency •

Character

• • • •

Mood • •

Stress

• •

Lack of mental firmness: lndecisive, hesitating Loss of self-confidence Lack of authority, submissiveness Chronic depression (may include crying spells, suicida! tendencies) Excessive anxiety, fear Excessive emotions Excessive sensitivity to difficulties Unnecessary worry

Progesterone deficiency • Emotional Anxiety, lack of inner peace Sleep

•

Superficial, nervous sleep

381

2. Overview of Physical Complaints of Hormone Deficiencies The table below is a quick overview of the main complaints a hormone deficient patient can have: PHYSICAL COMPLAINTS of HORMONE DEFICIENCIES Melatonin Deficiency •

Sleep

•

Muscles

•

Agitation Restless leQs syndrome at nig_ht Tense muscles, especially at night

Adult Growth Hormone/IGF-1 Deficiency • •

Energy/ Vitality

•

• •

Sleep

•

Exhaustion with poor or no recovery Difficulty in recovering when going late to bed (after midnight) Feeling of having collapsed into a state of profound physical degradation Feeling of rapidly aging Light sleep Excessive need for sleep - 9 hours or more

MSH deficiency Skin

•

Women Sexual Men

• • •

Easily sunburn Lower skin sensitivity to sexual caress lower orgasmic capacity Erectile dysfunction, especially poor firmness and duration of erection

Oxytocin deficiency Sexual

Women

•

Men

•

Absence or rareness of orgasm Few or no ejaculations

Vasopressin deficiency Thirst Urine

• • • •

Thirsty ali the time Drinks important quantities of water and other liquids Polyuria during the day (> 5x during daytime) Nocturia at night (� 2x/night)

Parathormone deficiency Bones Muscles, nerves

• • • •

Soft, painful bones Vertebral crushes, other pathological bone fractures Tensed muscles Spasmophilia

382

PHYSICAL COMPLAINTS of HORMONE DEFICIENCIES Thyroid Deficienc Health Appearance

• • • • •

Energy/ Vitality

• •

• • •

Temperature

• • • •

Hair

• • •

Head

• •

Skin

•

Nails

• •

Digestive

• • • •

Joints and muscles

• • •

Prone to ear, nose and throat infections Prone to weight gain, but difficult weight loss when dieting Overweight, obesity Swollen ali over Morning fatigue Lethargy, apathy Feels best in the evening and when physically or mentally active Tiredness when taking a rest lntolerance to cold and heat lnability to sweat in a hot climate Need to wear supplementary warm clothes in ali seasons Easily shivers (because of the cold) Poor circulation (white fingers in winter) Dry hair Slow growing hair Diffuse hair loss Diffuse headaches Migraine headaches Tinnitus (ringing in the ears) Dry skin Brittle, slow growing nails Bloated abdomen (increased risk of abnormally long colon at RX, dolichocolon) Dyspepsia (slow digestion) Constipation Muscle and joint stiffness upon waking Diffuse myalgia (muscle pains) and arthralgia Uoint pains), mostly in the morning Feet and leg cramps at night Carpa! tunnel syndrome Low back pain

Pregnenolone Deficiency in adults DIRECT SIGNS Energy

•

Skin

•

Moderate fatigue Dry skin (poor sebum production)

INDIRECT SIGNSn resulting from deficiencies in hormones derived from pregnenolone, mainly adrenal cortex and sex hormones

lnsulin deficiency Appetite

•

Weight

•

Thirst, urine

•

Sugar cravings WeiQht loss Excessive thirst, polydipsia, polyuria

383

PHVSICAL COMPLAINTS of HORMONE DEFICIENCIES Cortisol Deficiency

lntense hunger attacks Sweet cravings Nausea Lack of appetite (especially for meat) up to anorexia Salty food cravings Arthritis_(localized pain, joint deformities, etc.) Predisposition to inflammatory diseases Acute allergies: ear-nose-throat allergies (conjunctivitis, otitis, rhinitis, pharyngitis), asthma, food allergies Chronic inflammatory diseases: rheumatoid arthritis, connective tissue diseasesJe.g., lupus) lntolerance to medications

• • •

Food

•

•

Joints

• • •

lnflammations •

Medications

•

DHEA (& Androstenedione) Deficiency

Sex ual

I Women I Men

• •

Low sexual satisfaction Erectile dysfunction

Aldosterone Deficiency When STANDING UP OR SITTING •

Concentration

•

•

Food

•

Urine

•

Drowsiness, zombie-like feeling Feels better in head when laying flat on a bed or moving ali the time Salt and salty food cravings Thirsty, drinking water and other liquids ali the time Polyuria especially durinÇJ the day

PHYSICAL COMPLAINTS of HORMONE DEFICIENCIES in MEN Testosterone Deficiency Temperatur e Energy/ Vitality Muscles

Prostate

Sex

Hot flushes Sweating spells (mostly head and upper chest) • Persistent fatigue that increases with physical activity • Fatigability and lassitude • Decreased muscle mass and strength • Muscle pain • Prostate infections • Urination problems: difficulties to have a sufficient urine flow, painful urination, frequent night-time urination Decrease or absence of: • Sex drive • Erection volume, firmness, persistence, and frequency • Ejaculation volume • •

Progesterone deficiency

Prostate

• •

Enlarged prostate Difficulties to urinate

384

PHYSICAL COMPLAINTS of HORMONE DEFICIENCIES in WOMEN Estrogen Deficiency

Hot flushes with excessive night sweats (often more at night than during the day) Breasts Breast ptosis (droopy breasts) Menstrual cycle irregularities with polymenorrhea (shorter) Menstrual cycle and/or spanomenorrhea (longer cycles) Scant or no periods (hypo- or amenorrhea) Menstruation Vaginal dryness Vaginal itching (pruritus) Recurrent cystitis (bladder infections) Urological Urinary stress incontinence Prolapsed urinary bladder Progesterone Deficiency ( Estrogen excess) Premenstrual tension with painful swelling of breasts Breasts (breast tenderness) Menstrual cycle Premenstrual abdominal bloatinq Menstruation Menorrhagia (excessive menstruation) Face and chest

•

• •

•

•

• •

•

•

=

•

• •

Testosterone Deficiency Health Energy/ Vitality Sports Muscles

Hypochondriac or often sick Permanent fatigue that increases with physical activity Tires easily Lack of energy Lack of endurance when exercising Lack of interest in exercise Reduced muscle strength, volume Muscle pains Urinary incontinence (decreased smooth muscle tone) Vaqinal itchinq (pruritus), painful intercourse Decreased or absent: Libido Sensitivity of clitoris and nipple Orgasm • •

•

•

• •

•

•

Bladder

•

Vagina

•

Sex

• • •

385

3. Overview of Physical Signs of Hormone Deficiencies The principal physical signs of hormone deficiency are summarized in the following table: PHYSICAL SIGNS of HORMONE DEFICIENCIES Melatonin Deficiency Behavior Head and Body Face

• •

•

Muscle

•

Blood pressure

•

Nervous, anxious Prematurely aged appearance (pale, early greying, flabby muscles, etc.) Looking tired, impression of sleep loss (swollen lower eye-lids, etc.) Tense muscles Possibly high blood pressure

Adult Growth Hormone/IGF-1 deficiency:

worse facial and body_atrophy with IGF-1 deficiency Behavior Body Face Neck

• • • • • • • •

Hands

• •

•

Back

• •

Thighs: Feet

• • •

Nervous, overanxious Prematurely aged body Obese body Droopy eyelids Thin lips Sagging cheeks Thin jaw bones Loose skin folds under the chin Thin fingers (atrophic metacarpal bones) Prolonged pinched skin folds at the back of the hand Nails with striae (longitudinal fines) Atrophied palm and hypothenar eminence (diminished muscle tone at the palm of the hands, especially just beneath the forth and fifth (little) finger) Kyphosis (hunchback) lncreased fatty subscapular skin fold Sagging back muscles that look like drapery folds Sagging inner thighs Fatty "cushions" (fat deposits) above the knees Reduced foot arch, flat feet

I:

MSH deficienc\ Ha ir

•

Skin

•

Early graying hair, white, blond or red hair White face, white skin (Caucasian type)

Oxytocin deficiency Face

• •

Absence or rareness of a smile Pale cheeks that don't flush

386

PHVSICAL SIGNS of HORMONE DEFICIENCIES Vasopressin deficiency Face

•

Eyes

•

Tongue

•

•

Skin

•

Sharp wrinkles Sunken eyes, deep in orbit Tongue with teeth marks visible at tongue borders (tongue indentations) Tiny skin folds (caused by dehydration), more apparent when the skin is extended by pressure with a finger tip Prolonged stiff skin fold after pinching the skin of the back of the hand (skin tenting)

Parathormone deficiency in adults Bones

•

Muscles

•

Bowed back (kyphosis) Tensed muscles, especially of the chest, back and limbs

Hypothyroidism • •

Face

• •

Elbows

• • •

Hands

• • • •

Heart

• • •

Blood pressure

• •

Skin

•

Tendon reflexes

•

Puffy face Loss of outer third of the eyebrow Swollen eyelids (especially in the morning) Swollen lips, tongue Keratosis (dry, scaly skin) Cold hands Swollen hands Excessiva laxity of the fingers Vellowish palms (carotinemia) Brittle, slow growing nails Bradycardia Faint heart sounds High diastolic blood pressure Narrow differential blood pressure (small difference between systolic and diastolic blood pressure) Slow pulse rate Carotene color of hand palms and foot soles Dry skin on face, elbows, leg (follicular keratosis) Slow Achilles tendon reflexes (pathognomonic)

Pregnenolone Deficiency in adults DIRECT SIGNS Skin

• •

Joints

•

Dry skin Reduced mobility Pain with mobilization

INDIRECT SIGNS

resulting from deficiencies in hormones derived from preQnenolone lnsulin deficienc' Face Body

• • • •

Thin, hollow, emaciated face Loss of facial fat Thin body Low body weight, weight loss (BMI < 22 kg/m2)

387

PHYSICAL SIGNS of HORMONE DEFICIENCIES Cortisol Deficiency Behavior

•

•

Language

Physical appearance

•

• • •

Face

• • •

Eyes and eyelids

• • •

Abdomen

• •

Hands

• • • • •

Skin

•

Heart Blood pressure

• • •

Nervous, aggressive behavior with emotional outbursts of anQer or anxiety Accusatory or "being the victim" language Sharp verbal retorts with often melodramatic words that have negative and/or aggressive connotation ("terrible", "horrible", "impossible", etc.) Thin body Obese body (rarer: if sugar cravings predominate) Yellow-brownish face Hollow cheeks Brown (hyperpigmented) spots on face Painful sinus points Conjunctivitis (with inflamed eye globe) Dark circles under the eyes Bloated abdomen Pain upon abdominal palpation Contracted and painful colon (colitis) Palms: wet Palms: brownish skin folds Plaques of eczema, psoriasis; skin rashes (nettle rash ... ) Vitiligo (white depigmented spots) Cheloid (excessive) scar formation Irregular brown spots, melanoderma, darker brown birth spots (nevi) and scars, darker brown skin (in Caucasians), brown spots in buccal mucosa, brown skin folds Tachycardia Hypotension; orthostatic hypotension Possible hypertension in stressful situations

DHEA Deficiency •

•

Armpit Pubis

• • •

Few or scarcer axillarv hair Few or scarcer pubic hair Poor or decreased pubic fat (women)

Aldosterone Deficiency

Low Blood Pressure

Face

•

Expression

•

Blood

•

•

pressure Face Dehydration Eyes

Pale face A drowsy, absent-minded look Low blood pressure (Hypotension): Under 11 0/60 mm Hg Orthostatic hypotension Hollow face Sharp wrinkles Sunken eyeballs Soft eyes (eye balls feel soft under pressure) •

• • • •

388

PHYSICAL SIGNS of HORMONE DEFICIENCIES specific to WOMEN Estrogen Deficiency •

Pale face

Hollow face Dry mucous membranas of eyes, mouth Small, sharp wrinkles above upper lip & at the corner of the eyes Micromastia (Small breasts) Breasts Breast ptosis (Droopy breasts) Hands Small, sharp wrinkles on hand palms Pale skin Skin Dry, dehydrated skin Small, sharp wrinkles Vagina Atrophied vaginal mucous membranas resulting in a dry vagina Uterus Atrophied endometrium (uterine lining) Progesterone Deficiency ( Estrogen excess) Reddish face Face Swollen face Macromastia (enlarged breasts) Breast Mammary edema, mastalgia (swollen, painful breasts) Breast cvsts Skin Swollen skin Endometrial hyperplasia (glandulocystic) Uterus Fibroids Feet Swollen feet, ankles Face

• •

•

•

•

•

• • •

•

•

=

• •

• •

•

•

•

•

•

Testosterone Deficiency Physical appearance Face

•

Paie Slumped, fragile, older looking (adult-onset testosterone deficiency), younger-looking (puberty-onset testosterone deficiency)

•

Pale face

•

• •

Eyes

•

Limbs, ..

•

Abdomen

•

Thighs

•

Legs

• •

Body hair

• •

Vascular

•

Muscle

•

Clitoris

•

Hypotonic face (poorly muscled) Small wrinkles at corner of eyes. Small vertical wrinkles above lips Dry eyes

Poor muscle volume lncreased abdominal fat Cellulite Varicose veins Lack of body hair: Puberty type: small patches of dense body hair Adult type: less dense but larger patches of body hair Bruises easily Poor or reduced muscle volume, tone and strength Smaller clitoris

389

PHYSICAL SIGNS of HORMONE DEFICIENCIES specific to MEN Testosterone Deficiencv Physical appearance Fat

• • • • • •

Face

• • •

Eyes Hands

• • •

Chest

•

Abdomen

•

Penis

•

•

•

Testicles

•

Bodv hair

•

Anus

•

Thighs

•

Legs Voice Skin Prostate

• • • • • • •

Paie Slumped, older looking (adult-onset testosterone deficiency) Younoer lookino (oubertv-onset testosterone deficiencv Obesitv, esoeciallv on the breasts, the abdomen, the hips Pai e

Lacks muscle tone Small wrinkles at the corner of the eyes Small vertical wrinkles above the lips Poorlv developed facial hair Dry eyes(conjunctiva sicca) Small wrinkles on palms of hand Lonoitudinal lines on nails Gvnecomastia (enlaroed breasts) lncreased abdominal fat Pale, dry glans penis Loose prepuce Small, flaccid, atrophied Peyronie's disease Hvootroohic, flaccid (small, too soft) Lack or loss of (sexual) body hair Hemorrhoids Cellulite Hair loss on legs especially on externai sides Varicoseveins Hioher, more anxious tone Pale skin Dry, thin (atrophic) skin Prostate hypertrophy or atrophy Prostatitis

Proaesterone deficiencv Exoressed as sians of dihvdrotestosterone excess

Scalp hair

•

Male oattern baldness

Exoressed as sians of estroaen excess

Breasts

•

Muscles

•

Prostate

•

Enlaroed breasts (ovnecomastia) Tense muscles Hard and enlarged prostate (benign prostate hypertrophy)

390

4. Overview of Disease Susceptibility The following table is an overview of the most important age-related diseases each hormone deficiency could promete as suggested by animal and human studies:

Cardiovascular

Hormone Deficiency

c o

.t1l E

'(jj

"C

�

c Q)

Q)

:g.

1 I

t:: .c

t <(

::::::

-

:::1 � cn t1l c·- -�

�-ó 't1l

c t1l o o '- o o>-

ü::i!

Q) '-

:::1

Cancer

Neuropsy. cn 'Q)

Breast

o c

&

'«i prostate u.. cancer t:: t1l Q) I

t1l

o '-

Obesity

111 "iii

Diabetes

o ... o

a.

o

Q) .. 111 o

Q) .c

õ

Cl c :i c ·;: :: c :i! C/)

ui cn cn

.Q C' o

E Q) ::2: I "'

·a; E 'ãi

�

-

:c t1l cn cn

c o

'(jj cn Q) 'a. Q) o

�

0

c Q) ·x

.<: N

c

<(

<(

GH deficiency

+

+

+

+

+

+

+ (Dtype 2)

+

+

+?

+

+

IGF-1 deficiency

+

+

+

+

+

+

+ (type 1 & 2)

+

+

+?

+

+

+

+

+? (D1ype2)

+?

+

+

+?

+

+

+?

+

+

MSH-Iike deficiency Vasopressin def. Oxytocin defic. Melatonin defic .. Thyroid deficiency Calcitonin defic. Parathormone def.

Pregnenolone det. Cortisol def. DHEA deficiency Aldosterone def. lnsulin deficiency c Q)

Estrogen def.

+

-

+

+

+

+

+

+

+?

+?

+

+ (Dtype2)

+

+

+

+

+?

+

+

+ (Dtype2)

-

+

+? +?

+

+

-

+

+ +? +

-

+

+

+

+?

+

+

+

+

+

+

+

+

+?

-

deficiency

Progesterone deficiency

+

+

Progesterone

Testosterone deficiency

+

+

E deficiency o 3: Testosterone c Q) :E

+?

+

+?

+?

+

+

-

-

+ (Dtype2)

+

+?

+

+?

+

+

+

+

+

+

+ +

+ (Dtype 1)

-

+?

+

+?

+?

+

+?

+

+

+

+

+?

+

+

+?

+

+ (Dtype2)

+

+

+

+

+

+

+

+?

+

+

+?

+ (Dtype2)

+

+

+

+

+?

+?

+

Code: The "+ " sign signifies that there is data suggesting that a deficiency or lower leveis of the hormone are associated with an increased risk of the disease. The "-" sign signifies that scientific researchers generally report that a deficiency or lower leveis of the hormone reduce the risk of disease. "?" or brackets " ( )" signify that there is doubt or controversy about the information.

391

5. Overview of the Laboratory Tests: The lnitial Hormone Assessment The following charts contain lhe recommended lab tests for lhe initial endocrine assessment. As lhe focus of lhe Hormone handbook is hormone therapies, lhe chart is restricted to tests directly related to hormones, but usually a series of other lab tests are necessary such as a complete blood count, lipid panel, nutritional analyses, cancer screening tests, etc. Before reading the table below, please note the following: BLOOD SAMPLE: When and how to take lhe blood sample? Blood for the endocrine tests should be taken around 7-8 AM on an empty stomach except for water (lhe patient should drink about two-thirds of a liter of water (3 cups) before blood withdrawal to avoid blood concentration). COLUMNS •

Deficient or pathological levels: reflect a hormone deficiency or other endocrine pathology. However, for some of these tests such as serum TSH, a high levei reflects an endocrine deficiency.

•

Optimal levels: reflect lhe appropriate healthy endocrine status for adults of average-size and weight

(70-80 kg men,

55-65 kg women). For anabolic hormones such as IGF-1, testosterone,

DHEA, etc., values should be higher for tall and big individuais and lower for small and thin persons. The estimated value is based on lhe personal experience of lhe author and of some of his colleagues. not on thoroughly investigated studies. The optimal values should therefore not be considered as dogmatic leveis. For many patients lhe optimal value for each test may slightly differ from lhe one indicated, as individual differences in metabolism and hormone receptors may require different leveis. Nevertheless, these subjective values will often be helpful for lhe physician in his practice as patients whose leveis are at lhe optimal level or near it will rarely present symptoms or signs of lhe corresponding hormone deficiency, excess or imbalance. •

Reference leveis (or 95% confidence intervals) of young adults reflect endocrine states found in 95% of a young adult population, patients or volunteers. The young adult population is considered as lhe reference range that is closest to the optimal one, although many leveis, borderline low or borderline high, found in lhe reference range of young adults, do not correspond to values of optimal health.

•

Test value: A distinction is made between essential tests, i.e., tests to do in case of a limited budget, as they are lhe mos! helpful for diagnosis or follow-up. The remaining tests, auxiliary tests, may be of interest for lhe diagnosis, but are generally not as essential for hormone diagnosis or treatment. Again this evaluation is based on lhe author's personal experience.

•

Sex differences: Whenever sex differences exist for lhe optimal levels, deficiency and reference ranges, they are listed separately.

•

Bright yellow highlighted areas: these areas indicate lhe most important complaints, signs, tests or treatments related to lhe hormone (deficiency) following lhe author's experience

•

Laboratory tests: values in grams are typed in standard print, while va/ues in moles are typed in italic to improve discrimination.

392

Tables:

Laboratory tests for detection ofhormone deficiencies: lnitial assessment SERUM TESTS for 80TH GENDERS

Endogenous

HORMONE STATUS

Vaso-

pressin

Probably Deficient

TEST

&for Pathological

Trend Vasopressin TSH

hormones

Low

-ATG

-TSI• Thyroglobulin TSH after TRH stimulation1

hormone Pregnenolone

steroids

High or Low

Calcium

High

Pregnenolone

sulfate

{after activity) Sodium

Total cortisol steroids

1.8-3.7 ng/L 180-370 pg/dl

0-1.2

1.3-1.8

0.8-1.8 nq/dl

at8AM Free cortisol�

Low High

Low

CBG-Transcortin Glucose

(fasting)

10- 20X

o o o

<10 5-9.9 x the

or0-2 x initial TSH (15· init. TSH;

10-28 pmoi/L

Essential

Essential

30' after TRH)

10-55 pq/ml 8.6 - 10.5 mg/dl

:'>2.25

2.4

2.1 - 2.7 mmoi/L

70

90-100

40 -120 ng/ml

285-315

125-380 nmoi/L

0-10 0-100

>15 >150

0-2.8

> 4.2

141 4.3 18 180

0-360

550

0-13

20

10-30 ng/ml

55

28-83 nmoi/L

30 80-95

20-50 mg/L 60-11 O mg/dl

>40 Hi� h 0-80 or >95

High or

0-4.4

Low

4.4-5.2

Hb A1c

High

lnsulin

High

0-3 or>10

4.5-6 4- 9

0-25or >70

30-65

or

Essential Essential Essential

4-30 ng/dl 40-300 pg/ml Auxiliary

0-138 >4.8 0-13 0-130

0-36

Low

2-20 mU/L Auxiliary (mean= 16 mU/L}

30 9.5

or > 5.2 0-4.4 or> 6

(fasting)

0-50 U/ml Essential 0-50 U/ml Essential 0-10 U/ml Auxiliary 0-25 ng/mL-11g/L Auxiliary

0-20 $9.0

0-220

Low

Low

>

o-

Low

at8AM

lnsulin

0.4-2.5 miU/L (�IU/mL) Essential

2.8-5.7 pmoi/L

16.7-23

Test

V alue

ofyoung adults O to4.7 QQ!ml Auxiliary O to4.3 pmoi/L

3.9-5.2

>15 >15 >2 >15

Hiqh High High High

Hiqh

Potassium

Gluco-

Range

0-3.7 0-15.5

Parathormone*

Aldosterone Mineral

Low

2-3 1.8-2.8 1 2.5-3.4 250-340

Reference

Th. antibodies -ATPO

Parat-

0-1.5 o- 1.4 >2.5 0-2.4 0-240

High

Free T4 Thyroid

Leveis

Low

Free T3

Optimal

1.1-8.3 nmoi/L

136-145 I mEq/L Essential 3.5-5.1 1 mmoi!L Auxiliary 10-25 119/dl 100-250 ng/ml Essential 275-690 nmoi/L

3.3-6.1 mmoi/L

Essential Essential Essential

4-7% Auxiliary 4-25 11IU/ml Essential 30-160 pmoi/L

or obese

& elderly

Note: 1 TSH after an intravenous injection of TRH: Hvpothvroidism of pituitary origin is characterized by a serum TSH of /ess than 2 times the initia/ TSH 15 to 30' after TRH and/or a va/ue above the 20 JliU/ml, while hvpothalamic hvpothvroidism is characterized by a TSH greater than 10 times the initial value;

2

The free cortisol is best calculated from the cortisoi/CBG ratio; 3 TSI stands for thyroid stimulating

immunog/obulins.

393

Additional SERUM TESTS for WOMEN

Probably

Endogenous HORMONE

TEST

STATUS

Deficient &for

GH stimulated

Growth hormone

(GH)-

by ArginineVasopressin

Low

IGF-1

Low

IGF-1

IGF-BP-3

of young adults

0-15

>25

>5 or > 10 ng/ml

0-45

>90

> 15 or >30 miU/L

0-180

220-300

114-492 �g/L

0-24

29-40

15-65 nmoi/L

>4000

3000

Pathological Trend

High

Leveis

>

MSH

Alpha-MSH

Med

Oxytocin

Oxytocin

Med

DHEA sulfate

(DHEAs) Androstenedione Total testosterone

Low

Low Low

Androgens Free testosterone

Low

Androstanediol

Low

glucuronide SHBG

(orTeBG)

High

Reference Range Optimal

100

75

ng/ml

ng/ml

14

3-30 pg/ml

8

1.8-18 pmol/ml

7-15

1-22 pg/ml

7-18

1-22.2 pmol/1

280 2800

800-4800 ng/ml

0-6.9

9.7

2.8-16.6 f.lmoi!L

80-480

9716

0-1.8

2.2-2.5

1.0-3.5 ng/ml

0-7.0

7.7-8.7

3.5-12.2 nmoi/L

Auxiliary Auxiliary

Essential

Auxiliary

10-50 nQ/dL

0-25

35

0-250

350

100-500 pQ/mL

0-0.9

1.2

0.3-1.7 nmoi/L

0-5

8

Essential

2-15 pg/ml

0.007-0.052 nmo/1 L

Auxiliary

7-52 pmoi/L

0-17

28

0-2

3-3.9

0.1-6.0 ng/ml

0-7

10-23

0.3-20 nmoi/L

:2: 7.0

6.1

3.8-7.4 mg/ L

;? 75

65

41-79 pmoi/L

394

Essential

2800-16600 nmoi/L

0-6900

0.028

Essential

�g/dl

0-200 0-2000

0.017

Auxiliary

50-100 nmoi/L

0- 4

0-

Value

2000-4000 �g/ 1

0- 6

0- 5

Test

Essential Essential

Additional SERUM TESTS for WOMEN

Probably

Endogenous HORMONE

Deficient &/or

TEST

Pathological

STATUS

Trend

Leveis

> 30 Prolactin

High

> >

Too low or too high

LH Female Hormones PREme-

FSH

no12ausal Women: Check the 2151 dayof

a 28-day menstrual cycle

1.3

1300

200800

Test

Value

1-24 ng/mL 0.4-1. o nmoi/L

Auxiliary

40 -1000 pmoi/L

<1 (hypo·

halamlic insuff.)

or >12

2-4

0.2-12 lU/L, miU/mL

Auxiliary

3-5

2-131U/L, miU/mL

Essential

I(pêriménop.) <1 (hypo thalamlic def.) or >10

Estradiol (E2, luteal

High

phase) Estrone

(Et)

0-120

150

100-21O pg/mL

0-0.44

0.55

0.37-0.77 nmoi/L

0-440

550

370-770 pmoi/L

0-60

100

40-200 pg/mL

0-0.2

0.37

0.15-0.74 nmoi/L

0-220

370

150-740 pmoi/L

6.1

3.8-7.4 mg/L

65

41-79 pmoi/L

0-10

13-23

3.0-27 ng/mL

0-32

40-75

10-86 nmoi/L

High or low

> 20

2-20

> 30

15-70

0-120

150

10-35 pg/mL

High

0-0.44

0.55

0.035-0.130 nmoi/L

0-440

550

35-130 pmoi/L

High

0-5.1 or (TeBG)

Low

�8.4 0-55 or :?90

Progesterone (luteal

Low

phase) LH FSH

Estradiol

no!;!ausal Women: Checkblood

5-19 0.2-0.8

of young adults

(pêriménop.)

SHBG

POSTme-

Reference Range Optimal

Estrone (Et)

High

any day

(TeBG)

Low

Auxiliary

20-1381U/L, miU/mL

Essential

100 0.37

0.037- 0.22 nmoi/L

0-222

370

37-222 pmoi/L

6.1

3.8-7.4 mg/L

65

41-79 pmoi/L

0-55 or :?90

395

Essential

9-38 lU/L, miU/mL

0-60

o r�8.4

Auxiliary

Essential

0-0.22

0-5.1 SHBG

Essential

Essential

10-60 pQ/mL Auxiliary

Essential

Additional SERUM TESTS for MEN Endogenous

HORMONE

TEST

Trend

STATUS

IGF-1 Growth

Probably Deficient &for Pathological

(somatomedin C)

Leveis

Low

hormone

(GH)IGF-1

High

MSH

Alpha-MSH

Med

Oxytocin

Oxytocin

Med

Proge-

Progesterone

sterone

at 8AM

Adrenal And rogen s

DHEA sulfate

(DHEAs) Prolactin

Low

High

0-33

39-46

Testosterone Total Testosterone Free

Estradiol (E2)

Estrone (Et) Androstanediol glucuron.

3000

> 100

75

High

High Low

SHBG (TeBG) High Total PSA

High

Free PSA

Low

of young adults 114-492 �g/1, ng/ ml Essential 15-65 nmoi/L 2.0-4.0 mÇJ/L 2000-4000 �g/1 Essential

ng/ml 50-100 nmoi/L

20

10-45 pÇJ/ml

12

6-27 pmol!ml

7-15

1-17 pg/ml

7-18

1-17.1 pmol/1

0-0.9

1.2

0.1-1.3 ng/ml

0-2.9

3.8

0.3-4.1 nmoi/L

Auxiliary Auxiliary Auxiliary

200-61o IJQ/dl

0-300

400

0-3000

4000

0-10

14

0.7-21.2 Jimoi/L

0-1000

1400

700-21200 nmoi/L

�20

10

870

435

45-825 pmoi/L

2-4

1.2-7.4 miU/ml Auxiliary

2

0-550

700

0-5500

7000

0-19

24

0-18

25-35

0-180

250-350

0-0.6

0.8-1.2

�32

25

�0.12

0.09

�120

90

�50

40

�0.19

0.15

2000-6100 ng/ml

1-8 miU/ml Essential 300-1000 ng/dl 3000-1 OOOOpg/mL Essential

10-35 nmoi/L 5-25 ng/dl 50-250 pÇJ/ml Auxiliary 0.2-0.9nmoi/L 10-45 pg/ml o. 04-0.17 nmoi/L Essential

40-170 pmoi/L 15-65 pg/ml 0.05-0.24 nmoi/L Auxiliary

150

55-240 pmoi/L

0-13

15-18

3.4-22 ng/ml

0-43

50-59

11-73 nmoi/L

�3.7

2.3-2.8

1.9-5.1 mg/L

�40

25-30

2D-55 pmoi/L

>5:

0-1.8

0-40y: 0-1.8 ng/ml

0-10% =>

higher PC risk

396

> 70 y: 0-6.5 IJg/L >25%:

Essential

1-19 ng/ml Auxiliary

�190

PC risk Ratio free/total PSA =

Test Value

0- 6

or >7 (testis insuff.)

Low

Reference Range

0-10

<1 (hypothalamlic def.)

Low

3

>4000

<1 (hypothalamlic def.) o r >6 (testis insuff.)

FSH

Androgens

300-350

0-5

Low

LH

Testicular

0-250

>4

IGF-BP-3

Optimal

>25%: no or very

low PC risk-

Essential Essential Essential

Essential

24-HOUR URINE TESTS for both genders

Probably &for

DIETARY or HORMONE

URINE

Deficient

TEST

Pathological

STATUS

Trend Volume

Diet

Caleium Potassium Magnesium Phosphorus

Hormone

Low

GH

{GH) Melatonin

6-sulfatoxymelatonin

Leveis

Low- 0-800 or or hiÇJh >3000 Low 0-4 Low 0-45 Low 0- 45 Low 0-45

Growth

Low

{fT3)

Low

Free T4

{fT4)

Low

Thyroid Hormones

- normal salt diet -low-salt Mineral steroids

Gl c:

(urinary Na+ <100)

Gl .. UI

-high-salt diet

o ...

o "C

(urinary C( Na+>200) Glucosteroids

Free cortisol

Low or high

Essential

5-6 65 65 65

3.0-8.0 mmol/24h 35-80 mmol/24h 22-125 mmol/24h 22-42 mmol/24h

02000

25004500

500-6000 pg/24h

0-670

830 -1500

170-2000 piU/24h

Auxiliary to Essential

0-35

>40

10-55 ll9124h

Essential

0-1300

0-1800 >200

Low Low or normal

Low

Test Value

600-2500 mU24h

0-1.4

Sodium

of young adults

1600

0-0.8 Free T3

Reference Range Optimal

0.5-1. 7 J.LQ/24h 0.9-1.3 1400800-2500pmol/24h 2000 0.4-2.5 J.LQ/24h 1.6-1.9 2000550-3160 pmol/24h 2500 160 100-220 mmol/24h

0-8

13

5-20 llQ/24h

0-2.2

3.6

1.4- 5.5 pmol/24h

0-20

>20

17-40 ll9124h

0-5.5

>5.5

4.7-11.1 pmol/24h

0-4

9

0-1.1

2.5

0-40

70

0-11

19 19000

0-11000

397

Essential Essential Essential Essential

Essential

Essential Essential Essential

-

0-6 IJÇJ/24h 0-1.7 pmol/24h

-

10-100 IJQ/24h 2.8-27.5J.Lmol/24h �750-27500nmol/24h

Auxiliary

Additional 24-HOUR URINE TESTS for WOMEN

Probably

MUSCLE or HORMONE

URINE

Deficient &/or

TEST

Pathological

STATUS Muscle mass

Creatinine

Gluco-

17-OH-steroids

steroids

total (gas chrom.) 17-ketosteroids total (gas chrom.) - DHEA

Androgens

- Etiocholanolone

Reference Range Optimal

Trend

Leveis

Too low ortoo high

0-1.0 or >1.6

1.1-1.2

0.80-1.40 g/24h

0-0.9 or >1.4

1.0

0.7-1.3 pmol/24h

0-5.5

6.5-7

Low Low Low Low

0-15

18-19

0-5.5

6.5-7

2.9-8.9 mQ/24h

23.5

10-30 J1mOI!24h

0-0.35

0.45

0-0.65 mg/24h

0-1.2

1.6

0-2.3 J1mol/24h

0-1.6

2

0-5.5

6.8

0-1.7

2.2

O. 7-2.8 mg/24h

0-5.8

7.5

2.4-9.6 J1mOI!24h

0-12

15-17

3-23 J.lQ/24h

0-0.042

0.050.06

0.01-0.08 J1mol/24h

Testosterone

Low

Female

2-0H-estrone

Low

0-5

>5

Hormones

16-alpha-OH-

High

> 2.0

0-1.5

menstrual cycle}

Low

3.7-8.5 mg/24h 10-23 pmol/24h

0-19.0

Low

Pregnandiol 1 (21" day of

0-4

5-6

0-12.5

15.518.5

398

Test Value

Essential

- Androsterone

estrone

of young adults

0.7-2.7 mg/24h 2.4-9.3jl_mol/24h

Essential Essential Auxiliary Auxiliary Auxiliary

Auxiliary

2 -1o J.lQ/24h Auxiliary 1.2-2.0 J.lg/24h Essential 2-7 mg/24h 3-21.8 pmol/24h

Auxiliary

Additional 24-HOUR URINE TESTS for MEN

Probably

MUSCLE or HORMONE

Deficient &for

URINE

Pathological

TEST

STATUS Muscle mass

Creatinine

Progeste-

Pregnandiol

rone

(gas chromatogr.)

Glucosteroids

Androgens

Low

(gas chromat.)

-DHEA

Low Low

- Etiocholanolone

Testicular

0-1.2 or > 2.3

Low

17-ketosteroids

Androgens

Leveis

Too low or too h ig h

17-0H-steroids total

total Adrenal

Trend

Low

- Androsterone

Low

Testosterone

Low

0-1.1 or >

2. 0

Reference Range Optimal

of young adults

1.6-1.8

1.04-2.19 g/24h

1.4-1.6

0.9-1.9 f.Jmoi!L

Essential

0-0.5

0.65

0.16-0.86 mg/24h

0-1.6

2.0

0.5-2.7 f.Jmol/24h

0-10

13

5.8 -15.8 mg/24h

0- 27.6

36.0

16.0-43.6pmo//24h

0-9

11-12

4.7-13.3 mg/24h

0-30

38-41

16 -46 f.JmOI!24h

0-0.55

0.7

0-1.0 mg/24h

1.9 0-2.9

2.4

0-3.5 llmol/24h

3.5

0.09-4.6 mg/24h

0-8.5

12

O. 31-15.7 pmol/24h

0-2.9

3.5

1.10-4.09 mg/24h

0-8.5

12

3.8- 14.1pmol/24h

120

140

50-200 jlg/24h

<0.40

0.5

0. 17-0.70f.lmol/24h

<

399

Test Value

Auxiliary Essential Essential Auxiliary Auxiliary Auxiliary Auxiliary

6. Overview of Laboratory Tests: The Follow-up of Hormone Therapies

In the follow-up, every three to nine months, some tests should be repeated. Not ali of the tests that are useful for the initial lab assessment are necessary to repeat. Which tests need to be done? Ali tests that were pathological should be repeated, as well as the hormone tests needed to monitor the patient's hormone treatment.

A certain number of cheap, basic lab tests such as

serum cholesterol, glucose leveis, even if previously normal, deserve to be regularly checked too. How frequently should important tests be repeated? Every four to nine months. A more extensive, comprehensive battery of lab tests should be done once a year including cancer screening tests. Tests such as serum or urinary cortisol, as well total as free cortisol, and even its urinary 17hydroxysteroid metabolites, hardly poduce any meaningful results in the follow-up because of the short half-life of the hormone compounds administered. When and how to do blood tests? Most hormonal blood tests have to be taken in the morning. Just before the tests, the patient must avoid taking any medication, but should take them just after. Here too, the patient should be fasting before the blood test. Drinking two-thirds of a liter of water half-an-hour to two hours before the blood test is recommended to avoid blood concentration, which may lead to misinterpretation of hormone tests. Tests such as serum thyroid hormone and cortisol must be taken in the morning. For DHEA sulphate and testosterone-related tests, the patient should switch over from the habitual morning intake of oral DHEA and transdermal testosterone to taking them in the evening three days prior to testing. The change of intake time permits to measure with more accuracy the mean 24-hour values of serum testosterone and DHEA-sulphate, which are found about 8-14 hours after administration of these medications. The follow-up tests are not limited to the ones listed in the following tables. lf, for instance, a high serum levei of thyroid antibodies or prolactin has been found in a patient, it is wise to regularly check these leveis and check if the treatment efficiently lowers them.

400

The following charts are overviews of the most useful endocrine lab tests (highlighted in yellow) and the less useful tests (white background). FOLLOW-UP SERUM TESTS for 80TH GENDERS

Probably

HORMONE

SERUM

THERAPY

TEST

Still Deficient &/

or Pathological

Trend TSH

Oral THYROID

Free T3

High Low

HORMONES Free T4

Subcutaneous PARATHORMONE

Oral

Parathormone*

Caleium

Oral GLUCOSTEROIDS

(Hydrocortisone}1

High High High

or DIET

(type2 diabetes)

250-340

180-370 pg/dl

0-3.7

3.9-5.2

2.8-5.7 pmoi/L

0-1.2

1.3-1.8

0-15.5

16.7-23.2

30

10-55 pg/ml

9.5

8.6 - 10.5 mg/dl

2.4

�2.25 0-265

340-380

4.3

Free

(calculatedf Transcortin

Low High

(fasting)3

High

lnsulin

(fasting)

High High

150-450

mmoi/L nmoi/L

136-145 mEq/L

mmoi/L

3.5-5.1mEq/L

0-130

180

100-250 ng/ml

0-360

550

275-690

0-13

20

10-30 ng/ml

0-36

55

28-83

>40

30 4

> 7.2 Hypoglycemic

80-130/ 4

90-150

4.4-7.2 5.0-8.:t

>6 " 0-3 or >10

4.5-6

0-25or >7(/

30-65

4-9

Value

(& when

to test)

Essential

(to test 24h

after last intake) Essential Essential Essential

24h after Auxilia_ry_

10-25 �g/dl

18

ísk: >8.3

HbA1c

2.1 - 2.7

0-13

>130-150 Glucose

0.8-1.8 ng/dl

10.3-27.7 pmoi/L

0-20

>4.8

cortisol

1.8-3.7 ng/L

�9.0

High

Subcutaneous

(type 1 diabetes)

0-240

Potassium

Low

0.4-2.5 mU/ml

1 2.5-3.4

141

Total

of young adults

>2.5

0-138

cortisol

Range

0-2.4

Low

(CBG) INSULIN

Leveis

Sodium

FLUDROCORTISONE

Low

Reference Optimal

nmoi/L

nmoi/L

Auxiliary (test 824h

after intake}3

20-50 mg/L 70-105 mg/dl Esseritiat

(to test fasting in the 4-7% morning) 4-25 �IU/ml

3.9-5.8

mmoi/L

30- 160 pmoi/L

Notes: 1 The serum leveis of total and free cortisol are not helpful for the fol/ow-up of treatments with synthetic derivatives such as prednisolone and methyl-prednisolone becase they are not measured by the lab tests. 2 The free cortisol is calculated from the ratio cortisoi/CBG with a complicated formula to test 8 to 24h after intake to check the degree of inhibition of endogenous cortisol production. 8oth the serum total and free cortisol tests are not of great help in the fol/ow-up of a glucocorticoid treatment. 3 Avoid hypoglycaemia (0-80 mg/dL fasting serum glucose and a HbA 1C below the 4.4 mmoVI). 4 The acceptable upper limit of the fasting blood glucose for patients with diabetes who are at increased risk of hypoglycemia is higher than for people with stable diabetes. 5 Value typical for insulin resistance

401

Additional FOLLOW-UP SERUM TESTS in WOMEN

Probably HORMONE THERAPV

SERUM

Still Deficient

or Pathological

TEST

Trend

Subcutaneous

0-180

Low

IGF-1

and/or IGF-1

0-25 IGF-BP-3 (binding protein)

DHEA sulfate

(DHEAs)

Oral

High

Androstane-

Total testosterone

Transdermal or lntramuscular Testosterone

Testosterone free Androstanediol glucuron. SHBG

>

of young adults llQ/L ng/ml

Essential test

114-492

300

30-40 3000

15-65 nmoi/L

llQ/1 ng/ml

1300-5500

75 280

0-2000

2800

0-6.9

9.7

0-6900

9716

Low

0-2.5

3

0-25

35

Low

0-250

350

1 00-500 pg/ml

0-0.9

1.2

0.3-1.7 nmoi/L

0-5

8

0-0.017

0.03

Low

Low

32- 135 nmoi/L 80-480 IJQ/dl

ng/ml

800-4800

2.8-16.6 J1moi/L 2800-16600 nmoi!L

ng/ml

1-5 10-50

ng/dl

2-15 pQ/mL O. O1-0. 05 nmoi/L

0-17

28

0-2

3-3.9

0.1-6.0

0-7

10-23

0.3-20 nmoi/L

0-5.1 or � 8.4

6.1

Low

7-52 pmoi/L

ng/ml

3.8-7.4

mg/L

0-55orc90

65

41-79 pmoi/L

0-120

150

100-210 pg/ml

0-0.44

0.55

0.37-0.77 nmoi/L

0-440

550

370-770pmoi!L

0-60

100

0-0.2

0.37

O. 15-0.74 nmoi/L

Estradiol

0-220

370

150-740 pmoi/L

and Oral or Vaginal

0-5.1 or > 8.4

6.1

3.8-7.4

0-55orc90

65

41-79 pmoi/L

Estradiol

Transdermal

Estrone

SHBG

(E1)

(E1)

(TeBG)

High High Low

Progesterone Progesterone1

(P4)

0-1.2

1.4-15

0-4

4.6-50

Low

40-200

pQ/mL

mg/L

Premenopause: 3.0-27 ng/ml Postmenopause: 0-1.0 ng/ml Pre: 10-86 nmoi/L Post: 0-3.3 nmoi!L

Note:

Value

(& when to test)

100

High

(TeBG)

>4000

220-

Reference Range

Q-200

DHEA

diol glucuron.

Optimal

Leveis

Growth Hormone

&!

(to test 8-24 h after lastGH injection) Essential test

(to check 8-14 h after last intake) Essential & Auxiliary tests: to check 8-14 h after transderm. testost., or 3 wks after 50mg testes!. enanthate injection Essential & Auxiliary tests (ideal, but not always possible: 8-24 h after las! treatment) Auxiliary (to check 8-24 hours after las! intake)

1 The serum levei of progesterone· provides on/y rudimentary information on an on-going oral or vaginal

progesterone therapy, as progesterone being too weakly bound to its plasma transporting binding globulin, transcortin, in blood, does not remain measurable in the blood long enough after administration. Jt is difficult if not impossible, to measure the average

24 hour serum leve/ of progesterone during an oral treatment.

402

Additional FOLLOW-UP SERUM TESTS in MEN

Probably HORMONE THERAPY

SERUM TEST

Still Deficient Pathological

Trend Subcutaneous Growth Hormone and/or IGF-1

IGF-1 (somatomedin C)

Low

Leveis 0-250

0-33 >4

IGF-BP-3

High

>4000 >

Transdermal Progesterone

Oral

Progesterone

(P4) Progesterone

Progesterone

(P4)

Men: Oral* & Transdermal Progesterone

Estradiol (E2)

Oral or transdermal DHEA

DHEA sulfate

(DHEAs)

Testosterone Total Testosterone Free

Estradiol (E2)

Transdermal or intramuscular Testosterone

Estrone (E1) Androstanediol glucur. SHBG

{TeBG)

Low Low

High

Low

Low

Low

High

High

Low

High

Total PSA

High

Free PSA

Low

Free PSA I Total PSA

100

Low

300-350

39-46 3

Reference

Value

Range

(& when

of young adults

to test) Essential

114-492 119/l,n9/ ml

(check 8-

15-64 nmoi/L

24 h after

2.0-4.0 mg/L

last inject-

3000

2020-3990 1-lQ/1

tion; 119/l

75

50-100 nmoi/L

n9/ml)

0-0.9

1.2-1.5

0.1-1.3 ng/ml

0-2.9

3.8- 5

0.32-4.1 nmoi/L

0-0.9

1.2-4

0.1-1.3 ng/ml

0-2.9

3.8-13.3

0.3 -4.1 nmoi/L

<::32

25

c0.12 c 120

0.09 90

=

Auxiliary (check 8-

14 h after)

10-45 pg/ml

Essential (check 8-

O. 04-0.17

nmoi/L 40-170 pmoi/L

14 h after)

0-300

400

200 - 61 O 1-19/dl

Essential

0-3000

4000

2000-6100 nQ/ml

(to check 8-

0-10 0-1000

14 1400

0.7-21.2 J,1moi/L 700-21200 nmoi!L

14 h after

0-550

700

300-1000 ng/dl

Essential

0-5500

7000

0-19

24

0-18

25-35

0-180

250-350

50-250 pg/ml

0-0.6

0.8-1.2

0.2-0.9nmoi/L

;::: 32

25

c0.12 > 120

0.09 90

ther.)

& auxiliary

3000-1OOOOpg/mL

tests: to

10-35 nmoi/L 5-25 ng/dl

check

8-14 h after last transdermal

10-45 pg/ml testosterone

nmoi/L 40-170 pmo//L

treatment,

O. 04-0.17

;::: 50

40

0.15 150

0.05-0.24 nmoi/L 55-240 pmoi/L

testosterone

0-13

15-18

3.4-22 ng/ml

injection, or

0-43

50-59

11-73 nmoi/L

;::: 3.7

2.3-2.8

1.9-5.1 mg/L

c40

25-30

20-55 pmoi/L

0-1.8

0-40 y: 0-1.8 ng/ml >70 y: 0-6.5 1-lQ/L

>5: PC risk 0-10%

=>hi9h PC risk

>25%: =>no or very low PC risk

15-65 pg/ml

or 10-12 days after a

c0.19 c190

free PSA:

Ratio

Optimal

250 m9 enanthate

6 days after a 100 m9 injestion of testosterone

-

Note: *Oral progesterone treatment ís díffícult to tol/ow by /ab tests. See note on prevíous page.

403

enanthate Essential Essential (if high total PSA)

FOLLOW-UP 24-HOUR URINE TESTS for 80TH GENDERS

DIETARV

To collect in sedentary conditions (during the test & 24 hours before) Probably

STATUS or

URINE

HORMONE

TEST

THERAPV

Subcutaneous GH

&/ or Pathological Trend

Volume DIET

Still Deficient

High Low

Reference Optimal

Range

Leveis

�-800 or >2300

1600

600-2500 mU24h

Low

0-4

5-6

3.0-8.0 mmol/24h

Essential

Potassium

Low

0-45

65

35-80 mmol/24h

Essential

Magnesium

Low

Phosphorus

Low

GH

Free T3

THVROID HORMONES

Free T4

Sodium Oral

Low levei Low levei Low levei Low or high levei

65

22-125 mmol/24h

Essential

0-45

65

22-42 mmol/24h

Essential

0-2000 0-670

2500-4500 830-1500

500-6000 pg/24h 170-2000 piU/24h

0-45

Note: urinary GH must increase 0-0.85

0.9-1.3

0-1300

1400-2000 1.6-1.9

0-1.4 0-1800

> 200

0-4

FLUDROCORTISONE

Essential

Caleium

>30% above initial value Oral

Value

of young adults

Aldosterone

(normal salt diet)

Low levei

0-1.1

2000-2500

160

0.5-1. 7J1g/24h 800-2500pmol/24h 0.4-2.5J1.Q/24h

Essential

550-3160pmoV24h

100-220 mmol/24h

5-13

5-20 f1Q/24h

1.4-3.6

1.4-5.5 pmoi/L

Note: useful to check that the endogenous aldosterone secretion is not excessively suppressed

404

Essential to Auxiliary

Essential

Auxiliary

Additional FOLLOW-UP 24-HOUR URINE TESTS in WOMEN MUSCLE

Probably

STATUS or

URINE

Still Deficient &/

HORMONE

TEST

or Pathological

THERAPY Muscle Mass

Oral Hydrocortisone

Creatinine

17-0Hsteroids total

(gas chromat.)

17-0Hsteroids total

(gas chromat.) Oral structurally modified Glucosteroids (GS)

17-ketosteroids total

17-ketosteroids total

Transdermal DHEA

steroids total

Transdermal Testosterone

Testosterone

Transdermal

2-0H-estrone

Oral o r Vaginal Progesterone

Range

of young adults

Trend

Leveis

Low or High levei

0-1.0 or > 1.6

1.1-1.2

0.80-1.40 g/24h

0-0.9 or > 1.4

1.0

0.7-1.3 pmol/24h

0-8

8.5-12

3.7- 8.5 mg/24h

0-22

23-32

10-23 11mol/24h

Low levei

(gas chromat.) 17-keto-

(gas chromat.)

16-alpha-OHestrone

Low levei

Low levei Low levei

0-3

3.7-6

3.7- 8.5 mg/24h

0-8

10-16

10-23 J1mol/24h

0-8

8.5-12

2.9-8.9 mg/24h

0-28

30-42

10-30 11mol

0-8

8.5-12

2.9-8.9 mg/24h

0-28

30-42

10-30 J1mol

Auxiliary

Auxiliary (essential test for evaluation of the use of dexamethasone as treatment of hirsutism)

Auxiliary

Note: The excessive excretion values of urinary 17-ketosteroid metabolites, usually found in this test with oral DHEA, comes from the excessive liver breakdown (spilling) of about 50% of the ingested DHEA shortly after absorption before they evenpenetrate in the blood and exert anyaction.

0-5.5 0-19.0

0-12 0-0.04

0-4 Low levei

for follow-up

Note: The excessive excretion values of urinary 17hydroxy-steroid metabolites, usually found in this test with oral hydrocortisone, comes from the excessive liver breakdown (spilling) of about 50% of the ingested hydrocortisone shortly after absorption before they even penetrate in the blood and exert any action.

Very low Very low

Value

Essential

Note:The low urinary excretion values of the 17-hydroxy- and 17-ketosteroid metabolites, usual/y found in this test after oral intake of synthetic glucosteroids, result from the usual 20 to 35% suppression of the endogenous production of cortisol by the presence of synthetic glucosteroids and the inability of the urinary tests to detect the presence of synthetic glucosteroids. => The tests are mainly useful to check the degree of inhibition of endogenous cortisol or DHEA production byglucosteroid use.

Oral DHEA

Estradiol &

Reference Optimal

>

405

1.9

6.5-7

22.524.5

15-17

2.9-8.9 mg/24h 10-30 J.lmOI

Essential

3-23 1JQ/24h Essential

0.05-

0.01-0.08

0.06

J1mol/24h-

5-6

2-7 mg/24h

Auxiliary

0-1.9

1.5-1.9 llQ/24h

Essential

Additional FOLLOW-UP 24-HOUR URINE TESTS in MEN

Probably

MUSCLE STATUS or HORMONE

TEST

THERAPY Muscle Mass

Creatinine

Transdermal

Pregnandiol

Progesterone

(gas chromat.)

Oral Hydrocortisone

Still Deficient

or Pathological Trend Leveis Low p-1.2 or > 2.3 or high 0-1. 1 or > 2.O Low levei

Value

Range

for follow-up

of young adults 1.04-2.19 g/24h

1.4-1.6

0.9-1.9 J.Lmoi/L

0-0.5

0.65

0.16-0.86 m g/24h

0-1.6

2.0

0.5-2.7 J.Lmol/24h

0-10 27. 6

13-22

5.8-15.8 mg/24h

36.0- 60

16.0-43.6 Jlmol/24h

-

Test

Reference

1.6-1.8

0

17-0H steroids total

&/ Optimal

Essential

Essential

Auxiliary

Note: The excessive excretion values of urinary 17-

Low

(gas chromat.)

hydroxy-steroid metabolites, usual/y found in this test with oral hydrocortisone, comes from the excessive liver breakdown (spilling) of about 50% of the ingested hydrocortisone shortly after absorption before they even penetrate in the blood and exert any action.

17-OH-steroids total (gas chrom.)

Oral synthetically derived Glucosteroids

(GS)

17-keto-steroids total

Low levei Low levei

0-5.8

0-16

6-10

5.8 -15.8 mg/24h

Auxiliary

16.5-27 16.0-43.6 JlmOI/24h

0-9

11-12

4.7-13.3 mg/24h

0-30

38-41

16-46J1mol/24h

Auxiliary

Note: The low urinary excretion values of the 17-hydroxy- and 17-keto-steroid metabolites, usual/y found in this test after oral intake of synthetic glucosteroids, result from the usual 20 to 35% suppression of the endogenous production of cortisol by the presence of synthetic glucosteroids and the inability of the urinary tests to detect the presence of synthetic glucosteroids.

=> The tests are mainly useful to check the degree of inhibition of endogenous cortisol or DHEA production by glucosteroid use.

17-keto-

Oral DHEA

steroids total

Low levei

(gas chrom.)

0 -9

11-18

4.7-13.3 mg /24h

0-30

38-62

16 -46 J.Lmol/24h

I

AUXII T ary

Note: The excessive excretion values of urinary 17keto-steroid metabolites, usual/y found in this test with

oral DHEA, comes from the excessive liver breakdown (spilling) of about 50% of the ingested DH EA shortly after absorption before they even penetrate in the blood and exert any action.

Transdermal DHEA

Transdermal or intramusc. Testosterone

17-ketosteroids total

(gas ch.)_ Testosterone

Low levei Low levei

0 -9

11-12

4.7-13.3 mg/24h

0-30

38-41

16 -46 J.Lmol/24h

<

120

140

50-200 llQ/24h

<

0.40

0.5

O. 17-0.70 J1mol/24h

406

Essential

Essential

7. Overview of Corrective Hormone Therapies: the best hormone medications and doses

An overview of the most frequently used corrective hormone treatments is shown in the following tables.

The treatments that are the best to my experience are highlighted with a

yellow background. Note that the hormone therapies are only recommended when the hormone deficiency has been established by clinicai findings and lab tests; the range of physiological doses presented in the fifth column is adapted for adults.

407

Recommended CORRECTIVE HORMONE TREATMENTS for both genders

Hormone

Best route

When to

THERAPY

& product

take?

Melatonin

Sublingual melatonin

1x/day

10-20' at bedtime

doses

Physiol. dose

(mean)

range

Optimal

0.1-0.2 mg/day

0.05-0.5 mg/day

Q) :I

iii How to begin? >

:S

� o o

,..

Growth Hormone

�ubcutaneous GH

1x/day

10-20' at bedtime

0.1-0.3 mg/day

0.05-0.4 mg/day

:S

ª o o

,..

1x/day

�ubcutaneous

IGF-1

(somatomedin

C)

before a meal or, if Mecasermin combined (IGF-1) with GH, at bedtime

0.1 to 0.5 mg/day

0.05-1 mg/day

c

o

ã o o

,..

1x/day MSH

Subcutaneous Melanotan 11

6h prior sun exposure or sex

3x 0.5 mg/week

0.1-0.5 mg/day

Oxytocin

Sublingual oxytocin

2h prior social event or sex

,..

1x 51U to 2x 10 IU/day

5 - 30 IU/day

Vasopressin

Desmopres sin tablets

2x/day

(morning

& 2h prior

bedtime

Parat-

Subcutaneous

hormone

Teriparatide

1x/day

at bedtime

Start at a low dose of 5 miU/day and then slowly c .2 increase every 5-1O days cortisol (especially with o deficient patients)

�

o

,..

1x to

Oral

ã o o

1x to 2x/day

:S

Start at a low dose of 0.1 insufficient mg/day. If effects, slowly increase up to 0.15-0.2 or even 0.5 mg/day (caution with cortisol deficient patients!) Start at a low dose of 0.05 mg/day and then slowly increase every 7-14 days up to mg/day 0.15-0.25 (caution cortisol with deficient patients!) Start at a low dose of 0.1 mg/day and then slowly increase every 7-10 days up to 0.5 mg/day (caution with cortisol deficient patients!) or reduce to 0.05 mg/2days, if signs of excess appear Start at a dose of 2x 0.5 mg per week and then slowly increase every 10-14 days to 3 x or more /week or reduce up to 2x 0.1 mg/wk if signs of excess appear

100 to 250 119/day

20 119/day

50 - 400 llQ/day

Start at a low dose of 1 to 50 119/day and then slowly increase every 5-7 o ,.. days c

o 2x

ª

o

10-40 llQ/day

Start with 20 119/day and take calcium tablets 1 toi 2 drinking while g/day, c o sufficient amounts of water. lf bone density does not ã o increase well, increast ,.. teriparatide to 20 119/day o

408

Racommandad CORRECTIVE HORMONE TREATMENTS for both gandars

Calcitonin

Subcutaneous Calcitonin

Oral dasiccatad thyroid Thyroid hormonas

(Armour Thyroid®) Synthetic T3- T4 (Novothyral, Euthyral, Thyrolar®)

1xlday

at bedtime

25-50 IU/day

25-100 IU/day or per 2 days

1xlday

10-20' before breakfast

75-120 mg

30-240 mg/day

1-2xlday

10-20' before breakfast & lunch

1 to 1Y2 tablets

Y2 to 2 tablets

Fludrocortisona

hydro-

staroids

o

1xlday

before or after breakfast

100 llQ/day

Oral

2-4x/day

Woman:

hydro-

mainly before or after breakfast &lunch

30-35 mg/day

25-40 mg/day

5 mg/day

2.5-7.5 mg/day

Start at 5 mg/day; increase + 50% to +· 200% in 'ª o conditions of greater need C\J (stress, flu, etc.)

2-6 mg/day

Start at 4 mg/day; increase 50% to + 200% in 'ª o conditions of greater need C\J (stress, flu, etc.)

cortisona

(or fludrocortisone (Fiorinef®))

cortisona

Gluco-

o

o

Oral 9-a-fluoro-

Start at a low dose of 25 c .!2 IU/day and then slowly increase every 3-4 days up "ª o to 100 lU (especially with ... cortisol deficient patients) Start at a low dose of 15 c .!2 mg/day and then slowly increase every 10-14 days "ª o (especially with cortisol ... deficient patients) Start at a low dose of 25 ll9 c .!2 T4 & 5 ll9 T3 mg/day and then slowly increase every 2 o 14 days (especially with ... cortisol deficient patientsl Start at 100 llQ/day, except in persons with easy c .!2 edema, where doses as low as 50 llQ/day are used, and 2 o if more is needed, gradually ..- increase to a maximum of 200 llQ/day Start high enough at 20 c mg/day in women and 30 o mg/day in men, and then o adjust; increase + 50/ 200% ... in conditions of greater need (stress, flu, etc.)

(Cortef®, Hydrocortiso ne®) lnflammatory diseases:

(Prednicort®)

edema: Oral

1x/day

so(lo)na

pbesity, iBP, mathylpradnis(ol)ona

(Medro1®)3 Subcutaneous Shortacting insulin

Man:

Woman:

15-30 mg/day Man:

1xlday

before or after breakfast

Oral pradni-

20-25 mg/day

50-200 llQ/day

before or after breakfast 3xlday

Before meals

lnsulin

Subcutaneous 1-2xlday lntermediate prior longacting meals

o

�

o

c

4 mg/day

Weight i: 3x 2 U/d Diabetes: 3x 10 U/d Weight i: 5-10 U/d Diabetes: 10-30 U/

409

3-60 IU/day

o

o

c

o

o

Start at lower doses Weight wish to i Weight: 3x1 U o Diabetes: and check blood later slowly o glucose=> ... increase if results are insufficient c

� 8-140 U/day

+

o

Recommended CORRECTIVE HORMONE TREATMENTS for WOMEN Hormone

Best route &

THERAPY

product Transdermal Estradiol gel

0.6 mg/g ((O)Estrogel, Gynokadin, Oestrodose®)

Transdermal

When

Optimal

Physiol.

to

doses

dose

take?

(mean)

range

CP :I

iii

PREmenopausal:

1xlday

in the morning

How to begin?

>

r::

2.25

0.75-4.5

mg/day

mg/day

o :;::; Q. o o

,...

3 g/day

1-6 g/day

2.25 mg/day to take from the 5th to the 25th day of the menstrual cycle (no block of ovulation, not contraceptiva) POSTmenop.

women:

(0.5 mg "'c 1.5-.25 mg/day 50%E3 (1.5 mg E3 & E2 :: ·º ..... from the 1st to the 25th day 0 Q. 50 %E2 E3 /day; day up to � in the o of each month (Compound. morning 1.5 mg E2 3 mg E1 C\J For transdermal and pharmacy) /day) � E2/day) vaginal Biests: similar 1xlday 1.5Transdermal "'c days of intake as above, . o Biest 5 mg/g 0.5-4 ,... 2g/day .... ·..... but because compounded 0 80%E3 20% in the 6-8 mg E3; g/day �a. o preparations penetrate C\J E2 (Com.ph.) morning 1.5-2mgE2 less => use higher doses Biest 1 mg/g

1xlday

o

o

Female hormones in women

Vaginal

�riest 1 mg/g (80%E3; 10 %E2;10 % E1) (C. ph.)

1xlday

before sleep

1-2 g/day

0.8 to 1.6 mg E3; 0.1-0.2mg E2 & E1)

�

0.5-3 g/day

Method of Dr. Jonathan

s-· c Wright (Seattle): finds the ,.... o �� o a. �o o

C\J

vagina to be the best absorbable and safest route PREmenopausal:

Oral or vaginal Progesterone

(micronized; Prometrium, Utrogestan, Progestan, Utrogest®)

1xlday

before sleep

r::

100-150

50-200

mg/day

mg/day

o :;::; Q. o o

,...

410

100-150 mg/day from the 15th to the 25th day of the menstrual cycle (no block of ovulation, not contraceptive) POSTmenopausal women:

100 mg/day from the 1st to the 25th day of each month (to avoid menses) or 150 mg/day from the 13th to the 25th day of each month (to obtain mense�

Recommended CORRECTIVE HORMONE TREATMENTS for WOMEN Hormone

Best route

THERAPY

& product

When

Optimal

Physiol.

to

doses

dose

take?

(mean)

range

1x/day DHEA

Oral

before

inwomen

DHEA

or after

20 mg/day

5-30 mg/day

breakfa st

Cll

:::1

iii How to begin? >

s:: Start 20 mg/day in women; o :;::; increase + 50% to + 1 00% a. o in conditions of greater o ,.. need (stress, flu, etc.)

2x/day Sublingual

before or after

testosterone �reakfast

5-40 20 mg/day

mg/day

c o

"E. Start at 1 5 mg/day o

o

C')

&

supper

Testosterone Testosterone inwomen

1x/day

liposomal

before

gel1%

or after

(1 O mg/g)

breakfa

5 mg/day (2.5-10 mg/day)

s::

2-10 mg/day

st

o :;::; 1 a. Start at /3 of a gram o o ,..

Testosterone enanthate or cyprionate (Androtardyl,

25-50 1x/

40 mg

mg

month

/month

every month

Testoviron depot®)

411

c o

"+=' Q. o

o

C\1

Start

at

40 mg/month in

women with low libido and no orgasm and who are not responding

to

above-

mentioned treatments

Recommended Corrective Hormone Treatments for MEN

Hormone THERAPY

Best route & product

When to take?

Optimal doses (mean)

Physiol. dose range

1xlday DHEA for men

Progesterone for men

Oral DHEA Oral Proge sterone (micronized; Prometrium, Utrogestan, Progestan, Utrogest®)

Suppository Progesterone

before or after

35 mg/day

20-55 mg/day

Testo sterone for men

(comp. pharm.) IM lnjection testosterone enanthate or cyprionate (Androtardyl, Testoviron depot®)

Start 35 mg/day in men; increase + 50% to +

.. c. 200% the normal dose in

o o

...

conditions of stress, flu, etc.

c:

o

50-100 mg/day

100-150 mg

10-100 mg/day

10-100 mg/day

.. c.

o o

...

Start at 100 mg/day

May be useful for: milder and hard of forms c: enlarged prostate: o .. Start at 100 mg/3 days in c. hard and o moderate ... enlarged prostate; Start at 150 mg/2 days in hard and voluminous prostates o

months Transdermal testosterone liposomal gel 100mg/g

>

c:

1x/day

1 x/ 2-3 days before sleep, during 4-6

7ã How to begin?

o

breakfast

before sleep

Gl �

1x /day in the morning

150 mg/day

1x/ 1-3 weeks

250mg every 2 weeks

c:

50-300 mg

o o o

...

412

125-250 mg every 1-3 weeks

Start at 100-250 mg/day

.. c. depending on severity of

the deficiency

Start at 250 mg/2 weeks, used in men with severe E. o deficiency or above 55N 60 yrs c: o

o

8. Overview of the Hormone Diet The diet that our ancestors ate in the Paleolithic period is the best diet for most patients taking hormone therapies. The Paleolithic diet helps to optimize the hormone leveis and the effects of hormone therapies. In the Paleolithic times, agricultura did not yet exist. The human species had adapted to a number of foods that existed for millions of years on planet Earth. Humans ate fruits, vegetables, meat, poultry, eggs, fish, and possibly in small quantities, nuts and some seeds and roots. They drank water. The diet was free of agricultura and industrialized products. A Paleolithic diet consists of foods that are highly digestible when eaten raw, do not need to be cooked, and are fully adapted to the human digestiva tract. lt does not contain milk products, sweets, alcohol, caffeinated drinks, grains and cereais that are not sprouted, and many other foods that are not meant to be consumed by humans. The proportion of protein, fats and carbohydrates, and the amount of calorias in the diet will vary from one individual to the other depending on the type and degree of importance of the hormone deficiencies.

The Paleolithic Diet Depending on the hormone deficiencies, the patient should make the following dietary changes in order to increase the efficacy of the hormone treatment:

High protein (and possibly high fat) intake Eating lots of protein, especially from animal origin, such as meat, poultry, eggs and fish increases the production and effects of the somatomedins or IGF (insulin-like growth factors which express a great deal of growth hormone's (GH) effects.

lntake of protein-rich food also

strengthens the action of the steroid hormones such as the adrenal cortex hormones (cortisol, DHEA and aldosterone) and the sex hormones (testosterone, dihydrotestosterone, estrogens, progesterone). Moreover, a high protein intake counters the unwanted tissue-wasting effects of glucocorticoids such as cortisol. lt can also reduce high insulin leveis by minimizing hypoglycemia. Paradoxically, a high protein intake tends to lower the blood leveis of growth hormone, while at the same time it clearly stimulates GH activity, as reflected by increases of IGF-1. The (bioavailable) IGF-1 levei is a good marker of GH activity as IGF-1 is itself the result of GH's action on the liver. Humans need to eat a minimal amount of protein to optimize thyroid performance, but not high amounts as high amounts of protein-rich foods may make patients with borderline low thyroid function more thyroid-deficient by reducing the conversion of thyroxine to the more active thyroid hormone triiodothyronine.

On the other hand, eating meat, and especially red meat,

may beneficially influence thyroid function in hypothyroid patients who have iron deficiency, as (red) meat is rich in iron. The iron in red meat allows a replenishment of the iron stores and significantly accelerates the conversion of T4 into the active thyroid hormone T3, thereby increasing the serum levei of potent thyroid hormone T3. The protein intake can be checked by measuring phosphorus excretion and, in case of high intake, also creatinine excretion in a collection of 24-hour urine.

413

High saturated fat intake:

Eating foods rich in saturated fats, particularly cholesterol, such as eggs, liver, butter, meat, fish and poultry boosts the production and thereby the effects of hormones whose structures are built upon cholesterol. Such hormones are called the steroid hormones. They include the adrenal cortex hormones (pregnenolone, cortisol, DHEA, and aldosterone) and the sex hormones (estrogens, progesterone, testosterone). On the other hand, eating excessive amounts of fat is not beneficiai as an excessive intake of fats may lower GH secretion and thyroid hormone leveis. lt is important to eat saturated fats that are not denatured. Cooking at high temperatures such as grilling, frying and barbecuing changes the molecular structure of saturated fats, making them unfit for hormone production. Additionally, cooking at high temperatures produces numerous toxic chemicals.

The toxins may in turn attack the endocrine glands and further

deplete hormone production. Basically, cooking with water (boiling, steaming, water damp oven), slowly cooking at low temperature without oil or butter, or eating raw (parasite-free) food, are the only safe ways to prepare animal foods rich in fat and protein.

High carbohydrate intake

When you eat fruits and vegetables, the "safe" type of carbohydrates, you increase the production and activities of the peptide hormones such as the thyroid hormones (this accelerates the conversion of T4 to active T3 amongst other things) and melatonin.

As

cauliflower and other cruciferous vegetables may possess anti-thyroid activity and produce goiters, hypothyroid patients should avoid them, especially those who have a goiter. The intake of fruits and vegetables can be checked by measuring potassium excretion in the 24-hour urine.

High calorie intake

Eating too much, consuming an excessive amount of calories, boosts the production of sex hormones, growth hormone, somatomedins and thyroid hormones, but not of hormones produced by the adrenal cortex. The intake of calories can be indirectly checked by measuring calcium excretion in the 24-hour urine as calcium is found in many foods of ali types.

Fasting and low calorie intake:

Some recent controversial reports have stated that short-term fasting may be beneficiai for health.

Skipping a few meals every two days, without reducing the total calorie intake, may

show increased weight loss above that of controls who consumed the same amount of calories regularly divided over three meals a day. In ancient times, humans did not always find enough food to eat three to four times a day. Our body is probably better adapted to a diet that regularly includes small periods of fasting. Fasting sets in action compensatory mechanisms that order the release of energy from the fat

414

tissue and thus decrease the fat stores. Less fat means less hormone spilling by inappropriate penetration of hormones into the fat cells rather than into more important cells such as muscle fibers and neurons. In contrast, long-term fasting such as eating a very low-calorie diet for several weeks may work adversely. lt reduces, often severely, the production, leveis and effects of almost ali other important hormones such as thyroid hormones, sex hormones, somatomedins and growth hormone.

Eat regularly

At each meal, blood leveis of cortisol temporarily double.

Fasting also increases the levei of

cortisol, a compensatory mechanism to combat hypoglycaemia, but it does not work as efficiently to boost cortisol production as eating a meal.

Eat organic foods

Our ancestors ate foods that were unpolluted, free of the impressive amounts of chemicals that we can find now in industrialized foods. In many studies, adverse effects of the pollutants on endocrine function have been demonstrated - too many to sum up here. The presence of added chemicals has become so abundant that even so-called organic foods are not totally devoid of unwanted chemicals. However, organic foods, because of their relatively lower levei of endocrine pollutants, are preferable to non-organic ones.

Drink water

As two-thirds of the human body consists of water, drinking water, preferably still water that is not too acidic, is very beneficiai. Sparkling water is second choice as it contains high amounts of carbonic acid.

When you drink water, you increase the blood volume and dilute the

components of the blood. Water drinking has been associated with a decreased risk of various cancers and of ischemic heart disease. The mineral corticoid activity of aldosterone, cortisol and the sex hormones is improved by drinking lots of water as it relies on water and salt. An insufficient water intake weakens the ability of these hormones to further retain water. The water intake can be checked by measuring urinary volume in the 24-hour urine.

Eat sufficient salt

Eating too much salt (sodium) increases the blood pressure of individuais predisposed to hypertension.

And yet, there must be enough intake of sodium to permit the salt-retaining

activity of hormones such as aldosterone and other mineral steroids. A low salt diet triggers the secretion of aldosterone in order to retain salt, but at the same time reduce the efficacy of the mineral corticoids. The intake of salt can be checked by measuring sodium excretion in the 24-hour urine.

415

The Adverse Effects of the Modern Western Diet lt is not sufficient to eat healthy foods. lt is equally important to avoid eating unhealthy foods of the modern diet. lt is best to eat

safe Paleolithic foods at least tive days a week, and limit intake of some

unhealthy foods to a maximum of one or two days a week. The "safety valve" of one to two days a week of freedom to eat some unhealthy foods helps the patient feel less restricted. lt permits an adequate balance in the endocrine system in most patients that is not toa disturbed by two "bad" days on seven.

But eating wrong foods three days a week or more adversely

affects the hormone treatment outcome.

Cereais Cereais and grains such as bread, pastas, rice, are not easily digested by the intestines. They irritate the gastrointestinal tract and make it bloat. Cereais are food with a high glycemic index. High glycemic index foods raise the blood sugar toa much and toa quickly. Each time the blood sugar rises, the production of hyperglycemic hormones, hormones that raise the blood sugar levei, such as cortisol, growth hormone, testosterone, DHEA, androstenedione, estradiol, glucagons, go down.

These hyperglycemic hormones preserve health and body composition

and appearance when they are in appropriate balance in the body. A high and frequent intake of foods with a high glycemic index causes hormone deficiencies and premature aging. Moreover, cereais generate food allergies such as gluten and gliadine intolerance. lf a person regularly eats foods that he is allergic to, a persistent state of inflammation with abdominal bloating is entertained in the digestive tract.

After months and years of disturbances, the

inflammation may lead to an atrophy of the intestinal mucosa, which reduces the absorption of nutrients essential for the endocrine system. activities.

The nutrient depletion may impair endocrine

Furthermore, the intestinal inflammation causes nearby organs situated in the same

abdominal cavity such as the adrenal glands and the avaries to inflame and thus to further malfunction. As grains are, in the best case, only partially digested by the digestive enzymes of the human digestive tract, what remains in the digestive tract becomes an ideal food for yeast and bacterial pathogens in the intestinas. These pathogens may proliferate and cause yeast and bacterial overgrowth. Over a hundred metabolic reactions have been found in experiments with yeast where the yeast was found to breakdown hormones, thus causing a multiple hormone depletion. Eating sprouted grains, even sprouted rice (whole rice takes 4 days to sprout, other

grains generally two days) , may avoid the problems. When grains are sprouted, they become vegetables and are much safer and easier to digest.

Last but not least, whole grains such as whole grain bread and bran flakes are rich in indigestible fiber.

In the lumen of the digestive tract their fiber strongly binds to steroid

hormones that are brought there by the bile and meant to be reabsorbed by the intestinal tract further on.

The complexes of fiber with hormones are evacuated and thus lost in the stools,

leading to a 15-45% reduction of serum steroid hormone leveis. Under normal conditions free of cereal fiber, an entero-hepatic cycle exists with secretion by the liver in the bile of the steroid hormones such as estradiol, estrone, testosterone, DHEA, androstenedione, and many other sulfo-and glucuronoconj ugated forms of hormones. intestinal flora breaks off the sulfate and glucuronate compound from the hormones.

416

The Thus

deconjugated, these hormones are reabsorbed through the intestinal mucosa and return to the bloodstream where they can be used again in target organs.

Sweets and soft drinks

Sweets such as sugar, chocolate, cookies, cakes, soft drinks and fruit juice strongly and quickly increase blood sugar leveis within 1 O to 20 minutes. The hyperglycemia quickly reduces the production of cortisol and other hyperglycemic hormones, a half an hour or slightly more after being ingested. Regular consumption of sweets considerably imbalances and reduces the activity of the endocrine system.

Alcohol, caffeinated drinks

Alcohol intake reduces many hormones, possibly because of the sugar it contains, but also possibly because of the ethanol. Vinegar also belongs in this category as it is fermented wine. In a study, it was shown that daily drinking of two or more cups of caffeine-containing coffee or of one glass or more of alcohol elevates the estradiol leveis by an extra 60% in men.

High

estradiol leveis in men not only partially block the effects of endogenous testosterone, but also tend to feminize the body appearance of males and increase prostate stromal hyperplasia, resulting in a hard and enlarged prostate.

Patients who are deficient in aldosterone and

vasopressin need to avoid coffee (including decaffeinated) and alcohol because these drinks make the kidneys excrete more fluid, an effect more detrimental to persons who are already chronically dehydrated. Furthermore, beverages with caffeine (coffee, tea, cola) and alcohol should be avoided before bedtime as caffeine increases serum cortisol and may considerably reduce the secretion of melatonin at night. Last but not least, caffeine may increase the risk of some cancers.

In mice for example, daily

consumption of caffeine increased the breast cancer risk (doubling the risk in predisposed mice) by stimulating hyperplasia of glandular cells. A safe guideline is to assume that the same may be true in humans and that women predisposed to breast cancer on female hormone therapy should avoid regular caffeine intake. Decaffeinated drinks (where the label states that the caffeine has been extracted by the safer method based on water and carbonic acid) may be an acceptable alternative.

Milk products

The adult human digestive tract is not designed to digest milk products of cow, goat, sheep or horse origin, not even human milk that is fit for babies but not adults who generally lack the lactase and other enzymes to adequately digest it. There are many different reasons to avoid milk products - from lactose intolerance and various difficulties in milk digestion to milk's promotion of atherosclerosis and cardiovascular mortality. The adverse consequences of milk products are too many and too long to enumerate here. Let us simply mention that a high dairy intake may considerably reduce thyroid function and may cause undesired weight gain in conjunction with female hormone and cortisol therapies.

417

Pesticides and food additives Many pesticidas and food additives alter hormone secretions and effects. They are designed to kí/1 insects and bacteria. This can cause considerable harm to the human body with its delicate and complex endocrine system.

The traces of these chemicals that are contained in the

industrialized foods we eat can be strong enough to alter the hormone leveis in our body. Many of the pesticidas found in our food mimic the effects of estrogens as they have a structure that fits on the estrogen receptor, and can thereby imbalance the endocrine system or worse, they can damage the endocrine glands causing them to malfunction.

Overweight, obesity Obesity has adverse effects of its own on the endocrine system.

In women, obesity may

reduce ovulation and production of female hormones. Moreover, fat tissue is rich in the enzyme aromatase that inactivates male hormones by converting testosterone to estradiol. The excess in aromatase adversely affects men. The more they are obese, the more likely they are to be imbalanced in sex hormones, and have a low serum testosterone and a high serum estradiol.

Sleeping insufficiently A common problem with our modem lifestyle is sleep deprivation. People who are sleep deprived are more likely to have decreased functioning of their endocrine system such as decreased serum thyroid and sex hormone leveis. These lowered leveis trigger increased food intake (in particular sweets and starch) in order to increase hormone production. The excess sugar-containing food may trigger an excessiva insulin secretion, which in turn may cause hypoglycemia and bulimia.

418

The following table is an overview of the optimal hormone diet: The Optimal Hormone Diet Foods To Take Paleolithic diet: 1. Eat a sufficient amount of

calories: 1 ,500-3,500 calories/day depending on the activity 2. Eat organic foods 3. Eat raw parasite-free food, heat foods with water (steaming, boiling, etc.), or slowly bake them in a pan at low temperatura (do not exceed the boiling point: 100 degrees Celsius)

Foods to Avoid

Positive results from

Modern, western diet

dietetic improvement

Avoid eating so much that you get obese or even overweight • Avoid industrialized foods • Avoid alcohol, vinegar, caffeinated drinks • Avoid milk products • Do not burn foods by cooking at too high temperature (grilling, barbecue, pan frying) and in fat such as butter or oi i •

lncreases most hormones and preserves endocrine glands

4. Eat plenty of fruits and

lncreases thyroid

vegetables (a minimum of 400 grams or 5-9 servings a day) 5. Eat foods rich in iron (red meat), and iodine (seafood, seaweed (kelp, dulse etc.) 6. Eat sufficient amounts (200-300

grams a day or 3 servings a day) of meat, poultry, eggs, fish*)

hormone leveis (especially T3) and possibly melatonin

Avoid sugar, sweets, cakes, biscuits, cookies, soft drinks, bread, pastas and other cereais

7. In some cases supplement with

9. Eat sufficient salt

Avoid drinks that make the kidneys excrete more salt and fluid (e.g., coffee, tea, soft drinks, alcohol)

lncreases aldosterone and other mineral steroid activities lncreases cortisol function Sleep replenishes the

10. Eat small frequent meals 11. Fasting from time to time 12. Sleep sufficiently and deeply

androstenedione, estradiol, cortisol

lncreases GH secretion and IGF-1 leveis (but often temporarily)

amino acids (glutamine, arginine, lysine etc.), or a well-balanced, mixed amino acid supplement 8. Drink enough water

lncreases GH, testosterone, DHEA,

Avoid sleep deprivation

stores of hormones for

use durinÇJ the day Note: * Fish may be polluted by heavy metais. Choose fish that has been captured in co/d /ess polluted ocean areas (/celand, etc.).

419

Special Cases Patients suffering from hypothyroidism that is not (well) corrected with thyroid hormones should avoid eating high amounts of animal protein (meat, poultry, eggs, fish), because it lowers the conversion of T4 to the active T3, and thus reduces further the thyroid function. Eating too much fish rich in iodine may also adversely affect the thyroid function as shown in a Japanese study where 50% of patients with hypothyroidism who stopped eating seafood had a significant increase in the thyroid hormone leveis in a matter of weeks. The improvement may seem paradoxical as iodine is essential for the synthesis of thyroid hormones as a crucial component of the thyroid hormones. However, an excess of dietary iodine blocks the enzymes that produce thyroid hormones. The useful lesson is that eating too much of a good food may harm the endocrine activities, while finding the balance between deficient and excessive diet optimizes them. lt is worth noting that eating enough iron-rich foods is a must for hypothyroid patients as iron significantly accelerates the conversion of T4 into the active T3 and thus increases serum T3 leveis. Patients with hypocorticism who are not (sufficiently) treated with a glucocorticoid should eat small, frequent meals because cortisol levels temporarily double with each meal.

420

VIl.

Hormone References and B i bliog raphy

Selected hormone references:

Vou find here a selection of references of scientific studies on hormones, hormone deficiencies and hormone therapies. In particular, those studies have been selected where the roles of hormones in prevention or alleviation of aging and age-related diseases in adults were highlighted. The reference list contains also the major references of the pro and con studies on hormone therapy use, so important for the physician to know when s/he debates with colleagues or representatives of medicai institutions.

The knowledge of these studies should

help the physician become an excellent debater. The reader will find the list of references and the accompanying list of selected books on hormones also particularly valuable in his search for more information. Whenever possible, the references of human studies are mentioned preferably to those of animal studies. More extensive data and references will be published in the upcoming separate text books on each of the principal hormone therapies.

422

Chapter one:

Melatonin

Senescence is associated with a decline of the pineal-melatonin axis: Lower nocturnal serum melatonin and lower urinary melatonin metabolite with senescence 1. Waldhauser F, Weiszenbacher G, Tatzer E, Gisinger B, Waldhauser M, Schemper M, Frisch H. Alterations in nocturnal serum melatonin leveis in humans with growth and aging. J Clin Endocrinol Metab. 1988 Mar;66(3):648-52 2. Waldhauser F, Kovacs J, Reiter E. Age-related changes in melatonin leveis in humans and its potential consequences for sleep disorders. Exp Gerontol 1998 Nov-Dec;33(7-8):759-72 3. Langer M, Hartmann J, Turkof H, Waldhauser F. Melatonin in the human - an overview. Wien Klein 4.

Wochenschr. 1997 Oct 3;109(18):707-13e Schernhammer ES, Kroenke CH, Dowsett M, Folkerd E, Hankinson SE. Urinary 6-sulfatoxymelatonin leveis and their correlations with lifestyle factors and steroid hormone leveis. J Pineal Res. 2006 Mar;40(2):116-24

The circadian cycle of serum melatonin is altered with senescence: reduced amplitude and phase advance 5. van Coevorden A, Mockel J, Laurent E, Kerkhofs M, L'Hermite-Baleriaux M, Decoster C, Neve P, Van Cauter E. Neuroendocrine rhythms and sleep in aging men. Am J Physiol. 1991;260(4 Pt 1):E651-61 6.

Zhou JN, Liu RY, van Heerikhuize J, Hofman MA, Swaab DF. Alterations in the circadian rhythm of salivary melatonin begin during middle-age. J Pineal Res. 2003 Jan;34(1):11-6

Melatonin treatment may oppose and melatonin deficiency may trigger severa! mechanisms of senescence Excessive free radical formation

Higher leveis of free radicais in elderly persons 7.

8.

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IOPICS OE DISCUSSION

MELATONIN TREATMENT ANO PINEAL GLAND INHIBITION Melatonin treatment does not suppress the endogenous melatonin production by the pineal gland 1.

Lissoni P, Rovelli F, Pittalis S, Casati M, Giani L, Barni S, Fumagalli L, Laudon M. Therapy with melatonin does not suppress its endogenous production in healthy volunteers. Recenti Prog Med. 1999 Feb;90(2):84-5

438

MELATONIN: ABSENCE OF SERIOUS SCIENTIFIC STUDIES IN HUMANS? There are more than 10'000 studies on the Medline databank on melatonin. There are over the 100 placebo­

controlled studies of the effect of melatonin treatment on sleep in humans in the Medline databank: 101 (last search on 29-1-2006) with 83% (84/101) oi them showing significant beneficiai results of melatonin supplementation on sleep, and only one negative repor!.

104 PLACEBO-CONTROLLED STUDIES ON THE EFFECT OF MELATONIN ON SLEEP 87 placebo-controlled studies where a significant beneficiai effect of melatonin on sleep in children and adults was observed: the beneficiai effect mainly consists in a shortening of the time to fali asleep (quicker sleep onset) and a profound muscle relaxation, rarely an improvement of the REM or deep sleep

ÇJJi!!l.r�.l) 1.

Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset

insomnia in children: a randomised placebo-controlled trial. J Child Neural. 2001 Feb;16(2):86-92 2.

Smits MG, van Stel HF, van der Heijden K, Meijer AM, Coenen AM, Kerkhof GA. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003 Nov;42(11): 1286-93

3.

Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M. Clinicai trials oi controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res. 2000 Aug;29(1):34-9

4.

Jan JE, Espezel H, Appleton RE. The treatment oi sleep disorders with melatonin. Dev Med Child Neural. 1994 Feb;36(2):97-107

5.

Dodge NN, Wilson GA .Melatonin for treatment oi sleep disorders in children with developmental disabilities. J Child Neural. 2001 Aug;16(8):581-4

6.

McArthur AJ, Budden SS.Sieep dysfunction in Rett syndrome: a trial oi exogenous melatonin treatment. Dev Med Child Neural. 1998 Mar;40(3):186-92

7.

Coppola G, lervolino G, Mastrosimone M, La Torre G, Ruiu F, Pascotto A. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Brain Dev. 2004 Sep;26(6):373-6

8.

Niederhofer H, Staffen W, Mair A, Pittschieler K. Brief repor!: melatonin facilitates sleep in individuais with mental retardation and insomnia. J Autism Dev Disord. 2003 Aug;33(4):469-72

M!!!�$. 9.

Rahman SA, Kayumov L, Shapiro CM. Antidepressant action oi melatonin in the treatment of Delayed Sleep

Phase Syndrome. Sleep Med. 201O Feb;11(2):131-136 1O. Luthringer R, Muzet M, Zisapel N, Staner L. The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia.

lnt Clin Psychopharmacol.

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MELATONIN DEFICIENCIES with MELATONIN (METABOLITEl LEVELS within the REFERENCE RANGE Should individuais with symptoms and signs of melatonin deficiency, but serum and urinary melatonin and melatonin metabolite leveis within the normal reference range for their age, be supplemented with melatonin? Scientific publications support the view that Milder degrees of melatonin deficiency exist with leveis within the reference range. Individuais with melatonin or melatonin metabolite leveis wilhin lhe reference range (silualed in the lower segmenls of lhe reference range) have a significanl increased risk of various types of disease and dysfunctions. This suggesls that lhey suffer from a degree of pineal gland failure, as lhe increased risk may be reducible or prevenlable by increasing melalonin or melatonin metabolite leveis in the upper two lhirds, upper half, upper third or upper quarter of the reference range through supplemenlation with melalonin.

People with melatonin or melatonin metabolite leveis within the reference range are not necessarily may safely benefit from melatonin supplementation

heallhy, may suffer from melalonin deficiency and

Confirmation of this is found in a number of studies, including: Studies that show that subjects who are at or below the 90th percentile of serum or urinary melatonin (metabolitel levei have an increased risk of disease or dysfunction: this concerns most studies that show an inverse association between melatonin (metabolite) leveis and the risk of disease

Higher risk of mood disorder (increased depressive symptomatology, esp. sadness), bodily discomfort, inner tension, concentration difficulties, and pain 1.

Almay BG, von Knorring L, Wetterberg L. Melatonin in serum and urine in patients with idiopathic pain syndromes. Psychiatry Res. 1987 Nov;22(3):179-91 (The low melatonin concentrations in serum and urine in

patients with depression or pain syndrome were related to increased depressive symptomatology, especially sadness, bodily discomfort, inner tension, concentration difficulties, and pain)

Higher risk of overweight and obesity, higher body mass index 2.

P, Cocco ME, Paghi L, Avataneo G, Salis A, Meloni M, Atzeri S, Broccia G, Ennas MG, Erren TC, Reiter RJ. Urinary 6-sulfatoxymelatonin excretion in humans during domestic exposure to 50 hertz electromagnetic fields. Neuro Endocrinol Lett. 2005 Apr;26(2):136-42. Department of Public Health, Occupational Heallh Section, University of Cagliari, ltaly. [email protected] (The risk of a reduced urinary 6-sulfatoxymelatonin nocturnal

secretion was 2.2 -fold higher for body mass index (BMI) above the median)

3.

Schernhammer ES, Kroenke CH, Dowsett M, Folkerd E, Hankinson SE. Urinary 6-sulfatoxymelatonin leveis and their correlations with lifestyle factors and steroid hormone leveis. J Pineal Res. 2006 Mar;40(2): 116-24 Channing Laboratory, Department of Medicina, Brigham and Women's Hospital and Harvard Medicai School, Boston, MA 02115, USA. [email protected] (The BMI was significantly and inversely

associated with urinary 6-su/fatoxymelatonin leveis in healthy, primarily premenopausal, age range

33-50 years)

Higher risk of lower parity, possibly lower fertility 4.

Schernhammer ES, Kroenke CH, Dowsett M, Folkerd E, Hankinson SE. Urinary 6-sulfatoxymelatonin leveis and their correlations with lifestyle factors and steroid hormone leveis. J Pineal Res. 2006 Mar;40(2):116-24 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medicai School, Boston, MA 02115, USA. [email protected]

urinary 6-sutfatoxymelatonin leveis (p

(A positive association between parity and <0.01) in healthy, primarily premenopausal, age range 33-50 years)

Studies that show that subjects who are at or below the 25th percentile (in the lower guartilel of urinary melatonin leveis have an increased risk of the following disease Higher risk of invasive breast cancer 5.

Schernhammer ES, Hankinson SE. Urinary melatonin leveis and breast cancer risk. J Natl Cancer lnst. 2005 Jul 20;97(14):1084-7. Department of Medicina, Brigham and Women's Hospital, Harvard Medicai School, Boston, MA, USA. [email protected] (Breast cancer patients in the highest quartile of urinary melatonin had -41% less risk of invasive cancer than patients in the lowest quartile of urinary melatonin)

The many studies of diseases or dysfunctions that are associated with lower melatonin or melatonin metabolite leveis within the reference range, suggesting that the lower leveis might contribute to these conditions. The references of these studies are found in the references on 'melatonin' and 'psychic well-being' and/or 'age-related diseases'.

443

chapter two:

Growth hormone

Senescence is assoclated wlth a decline of the growth hormone CGHl axis: Senescence is is associated with lower GH production 1. Veldhuis JD, lranmanesh A. Physiological regulation of lhe human growth hormone (GH)-insulin-like growth factor type I (IGF-1) axis: predominant impact of age, obesity, gonadal function, and sleep. Sleep. 1996 Dec;19(10 Suppi):S221-4 Senescence is associated with lower GH and IGF-11evels and increased somatostatin 2. Rudman O, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. lmpaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin lnvest. 1981 May;67(5):1361-9 3. Bando H, Zhang C, Takada Y, Yamasaki R, Saito S. lmpaired secretion of growth hormone-releasing hormone, growth hormone and IGF-1 in elderly men. Acta Endocrinol (Copenh). 1991 Jan;124(1):31-3 4. lranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the lrequency and amplitude oi growth hormone (GH) secretory bursts and the half-life oi endogenous GH in healthy men. J Clin Endocrinol Metab. 1991 Nov;73(5):1081-8 5. Rudman O, Rao UMP. The hypothalamic-growth hormone-somatomedin C axis: The effect of Aging. In: Endocrinology & Metabolism in the Elderl y1992, Eds Morley JC & Korenman SO, Blackwell Se Publ, Boston­ USA 6. Rolandi E, Franceschini R, Marabini A, Messina V, Cataldi A, Salvemini M, Barreca T. Twenty-four-hour beta­ endorphin secretory pattern in the elderly. Acta Endocrinol (Copenh). 1987 Aug;115(4):441-6 Senescence is associated with alterations in the circadian cycle of serum GH and its pulses of secretion: a reduced amplitude and a phase advance 7. Mazzoccoli G, Correra M, Bianco G, De Cata A, Balzanelli M, Giuliani A, Tarquini R. Age-related changes of neuro-endocrine-immune interactions in healthy humans. J Biol Regul Homeost Agents. 1997 Oct­ Dec;11(4):143-7 8. Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogo! AO, Kaiser DL, Thorner MO. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 1987 Jan;64(1):51-8

GH treatment may oppose and GH deficiency may trigger several mechanisms of senescence Failure of repair systems: GH accelerates repair 9. Revhaug A, Mjaaland M. Growth hormone and surgery. Horm Res. 1993;40(1-3):99-101 1O. Dahlgren LA, van der Meulen MC, Bertram JE, Starrak GS, Nixon AJ. lnsulin-like growth factor-1 improves cellular and molecular aspects oi healing in a collagenase-induced model of flexor tendinitis. J Orthop Res. 2002 Sep;20(5):910-9 1mmune deficiency: GH stimulates the immune system 11. Wise T, Klindt J, Macdonald GJ, Ford JJ. Effects of neonatal sexual differentiation, growth hormone and testosterone on thymic weights and thymosin-beta 4 in hypophysectomized rats. J Reprod lmmunol. 1991 Jan;19(1):43-54 12. Knyszynski A, Adler-Kunin S, Globerson A. Effects of growth hormone on thymocyte development from progenitor cells in the bone marrow. Brain Behav lmmun. 1992 Dec;6(4):327-40 13. Beschorner WE, Divic J, Pulido H, Yao X, Kenworthy P, Bruce G. Enhancement of thymic recovery after cyclosporine by recombinant human growth hormone and insulin-like growth factor I. Transplantation. 1991 Nov;52(5):879-84 Murphy WJ, Durum SK, Longo DL. Role oi neuroendocrine hormones in murine T cell development. Growth 14. hormone exerts thymopoietic effects in vivo. J lmmunol. 1992 Dec 15;149(12):3851-7 15. Kappel M, Hansen MB, Diamant M, Jorgensen JO, Gyhrs A. Pedersen BK. Effects of an acute bolus growth hormone infusion on lhe human immune system. Horm Metab Res. 1993 Nov;25(11):579-85) 16. Kudsk KA, Mowatt-Larssen C, Bukar J, Fabian T, Oellerich S, Dent DL, Brown R. Effect of recombinant human insulin-like growth factor I and early total parenteral nutrition on immune depression following severe head injury.Arch Surg. 1994 Jan;129(1):66-70 17. Takada Y, Bando H, Miyamoto Y, Kosaka M, Sano T. Effect oi growth hormone on immune function in normal and hypophysectomised rats. Nippon Naibunpi Gakkai Zasshi. 1991 Oct 20;67(10):1162-77

444

18.

19.

20.

21.

22. 23.

24.

Manfredi R, Tumietto F, Azzaroli L, Zucchini A, Chiodo F, Manfredi G. Growth hormone (GH) and the immune system: impaired phagocytic function in children with idiopathic GH deficiency is corrected by treatment with biosynthetic GH. J Pediatr Endocrinol. 1994 Jui-Sep;7(3):245-51 Jardieu P, Clark R, Mortensen D, Dorshkind K. In vivo administration of insulin-like growth factor-1 stimulates primary B lymphopoiesis and enhances lymphocyte recovery after bane marrow transplantation. J lmmunol. 1994 May 1;152(9):4320-7 Vara-Thorbeck R, Guerrero JA, Rosell J, Ruiz-Requena E, Capitan JM. Exogenous growth hormone: effects on the catabolic response to surgically produced acute stress and on postoperative immune function. World J Surg. 1993 Jui-Aug;17(4):530-7 Edwards CK 3rd, Ghiasuddin SM, Yunger LM, Lorence RM, Arkins S, Dantzer R, Kelley KW. In vivo administration of recombinant growth hormone or gamma interferon activities macrophages: enhanced resistance to experimental Salmonella typhimurium infection is correlated with generation of reactive oxygen intermediates. lnfect lmmun. 1992 Jun;60(6):2514-21 Huang KF, Chung DH, Herndon DN. lnsulin-like growth factor 1 (IGF-1) reduces gut atrophy and bacterial translocation after severe burn injury. Arch Surg. 1993 Jan;128(1):47-53 Peake GT, Mackinnon LT, Sibbitt WL Jr, Kraner JC. Exogenous growth hormone treatment alters body composition and increases naturalkiller cell activity in women with impaired endogenous growth hormone secretion. Metabolism. 1987 Dec;36(12):1115-7 Crist DM, Kraner JC. Supplemental growth hormone increases the tumor cytotoxic activity of natural killer cells in healthy adults with normal growth hormone secretion. Metabolism. 1990 Dec;39(12):1320-4

Limits to healthy cell proliferation: GH/IGF-1 stimulates fibroblast proliferation and differentiation Clemmons DR, Van Wyk JJ. Somatomedin-C and platelet-derived growth factor stimulate human fibroblast

25.

26.

replication. J Cell Physiol. 1981 Mar;106(3):361-7 van Osch GJ, van der Veen SW, Verwoerd-Verhoef HL. In vitro redifferentiation of culture-expanded rabbit and human auricular chondrocytes for cartilage reconstruction. Plast Reconstr Surg. 2001 Feb;107(2):433-40

Poor gene polymorphism: poor GH gene polymorphisms may increase the risk of age-related diseases 27.

28.

29.

Costalonga EF, Antonini SR, Guerra-Junior G, Mendonca BB, Arnhold IJ, Jorge AA. The -202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP3 serum leveis and better growth response to growth hormone treatment in patients with severe growth hormone deficiency. J Clin Endocrinol Metab. 2009 Feb;94(2):588-95 Jensen RB, Vielwerth S, Larsen T, Greisen G, Leffers H, Juul A. The presence of the d3-growth hormone receptor polymorphism is negatively associated with fetal growth but positively associated with postnatal growth in healthy subjects. J Clin Endocrinol Metab. 2007 Ju1;92(7):2758-63 Dennison EM, Syddall HE, Rodriguez S, Voropanov A, Day IN, Cooper C; Southampton Genetic Epidemiology Research Group.Polymorphism in the growth hormone gene, weight in infancy, and adult bone mass. J Clin Endocrinol Metab. 2004 Oct;89(10):4898-903

Progressive telomere shortening: GHRH may stimulate telomerase Kiaris H, Schally AV. Decrease in telomerase activity in U-87MG human glioblastomas after treatment with an 30. antagonist of growth hormone-releasing hormone. Proc Natl Acad Sei USA. 1999 Jan 5;96(1):226-31

GH and psychic well-being Lower quality of life and fatigue: the association with lower GH and/or IGF-1 leveis 31. Barbosa JA, Salvatori R, Oliveira CR, Pereira RM, Farias CT, Britto AV, Farias NT, Blackford A, Aguiar­

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Oliveira MH. Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency. Psychoneuroendocrinology. 2009 Jul;34(6):894-900 Wexler T, Gunnell L, Omer Z, Kuhlthau K, Beauregard C, Graham G, Utz AL, Biller B, Nachtigall L, Loeffler J, Swearingen B, Klibanski A, Miller KK. Growth hormone deficiency is associated with decreased quality of life in patients with prior acromegaly. J Clin Endocrinol Metab. 2009 Jul;94(7):2471-7 Kottowska-Hãggstrõm M, Kind P, Monson JP, Jonsson B. Growth hormone (GH) replacement in hypopituitary adults with GH deficiency evaluated by a utility-weighted quality of life index: a precursor to cost-utility analysis. Clin Endocrinol (Oxf). 2008 Jan;68(1):122-9. Webb SM. Measurements of quality of life in patients with growth hormone deficiency. J Endocrinol lnvest. 2008 Sep;31(9 Supp1):52-5 Deijen JB, Arwert LI. lmpaired quality of life in hypopituitary adults with growth hormone deficiency : can somatropin replacement therapy help? Treat Endocrinol. 2006;5(4):243-50

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Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Delemarre-van deWaal HA, Drent ML. Growth hormone deficiency

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Murray RD, Skillicorn CJ, Howell SJ, Lissett CA, Rahim A, Shalet SM. Dose titration and patient selection increases lhe efficacy oi GH replacement in severely GH deficient adults. Clin Endocrinol (Oxf). 1999 Jun;50(6):749-57

Lower quality of life and fatigue: the improvement with GH treatment 40.

Cenci MC, Soares DV, Spina LD, de Lima Oliveira Brasil RR, Lobo PM, Mansur VA, Gold J, Michmacher E, Vaisman M, Conceição FL. Eflects of 5 years oi growth hormone (GH) replacement therapy on cardiac parameters and physical performance in adults with GH deficiency. Pituitary. 2009;12(4):322-9

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Webb SM. Measurements of quality of life in patients with growth hormone deficiency. J Endocrinol lnvest. 2008 Sep;31(9 Suppl):52-5

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Fazio S, Palmieri EA, Affuso F, Cittadini A, Castellano G, Russo T, Ruvolo A, Napoli R, Saccà L. Effects oi growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure. J Clin Endocrinol Metab. 2007 Nov;92(11):4218-23

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Feldt-Rasmussen B, Lange M, Sulowicz W, Gafter U, Lai KN, Wiedemann J, Christiansen JS, El Nahas M; APCD Study Group. Growth hormone treatment during hemodialysis in a randomized trial improves nutrition,

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Peker Y, Svensson J, Hedner J, Grote L, Johannsson G. Sleep apnoea and quality oi life in growth hormone

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Zhang MM, Wu XT, Luo T, Qian K, Yang G. Eflect oi growth hormone combined with nutritional support on postoperative fatigue syndrome in patients after abdominal operations. Sichuan Da Xue Xue Bao Yi Xue Ban. 2006 Nov;37(6):913-5

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Feldt-Rasmussen U, Abs R, Bengtsson BA, Bennmarker H, Bramnert M, Hernberg-Stahl E, Monson JP, Westberg B, Wilton P, Wuster C; KIMS lnternational Study Board on behalf of KIMS Study Group.Growth hormone deficiency and replacement in hypopituitary patients previously treated for acromegaly or Cushing's disease. Eur J Endocrinol. 2002 Jan;146(1):67-74

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increases

lhe

concentration

of

growth

hormone

in

the

cerebrospinal

fluid

and

affects

neurotransmitters. Neuroendocrinology. 1995 Jan;61(1):57-66 (GH increases endorphins, reduces dopamine)

Anxiety: the association with lower GH and/or IGF-1 leveis Tancer ME, Stein MB, Uhde TW. Growth hormone response to intravenous clonidine in social phobia: 87. comparison to patients with panic disorder and healthy volunteers. Biol Psychiatry. 1993 Nov 1;34(9):591-5 Cameron OG, Abelson JL, Young EA. Anxious and depressive disorders and their comorbidity: effect on 88. central nervous system noradrenergic function. Biol Psychiatry. 2004 Dec 1;56(11):875-83 89.

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Memory loss and Alzheimer's disease: the association with lower GH and/or IGF-1 leveis Falleti MG, Maruff P, Burman P, Harris A. The effects of growth hormone (GH) deficiency and GH replacement on cognitive performance in adults: a meta-analysis of the current literature. Psychoneuroendocrinology. 2006 Jul;31(6):681-91 Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Delemarre-van deWaal HA, Drent ML. Growth hormone 94. 93.

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Mar;47(3):343-9 Deijen JB, de Boer H, van der Veen EA. Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology. 1998 Jan;23(1 ):45-55 Koppeschaar HP. Growth hormone, insulin-like growth factor I and cognitive function in adults. Growth Horm IGF Res. 2000 Apr;10 Suppl 8:869-73

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lsmailogullari S, Tanriverdi F, Kelestimur F, Aksu M. Sleep architecture in Sheehan's syndrome before and 6 months after growth hormone replacement therapy. Psychoneuroendocrinology. 2009 Feb;34(2):212-9 Astrom C, Lindholm J. Growth hormone-deficient young adults have decreased deep sleep. Neuroendocrinology. 1990 Jan;51(1):82-4

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TOPICS OF DISCUSSION

GH TREATMENT'S INELUENCE ON GH ENDOGENOUS SECRETION: normally no adverse influence when used at physiological doses

Normal doses of GH do not change the endogenous GH secretion 1.

Wu RH, St Louis Y, DiMartino-Nardi J, Wesoly S, Sobe! EH, Sherman B, Saenger P. PreseNation of physiological growth hormone (GH) secretion in idiopathic short stature after recombinant GH therapy. J Clin Endocrinol Metab. 1990 Jun;70(6):1612-5 (data show that exogenous GH therapy does not interfere with lhe

maintenance of endogenous pulsatile secretion of GH: pre- and (48 hours after stopping) posttreatment GH secretory profiles were comparable with respect to the number of peaks, mean concentrations, peak amplitude, and secretory rale, even after 12 months of GH treatment) Pharmacological doses of GH mildly and temporarily reduce the GH-response to GRE in healthy and diabetics with insulin secretion, but does not influence it in diabetics without insulin secretion 2.

Wurzburger Ml, Prelevic GM, Sonksen PH, Balint-Peric LA, Wheeler M. The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes. J Clin Endocrinol Metab. 1993 Jul;77(1):267-72 (The response of GH to GRF in diabetics without residual

beta-ce/1 activity (C peptide negative) was almost unchanged after 7 days of high dose 4 IU!day of GH treatment, whereas it became lowered in diabetics with endogenous pancreatic beta-ce/1 activity (C peptide positive) and contrais)

EXERCISE AS AN ALTERNATIVE TO GH TREATMENT Claim: lt is enough to let elderly patients regularly exercise to increase their IGF-1 back to youthful leveis, GH therapy is no! necessary for !hem. Eact: Exercise does generally no! significantly increase GH and IGF-1 in elderly persons, and certainly no! to youthful levels.

Arguments contra GH therapy Exercise may increase GH, but more rarely IGE-1 leveis, in young adults persons to satisfying leveis Kraemer WJ, Aguilera BA, Terada M, Newton RU, Lynch JM, Rosendaal G, McBride JM, Gordon SE, Hakkinen K. Responses of IGF-1 to endogenous increases in growth hormone after heavy-resistance exercise.

1.

J Appl Physiol. 1995 Oct;79(4):1310-5. 2.

Nemet D, Connolly PH, Pontello-Pescatello AM, Rose-Gottron C, Larson JK, Galassetti P, Cooper DM. Negativa energy balance plays a major role in lhe IGF-1 response to exercise training. J Appl Physiol. 2004 Jan;96(1 ):276-82

Exercise causes 3.

a

significant GH response in elderly men, but not in elderly women (>70 yr)

Hakkinen K, Pakarinen A, Kraemer WJ, Newton RU, Alen M. Basal concentrations and acute responses of serum hormones and strength development during heavy resistance training in middle-aged and elderly men and women. J Gerontol A Biol Sei Med Sei. 2000 Feb;55(2):B95-105

Twice a week heavy exercise for 24 weeks in elderly men and women causes a significant GH response, but less than in young men Hakkinen K, Pakarinen A, Hannonen P, Hakkinen A, Airaksinen O, Valkeinen H, Alen M. Effects of strength 4. training on muscle strength, cross-sectional area, maximal electromyographic activity, and serum hormones in premenopausal women with fibromyalgia. J Rheumatol. 2002 Jun;29(6):1287-95 Hakkinen K, Pakarinen A, Newton RU, Kraemer WJ. Acute hormone responses to heavy resistance lower and 5. upper extremity exercise in young versus old men. Eur J Appl Physiol Occup Physiol. 1998 Mar;77(4):312-9 16 weeks of training causes a significant GH response after acute exercise in elderly men (60 yrs), but does not change the serum IGF-1 Nicklas BJ, Ryan AJ, Treuth MM, Harman SM, Blackman MR, Hurley BF, Rogers MA. Testosterone, growth 6. hormone and IGE-1 responses to acute and chronic resistive exercise in men aged 55-70 years. In! J Sports Med. 1995 Oct;16(7):445-50

465

Conclusion: Only heavy (unhealthy?) exercise acutely increases GH secretion in some studies with elderly persons, but not as much as in young people and it does not increase GH metabolic activity, reflected by serum IGF-1. Arguments pro GH therapy: Exercise alone does not really help to correct low GH and IGF-1 leveis in elderly persons who are usually lhe ones who need most Gh supplementation No significant (O to + 3 %) GH response to exercise in elderly persons 7. Pyka G, Wiswell RA, Marcus R. Age-dependent effect of resistance exercise on growth hormone secretion in people. J Clin Endocrinol Metab. 1992 Aug;75(2):404-7 Craig BW, Brown R, Everhart J. Effects of progressive resistance training on growth hormone and 8. testosterone leveis in young and elderly subjects. Mech Ageing Dev. 1989 Aug;49(2):159-69 Hakkinen K, Pakarinen A. Acute hormonal responses to heavy resistance exercise in men and women at 9. different ages. lnt J Sports Med. 1995 Nov;16(8):507-13 10. Figueroa A, Going SB, Milliken LA, Blew RM, Sharp S, Teixeira PJ, Lohman TG. Effects of exercise training and hormone replacement therapy on Jean and fat mass in postmenopausal women. J Gerontol A Biol Sei Med Sei. 2003 Mar;58(3):266-70 11. Hakkinen K, Pakarinen A, Kraemer WJ, Hakkinen A, Valkeinen H, Alen M. Selective muscle hypertrophy, changes in EMG and force, and serum hormones during strength training in older women. J Appl Physiol. 2001 Aug;91(2):569-80 12. Kiilavuori K, Naveri H, Leinonen H, Harkonen M. The effect of physical training on hormonal status and

13.

exertional hormonal response in patients with chronic congestive heart failure. Eur Heart J. 1999 Mar;20(6):456-64 Kostka T, Patricot MC, Mathian B, Lacour JR, Bonnefoy M. Anabolic and catabolic hormonal responses to experimental two-set low-volume resistance exercise in sedentary and active elderly people. Aging Clin Exp Res. 2003 Apr;15(2):123-30

GH TREATMENT ANO MUSCLE STRENGTH Claim: GH treatment does not increase muscle strength in adults, so it is not useful for them. Fact: GH treatment has been reported to help elderly adults increase their muscle strength. Welle S, Thornton C, Statt M, McHenry B.Growth hormone increases muscle mass and strength but does not rejuvenate myolibrillar protein synthesis in healthy subjects over 60 years old. J Clin Endocrinol Metab 1996 Sep;81(9):3239-43

GH TREATMENT ANO FUNCTIONAL CAPACITIES Claim: GH treatment does not increase functional capacities. Fact: lt does: breathing capacity in patients with chronic bronchitis for example. 1.

Pape GS, Friedman M, Underwood LE, Clemmons DR. The effect of growth hormone on weight gain and pulmonary function in patients with chronic obstructive lung disease. Chest. 1991 Jun;99(6):1495-500

GH TREATMENT ANO METABOLIC RATE Claim: GH treatment does not increase resting metabolic rale. Fact: On the contrary, it does. An association between GH production and resting metabolic rate has been found, at least in young adults 1. Jorgensen JO, Vahl N, Dali R, Christiansen JS. Resting metabolic rale in healthy adults: relation to growth hormone status and leptin leveis. Metabolism. 1998 Sep;47(9):1134-9 ("in lhe young subgroup, GH production

rale was a positive determinant of resting metabolic ratellean body mass'} 2.

Medicai Department M (Endocrinology and Diabetes), Aarhus University Hospital, Denmark.

GH therapy increases resting metabolic rate 3. Snel YE, Doerga ME, Brummer RJ, Zelissen PM, Zonderland ML, Koppeschaar HP. Resting metabolic rate, body composition and related hormonal parameters in growth hormone-deficient adults before and after growth hormone replacement therapy. Eur J Endocrinol. 1995 Oct;133(4):445-50

466

GH TREATMENT ANO ADVERSE EFFECTS Claim: GH treatment has substantial adverse elfects such as edema, etc. Fact: Substantial adverse elfects only appear at overdoses such as is lhe case for any other. medicai treatment, it is sufficient to reduce the dose to avoid them. 1.

Wuster C, Melchinger U, Eversmann T, Hensen J, Kann P, von zur Muhlen A, Ranke MS, Schmeil H, Steinkamp H, Tuschy U. Reduced incidence of side-elfects of growth hormone substitution in 404 patients with hypophyseal insufficiency. Results of a multicenter indications Study. Med Klin. 1998 Oct 15;93(10):58591

2.

Amato G, lzzo G, La Montagna G, Bellastella A. Low dose recombinant human growth hormone normalizes bone metabolism and cortical bone density and improves trabecular bone density in growth hormone deficient adults without causing adverse elfects. Clin Endocrinol (Oxf). 1996 Jul;45(1):27-32 (no adverse effects with

doses of 10f,1g!kg/day or a mean of 500-800 f.lg lday) 3.

Chihara K, Koledova E, Shimatsu A, Kato Y, Kohno H, Tanaka T, Teramoto A, Bates PC, Attanasio AF. An individualized GH dose regimen for long-term GH treatment in Japanese patients with adult GH deficiency. Eur J Endocrinol. 2005 Jul;153(1):57-65 ("The incidence of oedema and cases with high IGF-1/evel were less

frequent under the /GF-1 controlled regimen compared with those during the fixed-dose titration method'')

GH TREATMENT ANO THE DIABETES CONTROVERSY Suspicion: Can GH at physiological doses cause diabetes? Facts: GH's role is to preveni hypoglycaemia by elevating the low serum glucose leveis of GH deficient subjects back to normal. lt does not at physiological doses cause diabetes.

Arguments contra GH use GH is a hyperglycemic hormone 1.

Ward PS, Savage DC. Growth hormone responses to sleep, insulin hypoglycaemia and arginine infusion. Horm Res. 1985;22(1-2):7-11

Treatment of GH-deficient children: higher incidence of diabetes 2.

Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, Price DA . lncidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. : Lance!. 2000 Feb 19;355(9204):610-3 ("GH treatment did not affect the incidence of type 1

diabetes mellitus in any age group. ... the higher than expected incidence of type 2 diabetes mellitus with GH treatment may be an acceleration of the disorder in predisposed individuais. Type 2 diabetes did not resolve after GH therapy was stopped.·:· critics: very high GH doses are used in children; no increased incidence of type 2 diabetes has been seen in adults taking GH) Serum GH leveis are higher in diabetes patients (critics: yes, two times higher serum GH, but -50% /ow er serum /GF-1, which reflects GH activity; insulin treatment of diabetes significantly increases serum IGF-1 and lower GH) Shishko Pl, Sadykova RE, Kovalev PA, Goncharov BV. lnsulin-like growth factor I in patients with newly 3. detected insulin-dependent diabetes mellitus. Probl Endokrinol (Mosk). 1992 Jan-Feb;38(1):17-9 Acromegaly is associated with an increased incidence of diabetes 4.

Mercado M, Espinosa de los Monteros AL, Sosa E, Cheng S, Mendoza V, Hernandez I, Sandoval C, Guinto G, Molina M. Clinical-biochemical correlations in acromegaly at diagnosis and the real prevalence of biochemically discordant disease. Horm Res. 2004;62(6):293-9.

5.

Mestron A, Webb SM, Astorga R, Benito P, Catala M, Gaztambide S, Gomez JM, Halperin I, Lucas-Morante T, Moreno 8, Obiols G, de Pablos P, Paramo C, Pico A, Torres E, Varela C, Vazquez JA, Zamora J, Albareda M, Gilabert M. Epidemiology, clinicai characteristics, outcome, morbidity and mortality in acromegaly based on lhe Spanish Acromegaly Registry (Registro Espano! de Acromegalia, REA). Eur J Endocrinol. 2004 Oct;151(4):439-46

6.

Fukuda I, Hizuka N, Murakami Y, ltoh E, Yasumoto K, Sala A, Takano K. Clinicai features and therapeutic outcomes of 65 patients with acromegaly at Tokyo Women's Medicai University. lntern Med. 2001 Oct;40(10):987-92

467

Arguments pro GH use: lnsulin secretion: the tonic secretion of insulin from the beta-cells depends on IGF-1 7. Kulkarni RN, Holzenberger M, Shih DO, Ozcan U, Stoffel M, Magnuson MA, Kahn CR. Beta-cell-specific deletion of the lgf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet. 2002 May;31(1):111-5 GH is an anti-hypoglycemic hormone: it neutralizes hypoglycaemia 8. Ward PS, Savage DC. Growth hormone responses to sleep, insulin hypoglycaemia and arginine infusion. Horm Res. 1985;22(1-2):7-11 9.

West TE, Sonksen PH. ls the growth-hormone response to insulin due to hypoglycaemia, hyperinsulinaemia or a fali in plasma free fatty acids? Clin Endocrinol (Oxf). 1977 Oct;7(4):283-8 (hypoglycaemia per se was the

10.

Khaleeli A, Perumainar M, Spedding AV, Teale JD, Marks V. Treatment of tumour-induced hypoglycaemia with human growth hormone. J R Soe Med. 1992 May;85(5):303

important stimulus to GH secretion and not hyperinsulinaemia or a lowering of plasma free fatty acids)

IGF-1 therapy has insulin-like effects: it reduces glycemia and serum insulin in controls and type 2 diabetic patients 11. Moses AC, Young SC, Morrow LA, O'Brien M, Clemmons DR. Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type 11 diabetes. Diabetes. 1996 Jan;45(1):91100 Diabetes: the association with lower GH anclfor IGF-1 leveis 12. Nam SY, Kim KR, Cha BS, Song YD, Lim SK, Lee HC, Huh KB. Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients. lnt J Obes Relat Metab Disord. 2001 Aug;25(8):1101-7

a lower /GF-1 in insu/in­ dependent diabetes pubers is associated with a higher serum glycosylated hemoglobine HbA 1 C)

Diabetes patients have high GH, but low IGF-1, marker of GH metabolic activity: 13.

Clayton KL, Holly JM, Carlsson LM, Jones J, Cheetham TD, Taylor AM, Dunger DB. Loss of the normal relationships between growth hormone, growth hormone-binding protein and insulin-like growth factor-1 in adolescents with insulin-dependent diabetes mellitus. Clin Endocrinol (Oxf). 1994 Oct;41(4):517-24

Acromegaly: GH production in acromegaly is 10 to 100 times the normal production; 10 to 300 times the doses used in GH therapy. The pituitary GH-secreting tumor in the sella turcica crushes down the production of other pituitary hormones such as ACTH, LH, FSH, TSH, creating a polyhormonal deficit: hypothyroidism, hypogonadism, hypocorticism, .. , endocrine conditions that increase the risk of glucose intolerance and diabetes. These conditions are not found in corrective GH treatment of GH deficiency. 14. van den Berg G, Frolich M, Veldhuis JD, Roelfsema F. Growth hormone secretion in recently operated acromegalic patients. J Clin Endocrinol Metab. 1994 Dec;79(6):1706-15 ("Patients with active acromegaly

...secretion rate per 24 h was 25 times greater in tema/e acromegalics and 100 times greater in ma/e acromegalics than that in the contrais'? 15.

Lamberton RP, Jackson IM. lnvestigation of hypothalamic-pituitary disease. J Clin Endocrinol Metab. 1983 Nov;12(3):509-34 ('The possibility of deficiencies of the other pituitary hormones should then be addressed in

patients with secretory tumours. In patients with large macroadenomas pituitary hormone deficiencies are almost invariable with GH and FSH/LH being the most commonly affected, followed by TSH and ACTH in that arder. Basal thyroid function tests, serum oestradiol or testosterone, and basal gonodotrophins should be routinely obtained in patients with macroadenomas. Additionally, the integrity of the pituitary-adrenal axis should be determined and an overnight water deprivation test for assessment of neurohypophyseal function is also recommended.'? 16.

Snyder PJ, Bigdeli H, Gardner DF, Mihailovic V, Rudenstein RS, Sterling FH, Utiger RD. Gonadal function in fifty men with untreated pituitary adenomas. J Clin Endocrinol Metab. 1979 Feb;48(2):309-14

17.

Valenta LJ, Sostrin RD, Eisenberg H, Tamkin JA, Elias AN. Diagnosis of pituitary tumors by hormone assays and computerized tomography. Am J Med. 1982 Jun;72(6):861-73

GH therapy increases first the glycemia, then reduces it when given to HIV-infected patients with fat accumulation: 18. Lo JC, Mulligan K, Noor MA, Schwarz JM, Halvorsen RA, Grunfeld C, Schambelan M. The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab. 2001 Aug;86(8):3480-7

468

GH therapy at physiological doses to type 1 diabetic patients: no effect on glycemia 19. Bright GM, Melton RW, Rogol AD, Clarke WL. The effect of exogenous growth hormone on insulin requirements during closed loop insulin delivery in insulin-dependent diabetes mellitus. Horm Metab Res. 1984 Jun;16(6):286-9 GH therapy to type 1 diabetic patients: increased insulin requirements, but improved the control of hypoglycaemic attacks 20. Christ ER, Simpson HL, Breen L, Sonksen PH, Russeii-Jones DL, Kohner EM. The effect of growth hormone (GH) replacement therapy in adult patients with type 1 diabetes mellitus and GH deficiency. Clin Endocrinol (Oxf). 2003 Mar;58(3):309-15 Low dose GH therapy (0.10 mg/day) improves insulin sensitivity in young healthy adults 21. Yuen KC, Frystyk J, White DK, Twickler TB, Koppeschaar HP, Harris PE, Fryklund L, Murgatroyd PR, Dunger DB. lmprovement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency. Clin Endocrinol (Oxf). 2005 Oct;63(4):428-36 ('The low GH dose (0.10 mg/day) decreased fasting

glucose leveis (P < 0.01) and enhanced insu/in sensitivity (P mg/day) did not modify insu/in sensitivity")

<

0.02), the standard GH (mean dose 0.48

Diabetes: the improvement with GH treatment

23.

Gotherstrom G, Svensson J, Koranyi J, Alpsten M, Bosaeus I, Bengtsson B, Johannsson G. A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices. J Clin Endocrinol Metab. 2001 Oct;86(10):4657-65 Svensson J, Fowelin J, Landin K, Bengtsson BA, Johansson JO. Effects of seven years of GH-replacement

24.

therapy on insulin sensitivity in GH-deficient adults. J Clin Endocrinol Metab. 2002 May;87(5):2121-7 Clayton KL, Holly JM, Carlsson LM, Jones J, Cheetham TD, Taylor AM, Dunger DB. Loss of the normal

22.

25.

relationships between growth hormone, growth hormone-binding protein and insulin-like growth factor-1 in adolescents with insulin-dependent diabetes mellitus. Clin Endocrinol (Oxf). 1994 Oct;41(4):517-24 Yuen KC, Frystyk J, White DK, Twickler TB, Koppeschaar HP, Harris PE, Fryklund L, Murgatroyd PR, Dunger DB. lmprovement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency. Clin Endocrinol (Oxf). 2005 Oct;63(4):428-36

GH ANO CARDIOVASCULAR SYSTEM Claim: GH treatment has adverse effects on the cardiovascular system. Facts: Most studies are reports of beneficiai effects of GH on lhe heart and blood vessels. Arguments contra GH use: mainly based on studies of excess GH LEVELS and their correction Acromegalic patients have an increased heart disease mortality (critics: acromegaly is a disease with GH and .

IGF-1 leveis severa/ times those obtained with a safe corrective GH treatment, with a Gh production that is 25 to 100 times the normal daily production; the acromegalic heart has myocardial hypertrophy with proliferation of the myocardial fibrous tissue, resulting in impaired ventricular relaxation, and eventually heart failure, a condition that is not found in GH deficient adults treated with correct doses of GH) 1. 2.

Erfurth EM, Hagmar L. Cerebrovascular disease in patients with pituitary tumors. Trends Endocrinol Metab. 2005 Sep;16(7):334-42 Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug;83(8):2730-4

Critics: in acromegaly is the GH production 10 to 100 times the normal production, 10 to 300 times the doses used in GH therapy. The pituitary GH-secreting tumor in the sella turcica crushes down the production of other pituitary hormones such as ACTH, LH, FSH, TSH, creating a polyhormonal deficit: hypothyroidism, hypogonadism, hypocorticism, endocrine conditions that increase the risk of glucose intolerance anddiabetes. These conditions are not found in corrective GH treatment of GH deficiency. 3. van den Berg G, Frolich M, Veldhuis JD, Roelfsema F. Growth hormone secretion in recently operated acromegalic patients. J Clin Endocrinol Metab. 1994 Dec;79(6):1706-15 ("Patients with active acromegaly

... secretion rate per 24 h was 25 x greater in tema/e acromegalics & 100 x greater in ma/e acromegalics than that in the contrais'')

469

4.

5. 6.

Lamberton RP, Jackson IM. lnvestigation of hypothalamic-pituitary disease. Clin Endocrinol Metab. 1983 Nov;12(3):509-34 ("'n patients with /arge macroadenomas pituitary hormone deficiencies are almost invariable with GH and FSH/LH being the most commonly affected, fol/owed by TSH and ACTH in that arder") Snyder PJ, Bigdeli H, Gardner DF, Mihailovic V, Rudenstein RS, Sterling FH, Utiger RD. Gonadal function in fifty men with untreated pituitary adenomas. J Clin Endocrinol Metab. 1979 Feb;48(2):309-14 Valenta LJ, Sostrin RD, Eisenberg H, Tamkin JA, Elias AN. Diagnosis of pituitary tumors by hormone assays and computerized tomography. Am J Med. 1982 Jun;72(6):861-73

Octreotide therapy of acromegaly suppresses GH production and reverses the heart disease Sacca L, Cittadini A, Fazio S. Growth hormone and lhe heart. Endocr Rev. 1994 Oct;15(5):555-73 7. Merola B, Cittadini A, Colao A, Ferone D, Fazio S, Sabatini D, Biondi B, Sacca L, Lombardi G. Chronic 8. treatment with lhe somatostatin analog octreotide improves cardiac abnormalities in acromegaly. J Clin Endocrinol Metab. 1993 Sep;77(3):790-3 Arguments pro GH use: GH treatment improves lhe failing GH heart of GH deficient persons GH improves the heart function 9.

10. 11.

Cittadini A, Berggren A, Longobardi S, Ehrnborg C, Napoli R, Rosen T, Fazio S, Caidahl K, Bengtsson BA, Sacca L. Supraphysiological doses of GH induce rapid changes in cardiac rnorphology and function. J Clin Endocrinol Metab. 2002 Apr;87(4):1654-9 Napoli R, Guardasole V, Matarazzo M, Palmieri EA, Oliviero U, Fazio S, Sacca L. Growth hormone corrects vascular dysfunction in patients with chronic heart failure. J Am Coll Cardiol. 2002 Jan 2;39(1):90-5 Fazio S, Sabatini D, Capaldo B, Vigorito C, Giordano A, Guida R, Pardo F, Biondi B, Sacca L. A prelirninary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996 Mar 28;334(13):80914

GH deficient patients have a higher rate of myocardial infarction risk and mortality Svensson J, Bengtsson BA, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12

12.

The premature mortality in hypopituitarism (and thus GH deficiency) is due to cardiovascular disease 13.

Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lance!. 1990 Aug 4;336(871 0):285-8

Coronary heart disease: the association with lower GH ancl/or IGF-1 leveis Conti E, Andreotti F, Sciahbasi A, Riccardi P, Marra G, Menini E, Ghirlanda G, Maseri A. Markedly reduced

14.

insulin-like growth factor-1 in lhe acute phase of myocardial infarction. J Am Coll Cardiol. 2001 Jul;38(1):26-32 Hypopituitarism increases the cerebrovascular mortalily Bulow B, Hagmar L, Mikoczy Z, Nordstrom CH, Erfurth EM. lncreased cerebrovascular mortality in patients 15. with hypopituitarism. Clin Endocrinol (Oxf). 1997 Jan;46(1):75-81 GH deficient patients have a higher incidence of cerebrovascular events 16.

17.

Svensson J, Bengtsson BÁ, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12 Cittadini A, Cuocolo A, Merola B, Fazio S, Sabatini D, Nicolai E, Colao A, Longobardi S, Lombardi G, Sacca L. lmpaired cardiac performance in GH-deficient adults and its improvement after GH replacement. Am J Physiol. 1994 Aug;267(2 Pt 1):E219-25

GH TREATMENT GH therapy to GH deficient patients: normalizes the (excessive) rate of myocardial infarction and its mortality 18. Svensson J, Bengtsson BÁ, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12 GH treatment may improve coronary heart disease 121. Castagnino HE, Lago N, Centrella JM, Calligaris SD, Farina S, Sarchi Ml, Cardinali DP. Cytoprotection 19. by melatonin and growth hormone in early rat myocardial infarction as revealed by Feulgen DNA staining. Neuroendocrinol Lett 2002 Oct-Dec;23(5/6):391-395

470

GH therapy partially normalizes the higher incidence of cerebrovascular events found in GH deficient patients 20.

Svensson J, Bengtsson BA, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular

21.

Cittadini A, Cuocolo A, Merola B, Fazio S, Sabatini D, Nicolai E, Colao A, Longobardi S, Lombardi G, Sacca L.

morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7}:3306-12

lmpaired cardiac performance in GH-deficient adults and its improvement after GH replacement. Am J

Physiol. 1994 Aug;267(2 Pt 1):E219-25

GH ANO CANCER Claim: GH increases the risk of cancer

Facts: The epidemiological studies, which indicate an association between serum IGF-1 and cancer risk, have not established causality. An increased cancer risk with GH therapy has not been proven in humans.

Arguments contra GH use: GH LEVELS: Studies where positive associations between higher serum GH and/or IGF-1 leveis and an increased risk of prostate or breast cancer Studies where a higher serum IGF-1 and/or high IGF-1 to IGFBP-3 molar ratio was found associated with an increased risk of prostate cancer (critics: the increased IGF-1 may be due to local production of IGF-1 by the

tumour and may thus be a marker, and not a cause of cancer, or a bias due to nutritional fators - see further) Peng L, Tang S, Xie J, Luo T, Dai B. Quantitative analysis oi IGF-1 and its application in lhe diagnosis of

1. 2.

3.

4.

prostate cancer. Hua Xi Yi Ke Da Xue Xue Bao. 2002 Jan;33(1):137 Li L, Yu H, Schumacher F, Casey G, Witte JS. Relation of serum insulin-like growth factor-1 (IGF-1) and IGF

binding protein-3 to risk of prostate cancer (United States). Cancer Causes Control. 2003 Oct;14(8):721-6

Chokkalingam AP, Pollak M, Fillmore CM, Gao YT, Stanczyk FZ, Deng J, Sesterhenn IA, Mostofi FK, Fears TR, Madigan MP, Ziegler RG, Fraumeni JF Jr, Hsing AW. lnsulin-like growth factors and prostate cancer: a

population-based case-control study in China. Cancer Epidemiol Biomarkers Prev. 2001 May;10(5):421-7

Harman SM, Metter EJ, Blackman MR, Landis PK, Carter HB. Baltimore Longitudinal Study on Aging. Serum leveis of IGF-1, IGF-11, IGF-BP-3, and PSA as predictors of clinicai prostate cancer. J Clin Endocrinol Metab. 2000 Nov;85(11):4258-65

Studies where a higher serum GH was found associated with an increased risk of breast cancer (critic: based

on the measurement of the daytime serum GH teve/, which is not representative of GH 24-hour secretion) Emerman JT, Leahy M, Gout PW, Bruchovsky N. Elevated growth hormone leveis in sera from breast cancer

5.

patients. Horm Metab Res. 1985 Aug;17(8):421-4 Studies where a higher serum IGF-1 or IGF-1/IGF-BP-3 ratio is found associated with an increased risk of breast cancer, in particular in women with;:: 19 CA repeats in IGF-1 gene

6.

Yu H, Li BD, Smith M, Shi R, Berkel HJ, Kato 1.. Polymorphic CA repeats in the IGF-1 gene and breast cancer.

7.

Vadgama JV, Wu Y, Datta G, Khan H, Chillar R. Plasma insulin-like growth factor-1 and serum IGF-binding

Breast Cancer Res Treat. 2001 Nov;70(2}:117-22

protein 3 can be associated with lhe progression of breast cancer, and predict lhe risk of recurrence and lhe probability of survival in African-American and Hispanic women. Oncology. 1999 Nov;57(4):330-40 (up to 7x

greater breast cancer incidence in women in the highest quintile of serum IGF-1: serum IGFBP-3 ratio compared to women in the lowest quintile) A study where a lower serum IGF-BP-3 was found in breast cancer patients

8.

Bruning PF, Van Doorn J, Bonfrer JM, Van Noord PA, Korse CM, Linders TC, Hart AA. lnsulin-like growth­

factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer. lnt J Cancer.

1995 Jul 28;62(3):266-70

A study where a higher serum IGF-1 / IGF-BP-3 was found associated with an increased colon cancer risk

(the colon cancer risk was 4 times increased on/y for subjects in the upper tertile of IGF-1 and Jower tertile of /GF-BP3; for other tertiles or a combination of tertiles there was: no significant association) 9. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ. Prospecftive study of colorectal cancer risk in men and plasma leveis of IGF-1 and IGF-BP-3. J Natl Cancer lnst. 1999; 91: 620-5

471

In acromegaly, the incidence of and/or mortality from digestive cancer is increased 10.

Ron E, Gridley G, Hrubec Z, Page W, Arara S, Fraumeni JF Jr. Acromegaly and gastrointestinal cancer. Cancer. 1991 Oct 15;68(8):1673-7 (but no increase in overa/1 cancer incidence)

11.

Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug;83(8):2730-4 (but decreased overa/1 incidence of cancer in acromegaly, and no increased overa/1 cancer

mortality) Critics: in acromegaly the GH production is 10 to 100 times the normal production, 10 to 300 times the daily doses used in GH therapy. The pituitary GH-secreting tumor in lhe sella turcica crushes down lhe production of other pituitary hormones such as ACTH,

LH, FSH, TSH, creating a polyhormonal deficit: hypothyroidism,

hypogonadism, hypocorticism, .., endocrine conditions that increase lhe risk of glucose intolerance and diabetes These conditions are not found in corrective GH treatment oi GH deliciency. 12.

van den Berg G, Frolich M, Veldhuis JD, Roellsema F. Growth hormone secretion in recently operated acromegalic patients. J Clin Endocrinol Metab. 1994 Dec;79(6):1706-15 ("Patients with aclive acromegaly

...secretion rate per 24 h was 25 x greater in tema/e acromegalics & 100 x greater in mate acromegalics than that in the contrais'] 13.

Lamberton RP, Jackson IM. lnvestigation oi hypothalamic-pituitary disease. Clin Endocrinol Metab. 1983 Nov;12(3):509-34 ('In patients with large macroadenomas pituitary hormone deficiencies are almost invariable

14. 15.

with GH and FSH/LH being the most commonly affected, followed by TSH and ACTH in that arder 'J Gonadal lunction in lifty men with untreated pituitary adenomas. J Clin Endocrinol Metab. 1979 Feb;48(2):309-14 Valenta LJ, Sostrin RD, Eisenberg H, Tamkin JA, Elias AN. Diagnosis oi pituitary tumors by hormone assays and computerized tomography. Am J Med. 1982 Jun;72(6):861-73 Snyder PJ, Bigdeli H, Gardner DF, Mihailovic V, Rudenstein RS, Sterling FH, Utiger RD.

GH TREATMENT WITH HUMAN PITUITARY GH HORMONE A study where lhe use of human pituitary GH as therapy to GH-deficient patients treated during childhood and early adulthood up to 1985 was associated with an increased risk of colon cancer and overall cancer mortality (critics: the data are based on patients having taken GH extracted from human cadavers, now only biosynthetic growth hormone is used; moreoever, the doses used in childhood are extremely high - at Jeast seven times those used in treatment of GH-deficiency in adults) 16. Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in lhe UK, 1959-85: a cohort study. Lancei. 2002 Jul 27;360(9329):273-7

Neutra! information and alternative explanations on a possible GH and cancer relation

ªjª{>.J.: The diagnosis of cancer may be more rapidly made in patients with high IGF-1 because they may undergo more intensive scrutiny: As raised /GF-1 may cause tissue hyperplasia, inc/uding increase in size of prostate and breast tissue, the existence of these bigger tissues and possibly of the symptoms they may cause, may lead to more intensive scrutiny, from increased rate of PSA, CEA or C1.25 measurements, to ultrasound and RX examinations, prostate or breast biopsies, and thus an increased rate of detection of very slow, asymptomatic prostate or breast cancers that would have remained undiagnosed or diagnosed much /ater in patients with low IGF-1. Such higher rate of cancer detection may be particular/y the case for prostate cancer, where the number of detected prostate cancer cases is very low compared to the total number of cases found at autotopsy, and premenopausal breast cancer patients who were diagnosed within the 2 years after the first blood sample. 17.

Cohen P, Clemmons DR, Rosenfeld RG. Does lhe GH-IGF axis play a role in cancer pathogenesis? Growth Horm IGF Res. 2000 Dec;10(6):297-305

Higher leveis of IGF-1 or GH or acromegaly have been associated with benign prostatic hyperplasia, but not necessarily with prostate cancer 18. Chokkalingam AP, Gao YT, Deng J, Stanczyk FZ, Sesterhenn IA, Mostoli FK, Fraumeni JF Jr, Hsing AW. lnsulin-like growth lactors and risk of benign prostatic hyperplasia. Prostate. 2002 Jul 1;52(2):98-105. 19.

Colao A, Marzullo P, Ferone D, Spiezia S, Cerbone G, Marino V, Di Sarna A, Merola B, Lombardi G. Prostatíc hyperplasia: an unknown feature of acromegaly. J Clin Endocrinol Metab. 1998 Mar;83(3):775-9

472

GH and IGF-1 treament of primates can increase breast hyperplasia, not specifically breast cancer Ng ST, Zhou J, Adesanya 00, Wang J, LeRoith O, Bondy CA. Growth hormone treatment induces mammary

20.

gland hyperplasia in aging primates. Nat Med. 1997 Oct;3(10):1141-4

�!!!!l ?.: After adjustment for prostate volume, no longer significant associations between serum IGF-1 and ..

prostate cancer risk may persist (Serum /GF-1 is not useful for diagnosis of prostate cancer, but a marker

of benign prostatic hyperplasia and enlargement) Finne P, Auvinen A, Koistinen H, Zhang WM, Maattanen L, Rannikko S, Tammela T, Seppala M, Hakama M,

21.

Stenman UH.

lnsulin-like growth factor

I is not a useful marker of prostate cancer in men with elevated leveis

of prostate-specific antigen. J C/in Endocrinol Metab. 2000 Aug;85(8):2744-77

�!!!ll �: Serum IGF-1 may actually be a surrogate marker of nutritional factors that may increase the cancer risk ..

such as meat and milk intake (persons who eat a lot of protein, especially red meat, have higher /GF-1 leveis and an increased cancer risk) Dai O, Xiao-ou Shu, Fan Jin, Yu-Tang Gao, Zhi-Xian Ruan, Zheng W. Consumption of animal foods, cooking methods, and risk of breast cancer. Cancer Epidemia/ Biom Prev. 2002;11 :801-8

22.

Link between meat, milk and/or protein intake, and prostate or breast cancer 23.

Zheng W, Deitz AC, Campbe/1 DR, Wen WQ, Cerhan JR, Sel/ers TA, Folsom AR, Hein DW. N­ acetyltransferase 1 genetic polymorphism, cigarette smoking, we/1-done meat intake, and breast cancer risk. Cancer Epidemia/ Biomarkers Prev. 1999 Mar;8(3):233-9

24.

Norrish AE, Lynnette R. Ferguson, Mark G. Knize, James S. Felton, Susan J. Sharpe, Jackson RT. Heterocyclic Amine Content of Cooked Meat and Risk of Prostate Cancer. J Nat Cancer lnst. 1999; 91 (23):2038-44 Sinha R, Chow WH, Kul/dorff M, Denobile J, Butler J, Garcia-Ciosas M, Weil R, Hoover RN, Rothman N. We/1-

25.

done, grilled red meat increases lhe risk of colorectal adenomas. Cancer Res. 1999;59(17):4320-4 Butler LM, Sinha R, Millikan RC, Martin CF, Newman B, Gammon MO, Ammerman AS, Sandler RS.

26.

Heterocyclic amines, meat intake, and association with colon cancer in a population-based study. Am J Epidemia/. 2003;157(5):434-45 27.

Wolk A. Diet, lifestyle and risk of prostate cancer. Acta Oncol. 2005;44(3):277-81

28.

Grant WB.

29.

more than 14 European countries) Cho E, Spiegelman O, Hunter DJ, Chen WY, Stampfer MJ, Colditz GA, Willett WC. Premenopausa/ fat intake and risk of breast cancer. J Natl Cancer lnst. 2003 Ju/ 16;95(14):1079-85

An eco/ogic study of dietary links to prostate cancer. Altern Med Review 1999; 4(3): 162-9 (in

Red meat and milk intake is correlated with high /GF-1 30.

Kak/amani VG, Linos A, Kaklamani E, Markaki I, Koumantaki Y, Mantzoros CS. Dietary fat and carbohydrates are independently associated with circulating insulin-/ike growth factor 1 and insulin-/ike growth factor-binding protein 3 concentrations in healthy adults. J Clin Oncol. 1999 Oct;17(10):3291-8

31.

Larsson SC, Wolk K, Brismar K, Wolk A. Association of diet with serum insulin-like growth factor I in middle­ aged and elderly men. Am J Clin Nutr. 2005 May;81(5):1163-7

32.

Allen NE, Appleby PN, Davey GK, Kaaks R, Rinaldi S, Key TJ. The associations of diet with serum insu/in-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans. Cancer Epidemia/ Biomarkers Prev. 2002 Nov;11(11):1441-8 Hoppe C, Molgaard C, Juul A, Michaelsen KF. High intakes of skimmed milk, but not meat, increase serum

33.

IGF-1 and IGFBP-3 in eight-year-old boys. Eur J Clin Nutr. 2004 Sep;58(9):1211-6

�!!!ll 4: The increases of serum IGF-1 may be produced by the malignant tumour and constitute a ...

consequence and not a cause as suggested in some animal studies. DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Boi DK, Beltran L, Moats S, Ramirez A, Jorcano J, Conti C.

34.

Deregulated expression of insulin-/ike growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sei USA. 2000 Mar 28;97(7):3455-60 Kap/an PJ, Mohan S, Cohen P, Foster BA, Greenberg NM.

35.

The insulin-like growth factor axis and prostate

cancer: lessons from lhe transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res. 1999 May 1 ;59(9):2203-9

ª!í!ll !?: the variability of serum IGF-1 makes that if two weeks after the initial blood test another ...

measurement of IGF-1 was done, the results of the studies would have been different (about 40°% of participants of the study would have switched from one quartile to the other) 36.

Milani D, Carmichael JD, Welkowitz J, Ferris S, Reitz RE, Danoff A, Kleinberg DL. Variability and reliability of single serum /GF-1 measurements: impact on determining predictability of risk ratios in disease development.

/GF-1 is measured twice, two weeks apart, individual/ differences range from -36.25 to +38.24%, while the mean value for the group of 84 shows high

J Clin Endocrinol Metab. 2004 May;89(5):2271-4 ("/f fasting serum

473

correlation between the two IGF-Is (r=0.922; p<0.0001) and varies much less (mean 120 at first visit) versus 115; p=0.03) in normal volunteers between the ages of 50 and 90 years. When considered in quartiles, IGF-1 changed from one quartile to another in 34184 (40.5%) of the volunteers. When the group was divided in halves, tertiles, quartiles, ar quintiles there was an increasing number of subjects who changed from one subdivision to another as the number of gradations increased. These results suggest that the predictive outcomes of earlier studies that used single IGF-1 samples for analysis of risk ratios according to tertiles, quartiles, ar quintiles could have been different if a second IGF-1 was used to establish the risk ratio. '}

No difference in plasma GH or IGF-1 between prostate cancer patients and controls

37.

38.

39. 40. 41.

42.

43.

44.

45.

Yu H, Nicar MR, Shi R, Berkel HJ, Nam R, Trachtenberg J, Diamandis EP. Leveis of IGF-1 and IGF BP- 2 and -3 in serial postoperative serum samples and risk of prostate cancer recurrence. Urology. 2001 Mar;57(3):4715. Hill M, Bilek R, Safarik L, Starka L. Analysis oi relations between serum leveis oi epitestosterone, estradiol, testosterone, IGF-1 and prostatic specific antigen in men with benign prostatic hyperplasia and carcinoma of the prostate. Physiol Res. 2000;49 Suppl 1 :8113-8 Kurek R, Tunn UW, Eckart O, Aumuller G, Wong J, Renneberg H. The significance of serum leveis of insulin­ like growth factor-1 in patients with prostate cancer. BJU In!. 2000 Jan;85(1):125-9 Cutting CW, Hunt C, Nisbet JA, Bland JM, Dalgleish AG, Kirby RS. Serum insulin-like growth factor-1 is no! a useful marker oi prostate cancer. BJU In!. 1999 Jun;83(9):996-9 lsmail HA, Pollak M, Behlouli H, Tanguay S, Begin LR, Aprikian AG. Serum insulin-like growth factor (IGF)-1 and IGF-binding protein-3 do not correlate with Gleason score or quantity of prostate cancer in biopsy samples. BJU lnt. 2003 Nov;92(7):699-702 Woodson K, Tangrea JA, Pollak M, Copeland TD, Taylor PR, Virtamo J, Albanes D. Serum insulin-like growth factor 1: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. Cancer Res. 2003 Jul 15;63(14):3991-4 lsmail A H, Pollak M, Behlouli H, Tanguay S, Begin LR, Aprikian AG. lnsulin-like growth factor-1 and insulin­ like growth factor binding protein-3 for prostate cancer detection in patients undergoing prostate biopsy. J Urol. 2002 Dec;168(6):2426-30 Bubley GJ, Balk SP, Regan MM, Duggan S, Morrissey ME, Dewolf WC, Salgami E, Mantzoros C. Serum leveis of insulin-like growth factor-1 and insulin-like growth factor-1 binding proteins after radical prostatectomy. J Urol. 2002 Nov;168(5):2249-52 DeLellis K, Rinaldi S, Kaaks RJ, Kolonel LN, Henderson B, Le Marchand L. Dietary and lifestyle correlates of plasma insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3): lhe multiethnic cohort. Cancer Epidemiol Biomarkers Prev. 2004 Sep;13(9):1444-51.

In acromegaly, the incidence of cancer, other than possibly colon cancer, does not appear to be significantly increased; in one study it was even significantly reduced by -14 %. Overa/1 mortalily is normal for palienls with low posttrealment GH,bul increased for palients wilh high posttrealmenl GH. 46. J. Svensson, B.-A. Bengtsson, T. Rosén, Odén A, Johannsson G. Malignant Disease and Cardiovascular

47.

Morbidity in Hypopituitary Adults with or without GH Replacement Therapy . J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12 Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug;83(8):2730-4 ("The overa/1 cancer incidence rale was 24 % lower than thal in lhe general populalion of lhe U.K.; lhe overa/1 cancer mortality rate was nol increased, bul the colon cancer mortality rale was increased. '}

No difference in serum IGF-1 between breast cancer patients and controls 48. Li BD, Khosravi MJ, Berkel HJ, Diamandi A, Dayton MA, Smith M, Yu H. Free insulin-like growth factor-1 and

49.

breast cancer risk. In! J Cancer. 2001 Mar 1;91(5):736-9 DeLellis K, Rinaldi S, Kaaks RJ, Kolonel LN, Henderson B, Le Marchand L. Dietary and lifestyle correlates of plasma insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3): lhe multiethnic cohort. Cancer Epidemiol Biomarkers Prev. 2004 Sep;13(9):1444-51.

GH transgenic mice with high serum IGF-1 do not develop breast, prostate, or colonic malignancies 50. Wennbo H, Gebre-Medhin M, Gritli-Linde A, Ohlsson C, lsaksson OG, Tornei! J. Activation of the prolactin receptor but not lhe growth hormone receptor is important for induction oi mammary tumors in transgenic mice. J Clin lnvest. 1997 Dec 1;100(11):2744-51 51. Wennbo H, Tornei! J. The role oi prolactin and GH in breast cancer. Octogene. 2000;19:1072-6

474

Arguments pro

GH use:

Untreated GH deficient patients have an increased overall cancer incidence (2x the normal incidence) and cancer mortality (4x) 52.

Svensson J, Bengtsson BA, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12

53.

Finne P, Auvinen A, Koistinen H, Zhang WM, Maattanen L, Rannikko S, Tammela T, Seppala M, Hakama M, Stenman UH. lnsulin-like growth factor I is not a useful marker of prostate cancer in men with elevated leveis

54.

55.

of prostate-specific antigen. J Clin Endocrinol Metab. 2000 Aug;85(8):2744-7 Woodson K, Tangrea JA, Pollak M, Copeland TO, Taylor PR, Viriamo J, Albanes D. Serum IGF-1: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. Cancer Res. 2003;15;63(14):3991-4 (- 48% for men in lhe highest quattile of serum /GF-1) Baffa R, Reiss K, EI-Gabry EA, Sedor J, Moy ML, Shupp-Byrne D, Strup SE, Hauck WW, Baserga R, Gomella LG. Low serum insulin-like growth factor 1 (IGF-1): a significant association with prostate cancer. Tech Urol 2000 Sep;6(3):236-9

GH therapy increases serum IGF-BP-3,

which may protect against cancer: /GFBP-3 causes apoptosis of cancer

cells and inhibits /GF action on cancer cells in vitro

=>

Serum IGFBP-3 is in general negatively correlated with the

cancer risk cancer: the higher IGF-BP-3, the lower the cancer risk

56.

57.

Wollmann HA, Schonau E, Blum WF, Meyer F, Kruse K, Ranke MS. Dose-dependent responses in insulin-like growth factors, insulin-like growth factor-binding protein-3 and parameters of bone metabolism to growth hormone therapy in young adults with growth hormone deficiency. Horm Res. 1995;43(6):249-56 Grimberg A, Cohen P. GH & prostate cancer: guilty by association? J Endocrinol lnvest. 1999;22(5 Suppl):6473

A high serum IGF-BP-3 is associated with a reduced prostate cancer risk (-30%), and/or prostate cancer recurrence 58. Harman SM, Metter EJ, Blackman MR, Landis PK, Carter HB. Baltimore Longitudinal Study on Aging. Serum leveis of IGF-1, IGF-11, IGF-BP-3, and PSA as predictors of clinicai prostate cancer. J Clin Endocrinol Metab. 2000 Nov;85(11):4258-65 Studies where

GH therapy given to cancer patients reduced the cancer recurrence, and reduces the cancer

mortality or increases survival time 59. Swerdlow AJ, Reddingius RE, Higgins CO, Spoudeas HA, Phipps K, Qiao Z, Ryder WD,Brada M, Hayward RD, Brook CG, Hindmarsh PC, Shalet SM. Growth hormone treatment of children with brain tumors and risk of tumor recurrence. J Clin Endocrinol Metab. 2000 Dec;85(12):4444-9 Tacke J, Bolder U, Herrmann A, Berger G, Jauch KW. Long-term risk of gastrointestinal tumor recurrence 60. after postoperative treatment with recombinant human growth hormone. JPEN J Parenter Enteral Nutr 2000 May-Jun;24(3):140-4 Long-term GH replacement (60 months) reduced the increased cancer risk and mortality of GH deficient patients by half 61. Svensson J, Bengtsson BÀ, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12

GH or IGF-1 therapy to animais with cancer: may reduce the tumour incidence and/or progression Combined GH- insulin therapy reduced the development of mammary carcinoma in tema/e rats Bartlett DL, Charland S, Torosian MH. Growth hormone, insulin, and somatostatin therapy of cancer cachexia. 62. Cancer. 1994 Mar 1;73(5):1499-504 GH-therapy reduced the development of /ung metastases in rats with prostate cancer 63.

Torosian MH. Growth hormone and prostate cancer growth and metastasis in tumor-bearing animais. J Pediatr Endocrinol. 1993 Jan-Mar;6(1):93-7

475

A lower serum GH levei is found in gastric cancer patients 64. Colombo F, lannotta F, Fachinetti A, Giuliani F, Cornaggia M, Finzi G, Mantere G, Fraschini F, Malesci A, Bersani M, et ai. [Changes in hormonal and biochemical parameters in gastric adenocarcinoma] Minerva Endocrinol. 1991 Jui-Sep;16(3):127-39 GH-therapy inhibits the development of tiver cancer due to carcinogens (aflatoxin 81 or N-OH-acetyl­ aminofluoren) in mate rats 65. Liao D, Porsch-Hallstrom I, Gustafsson JA, Blanck A. Sex differences at lhe initiation stage of rat liver carcinogenesis-influence of growth hormone. Carcinogenesis. 1993 Oct;14(1 0):2045-9 /GF-1-therapy preserved lean mass in rats with sarcoma and cachexia 66. Ng EH, Rock CS, Lazarus DD, Stiaino-Coico L, Moldawer LL, Lowry SF. lnsulin-like growth factor I preserves host lean tissue mass in cancer cachexia. Am J Physiol. 1992 Mar;262(3 Pt 2):R426-31

GH therapy raises both the leveis of both IGF-1 and IGFBP-3. IGF-BP-3 is a potent inhibitor of IGF action in breast and prostate tissues. Autocrine production of IGF's and GH, have been identified in cancer cells and tissues. Thus, serum IGF-1 may actually be a confounding variable, serving as a marker for local prostatic IGF-1 production. •

•

Since GH-deficient patients often have a subnormai iGF-1 serum levei, which normalizes on therapy, lhe cancer risk on GH therapy does probably not substantially increase above that of the normal population. On the contrary, lhe evidence points to a normalization of lhe risk. lt seems prudent that when we treat adult GH deficiency, we should aim to maintain serum IGF-1 in lhe normal range.

GH ANO LIFE SPAN

Claim: GH may have adverse effects on life span Facts: GH treatment appears to reduce mortality, except for special mice species and humans put in ex1reme conditions.

Arguments contra GH use

A high serum GH was associated with premature death in humans (critics: an old fashioned technique, which /acked assay precision, was used to measure GH; the daytime serum GH were measured, which is not accurate except for acromegaly patients; serum GH does not reflect GH activity, serum IGF-1 does it, but up to a certain degree; an increased serum GH may possibly reflect increased binding of GH to increased serum GHBP and thus inactivation of GH, but the serum GHBP levei was not checked in the study) 2. Maison P, Balkau B, Simon D, Chanson P, Rosselin G, Eschwege E. Growth hormone as a risk for premature mortality in healthy subjects: data from lhe Paris prospective study. BMJ. 1998 Apr 11;316(7138):1132-3 Acromegaly adults have premature death only when they keep high posttreatment GH and thus a probably continuing active growth hormone-secreting tumor that crushes down ali the other pituitary cells, overa/1 mortality is normal for patients with low posttreatment GH, 3. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug;83(8):2730-4. Mice models of genetic pituitary failure with multiple hormone deficiency (Ames and Snell mice) and GH receptor knockout mice (primary IGF1-deficiency) may have a significant higher longevity (critics: the heterozygous /GF-1 receptor knock-out mutants are special mice species, as are Ames and Snell mice . They react in a completely different way to GH than normal mice species. They have a 50 % decrease in IGF-1 receptors, but a 32% higher serum IGF-1; they have more glucose intolerance; are slightly smaller; the

476

/ifespan was only significantly longer in tema/e mice 4. 5. 6.

7.

(+33%), not in ma/e mice (+16%); lhe results based on a

shortliving species (mise) may not be necessarily true for species with a long fite such as humans) Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A. Genetic mouse models of extended lifespan. Exp Gerontol. 2003 Nov-Dec;38(11-12):1353-64 Holzenberger M. The GH/IGF-1 axis and longevity. Eur J Endocrinol. 2004 Aug;151 Suppi1:S23-7 Kulkarni RN, Holzenberger M, Shih DO, Ozcan U, Stoffel M, Magnuson MA, Kahn CR. beta-cell-specific deletion of the lgf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet. 2002 May;31(1):111-5 (lack /GF-1 receptors on beta-cells => glucose interance and less beta-cells) Hauck SJ, Aaron JM, Wright C, Kopchick JJ, Bartke A. Antioxidant enzymes, free-radical damage, and response to paraquat in liver and kidney of long-living growth hormone receptor/binding protein gene­ disrupted mice. Horm Metab Res. 2002 Sep;34(9):481-6

GH therapy to critically ill patients: doubles the mortality rate 8. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. l ncreased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999 Sep 9;341(11):785-92 (Critics on lhe study: lhe doses used were too high doses: 10 to 70 times lhe normal dose in very weak persons; lhe control group had an abnormally lower mortality rale than predicted; combined to the high mortality rales of the treatment group, the average mortality rale was very similar to that of a historical cohort; GH treatment lowers cortisol levels, which are crucial to critically i/1 patients) Freeman BD, Danner RL, Banks SM, Natanson C. Safeguarding patients in clinicai trials with high mortality rates. Am J Respir Crit C are Med. 2001 Jul 15; 164(2): 190-2

9.

BUT: Studies where GH therapy lowered the leveis of cortisol and its metabolites by 20 to 40 %, which is dangerous for critically-il/ patients who desperately need cortiso/ for their survival 10. Vierhapper H, Nowotny P, Waldhausl W. Treatment with growth hormone suppresses cortisol production in man. Metabolism 1998 Nov;47(11):1376-8 ; 11. Rodriguez-Arnao J, Perry L, Besser GM, Ross RJ. Growth hormone treatment in hypopituitary GH deficient adults reduces circulating cortisol leveis during hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 1996 Jul;45(1):33-7 12.

Weaver JU, Thaventhiran L, Noonan K, Burrin JM, Taylor NF, Norman MR, Monson JP. The effect of growth hormone replacement on cortisol rnetabolism and glucocorticoid sensitivity in hypopituitary adults. Clin Endocrinol (Oxf). 1994 Nov;41(5):639-48

... and a study where patients who have poor responsive adrenals (poorly able to increase their cortisol production) and are in septic shock, die easier 13. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet. 1991 Mar 9;337(8741):582-3 •.

and studies where glucocorticoid treatments considerably increased survival of critically-ill patients

survival of HIV patient from pneumonia 14. Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A double-blind, placebo­ controlled trial. N Engl J Med. 1990 Nov 22;323(21):1444-50 survival from typhus Hoffman SL, Punjabi NH, Kumala S, Moechtar MA, Pulungsih SP, Rivai AR, Rockhill RC, Woodward TE, 15. Loedin AA. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med. 1984 Jan 12;310(2):82-8

NEUTRAL information on GH and lonqevity No increased mortality in acromegaly if leveis of GH are less than 2.5 ng/ml 16. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug;83(8):2730-4 Arquments pro GH use

477

Persistent GH deficiency (without GH therapy) in humans, is associated with a shorter life expectancy: increased overall and cardiovascular mortality 17.

Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lance!. 1990 Aug 4;336(8710):285-8

18.

AS Bates, W Van't Hoff, PJ Jones and RN Clayton. The effect of hypopituitarism on life expectancy. J Clin Endocrin Metab. 1996 Mar;81(3):1169-72

Higher mortality in GH deficient women 19.

Svensson J, Bengtsson BÁ, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12

Higher mortality in 11 GH deficient adults suffering from a genetic defect (6.7-kb spanning deletion of genomic DNA of lhe GH-1 gene) that causes isolated GH deficiency (hereditary dwarfism), untreated men los! 21 years

of lífe (-25% compared to lhe unaffected brothers) and women 34 years less (-44% versus unaffected sísters) 20.

Besson A, Salemi S, Gallati S, Jenal A, Horn R, Mullis PS, Mullis PE. Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab. 2003;88(8):3664-7

Patients with hypopituitarism have increased overall and cardiovascular mortality; the increased mortality from cerebrovascular disease (esp. in women) was the main contributor to the increased cardiovascular mortality 21. Bulow B, Hagrnar L, Mikoczy Z, Nordstrom CH, Erfurth EM.Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxl). 1997 Jan;46(1):75-81 22. Bengtsson BA, Koppeschaar HP, Abs R, Bennmarker H, Hernberg-Stahl E, Westberg B, Wilton P, Monson JP, Feldt-Rasmussen U, Wuster C. Growth hormone replacement therapy is not associated with any increase in mortality. KIMS Study Group. J Clin Endocrinol Metab. 1999 Nov;84(11):4291-2

GH replacement therapy of GH deficient adults Jowers the excessive mortality back to normal 23.

Bengtsson BA, Koppeschaar HP, Abs R, Bennmarker H, Hernberg-Stahl E, Westberg B, Wilton P, Monson JP, Feldt-Rasmussen U, Wuster C. Growth hormone replacement therapy is not associated with any increase in mortality. KIMS Study Group. J Clin Endocrinol Metab. 1999 Nov;84(11):4291-2

24.

Svensson J, Bengtsson BÁ, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12

89 GH treatment of normal elderly mice, extended the mean and maximal life span · . 25. Khansari DN, Gustad T. Effects of long-term, low-dose growth hormone therapy on immune function and life expectancy of mice. Mech Ageing Dev. 1991 Jan;57(1):87-100 GH treatment of GH deficient mice extended life span, but lífespan of (non GH treated) míce was símílar to that of

normal míce. 26.

Sonntag WE, Carter CS, lkeno Y, Ekenstedt K, Carlson CS, Loeser RF, Chakrabarty S, Lee S, Bennett C, lngram R, Moore T, Ramsey M. Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease modifies age-related pathology, and increases life span. Endocrinology. 2005 Jul;146(7):2920-32

Conclusion: Persistent GH deliciency reduces lhe lile expectancy, while GH treatment of GH-deficient patients improves it. Caution should be applied when using GH treatment in critically-ill patients.

478

Chapter three:

MS H

Senescence is associated with a decline of the hypothalamic-MSH axis Senescence is associated with alterations of the circadian cycle of serum alpha-MSH in people with skin types 1 and 2 1.

Altmeyer P, Stõhr L, Holzmann H. Seasonal rhythm oi lhe plasma levei oi alpha-melanocyte stimulating hormone. J lnvest Dermatol. 1986 Apr;86(4):454-6

MSH treatment may oppose and MSH deficiency may triqqer several mechanisms of senescence Excessive free radical formation: MSH reduces free radical damage 2.

Kolgazi M, Arbak S, Alican I. The effect oi alpha-melanocyte stimulating hormone on gentamicin-induced acute nephrotoxicity in rats. J Appl Toxicol. 2007 Mar-Apr;27(2):183-8

3.

Jahovic N, Erkanli G, l�eri S, Arbak S, Alican I. Gastric protection by alpha-melanocyte-stimulating hormone against ethanol in rats: involvement oi somatostatin. Lile Sei. 2007 Feb 20;80(11):1040-5

lnflammation: lhe reduction with MSH treatment 4.

Doi K, Hu X, Yuen PS, Leelahavanichkul A, Yasuda H, Kim SM, Schnermann J, Jonassen TE, Fmkiaer J, Nielsen S, Star RA. AP214, an analogue oi alpha-melanocyte-stimulating hormone, ameliorates sepsis­ induced acute kidney injury and mortality. Kidney lnt. 2008 Jun;73(11):1266-74

5.

Luger TA, Brzoska T. alpha-MSH related peptides: a new class oi anti-inflammatory and immunomodulating drugs. Ann Rheum Ois. 2007 Nov;66 Suppl 3:iii52-5

6.

Nicolaou A, Estdale SE, Tsatmali M, Herrero DP, Thody AJ. Prostaglandin production by melanocytic cells and lhe effect oi alpha-melanocyte stimulating hormone. FEBS Lett. 2004 Jul 16;570(1-3):223-6

7.

Raap U, Brzoska T, Sohl S, Pii.th G, Emmel J, Herz U, Braun A, Luger T, Renz H. Alpha-melanocyte­ stimulating hormone inhibits allergic airway inflammation. J lmmunol. 2003 Jul 1; 171(1):353-9

lmmune deficiency:

lmmune deficiency: the improvement with MSH treatment 8.

Carotenuto A, Saviello MR, Auriemma L, Campiglia P, Catania A, Novellino E, Grieco P. Structure-function relationships and conformational properties oi alpha-MSH(6-13) analogues with candidacidal activity. Chem Biol Drug Des. 2007 Jan;69(1):68-74

9.

Doi K, Hu X, Yuen PS, Leelahavanichkul A, Yasuda H, Kim SM, Schnermann J, Jonassen TE, Fr0kiaer J, Nielsen S, Star RA. AP214, an analogue oi alpha-melanocyte-stimulating hormone, ameliorates sepsis­ induced acute kidney injury and mortality. Kidney lnt. 2008 Jun;73(11):1266-74

Auto-immunity: the improvement with MSH treatment 10.

Brod SA, Hood ZM. lngested (oral) alpha-MSH inhibits acute EAE. J Neuroimmunol. 2008 Jan;193(1-2):10612

DNA damage: Alpa-MSH or an analogue repairs DNA damage Abdei-Malek ZA, Kadekaro AL, Kavanagh RJ, Todorovic A, Koikov LN, McNulty JC, Jackson PJ, Millhauser GL, Schwemberger S, Babcock G, Haskeii-Luevano C, Knittel JJ.Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs lha! protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASES J. 2006 Jul;20(9):1561-3

11.

Excessive apoptosis: Alpa-MSH or an MSH analogue inhibits excessive apoptosis 12. Abdei-Malek ZA, Kadekaro AL, Kavanagh RJ, Todorovic A, Koikov LN, McNulty JC, Jackson PJ, Millhauser GL, Schwemberger S, Babcock G, Haskeii-Luevano C, Knittel JJ.Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs lha! protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASES J. 2006 Jul;20(9):1561-3 Abnormal MSH gene polymorphism: may favor obesity 13. Dubern B, Lubrano-Berthelier C, Mencarelli M, Ersoy B, Frelut ML, Bouglé O, Gostes B, Simon C, Tounian P, Vaisse C, Clement K. Mutational analysis oi lhe pro-opiomelanocortin gene in French obese children led to lhe identification oi a novel deleterious heterozygous mutation located in lhe alpha-melanocyte stimulating hormone domain. Pediatr Res. 2008 Feb;63(2):211-6

479

MSH and psychic well-being Depression: lhe associalion wilh lower MSH leveis 14.

Maes M, DeJonckheere C, Vandervorst C, Schotte C, Cosyns P, Raus J, Suy E. Abnormal pituitary function during melancholia: reduced alpha-melanocyte-stimulating hormone secretion and increased intact ACTH non-suppression. J Affect Disord. 1991 Jul;22(3):149-57 (A signiticantly lower baseline alpha-MSH secretion

in melancholic patients was found in comparison to healthy contrais) 15.

Sonino N, Fava GA, Morphy MA, Pedersen RC. Effects of metyrapone and dexamethasone on pro-gamma­

16.

Morphy MA, Fava GA, Pedersen RC, Zielezny M, Sonino N, Brownie AC. Effects of metyrapone and

MSH and ACTH leveis in depressed patients. Eur Neuropsychopharmacol. 1990 Nov;1(1):63-5 dexamethasone upon pro-gamma-MSH plasma leveis in depressed patients and healthy controls. J Affect Disord. 1990 Jul;19(3):183-9

Anxiely: lhe associalion wilh lower MSH precursor leveis 17.

Asakawa A, Toyoshima M, lnoue K, Koizumi A. lns2Akita mice exhibit hyperphagia and anxiety behavior via the melanocortin system. In! J Moi Med. 2007 Apr;19(4):649-52 (Low proopiomelanocortin mRNA expression)

Anxiely: lhe improvement wilh (humans) or worsening (rats) 18.

Den Boer JA, Westenberg HG, De Vries H. The MSH/ACTH analog ORG 2766 in anxiety disorders. Peptides. 1992 Jan-Feb;13(1):109-12

19.

Sandman CA, George JM, Nolan JD, van Riezen H, Kastin AJ. Enhancement of attention in man with ACTH/MSH 4-10. Physiol Behav. 1975 Oct;15(5):427-31

20.

Kokare DM, Chopde CT, Subhedar NK. Participation of alpha-melanocyte stimulating hormone in ethanol­ induced anxiolysis and withdrawal anxiety in rats. Neuropharmacology. 2006 Sep;51(3):536-45

21.

Kokare DM, Dandekar MP, Chopde CT, Subhedar N. lnteraction between neuropeptide Y and alpha­ melanocyte stimulating hormone in amygdala regulates anxiety in rats. Brain Res. 2005 May 10;1043(12):107-14

22.

Rao TL, Kokare DM, Sarkar S, Khisti RT, Chopde CT, Subhedar N. GABAergic agents preveni alpha­ melanocyte stimulating hormone induced anxiety and anorexia in rats. Pharmacol Biochem Behav. 2003 Dec;76(3-4):417-23

Memory loss: the improvemenl wilh MSH lrealment (better visual memory and attention) 23.

Sandman CA, George JM, Nolan JD, van Riezen H, Kastin AJ. Enhancement of attention in man with ACTH/MSH 4-10. Physiol Behav. 1975 Oct;15(5):427-31

24.

Gonzalez PV, Schiõth HB, Lasaga M, Scimonelli TN. Memory impairment induced by IL-1beta is reversed by alpha-MSH through central melanocortin-4 receptors. Brain Behav lmmun. 2009 Aug;23(6):817-22

25.

McBride RB, Beckwith BE, Swenson RR, Sawyer TK, Hadley ME, Matsunaga TO, Hruby VJ. The actions of melanin-concentrating hormone (MCH) on passive avoidance in rats: a preliminary study. Peptides. 1994;15(4):757-9

26.

Pitsikas N, Spruijt BM, Algeri S, Gispen WH. The ACTH/MSH (4-9) analog Org2766 improves retrieval of information afier a fimbria fornix transection. Peptides. 1990 Sep-Oct;11(5):911-4.

27.

Yehuda S. Effects of alpha-MSH, TRH and AVP on learning and memory, pain threshold, and motor activity:

28.

Handelmann GE, O'Donohue TL, Forrester D, Cook W. Alpha-melanocyte stimulating hormone facilitates

29.

Sandman CA, Beckwith BE, Kastin AJ. Are learning and attention related to lhe sequence of amino acids in

30.

Miller LH, Harris LC, Van Riezen H, Kastin AJ. Neuroheptapeptide influence on attention and memory in man.

preliminary results. lnt J Neurosci. 1987 Feb;32(3-4):703-9 learning of visual but not auditory discriminations. Peptides. 1983 Mar-Apr;4(2):145-8 ACTH/MSH peptides? Peptides. 1980 Winter;1(4):277-80. Pharmacol Biochern Behav. 1976;5(Suppl 1):17-21

Loss of sexual drive, sensilivily and potency: the improvemenl wilh MSH (analog) lrealmenl 31.

Hadley ME. Discovery that a melanocortin regulates sexual functions in male and femalehumans. Peptides. 2005 Oct;26(10):1687-9.

In women: 32.

Safarinejad MR. Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose, randomized study. J Sex Med. 2008 Apr;5(4):887-97

33.

Diamond LE, Earle DC, Heiman JR, Rosen RC, Perelman MA, Harning R. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. 2006 Jul;3(4):628-38

34.

Part 2 of Phase lia trials involving post-menopausal women presented at lhe lnternational Society for the Study of Women's Sexual Health (ISSWSH) 2007 Annual Meeting.

480

35.

Pfaus J, Giuliano F, Gelez H. Bremelanotide: an overview of preclinical CNS effects on female sexual

36.

function. J Sex Med. 2007 Nov;4 Suppl 4:269-79 Rõssler AS, Pfaus JG, Kia HK, Bernabé J, Alexandre L, Giuliano F. The melanocortin agonist, melanotan 11, enhances proceptive sexual behaviors in lhe female rat.Pharmacol Biochem Behav. 2006 Nov;85(3):514-21

lnmen 37. Safarinejad MR, Hosseini SY. Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study.J Urol. 2008 Mar;179(3):1066-71 Ter Laak MP, Brakkee JH, Adan RA, Hamers FP, Gispen WH. The potent melanocortin receptor agonist 38.

39. 40.

41. 42.

melanotan-11 prometes peripheral nerve regeneration and has neuroprotective properties in lhe rat. Eur J Pharmacol. 2003 Feb 21;462(1-3):179-83 Wessells H, Levine N, Hadley ME, Dorr R, Hruby V. Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan 11. lnt J lmpot Res.2000 Oct;12 Suppi 4:S74-9 Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ, Dorr R, Levine N. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol.1998 Aug;160(2):389-93 Giuliano F, Clément P, Droupy S, Alexandre L, Bernabé J. Melanotan-11: lnvestigation of the inducer and facilitator effects on penile erection in anaesthetized rat.Neuroscience. 2006;138(1):293-301 Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Evaluation of lhe safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. lnt J lmpot Res.2004 Apr;16(2):135-42

Physical appearance and MSH Low skin pigmentation: the association with lower MSH leveis 43. 44. 45.

Abe K, Nicholson WE, Liddle GW, lsland DP, Orth DN. Radioimmunoassay of beta-MSH in human plasma and tissues. J Clin lnvest. 1967 Oct;46(10):1609-16. Bartelt RN, Altmeyer P, Stõhr L, Gornik P, HOizmann H. Endocrinologic reactions following exposure to fluorescent lamps.Z Hautkr. 1986 Feb 1;61(3):105-10. Schiller M, Brzoska T, Bõhm M, Metze D, Scholzen TE, Rougier A,Luger TA. Solar-Simulated Ultraviolet Radiation-lnduced Upregulation of the Melanocortin-1 Receptor, Proopiomelanocortin, and Melanocyte­ Stimulating Hormone in Human Epidermis In Vivo. J lnvest Derm. 2004;122, 468-476

Low skin pigmentation: the improvement with MSH (analog) treatment 46. Ugwu SO, Blanchard J, Dorr RT, Levine N, Brooks C, Hadley ME, Aickin M, Hruby VJ.Skin pigmentation and 47.

48.

49.

pharmacokinetics of melanotan-1 in humans. Biopharm Drug Dispos.1997 Apr;18(3):259-69 Barnetson RS, Ooi TK, Zhuang L, Halliday GM, Reid CM, Walker PC, Humphrey SM, Kleinig MJ. [Nie4-D­ Phe7]-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers. J lnvest Dermatol. 2006 Aug;126(8):1869-78 Dorr RT, Ertl G, Levine N, Brooks C, Bangert JL, Powell MB, Humphrey S, Alberts DS. Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of lhe skin in human volunteers.Arch Dermatol. 2004 Jul;140(7):827-35 Fitzgerald LM, Fryer JL, Dwyer T, Humphrey SM. Effect of MELANOTAN, [Nie(4), D-Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles. Peptides. 2006 Feb;27(2):388-94

Light hair pigmentation: the association with low MSH leveis (light hair) or low (gray, white) or abnormal MSH receptor leveis (red hair) Bartelt RN, Altmeyer P, Stõhr L, Holzmann H. Endocrinological reactions following UV A whole body 50. irradiation] Derm Beruf Umwelt. 1985;33(2):50-5 Nanninga PB, Ghanem GE, Lejeune FJ, Bos JD, Westerhof W. Evidence for alpha-MSH binding sites on 51. human scalp hair follicles: preliminary results. Pigment Cell Res. 1991 Oct;4(4):193-8 Light hair or premature gray hair: the coroing/darkening with MSH treatment in animais Teed SK, Crossland JP, Dawson WD. Coat color genetics of Peromyscus. I.Ashiness, an age-dependent coat 52. colormutation in the deer mouse.: J Hered. 1990 Jui-Aug;81(4):309-13 Levitin HP, Gómez Dumm CL, lturriza FC. Alteration of lhe Agouti mouse coat color pattern by 53. bromoergocryptine.Possible involvement of MSH.Neuroendocrinology.1979;29(6):391-8

481

MSH and aqe-related diseases Nerve injury: regeneration with MSH (analog) 54.

55.

56.

57.

58.

Ter Laak MP, Brakkee JH, Adan RA, Hamers FP, Gispen WH. The potent melanocortin receptor agonist me/anotan-11 prometes peripheral nerve regeneration and has neuroprotective properties in the rat. Eur J Pharmacol. 2003 Feb 21;462(1-3):179-83 Ter Laak MP, Brakkee JH, Adan RA. Hamers FP, Gispen WH. The potent melanocortin receptor agonist me/anotan-11 prometes peripheral nerve regeneration and has neuroprotective properties in the rat. Eur J Pharmacol. 2003 Feb 21;462(1-3):179-83 Joosten EA, Majewska B, Houweling DA, Bar PR, Gispen WH. Alpha-melanocyte stimulating hormone prometes regrowth of injured axons in lhe adult rat spinal cord. J Neurotrauma. 1999 Jun;16(6):543-53. PubMed PMID: 10391370 Lankhorst AJ, Duis SE, ter Laak MP, Joosten EA, Hamers FP, Gispen WH. Functional recovery after central infusion of alpha-melanocyte-stimulating hormone in rats with spinal cord contusion injury. J Neurotrauma. 1999 Apr;16(4):323-31 van de Meent H, Hamers FP, Lankhorst AJ, Joosten EA, Gispen WH. Beneficiai effects of lhe melanocortin a/pha-melanocyte-stimulating hormone on clinicai and neurophysiologica/ recovery after experimental spinal cord injury. Neurosurgery. 1997 Jan;40(1):122-30

Arterial hypertension: the association with lower MSH leveis 59. Ni XP, Humphreys MH. Prevention of salt-induced hypertension by an analog of gamma-me/anocyte­ stimulating hormone in lhe rat. Am J Hypertens. 2007 Aug;20(8):862-5 Arterial hypertension: the improvement with MSH treatment 60. Tai MH, Weng WT, Lo WC, Chan JY, Lin CJ, Lam HC, Tseng CJ. Role of nitric oxide in alpha-melanocyte­ stimulating hormone-induced hypotension in lhe nucleus tractus solitarii of lhe spontaneously hypertensive rats. J Pharmacol Exp Ther. 2007 May;321(2):455-61 61. Ni XP, Humphreys MH. Prevention of salt-induced hypertension by an analog of gamma-melanocyte­ stimulating hormone in lhe rat. Am J Hypertens. 2007 Aug;20(8):862-5 Stroke: the protection with MSH treatment 62. Chang SH, Jung EJ, Lim DG, Park YH, Wee YM, Kim JH, Kim YH, Choi MY, Koo SK, Choi KD, Han DJ, Kim SC. Anti-inflammatory action of alpha-melanocyte stimulating hormone (alpha-MSH) in anti-CD3/CD28mediated sp/een and CD4(+)CD25{-) T cells and a partia/ participation of /L-10. lmmunol Lett. 2008 Jun 63.

15;118(1):44-8 Spulber S, Moldovan M, Oprica M, Aronsson AF, Post C, Winb/ad B, Schultzberg M. Alpha-MSH decreases

64.

core and brain temperature during global cerebral ischemia in rats. Neuroreport. 2005 Jan 19;16(1):69-72 Forslin Aronsson A. Spu/ber S, Oprica M, Winblad B, Post C, Schultzberg M. A/pha-MSH rescues neurons from excitotoxic ce/1 death. J Moi Neurosci. 2007;33(3):239-51

Excess appetite: the association with low MSH leveis MacNeil DJ, Howard AD, Guan X, Fong TM, Nargund RP, Bednarek MA, Goulet MT, Weinberg DH, Strack AM, Marsh DJ, Chen HY, Shen CP, Chen AS, Rosenb/um C/, MacNeil T, Tola M, Maclntyre ED, Van der Ploeg LH.. The role of melanocortins in body weight regu/ation: opportunities for lhe treatment of obesity. Eur J Pharmaco/ 2002 Apr 12;440(2-3):141-57

65.

Excessive appetite: the reduction with MSH (analog) 66.

67.

Wang J, Ling S, Usami T, Murata T, Narita K, Higuchi T. Effects of ghrelin, corticotrophin-re/easing hormone, and me/anotan-11 on food intake in rats with paraventricular nuc/eus lesions. Exp C/in Endocrinol Diabetes. 2007 Nov;115(10):669-73 Glavas MM. Joachim SE, Draper SJ, Smith MS, Grave KL. Melanocortinergic activation by melanotan 11 inhibits feeding and increases uncoup/ing protein 1 messenger ribonucleic acid in lhe developing rat. Endocrinology. 2007 Ju/;148(7):3279-87

68.

69. 70. 71.

Li G, Zhang Y, Wilsey JT, Scarpace PJ. Unabated anorexic and enhanced thermogenic responses to melanotan 11 in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression. J Endocrinol. 2004 Ju/;182(1):123-32 Hillebrand JJ, Kas MJ, Adan RA. a-MSH enhances activity-based anorexia. Peptides. 2005 Oct;26{10):1690-6 Hansen MJ, Ba/1 MJ, Morris MJ. Enhanced inhibitory feeding response to a/pha-melanocyte stimulating hormone in the diet-induced obese rat. Brain Res. 2001 Feb 16;892(1):130-7 Raposinho PD, White RB, Aubert ML. The melanocortin agonist Me/anotan-11 reduces the orexigenic and adipogenic effects of neuropeptide Y (NPY) but does not affect the NPY-driven suppressive effects on lhe gonadotropic and somatotropic axes in lhe ma/e rat. J Neuroendocrinol. 2003 Feb;15{2): 173-81.

482

Obesity: the association with insufficient MSH leveis or abnormal MSH receptor leveis 72.

Dubern B, Clément K, Pelloux V, Frogue/ P, Girardet JP, Guy-Grand B, Tounian P. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. J Pediatr. 2001 Aug;139(2):204-9

73.

Tian DR, Li XD, Shi YS, Wan Y, Wang XM, Chang JK, Yang J, Han JS. Changes of hypothalamic a/pha-MSH and CART peptide expression in diet-induced obese rats. Peptides. 2004 Dec;25(12):2147-53

74.

Savontaus E, Breen TL, Kim A, Yang LM, Chua SC Jr, Wardlaw SL. Metabolic effects of transgenic melanocyte-stimulating

hormone

overexpression

in

lean

and

obese

mice.

Endocrinology.

2004

Aug;145(8):3881-91 75.

Smart JL, Low MJ. Lack of proopiomelanocortin peptides results in obesity and defective adrenal function but normal melanocyte pigmentation in the murine C57BU6 genetic background. Ann N Y Acad Sei. 2003 Jun;994:202-1O

76.

Kim EM, O'Hare E, Grace MK, Welch CC, Billington CJ, Levine AS. ARC POMC mANA and PVN a/pha-MSH are lower in obese relative to lean zucker rats. Brain Res. 2000 Apr 17;862(1-2):11-6 (The paraventricular nucleus neurons contain less a/pha-MSH in obese relative to lean rats

Obesity: the improvement with MSH or analogue treatment in rats 77.

Li G, Zhang Y, Wilsey JT, Scarpace PJ. Unabated anorexic and enhanced thermogenic responses to melanotan 11 in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression. J Endocrinol. 2004 Jul;182(1):123-32

78.

MacNeil DJ, Howard AO, Guan X, Fong TM, Nargund RP, Bednarek MA, Goulet MT, Weinberg OH, Strack AM, Marsh DJ, Chen HY, Shen CP, Chen AS, Rosenblum Cl, MacNeil T, Tota M, Maclntyre ED, Van der Ploeg LH.. The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. Eur J Pharmacol 2002 Apr 12;440(2-3):141-57

79.

McMinn JE, Wilkinson CW, Havei PJ, Woods SC, Schwartz MW. Effect of intracerebroventricular alpha-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression. Am J Physiol Regul lntegr Comp Physiol. 2000 Aug;279(2):R695-703

80.

Li G, Zhang Y, Wilsey JT, Scarpace PJ. Unabated anorexic and enhanced thermogenic responses to melanotan 11 in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression. J Endocrinol. 2004 Jul;182(1):123-32

81.

Hsiung HM, Hertel J, Zhang XY, Smith DP, Smiley DL, Heiman ML, Yang DO, Husain S, Mayer JP, Zhang L, Mo H, Yan LZ. A novel and selective beta-melanocyte-stimulating hormone-derived peptide agonist for melanocortin 4 receptor potently decreased food intake and body weight gain in diet-induced obese rats. Endocrinology. 2005 Dec;146(12):5257-66

In vitro 82.

Cho KJ, Shim JH, Cho MC, Choe YK, Hong JT, Moon DC, Kim JW, Yoon DY. Signaling pathways implicated in alpha-melanocyte stimulating hormone-induced lipolysis in 3T3-L1 adipocytes. J Cell Biochem. 2005 Nov 1 ;96(4):869-78

Diabetes: the improvement with MSH treatment 83.

Heijboer

AC,

van

den

Hoek

AM,

Pijl

H,

Voshol

PJ,

Havekes

LM,

Romijn

JA,

Corssmit

EP.

lntracerebroventricular administration of melanotan 11 increases insulin sensitivity of glucose disposal in mice. Diabetologia. 2005 Aug;48(8):1621-6 84.

Banno R, Arima H, Sato I, Hayashi M, Goto M, Sugimura Y, Murase T, Oiso Y. The melanocortin agonist melanotan 11 increases insulin sensitivity in OLETF rats. Peptides. 2004 Aug;25(8):1279-86

85.

Savontaus E, Breen TL, Kim A, Yang LM, Chua SC Jr, Wardlaw SL. Metabolic effects of transgenic melanocyte-stimulating hormone overexpression in /ean and obese mice. Endocrinology 2004; 145 (8):388191

Cancer: the improvement with MSH treatment in vitro Melanoma 86.

Abdei-Malek ZA, Kadekaro AL, Kavanagh RJ, Todorovic A, Koikov LN, McNulty JC, Jackson PJ, Millhauser GL, Schwemberger S, Babcock G, Haskeii-Luevano C, Knittel JJ.Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASES J. 2006 Ju/;20(9):1561-3

87.

Nicolaou A, Estdale SE, Tsatmali M, Herrero DP, Thody AJ. Prostag/andin production by melanocytic cells and the effect of a/pha-melanocyte stimulating hormone. FEBS Lett. 2004 Ju/ 16;570(1-3):223-6

Mesothelioma 88.

Colombo G, Sordi A, Turcatti F, Carlin A, Rossi C, Lonati C, Santambrogio L, Gatti S, Catania A. Change in gene expression profile induced by alpha-melanocyte stimulating hormone in a malignant mesothelioma cell line. Cell Mo/ Biol (Noisy-/e-grand). 2006 May 30;52(2):69-74

483

Longevity: the association with higher MSH leveis 89. Catania A, Cutuli M, Garofalo L, Airaghi L, Valenza F, Lipton JM, Gattinoni L. Plasma concentrations and anti­ L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients. Crit Care Med. 2000 May;28(5):1403-7 90. Airaghi L, Manfredi MG, Vivirito MC, Milazzo F, Lipton JM, Zanussi C. Correlation of MSH with survival Clin lmmunol lmmunopathol. 1993 Jan;66(1 ):73-9 91. Magnoni S, Stocchetti N, Colombo G, Carlin A, Colombo A, Lipton JM, Catania A. Alpha-melanocyte­ stimulating hormone is decreased in plasma of patients with acute brain injury. J Neurotrauma. 2003 Mar;20(3):251-60 Longevity: the improvement with MSH (analog) treatment in animais 92. Doi K, Hu X, Yuen PS, Leelahavanichkul A, Yasuda H, Kim SM, Schnermann J, Jonassen TE, Fmkiaer J, Nielsen S, Star RA.AP214, an analogue of alpha-melanocyte-stimulating hormone, ameliorates sepsis­ induced acute kidney injury and mortality. Kidney lnt. 2008 Jun;73(11):1266-74 93. Bertolini A, Guarini S, Rompianesi E, Ferrari W. Alpha-MSH and other ACTH fragments improve cardiovascular function and survival in experimental hemorrhagic shock. Eur J Pharmacol. 1986 Oct 14;130(12):19-26

MSH diagnosis Serum MSH tests 94. Gavrila A, Chan JL, Miller LC, Heist K, Yiannakouris N, Mantzoros CS. Circulating melanin-concentrating hormone, agouti-related protein, and alpha-melanocyte-stimulating hormone leveis in relation to body composition: alterations in response to food deprivation and recombinant human leptin administration. J Clin Endocrinol Metab. 2005 Feb;90(2):1047-54.

MSH treatment: MSH treatment: safety, minimal side effects 95. Ugwu 80, Blanchard J, Dorr RT, Levine N, Brooks C, Hadley ME, Aickin M, Hruby VJ. Skin pigmentation and pharmacokinetics of melanotan-1 in humans. BiopharmDrug Dispos. 1997 Apr;18(3):259-69

484

Chapter four:

Oxytocin

Senescence is associated with a decline of the hypothalamic-oxvtocin axis

Senescence is associated with an apparent maintenance in the number of oxytocin-secreting cells in humans, but a decline in animais 1. Wierda M, Goudsmit E, Van der Woude PF, Purba JS, Hofman MA, Bogte H, Swaab DF. Oxytocin cell number in the human paraventricular nucleus remains constant with aging and in Alzheimer's disease. Neurobiol Aging. 1991 Sep-Oct;12(5):511-6 2. Fliers E, Swaab DF, Pool CW, Verwer RW. The vasopressin and oxytocin neurons in the human supraoptic and paraventricular nucleus; changes with aging and in senile dementia. Brain Res. 1985 Sep 2;342(1):45-53. 3. Lolova IS, Davidoff MS, Yakimoff NA. Vasopressin- and oxytocin-immunoreactive nerve cells in the aging rat hypothalamus. Acta Physiol Pharmacol Bulg. 1996;22(1):7-16 4.

Kawamoto K, Kawashima S. Changes of vasopressin- and oxytocin-immunoreactive neurons after hypophysectomy in young and old mice. Exp Gerontol. 1985;20(5):295-304.

Senescence is associated with a decline in oxytocin secretion to stimuli 5. 6.

7. 8.

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(45%

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Psychoneuroendocrinology. 1998 Nov;23(8):819-35 Detillion CE, et ai. Social facilitation of wound healing. Psychoneuroendocrinology. 2004 Sep;29(8):1004-11

Longevity: the improvement with oxytocin treatment 191. Bodanszky M, Engel SL. Oxytocin and lhe life-span of male rats. Nature. 1966 May 14;210(5037):751 192.

(Treatment with oxytocin, not vasopressin, prolonged the fite of aged rats) Friedman SM, Friedman CL. Effect of posterior pituitary extracts on lhe life-span o! old rats. Nature. 1963 Oct 19;200:237-8 (Life-extrension effects of posterior extracts were shown /ater by Bogdansky and Engel to be due to oxytocin)

Oxvtocin diagnosis Oxytocin tests Saliva 193. White-Traut R, Watanabe K, Pournajafi-Nazarloo H, Schwertz D, Bell A, Carter CS. Detection of salivary oxytocin leveis in lactating women. Dev Psychobiol. 2009 May;51(4):367-73

Plasma 194. Ozsoy S, Esel E, Kula M. Serum oxytocin leveis in patients with depression and lhe effects o! gender and 195.

antidepressant treatment. Psychiatry Res. 2009 Oct 30;169(3):249-52 Rao PS, Weinstein GS, Wilson DW, Rujikarn N, Tyras DH. lsocratic high-performance liquid chromatography­ photodiode-array detection method for determination of lysine- and arginine-vasopressins and oxytocin in biological samples. J Chromatogr. 1991 Jan 4;536(1-2):137-42

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Blaicher W, Gruber D, Bieglmayer C, Blaicher AM, Knogler W, Huber JC. The role oi oxytocin in relation to lemale sexual arousal Gynecol Obstet lnvest. 1999;47(2):125-6

Social stress Taylor SE, Gonzaga GC, Klein LC, Hu P, Greendale GA, Seeman TE. Relation oi oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women. Psychosom Med. 2006 Mar-Apr;68(2):238-45 203. Wallner 8, Dittami J, Machatschke I. Social stimuli cause changes oi plasma oxytocin and behavior in guinea pigs. Biol Res. 2006;39(2):251-8

202.

Other hormone therapies: Female hormone replacement therapy: 204.

Taylor SE, Gonzaga GC, Klein LC, Hu P, Greendale GA, Seeman TE. Relation oi oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women. Psychosom Med. 2006 Mar-Apr;68(2):238-45

Testosterone and LH: 205.

Frayne J, Nicholson HD. Regulation oi oxytocin production by purilied adult rat Leydig cells in vitro: effects oi LH, testosterone and lipoproteins. J Endocrinol. 1994 Nov;143(2):325-32

/GF-1: 206.

Sirotkin AV, Florkovicova I, Makarevich AV, Schaeffer HJ, Kotwica J, Marnet PG, Sanislo P.

Oxytocin

mediates some effects oi insulin-like growth lactor-1 on porcine ovarian lollicles. J Reprod Dev. 2003 Apr;49(2): 141-9

Oxytocin treatment: lntranasal spray Hoover RT. lntranasal oxytocin in eighteen hundred patients. A study on its salety as used in a community hospital. Am J Obstet Gynecol. 1971 Ju115;110(6):788-94

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Burri A, Heinrichs M, Schedlowski M, Kruger TH. The acute effects oi intranasal oxytocin administration on endocrine and sexual lunction in males. Psychoneuroendocrinology. 2008 Jun;33(5):591-600

lnjectable oxytocin Syntocinon Official FDA inlormation, side effects and uses. at http://www.drugs.com/prolsyntocínon.html

209.

Oxytocin treatment: Products Sandrepa ®-Sandoz (withdrawn lorm the market), USNAustralian compounding pharmacies

Sublingual

www.lilespan-products.com University Compounding Pharmacy

10 U per tablet

5 to 10 Ulday

www.ucprx.com Australian Customs Pharmaceuticals www.oxytocinprotocol.com

Oral longacting lntranasal spray Subcutaneous lntramuscular injection + lidocaine 14 cc

Belmar compounding pharmacy -USA www.belmarpharmacy.com (Syntocinon®-Novartis):

10 U per tablet less efficient 10 units per

Syntocinon®-Novartis

1cc

5 to 10 U/day 1 to 3x 8 U/day

10 - 40 IU/day

lntravenous injection Caution: excessive parenteral oxytocin at the end of pregnancy can induce cardiovascular changes 210.

Higher serum oxytocin at lhe end oi pregnancy and after delivery in pregnancy induced hypertension Gu H, Rong L, Sha JY. Changes in blood oxytocin leveis in cases oi pregnancy induced hypertension. Zhonghua Fu Chan Ke Za Zhi. 1994 May;29(5):268-70

211.

Thomas JS, Koh SH, Cooper GM. Haemodynamic effects of oxytocin given as i.v. bolus or infusion on women undergoing Caesarean section. Br J Anaesth. 2007 Jan;98(1):116-9 (Heart rate íncrease)

495

chaptertive:

Vasopressin

Senescence is associated with a decline of the hypothalamic-vasopressin axis

Senescence is associated with an atrophy of the suprachiasmatic nuclei, which contain vasopressin­ containing neurons 1.

Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res. 1985 Sep 2;342(1):37-44

Senescence is associated with a decline in vasopressin leveis in serum, suprachiasmatic nuclei and hypothalamus in rats 2.

Zbuzek VK, Wu WH. Age-related vasopressin changes in rat plasma and the hypothalamo-hypophyseal system. Exp Gerontol. 1982;17(2):133-8

3.

Lucassen PJ, Hofman MA, Swaab DF. lncreased light intensity prevents the age related loss of vasopressin­ expressing neurons in the rat suprachiasmatic nucleus. Brain Res. 1995 Sep 25;693(1-2):261-6

Senescence is associated with a gradual decrease in vasopressin leveis and size of vasopressin-secreitng cells up to the sixth decade, activation after age 80 4. Fliers E, Swaab DF, Pool CW, Verwer RW. The vasopressin and oxytocin neurons in the human supraoptic and paraventricular nucleus; changes with aging and in senile dementia. Brain Res. 1985 Sep 2;342(1):45-53 (Humans: gradual decrease in vasopressin leveis and size of vasopressin-secreitng cel/s up to the sixth decade, activation after age 80

Senescence is associated with no change in vasopressin leveis in humans 5.

Duggan J, Kilfeather S, Lightman SL, O'Malley K. The association of age with plasma arginine vasopressin and plasma osmolality. Age Ageing. 1993 Sep;22(5):332-6.

Senescence is associated with higher vasopressin leveis in men 6. Os I, Kjeldsen SE, Aakesson I, Skj0t0 J, Eide I, Hjermann I, Leren P. Evidence of age-related variation in plasma vasopressin of normotensive men. Scand J Clin Lab lnvest. 1985 May;45(3):263-8 Senescence is associated with decline in amplitude of the circadian cycle of serum vasopressin Jolkkonen J, Tuomisto L, van Wimersma Greidanus TB, Lããrii. E, Riekkinen PJ. Vasopressin leveis in the 7. cerebrospinal fluid in rats of different age and sex. Neuroendocrinology. 1986;44(2):163-7

Senescence is associated with a delayed or gradual loss of adaptation to stimuli:

Less vasopressin is additionally secreted in reaction to exercise 8.

Biemans BA, Van der Zee EA, Daan S. Age-dependent effects of conditioning on cholinergic and vasopressin systems in the rat suprachiasmatic nucleus. Biol Chem. 2003 May;384(5):729-36

Senescence is associated with an excessive and quicker increase in vasopressin levei in reaction to dehydration Davies I, O'Neill PA, McLean KA, Catania J, Bennett D. Age-associated alterations in thirst and arginine 9. vasopressin in response to a water or sodium load. Age Ageing. 1995 Mar;24(2):151-9 10. Anpalahan M. Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. J Am Geriatr Soe. 2001 Jun;49(6):788-92 11. Goldstein CS, Braunstein S, Goldfarb S. ldiopathic syndrome of inappropriate antidiuretic hormone secretion possibly related to advanced age. Ann lntern Med. 1983 Aug;99(2):185-8 12. Helderman JH, Vestal RE, Rowe JW, Tobin JD, Andres R, Robertson GL. The response of arginine vasopressin to intravenous ethanol and hypertonic saline in man: the impact of aging. J Gerontol. 1978 Jan;33(1):39-47

Senescence is associated with a decline in vasopressin receptors paralleling age-related defects in urine concentration 13. Tian Y, Serino R, Verbalis JG. Downregulation of renal vasopressin V2 receptor and aquaporin-2 expression parallels age-associated defects in urine concentration. Am J Physiol Renal Physiol. 2004 Oct;287(4):F797-805

496

Senescence is associated with a decline in target cell sensitivity to vasopressin actions:

Decline or delay in vasopressin-induced renal concentrating ability 14. Wilson PD, Dillingham MA. Age-associated decrease in vasopressin-induced renal water transpor!: a role for adenylate cyclase and G protein malfunction. Gerontology. 1992;38(6):315-21 15. Hvistendahl GM, Frokiaer J, Nielsen S, Djurhuus JC. Gender differences in nighttime plasma arginine vasopressin and delayed compensatory urine output in the elderly population after desmopressin. J Urol. 2007 Dec;178(6):2671-6

Decline in dilatation of brain arteries 16. Gurevich Ml, Frol'kis IV, Kovalenko TN, Dibrova VA. The age-related characteristics of the effect of vasopressin on the vascular smooth muscles of the human brain] Fiziol Zh SSSR lm I M Sechenova. 1989 Nov;75(11):15549. Decline in behavioral and cardiovascular responses 17. Buwalda B, Nyakas C, Koolhaas JM, Luiten PG, Bohus B. Vasopressin prolongs behavioral and cardiac responses to mild stress in young but not in aged rats. Physiol Behav. 1992 Dec;52(6):1127-31.

Deficient vasopressin gene polymorphism may trigqer severa! mechanisms of senescence Poor gene polymorphisms: A poor vasopressin gene polymporphism may be associated with higher diastolic blood pressure leveis and body mass index, correctable with interval walking training 18. Masuki S, Mori M, Tabara Y, Miki T, Sakurai A, Morikawa M, Miyagawa K, Higuchi K, Nose H; Shinshu University Genetic Research Consortium. Vasopressin V1a receptor polymorphism and interval walking training effects in middle-aged and older people. Hypertension. 2010 Mar;55(3):747-54

Vasopressin and psychic well-beinq Lower quality of life: the improvement with vasopressin treatment 19. Carraro A, Fano M, Cuttica M, Bernareggi V, Giusti M, Giordano G. Long-term treatment of central diabetes insipidus with oral DDAVP]. Minerva Endocrinol. 1992 Oct-Dec;17(4):189-9 20. Donahue JL, Lowenthal DT. Nocturnal polyuria in the elderly person. Am J Med Sei. 1997 Oct;314(4):232-8 Depression: the association with lower vasopressin leveis 21. Gjerris A, Hammer M, Vendsborg P, Christensen NJ, Rafaelsen OJ. Cerebrospinal fluid vasopressin--changes in depression. Br J Psychiatry. 1985 Dec;147:696-701 (Lower vasopressin in CSF, but normal in plasma in endogenous and non-endogenous depression) Depression: the association with excessive vasopressin leveis 22. van Londen L, Goekoop JG, Kerkhof GA, Zwinderman KH, Wiegant VM, De Wied D. Weak 24-h periodicity of body temperature and increased plasma vasopressin in melancholic depression. Eur Neuropsychopharmacol. 2001 Feb;11(1):7-14 23. van Londen L, Goekoop JG, van Kempen GM, Frankhuijzen-Sierevogel AC, Wiegant VM, van der Velde EA, De Wied D. Plasma leveis of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacology. 1997 Oct;17(4):284-92 Memory loss and Alzheimer's disease: the association with lower vasopressin leveis 24. Raskind MA, Peskind ER, Lampe TH, Risse SC, Taborsky GJ Jr, Dorsa D. Cerebrospinal fluid vasopressin, oxytocin, somatostatin, and beta-endorphin in Alzheimer's disease. Arch Gen Psychiatry. 1986 Apr;43(4):382-8 25. Emsley RA, Roberts MC, Aalbers C, Taljaard FJ, Kapnias S, Pieters HC, Kotze TJ.Vasopressin secretion and memory impairment in alcoholic Korsakoff's syndrome. Alcohol Alcohol. 1995 Mar;30(2):223-9 Memory loss: the improvement with vasopressin treatment 26. Van Londen L, Goekoop JG, Zwinderman AH, Lanser JB, Wiegant VM, De Wied O. Neuropsychological performance and plasma cortisol, arginine vasopressin and oxytocin in patients with major depression. Psychol Med. 1998 Mar;28(2):275-84 27. Perras B, Droste C, Born J, Fehm HL, Pietrowsky R. Verbal memory after three months of intranasal vasopressin in healthy old humans. Psychoneuroendocrinology. 1997 Aug;22(6):387-96 28. Bruins J, Kumar A, Schneider-Helmert O. lnfluence of desglycinamide-(arg8) vasopressin on memory in healthy subjects. Neuropsychobiology. 1990;23(2):82-8

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29. Millar K, Jeffcoate WJ, Walder CP. Vasopressin and memory: improvement in normal short-term recall and reduction of alcohol-induced amnesia. Psychol Med. 1987 May;17(2):335-41 30. Hamburger-Bar R, Eisenberg J, Belmaker RH Animal and clinicai studies of vasopressin effects on learning and memory. lsr J Med Sei. 1987 Jan-Feb;23(1-2):12-8 31. Till RE, Beckwith BE. Sentence memory affected by vasopressin analog (DDAVP) in cross-over experiment. Peptides. 1985 May-Jun;6(3):397-402 32. Beckwith BE, Till RE, Schneider V. Vasopressin analog (DDAVP) improves memory in human males. Peptides. 1984 Jui-Aug;5(4):819-22 33. Nebes RD, Reynolds CF 3rd, Horn LC. The effect of vasopressin on memory in lhe healthy elderly. Psychiatry Res. 1984 Jan;11 (1):49-59 34. László FA. Effect of vasopressin on memory in healthy probands and patients with central diabetes insipidus. Z Gesamte lnn Med. 1983 Aug 1;38(15):413-5 35. Laczi F, van Ree JM, Wagner A, Valkusz Z, Járdánházy T, Kovács GL, Telegdy G, Szilárd J, László FA, de Wied D. Effects of desglycinamide-arginine-vasopressin (DG-AVP) on memory processes in diabetes insipidus patients and non-diabetic subjects. Acta Endocrinol (Copenh). 1983 Feb; 102(2):205-12 36. Laczi F, Valkusz Z, Lászlo FA, Wagner A, Járdánházy T, Szász A, Szilárd J, Telegdy G. Effects of lysine­ vasopressin and 1-deamino-8-D-arginine-vasopressin on memory in healthy individuais and diabetes insipidus patients. Psychoneuroendocrinology. 1982;7(2-3):185-93 37. Gold PW, Weingartner H, Ballenger JC, Goodwin FK, Post RM. Effects of 1-desamo-8-D-arginine vasopressin on behaviour and cognition in primary affective disorder. Lancei. 1979 Nov 10;2(8150):992-4 Schizophrenia (negative symptoms): the improvement with vasopressin treatment 38. Brambilla F, Bondiolotti GP, Maggioni M, Sciascia A, Grillo W, Sanna F, Latina A, Picotti GB. Vasopressin (DDAVP) therapy in chronic schizophrenia: effects on negative symptoms and memory. Neuropsychobiology. 1989;20(3):113-9 Sleep disorder: the improvement with vasopressin treatment 39. Lose G, Lalos O, Freeman RM, van Kerrebroeck P; Nocturia Study Group. Efficacy of desmopressin (Minirin) in lhe treatment of nocturia: a double-blind placebo-controlled study in women. Am J Obstei Gynecol. 2003 Oct;189(4):1106-13 40. Perras B, Wagner U, Born J, Fehm HL.Improvement of sleep and pituitary-adrenal inhibition after subchronic intranasal vasopressin treatment in elderly humans. J Clin Psychopharmacol. 2003 Feb;23(1):35-44 (lntranasal

AVP increased slow wave sleep on average by +21.5 min) 41. Nevéus T, Bader G, Sillén U. Enuresis, sleep and desmopressin treatment. Acta Paediatr. 2002;91(10):1121-5 (Enuretic children responding to desmopressin treatment have more rapid eye movement sleep than therapy­ resistant children) 42. Perras B, Pannenborg H, Marshall L, Pietrowsky R, Born J, Lorenz Fehm H. Peptides. 1996;17(7):1253-5. Beneficiai treatment of age-related sleep disturbances with prolonged intranasal vasopressin. Clin Psychopharmacol. 1999 Feb;19(1):28-36 43. Perras B, Mõlle M, Born J, Fehm HL. Sleep and signs of attention during 3 months of intranasal vasopressin: a pilot study in two elderly subjects. Biol Psychiatry. 1995 Sep 1;38(5):330-5 (VP improved sleep by markedly

enhancing nocturnal slow-wave sleep)

Vasopressin and age-related diseases Nocturia; the association with lower vasopressin leveis 44. Natsume O. A clinicai investigation of nocturnal polyuria in patients with nocturia: a diurnal variation in arginine vasopressin secretion and its relevance to mean blood pressure. J Urol. 2006 Aug;176(2):660-4 45. Sakakibara R, Uchiyama T, Liu Z, Yamamoto T, lto T, Yamanishi T, Hattori T. Nocturnal polyuria with abnormal circadian rhythm of plasma arginine vasopressin in post-stroke patients. lntern Med. 2005 Apr;44(4):281-4 46. Asplund R. Diuresis pattern, plasma vasopressin and blood pressure in healthy elderly persons with nocturia and nocturnal polyuria. Neth J Med. 2002 Aug;60(7):276-80 47. Kikuchi Y. Participation of atrial natriuretic peptide leveis and arginine vasopressin in aged persons with nocturia. Nippon Hinyokika Gakkai Zasshi. 1995 Nov;86(11):1651-9 Nocturia: the improvement with vasopressin/desmopressin treatment 48. Zahariou A, Karamouti M, Karagiannis G, Papaioannou P. Maximal bladder capacity is a positive predictor of response to desmopressin treatment in patients with MS and nocturia. lnt Urol Nephrol. 2008;40(1 ):65-9 (Vasopressin reduced episodes of nocturia per night decreased more in patients with high bladder capacity)

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49. Bae JH, Oh MM, Shim KS, Cheon J, Lee JG, Kim JJ, Moon DG. The effects oi long-term administration oi oral desmopressin on lhe baseline secretion oi antidiuretic hormone and serum sodium concentration for lhe treatment oi nocturia: a circadian study. J Urol. 2007 Jul;178(1):200-3 50. van Kerrebroeck P, Rezapour M, Cortesse A, Thüroff J, Riis A, Norgaard JP. Desmopressin in lhe treatment oi nocturia: a double-blind, placebo-controlled study. Eur Urol. 2007 Jul;52(1):221-9 51. Terada N, Arakaki R, Okada Y, Kitahara M, Kaneko Y, Omori K, Nishimura K. Efficacy oi intranasal desmopressin in lhe treatment oi nocturia due to nocturnal polyuria. Hinyokika Kiyo. 2005 Mar; 51(3):151-4 52. Hvistendahl GM, Riis A, Norgaard JP, Djurhuus JC. The pharmacokinetics oi 400 microg oi oral desmopressin in elderly patients with nocturia, and the correlation between lhe absorption oi desmopressin and clinicai effect. BJU In!. 2005 Apr;95(6):804-9 53. Cvetkovié RS, Plosker GL. Desmopressin: in adults with nocturia. Drugs. 2005;65(1):99-107 54. Lose G, Lalos O, Freeman RM, van Kerrebroeck P; Nocturia Study Group. Efficacy oi desmopressin (Minirin) in the treatment oi nocturia: a double-blind placebo-controlled study in women. Am J Obstei Gynecol. 2003 Oct;189(4):1106-13 55. Rembratt A, Norgaard JP, Andersson KE. Desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patterns. BJU lnt. 2003 May;91(7):642-6 56. Nevéus T, Bader G, Sillén U. Enuresis, sleep and desmopressin treatment. Acta Paediatr. 2002;91(10):1121-5 57. Kuo HC. Efficacy oi desmopressin in treatment oi refractory nocturia in patients older than 65 years. Urology. 2002 Apr;59(4):485-9 58. Chancellor MB, Atan A, Rivas DA, Watanabe T, Tai HL, Kumon H. Beneficiai effect oi intranasal desmopressin for men with benign prostatic hyperplasia and nocturia: preliminary results. Tech Urol. 1999 Dec;5(4):191-4 59. Granados Loarca EA, Garat Barredo JM, Villavicencio Mavrich H. The use oi desmopressin as an alternative in the treatment oi nycturia in patients with benign prostatic hyperplasia. Actas Urol Esp. 1999 Jan;23(1):56-9 60. Valiquette G, Herbert J, Maede-D'Aiisera P. Desmopressin in lhe management oi nocturia in patients with multiple sclerosis. A double-blind, crossover trial. Arch Neurol. 1996 Dec;53(12):1270-5 61. Eckford SD, Swami KS, Jackson SR, Abrams PH. Desmopressin in lhe treatment oi nocturia and enuresis in patients with multiple sclerosis. Br J Urol. 1994 Dec;74(6):733-5 62. Obara K, Takahashi H, Takeda M, Sato S. The effect oi desmopressin in patients complaining oi nocturia. Nippon Hinyokika Gakkai Zasshi. 1993 Dec;84(12):2131-6 63. Hilton P, Hertogs K, Stanton SL. The use oi desmopressin for nocturia in women with multiple sclerosis. J Neurol Neurosurg Psychiatry. 1983 Sep;46(9):854-5 64. Mànsson W, Sundin T, Gullberg B. Evaluation oi a synthetic vasopressin analogue for treatment oi nocturia in benign prostatic hypertrophy. A double-blind study. Scand J Urol Nephrol. 1980;14(2):139-41

Hemorrhages: the improvement with vasopressin/desmopressin treatment 65. Kongnyuy EJ, Wiysonge CS. lnterventions to reduce haemorrhage during myomectomy for fibroids. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005355 66. Martin-Hirsch PL, Kitchener H. lnterventions for preventing blood loss during lhe treatment oi cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2000;(2):CD001421 67. Jelínek J, Huvar I, Roztocil A, Pilka L. Hemostasis using vasopressin analogs during conization oi lhe uterine cervix and minor vaginal operations. Ceska Gynekol. 1997 Jun;62(3):142-4 68. Mariana G, Ciavarella N, Mazzucconi MG, Antoncecchi S, Solinas S, Ranieri P, Pettini P, Agrestini F, Mandelli F. Evaluation oi lhe effectiveness oi DDAVP in surgery and in bleeding episodes in haemophilia and von Willebrand's disease. A study on 43 patients. Clin Lab Haematol. 1984;6(3):229-38 69. Bolton-Maggs P, Wilkinson LS. Mild bleeding disorders: review oi 120 patients. Clin Lab Haematol. 1984;6(3):247-56 70. Cavus E, Meybohm P, Doerges V, Hugo HH, Steinfath M, Nordstroem J, Scholz J, Bein B. Cerebral effects oi three resuscitation protocols in uncontrolled haemorrhagic shock: a randomised controlled experimental study. Resuscitation. 2009 May;80(5):567-72 71. Wenzel V, Lindner KH. Vasopressin combined with epinephrine during cardiac resuscitation: a solution for lhe future? Cri! Care. 2006 Feb;10(1):125

Hypercholesterolemia: the improvement with vasopressin treatment in rats 72. Caisová D, Stajner A, Suva J. Modification oi fat and carbohydrate metabolism by neurohypophyseal hormones. I. Effect oi lysine-vasopressin on non-esterified fatty acid, glucose, triglyceride and cholesterol leveis in lhe serum oi female rats. Endokrinologie. 1980 Dec;76(3):315-25 Arterial hypertension: the association with lower vasopressin leveis 73. Asplund R. Diuresis pattern, plasma vasopressin and blood pressure in healthy elderly persons with nocturia and nocturnal polyuria. Neth J Med. 2002 Aug;60(7):276-80 74. Rascher W, Weidmann E, Gross F. Vasopressin in the plasma oi stroke-prone spontaneously hypertensive rats. Clin Sei (Lond). 1981 Sep;61(3):295-8

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Portal and pulmonary hypertension: the improvement with vasopressin 75. Tayama E, Ueda T, Shojima T, Akasu K, Oda T, Fukunaga S, Akashi H, Aoyagi S. Arginine vasopressin is an ideal drug after cardiac surgery for the management of low systemic vascular resistant hypotension concomitant with pulmonary hypertension. lnteract Cardiovasc Thorac Surg. 2007 Dec;6(6):715-9 76. Price LC, Forrest P, Sodhi V, Adamson DL, Nelson-Piercy C, Lucey M, Howard LS. Use of vasopressin after Caesarean section in idiopathic pulmonary arterial hypertension. Br J Anaesth. 2007 Oct;99(4):552-5 77. Wang HJ, Wong CS, Chiang CY, Yeh CC, Cherng CH, Ho ST, Wu CT. Low-dose vasopressin infusion can be an alternativa in treating patients with refractory septic shock combined with chronic pulmonary hypertension--a case report. Acta Anaesthesiol Sin. 2003 Jun;41(2):77-80 78. Ohnishi K, Saito M, Nakayama T, Hatano H, Okuda K. Ettects of vasopressin on portal hemodynamics in patients with portal hypertension. Am J Gastroenterol. 1987 Feb;82(2):135-8 79. Kaufman SL, Maddrey WC, Harrington DP, White RI Jr. Hemodynamic effects of superior mesenteric arterial and intravenous vasopressin infusions in patients with portal hypertension. lnvest Radiol. 1977 May­ Jun;12(3):210-4 80. Rabol A, Juhl E, Schmidt A, Winkler K. The effect of vasopressin and triglycyl lysine vasopressin (glypressin) on the splanchnic circulation in cirrhotic patients with portal hypertension. Digestion. 1976;14(3):285-9

Cardiac arrest: the improvement with vasopressin 81. Aung K, Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis. Arch lntern Med. 2005 Jan 10;165(1):17-24 Obesity: the association with lower vasopressin leveis 82. Chiodera P, Capretti L, Davoli C, Caiazza A, Bianconi L, Coiro V. Effect of obesity and weight loss on arginine vasopressin response to metoclopramide and nicotine from cigarette smoking. Metabolism. 1990 Aug;39(8):7836 (The arginine vasopressin increase during nicotine and metoclopramide tests were significantly lower in the obese men. After weight loss the A VP response to nicotine and metoclopramide administration was significantly higher than before slimming and did not differ from that observed in the normal weight subjects.) 83. Coiro V, Chiodera P. Effect of obesity and weight loss on the arginine vasopressin response to insulin-induced hypoglycaemia. Clin Endocrinol (Oxf). 1987 Aug;27(2):253-8 (The arginine vasopressin rise during the insulin tolerance test was significantly lower in the obese patients) 84. Cairo V, Volpi R, Capretti L, Bacchi-Modena A, Cigarini C, Bianconi L, Rossi G, Gramellini D, Chiodera P. Arginine vasopressin secretion in non-obese women with polycystic ovary syndrome. Acta Endocrinol (Copenh). 1989 Dec;121(6):784-90 (Normal basal levels of vasopressin, but lower vasopressin response to insulin-induced hypoglycaemia in women with polycystic avaries) Longevity, survival: the improvement with vasopressin treatment 85. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, Katsios N, Papastylianou A, Gkisioti S, Stathopoulos A, Kollintza A, Stamataki E, Roussos C. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch lntern Med. 2009 Jan 12;169(1):15-24 86. Sillberg VA, Perry JJ, Stiell IG, Wells GA. ls the combination of vasopressin and epinephrine superior to repeated doses of epinephrine alone in the treatment of cardiac arrest-a systematic review. Resuscitation. 2008 Dec;79(3):380-6 87. Russell JA, Walley KR, Gordon AC, Cooper DJ, Hébert PC, Singer J, Holmes CL, Mehta S, Granton JT, Storrns MM, Cook DJ, Presneill JJ; Dieter Ayers for the Vasopressin and Septic Shock Trial lnvestigators. lnteraction of vasopressin infusion, corticosteroid treatment, and rnortality of septic shock. Crit Care Med. 2009 Mar;37(3):8118 (In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% versus 44.7%, respectively, p 0.03). In contras!, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p 0.06) 88. Luckner G, Torgersen C, Mayr VD, Jochberger S, Wenzel V, Hasibeder WR, Dünser MW. Advanced vasodilatory shock. One-year survival after arginine vasopressin therapy. Anaesthesist. 2009 Feb;58(2):144-8

=

=

Vasopressin diaqnosis Clinicai evaluation of vasopressin deficiency 89. Buonocore CM, Robinson AG. The diagnosis and management of diabetes insipidus during medicai emergencies. Endocrinol Metab Clin North Am. 1993 Jun;22(2):411-23 90. Ferry RJ Jr, Kesavulu V, Kelly A, Levitt Katz LE, Moshang T Jr. Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management. J Pediatr. 2001 May;138(5):744-7 91. Cheetham T, Baylis PH. Diabetes insipidus in children: pathophysiology, diagnosis and management. Paediatr Drugs. 2002;4(12):785-96

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Laboratory tests Serum vasopressin determination after infusion or drinking of a salted solution (2.5%): the absent or insufficient increase of the serum vasopressin leve/ suggests vasopressin deficiency 92. Martinez Vea A, Calderón MD, Camps J, Rivera F, Vilardell E, Rever! L. [Use of the hypertonic saline serum test and vasopressin determination for the differential diagnosis of diabetes insipidus]. Med Clin (Barc). 1984 Jun 9;83(2):54-7 93. Laczi F, lványi T, Julesz J, Janáky T, László FA. Plasma arginine-8-vasopressin responses to osmotic or histamine stimulation contribute to the differential diagnosis of central diabetes insipidus. Acta Endocrinol (Copenh). 1986 Oct;113(2):168-74

Comparing urine and plasma osmolality (vasopressin deficiency: low plasma and urine osmolality!osmolarity and high urine output) 94. Cheetham T, Baylis PH. Diabetes insipidus in children: pathophysiology, diagnosis and management. Paediatr Drugs. 2002;4(12):785-96 95. Kovács L, Némethova V, Gucalová Y, Lehotská V, Cintala J, Michajlovskij N, Michalicková J, Lichardus B. Simple diagnosis of diabetes insipidus and antidiuretic hormone excess. Exp Clin Endocrinol. 1985 Apr;85(2):228-34 96. Notman DD, Mortek MA, Moses AM. Permanent diabetes insipidus following head trauma: observations on ten patients and an approach to diagnosis. J Trauma. 1980 Jul;20(7):599-602

Water deprivation test 97. Leung AK, Robson WL, Halperin ML. Polyuria in childhood. Clin Pediatr (Phila). 1991 Nov;30(11):634-40

24-hour urine test: determinationa of the 24-hour urine volume 98. Wu LQ, Xiong CQ, Wu M, Dong RL, Chen YQ, Gao J, Chen OJ, Huang YP. Clinicai characteristics of 7 patients with gestational diabetes insipidus. Zhonghua Fu Chan Ke Za Zhi. 2008 Apr;43(4):266-8

Magnetic resonance imaging (for severe cases) 99. Ghirardello S, Garre ML, Rossi A, Maghnie M. The diagnosis of children with central diabetes insipidus. J Pediatr Endocrinol Metab. 2007 Mar;20(3):359-75 100.Cheetham T, Baylis PH. Diabetes insipidus in children: pathophysiology, diagnosis and management. Paediatr Drugs. 2002;4(12):785-96 Difficulies in diagnosis and management 101.Ferry RJ Jr, Kesavulu V, Kelly A, Levitt Katz LE, Moshang T Jr. Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management. J Pediatr. 2001 May;138(5):744-7 102.Durr JA, Lindheimer MD. Diagnosis and management of diabetes insipidus during pregnancy. Endocr Pract. 1996 Sep-Oct;2(5):353-61 103.Buonocore CM, Robinson AG. The diagnosis and management of diabetes insipidus during medicai emergencies. Endocrinol Metab Clin North Am. 1993 Jun;22(2):411-23

Discriminate between central diabetes insipidus (vasopressin deficiency) and nephrogenic diabetes insipidus (kidney resistance to vasopressin) 104.Makaryus AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of a complex disease. Cleve Clin J Med. 2006 Jan;73(1):65-71 105.Valtin H. Differential diagnosis and pathophysiology of diabetes insipidus. Nippon Jinzo Gakkai Shi. 1995 Nov;37(11):601-9

Corrective vasopressin treatment Vasopressin medications for management of central diabetes insipidus 106.Rivkees SA, Dunbar N, Wilson TA. The management of central diabetes insipidus in infancy: desmopressin, low renal solute load formula, thiazide diuretics. J Pediatr Endocrinol Metab. 2007 Apr;20(4):459-69 107.Atasay B, Berberoglu M, Günlemez A, Evliyaoglu O, Adiyaman P, Unal S, Arsan S, Ocal G. Management of central diabetes insipidus with oral desmopressin in a premature neonate. J Pediatr Endocrinol Metab. 2004 Feb;17(2):227-30 108.Ferry RJ Jr, Kesavulu V, Kelly A, Levitt Katz LE, Moshang T Jr. Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management. J Pediatr. 2001 May;138(5):744-7

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109.Pogacar PR, Mahnke S, Rivkees SA. Management of central diabetes insipidus in infancy with low renal solute load formula and chlorothiazide. Curr Opin Pediatr. 2000 Aug;12(4):405-11 110.Lugo N, Silver P, Nimkoff L, Caronia C, Sagy M. Diagnosis and management algorithm of acute onset of central diabetes insipidus in critically ill children. J Pediatr Endocrinol Metab. 1997 Nov-Dec;10(6):633-9 Oral desmopressin 111.Boulgourdjian EM, Martinez AS, Ropelato MG, Heinrich JJ, Bergadá C. Oral desmopressin treatment of central diabetes insipidus in children. Acta Paediatr. 1997 Nov;86(11):1261-2 112.Merola B, Caruso E, De Chiara G, Rossi E, Longobardi S, Colao A, Brusco G, Lombardi G, Biraghi M. Effectiveness of and tolerability to oral desmopressin in the treatment of central diabetes insipidus. Minerva Med. 1992 113.Westgren U, Wittstrõm C, Harris AS. Oral desmopressin in central diabetes insipidus. Arch Dis Child. 1986 Mar;61(3):247-50 lntranasal desmopressin spray 114.Robson WL, Leung AK, Norgaard JP. The comparative safety of oral versus intranasal desmopressin for the treatment of children with nocturnal enuresis. J Urol. 2007 Jul;178(1):24-30 115.Law SL, Huang KJ, Chou HY. Preparation of desmopressin-containing liposomes for intranasal delivery. J Control Release. 2001 Feb 23;70(3):375-82 Subcutaneous lnjectable vasopressin 116.Kõhler M, Hellstern P, Tarrach H, Bambauer R, Wenzel E, Jutzler GA. Subcutaneous injection of desmopressin (DDAVP): evaluation of a new, more concentrated preparation. Haemostasis. 1989;19(1):38-44

Vasopressin: dosage For diabetes insipidus, oral 117.Fukuda I, Hizuka N, Takano K. Oral DDAVP is a good alternative therapy for patients with central diabetes insipidus: experience of five-year treatment. Endocr J. 2003 Aug;50(4):437-43 (One tablet 100f.lg; The average oral DDAVP dose required to obtain a correct contra/ of diuresis was 19 (range: 15-30) times more than that of =

prior intranasal treatment) For enuresis, intranasal, oral 118.Butler R, Holland P, Devitt H, Hiley E, Roberts G, Redfern E. The effectiveness of desmopressin in the treatment of childhood nocturnal enuresis: predicting response using pretreatment variables. Br J Urol. 1998 May;81 Suppl 3:29-36 (Starting with a standard dose of 20 f.19 (0.02 mg oral) and increasing after 2 weeks where no progress was apparent to 40 f.19 (0.04 mg oral)) For memory, intranasa/ 119.Bruins J, Hijman R, Van Ree JM. Effect of a single dose of 120.des-glycinamide-[Arg8]vasopressin or oxytocin on cognitive processes in young healthy subjects. Peptides. 1992 May-Jun;13(3):461-8des-glycinamide-[Arg8]vasopressin (DGAVP, 2 mg intranasal) For shock 121.Cavus E, Meybohm P, Doerges V, Hugo HH, Steinfath M, Nordstroem J, Scholz J, Bein B. Cerebral effects of three resuscitation protocols in uncontrolled haemorrhagic shock: a randomised controlled experimental study. Resuscitation. 2009 May;80(5):567-72 (Bo/us 0.2U/kg of vasopressin, continuously 0.04 Ulkglmin) 122.Wenzel V, Lindner KH. Vasopressin combined with epinephrine during cardiac resuscitation: a solution for the future? Crit Care. 2006 Feb;10(1):125 (40 lU vasopressin i. v. every 3-5 minutes) 123.Torgersen C, Dünser MW, Wenzel V, Jochberger S, Mayr V, Schmittinger CA, Lorenz I, Schmid S, Westphal M, Grander W, Luckner G. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. lntensive Care Med. 2010 Jan;36(1):57-65 (A supp/ementary AVP infusion of 0.067 IU/min restares cardiovascular function in patients with advanced vasodilatory shock more effectively than AVP at 0.033 /Uimin.)

Vasopressin treatment: safety, side effects 124.Rembratt A, Riis A, Norgaard JP. Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia. Neurourol Urodyn. 2006;25(2):1 05-9 125.Callréus T, Ekman E, Andersen M. Hyponatremia in elderly patients treated with desmopressin for nocturia: a review of a case series. Eur J Clin Pharmacol. 2005 Jun;61(4):281-4 126.Weatherall M. The risk of hyponatremia in older adults using desmopressin for nocturia: a systematic review and meta-analysis. Neurourol Urodyn. 2004;23(4):302-5

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127.Rembratt A, Norgaard JP, Andersson KE. Desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patterns. BJU lnt. 2003 May;91(7):642-6 128.Escorsell A, Bandi JC, Moitinho E, Feu F, García-Pagan JC, Bosch J, Rodés J. Tirne profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol. 1997 Mar;26(3):621-7 (No sustained

(>

1 h) increase in blood pressure with vasopressin or long-acting terlipressin) 129.Cases Amenós A, Mufioz Ruiz I, Gaya Beltrán J, Botey Puig A, Rivera Filial F, Sanz Romero G, Rever! Torrellas L. Vascular hyperreactivity to vasopressin in mild essential arterial hypertension. Med Clin (Barc). 1989 Jun

10;93(2):46-9 (After high dose vasopAressinr infusion, mean atterial pressure increased only in hypettensive patients (from 125.8 to to 135.6 mmHg, p <0.01)) 130.von Gontard A, Lehmkuhl G. Desmopressin side effects. J Am Acad Child Adolesc Psychiatry. 1996 Feb;35(2):129-30 131.Robson WL, Leung AK. Side effects and complications of treatment with_desmopressin for enuresis. J Natl Med Assoe. 1994 Oct;86(10):775-8 132.Monterrubio Villar J, Córdoba López A, Corcho Sánchez G. Severe hyponatremia and intranasal desmopressin­ associated water intoxication in a female patient with diabetes insipidus and histiocytosis X. Med Clin (Barc). 2003 Apr 26;120(15):597 133.Rizzo V, Albanese A, Stanhope R. Morbidity and mortality associated with vasopressin replacement therapy in children. J Pediatr Endocrinol Metab. 2001 Jui-Aug;14(7):861-7 (The incidence of total complications was significantly higher in cottisol deficient patients than in those with normal cottisol reserve (36% vs 6%)

503

Chapter six:

Thyroid

Senescence is associated with a decline of the thyroid axis Senescence is associated with reductions of the serum leveis of TSH, T3 and T4 1. Wiener R, Utiger RD, Lew R, Emerson CH. Age, sex, and serum thyrotropin concentrations in primary hypothyroidism. Acta Endocrinol (Copenh).1991 Apr;124(4):364-9 2.

Bermudez F, Surks Ml, Oppenheimer JH. High incidence of decreased serum triiodothyronine concentration in patients with nonthyroidal disease.J Clin Endocrinol Metab.1975 Jul;41(1):27-40

3.

5.

Hesch RD, Gatz J, Juppner H, Stubbe P. TBG-dependency of age related variations of thyroxine and triiodothyronine.Horm Metab Res.1977 Mar;9(2):141-6 Herrmann J, Heinen E, Kroll HJ, Rudorff KH, Kruskemper HL. Thyroid function and thyroid hormone metabolism in elderly people. Low T3-syndrome in old age? Klin Wochenschr. 1981 Apr 1;59(7):315-23 Djordjevic MZ, Paunkovic ND, Djordjevic-Lalosevic VB, Paunkovic Dz S. The effect of age on in vitro thyroid

6. 7.

8):291-3 Spaulding SW. Age and the thyroid.Endocrinol Metab Clin North Am. 1987 Dec;16(4):1013-25 Smeulers J, Visser TJ, Burger AK, Docter R, Hennemann G. Decreased triiodothyronine (T3) production in

4.

function tests in adult patients on a chronic hemodialysis program. Srp Arh Celok Lek. 1990 Jui-Aug;118(7-

constant reverse T3 production in advanced age. Ned Tijdschr Geneeskd.1979 Jan 6;123(1):12-5 Senescence is associated with a reduction of the metabolic clearance of thyroid hormones Gregerman RI, Gaffney GW, Shock NW, Crowder SE. Thyroxine turnover in euthyroid man with special

8.

9.

reference to changes with age.J Clin lnvest. 1962 Nov;41 :2065-74 Katzeff HL. lncreasing age impairs the thyroid hormone response to overfeeding. Proc Soe Exp Biol Med. 1990 Jul;194(3):198-203

Senescence is associated with a reduction of the amount of thyroid hormone (cellular) receptors 1O.

Kvetny J. Nuclear thyroxine and triiodothyronine binding in mononuclear cells in dependence of age. Horm Metab Res.1985 Jan;17(1):35-8

Senescence is associated with alterations of the circadian cycle of serum TSH: Lower amplitude and phase advance 11. Greenspan SL, Klibanski A, Rowe JW, Elahi D. Age-related alterations in pulsatile secretion of TSH: role of dopaminergic regulation. Am J Physiol.1991 Mar;260(3 Pt 1):E486-91 12. Barreca T, Franceschini R, Messina V, Bottaro L, Rolandi E. 24-hour thyroid-stimulating hormone secretory pattern in elderly men. Gerontology. 1985;31(2):119-23

Thyroid hormones may oppose and thyroid hormones deficiency may triqqer severa! mechanisms of senescence Excessive free radical formation: thyroid hormones stimulate antioxidant activity Nanda N, Bobby Z, Hamide A. Association of thyroid stimulating hormone and coronary lipid risk factors with lipid peroxidation in hypothyroidism.Clin Chem Lab Med. 2008;46(5):674-9 Antipenko AYe, Antipenko YN. Thyroid hormones and regulation of cell reliability systems. Adv Enzyme 14. Regul. 1994;34:173-98 15. Tseng YL, Latham KR. lodothyronines: oxidative deiodination by hemoglobin and inhibition of lipid peroxidation. Lipids. 1984 Feb;19(2):96-102 16. Bozhko AP, Gorodetskaia IV. The role of thyroid hormones in prevention of disorders of myocardial contractile function and antioxidant activity during heat stress. Ross Fiziol Zh lm I M Sechenova. 1998 Mar;84(3):226-32 Faure P, Oziol L, Artur Y, Chomard P. Thyroid hormone (T3) and its acetic derivative (TA3) protect low-density 17. lipoproteins from oxidation by different mechanisms.Biochimie.2004 Jun;86(6):411-8 18. Brzezinska-Siebodzinska E. lnfluence of hypothyroidism on lipid peroxidation, erythrocyte resistance and antioxidant plasma properties in rabbits. Acta Vet Hung.2003;51(3):343-51 Oziol L, Faure P, Bertrand N, Chomard P. lnhibition of in vitro macrophage-induced low density lipoprotein 19. oxidation by thyroid compounds. J Endocrinol. 2003 Apr;177(1):137-46 13.

lmbalanced apoptosis: TSH inhibits undesirable apotosis Feldkamp J, Pascher E, Perniok A, Scherbaum WA. Fas-Mediated apoptosis is inhibited by TSH and iodine in 20. moderate concentrations in primary human thyrocytes in vitro. Horm Metab Res.1999 Jun;31(6):355-8

504

Malaborption of important nutrients: thyroid hormones improve macronutrient uptake 21.

Misra GC, Bose SL Samal AK. Malabsorption in thyroid dyslunctions. J lndian Med Assoe.1991 Jul;89(7): 1957

Failure of repair systems: thyroid hormones reduce damage and accelerate repair 22.

Palmer KC, Mari F, Malian MS. Cadmium-induced acute lung injury: compromised repair response following thyroidectomy. Environ Res. 1986 Dec;41(2):568-84

23.

Saler JD, Crawford TM, Holick MF. A role for thyroid hormone in wound healing through keratin gene expression. Endocrinology. 2004 May;145(5):2357-61

lmmune deficiency: thyroid hormones stimulate lhe immune system

Low thyroid hormone leveis are associated with immune deficiency Kmiec Z, Mysliwska J, Rachon D, Kotlarz G, Sworczak K, Mysliwski A. Natural killer activity and thyroid

24.

hormone leveis in young and elderly persons.Gerontology.2001 Sep-Oct;47(5):282-8 25.

Mariani E, Ravaglia G, Forti P, Meneghetti A, Tarozzi A, Maioli F, Boschi F, Pratelli L, Pizzolerrato A, Piras F, Facchini A.

Vitamin D, thyroid hormones and muscle mass inlluence natural killer (NK) innate immunity in

healthy nonagenarians and centenarians. Clin Exp lmmunol. 1999 Apr;116(1):19-27 26.

Basso A, Piantanelli L, Rossolini G, Piloni S, Vitali C, Masera N.

Role oi triiodothyronine in down-regulation

and recovery ol lymphocyte beta-adrenoceptors in thyroidectomized patients. J Clin Endocrinol Metab. 1991 Dec;73(6):1340-4 27.

Chow CC, Mak TW, Chan CH, Cckram CS. Euthyroid sick syndrome in pulmonary tuberculosis belore and alter treatment. Ann Clin Biochem. 1995 Jul; 32 (Pt 4): 385-91

Thyroid treatment improves the immune defences 28.

Padberg S, Heller K, Usadel KH, Schumm-Draeger PM. One-year prophylactic treatment oi euthyroid Hashimoto's thyroiditis patients with levothyroxine: is there a benelit? Thyroid. 2001 Mar; 11(3):249-55

29.

Aksoy DY, Kerimoglu U, Okur H, Canpinar H, Karaagaoglu E, Yetgin S, Kansu E, Gedik O. Effects oi prophylactic thyroid hormone replacement in euthyroid Hashimoto's thyroiditis. Endocr J. 2005 Jun;52(3):33743

30.

Bloehr H, Bregengaard C, Povlsen JV. Triiodothyronine stimulates growth oi peripheral blood mononuclear cells in serum-lree cultures in uremic patients. Am J Nephrol. 1992;12(3):148-54

31.

Paavonen T. Enhancement oi human B lymphocyte differentiation in vitro by thyroid hormone. Scand J lmmunol.1982 Feb;15(2):211-5

32.

Botella-Carretero Jl, Prados A, Manzano L, Montero MT, Escribano L, Sancho J, Escobar-Morreale HF. The ellects oi thyroid hormones on circulating markers of cell-mediated immune response, as studied in patients with dillerentiated thyroid carcinoma before and during thyroxine withdrawal. Eur J Endocrinol. 2005 Aug;153(2):223-30

33.

Balazs C, Leovey A, Szabo M, Bako G.Stimulating effect of triiodothyronine on cell-mediated immunity. Eur J Clin Pharmacol. 1980 Jan;17(1):19-23

34.

Fabris N, Mocchegiani E, Mariotti S, Pacini F, Pinchera A. Thyroid function modulates thymic endocrine activity. J Clin Endocrinol Metab. 1986 Mar;62(3):474-8

35.

Dorshkind K, Horseman NO. The roles of prolactin, growth hormone, insulin-like growth lactor-1, and thyroid hormones in lymphocyte development and function: insights lrom genetic models of hormone and hormone receptor deliciency. Endocr Rev. 2000 Jun;21(3):292-312

36.

Kvetny J, Matzen LE. Thyroid hormone induced oxygen consumption and glucose-uptake in human

37.

McCormack PD, Thomas J, Malik M, Staschen CM. Cold stress, reverse T3 and lymphocyte lunction. Alaska

mononuclear cells. Thyroidology. 1989 Apr;1(1 ):5-9 Med. 1998 Jui-Sep;40(3):55-62 Limits to healthy cell proliferation: thyroid hormones stimulate fibroblast proliferation and differentiation 38.

Ahsan MK, Urano Y, Kato S, Oura H, Arase S. lmmunohistochemical localization oi thyroid hormone nuclear receptors in human hair lollicles and in vitro effect of L-triiodothyronine on cultured cells oi hair lollicles and skin. J Med lnvest. 1998 Feb;44(3-4):179-84

Poor gene polymorphisms: poor thyroid gene polymorphisms may increase the risk oi age-related diseases, and thyoid dysfunction may increase the risk of phenotypic expression oi other unfavourable gene polymorphisms 39.

Hustad S, Nedrebo BG, Ueland PM, Schneede J, Vollset SE, Ulvik A, Lien EA. Phenotypic expression of the methylenetetrahydrofolate reductase 677C-->T polymorphism and llavin colactor availability in thyroid dysfunction. Am J Clin Nutr. 2004 Oct;80(4):1050-7

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Silva JM, Dominguez G, Gonzalez-Sancho JM, Garcia JM, Silva J, Garcia-Andrade C, Navarro A, Munoz A, Bonilla F. Expression oi thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene. 2002 Jun 20;21(27):4307-16

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Lower quality of life, performance and fatigue: the improvement with thyroid treatment 50. Mainenti MR, Vigário PS, Teixeira PF, Maia MD, Oliveira FP, Vaisman M. Effect of levothyroxine replacement on exercise performance in subclinical hypothyroidism. J Endocrinol lnvest. 2009 May;32(5):470-3 51. Razvi S, lngoe L, Keeka G, Oates C, McMillan C, Weaver JU. The beneficiai effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab. 2007 May;92(5):1715-23 52. Dzurec LC. Experiences of fatigue and depression before and after low-dose L-thyroxine supplementation in 53. 54.

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Memory loss and Alzheimer's disease: the association with lower thyroid hormone leveis 76. Correia N, Mullally S, Cooke G, Tun TK, Phelan N, Feeney J, Fitzgibbon M, Boran G, O'Mara S, Gibney J. Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol Metab. 2009 Oct;94(10):3789-97 77. Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, mood, and cognition in experimentally induced subclinical hypothyroidism. J Clin Endocrinol Metab. 2007 Ju1;92(7):2545-51 78. Miller KJ, Parsons TO, Whybrow PC, Van Herle K, Rasgon N, Van Herle A, Martinez D, Silverman OH, Bauer M. Verbal memory retrieval deficits associated with untreated hypothyroidism. J Neuropsychiatry Clin Neurosci. 2007 Spring;19(2):132-6 79. Zhu DF, Wang ZX, Zhang DR, Pan ZL, He S, Hu XP, Chen XC, Zhou JN. fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism. Brain. 2006 Nov;129(Pt 11):2923-30 80. Nakanishi T. Consideration on serum triiodothyronine (T3), thyroxine (T4) concentration and T3ff4 ratio in lhe patients of senile dementia - is it possible to preveni cerebro-vascular dementia? lgaku Kenkyu. 1990 Feb;60(1):18-25 81. lchibangase A, Nishikawa M, lwasaka T, Kobayashi T, !nada M. Relation between thyroid and cardiac functions and the geriatric rating scale. Acta Neurol Scand. 1990 Jun;81(6):491-8 Molchan SE, Lawlor BA, Hill JL, Mellow AM, Davis CL, Martinez R, Sunderland T. The TRH stimulation test in 82. Alzheimer's disease and major depression: relationship to clinicai and CSF measures. Biol Psychiatry. 1991 Sep 15;30(6):567-76 83. Burmeister LA, Ganguli M, Dodge HH, Toczek T, DeKosky ST, Nebes RD. Hypothyroidism and cognition: preliminary evidence for a specific defect in memory. Thyroid. 2001 Dec;11(12):1177-85 Monzani F, Pruneti CA, De Negri F, Simoncini M, Neri S, Di Bello V, Baracchini Muratorio G, Baschieri L. 84. Preclinical hypothyroidism: early involvement of memory function, behavioral responsiveness and myocardial contractility. Minerva Endocrinol. 1991 Jui-Sep;16(3):113-8 85. Baldini IM, Vila A, Maura MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L. Psychopathological and cognitiva features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925-35 86. Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry. 1996 Oct 15;40(8):714-25 Memory loss and Alzheimer's disease: the improvement with thyroid treatment Correia N, Mullally S, Cooke G, Tun TK, Phelan N, Feeney J, Fitzgibbon M, Boran G, O'Mara S, Gibney J. Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol Metab. 2009 Oct;94(10):3789-97 88. Miller KJ, Parsons TO, Whybrow PC, van Herle K, Rasgon N, van Herle A, Martinez D, Silverman OH, Bauer M. Memory improvement with treatment of hypothyroidism. lnt J Neurosci. 2006 Aug;116(8):895-906 89. Monzon Monguilod MJ, Perez Lopez-Fraile I. Subclinical hypothyroidism as a cause of reversible cognitiva deterioration. Neurologia. 1996 Nov;11(9):353-6 90. Kinuya S, Michigishi T, Tonami N, Aburano T, Tsuji S, Hashimoto T. Reversible cerebral hypoperfusion observed with Tc-99m HMPAO SPECT in reversible dementia caused by hypothyroidism. Clin Nucl Med. 1999 Sep;24(9):666-8 Monzani F, De! Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, Baschieri L. Subclinical hypothyroidism: 91. neurobehavioral features and beneficiai effect of L-thyroxine treatment. Clin lnvestig. 1993 May;71(5):367-71 92. Baldini IM, Vila A, Maura MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925-35 87.

Sleep apnea: the association with lower thyroid hormone leveis 93. Jha A, Sharma SK, Tandon N, Lakshmy R, Kadhiravan T, Handa KK, Gupta R, Pandey RM, Chaturvedi PK. Thyroxine replacement therapy reverses sleep-disordered breathing in patients with primary hypothyroidism. Sleep Med. 2006 Jan;7(1):55-61 Sleep disorders: the improvement with thyroid treatment Jha A, Sharma SK, Tandon N, Lakshmy R, Kadhiravan T, Handa KK, Gupta R, Pandey RM, Chaturvedi PK. Thyroxine replacement therapy reverses sleep-disordered breathing in patients with primary hypothyroidism. Sleep Med. 2006 Jan;7(1):55-61 95. Misiolek M, Marek B, Namyslowski G, Scierski W, Zwirska-Korczala K, Kazmierczak-Zagorska Z, Kajdaniuk D, Misiolek H. Sleep apnea syndrome and snoring in patients with hypothyroidism with relation to overweight. J Physiol Pharmacol. 2007 Mar;58 Suppl 1 :77-85 Ruiz-Primo E, Jurado JL, Solis H, Maisterrena JA, Fernandez-Guardiola A, Valverde C. Polysomnographic 96. effects of thyroid hormones primary myxedema. Electroencephalogr Clin Neurophysiol. 1982 May;53(5):55964 Orr WC, Males JL, lmes NK. Myxedema and obstructive sleep apnea. Am J Med. 1981 May;70(5):1061-6 97. 94.

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Sexual dysfunction: the association with lower thyroid hormone leveis Veronelli A, Mauri C, Zecchini B, Peca MG, Turri O, Valitutti MT, daii'Asta C, Pontiroli AE. Sexual dysfunction is frequent in premenopausal women with diabetes, obesity, and hypothyroidism, and correlates with markers

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DISCUSSIONS ON THYROID DIAGNOSIS

SERUM TSH: IS THE TSH SERUM MEASUREMENT ALONE SUFFICIENT FOR DIAGNOSIS ANO FOLLOW-UP OF THYROID DEFICIENCY? Claim: TSH is lhe first line test to do. 11 is sufficient to diagnose ali forms of eu-, hypo- and hyperthyroidism. No olhe r test is necessary for lhe diagnosis. Facts: TSH is often insufficient on its own to diagnose between eu-, hypo- and hyperthyroidism, particularly to diagnose milder, borderline states of hypothyroidism. Other tests are necessary, as is a complete clinicai evaluation (medicai history, actual complaints, physical examination) of lhe patient. Article defending the serum TSH test as the first line approach to diagnose thyroid dysfunction 1. Nunez S, Leclere J. Diagnosis of hypothyroidism in lhe adult. Rev Prat. 1998; 48(18): 1993-8. Doubts on the usefulness of the serum TSH test alone for diagnosis Overreliance on laboratory tests without clinicai evaluation may lead to considerable diagnostic errors 2.

Nicoloff JT, Spencer CA. The use and misuse of lhe sensitive thyrotropin assay. J Clin Endocrinol Metab. 1990;71 :553-8.

3.

De Los Santos ET, Mazzaferri EL. Sensitive thyroid-stimulating hormone assays: Clinicai applications and limitations. Compr Ther.1988; 14(9): 26-33.

4.

Becker DV, Bigos ST, Gaitan E, Morris JCrd, rallison ML, Spencer CA, Sugarawa M, Van Middlesworth L, Wartofsky L. Optimal use of blood tests for assessment of thyroid function. JAMA i 993 Jun 2; 269: 273 ("lhe decision to initiate therapy shoul be based on both clinicai and laboratory findings and no! solely on lhe results of a single laboratory test")

5.

Rippere V. Biochemical victims: False negative diagnosis through overreliance on laboratory results-a personal repor!. Med Hypotheses. 1983; 10(2}: 113.

Discussions and controversy in medicai associations and journals on the TSH reference range Surks Ml, Ortiz E, Daniels GH, Sawin CT, Gol NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke 6. MA, Gorman C, Cooper AS, Weissman NJ. Subclinical thyroid disease: scientific review and guidelines for

7.

diagnosis and management. JAMA. 2004;291:228-38 (conclusions of a consensus pane/ of the Endocrine Society, the American Thyroid Association,and American Association of Clínica/ Endocrinology. Although the pane/ concluded that there was good data that patients with slight elevations of TSH above 4.5 may progress to overt hypothyroidism, and that /evothyroxine therapy wou/d preveni symptoms, they did not agree that early treatment provided any benefit!) Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin levei: normal ranges and reference intervals are no! equivalent. Thyroid. 2005 Sep;15(9):1035-9

8.

Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8 (remarkable article of which a lot of the following information is extracted) 9. Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dyslunction: a joint statement on management lrom lhe American Association oi Clinicai Endocrinologists, lhe American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:581-5 10. Surks Ml. Commentary: subclinical thyroid dyslunction: a joint statement on management from lhe American Association oi Clinicai Endocrinologists, lhe American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:586-7 11. Ringel MD, Mazzaferri EL. Editorial: subclinical thyroid dyslunction: can there be a consensus about lhe consensus? J Clin Endocrinol Metab. 2005;90:588-90 12. Pinchera A. Subclinical thyroid disease: to treat or not to !real? Thyroid. 2005;15:1-2 Studies that show that the serum TSH reference range of 0.1-5.1 mU/Iiter for a POPULATION is too large Studies indicating a population mean value of 1.5 mU/Iiter for an iodine-sufficient population 13. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence oi thyroid disorders in the community: a twenty-year lollow-up oi lhe Whickham Survey. Clin Endocrinol (Oxf). 1995;43:55-68 14. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in lhe United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES 111). J Clin Endocrinol Metab. 2002; 87:489-99

518

15. Andersen S, Petersen KM, Brunn NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068-72 16. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138-40 17. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003 Jan;13(1):3-126 A longitudinal study in diabetics where a baseline TSH leveis above the 1.53 mU/Iiter predicted subsequent thyroid dysfunction, whereas no thyroid dysfunction if TSH leveis < 1.53 mU/Iiter, the reference range for diabetics should then be 0.4-1.52 mU/Iiter 18. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of tuture thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853-7 lf the serum TSH reference range would be based upon a cohort of truly normal individuais with no personal or family history of thyroid dysfunction, no visible or palpable goiter, not taking any medication, who are seronegative for thyroid preoxidase antibodies, and whose blood samples are drawn fasting in the morning hours (06-1O h), the TSH reference range would become 0.4-2.5 mU/L (Demers & co, Baloch & co.) 19. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138-40 20. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES 111). J Clin Endocrinol Metab. 2002; 87:489-99 21. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan; 13(1 ):3-126 When data for subj ects with positive TPOAb or a family history of autoimmune thyroid disease are excluded, the normal reference interval becomes much tighter, i.e. 0.4-2.0 mU/Iiter. This tighter reference range may certainly be more applicable to African-Americans, who have a /ower mean TSH 22. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES 111). J Clin Endocrinol Metab. 2002; 87:489-99 23. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138-40 Publications with data to support a more narrow reference range for serum TSH that would be obtained when persons with dittuse hypoechogenicity of the thyroid on ultrasound, a condition that precedes thyroid peroxidase antibody positivity in autoimmune thyroid disease, would be excluded 24. Pedersen OM, Aardal NP, Larssen TB, Varhaug JE, Myking O, Vik-Mo H. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid. 2000;10:251-9 For the American Association of Clinicai Endocrinologists the revised reference TSH range is 0.3-3.0 mU/L 25. American Association of Clinicai Endocrinologists. American Association of Clinicai Endocrinologists medicai guidelines for clinicai practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457-69 Ethnic differences: the mean TSH levei in African-Americans is 1.18 mU/Iiter, in contrast to a mean of 1.40 mU!Iiter in Caucasians, due to the greater frequency of autoimmune thyroid disease in whites (12.3%) than in blacks (4.3%), which may have unjustifiedly skewed lhe upper end of lhe TSH curve (NHANES data). For African­ Americans, the TSH reference range should therefore be lower than in whites 26. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES 111). J Clin Endocrinol Metab. 2002;87:489-9 A study, which suggests that the serum TSH cut-off point between hypo- and euthyroidism is 2, not 4 or 5.5 27. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adampoulos P, Koutras DA. High serum cholesterol levels in persons with 'high-normal' TSH leveis: Should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998 Feb;138(2):141-5( Treating TPO antibody-positive hypercholesterolemic

519

patients with TSH leveis between 2-4 mU/L with /ow dose /evothyroxine normalizes TSH leveis and improves the lipid profile) In 2003, the National Academy of Clinicai Biochemistry (NACB) has reduced the upper limit of the reference

range from 5.5 to 4.1 mU/L, but stating also that "greater than 95% of healthv. euthyroid subjects have a serum TSH concentration between 0.4 - 2.5 mU/L". ".. patients with a serum TSH >2.5 mU/L. when confirmed by repeat TSH measurement made after 3 to 4 weeks. may be in the early stages of thyroid failure, especially if thyroid peroxidise antibodies are detected" 28. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan; 13(1):3-126 Supporters of the recommendations of the consensus panel (Endocrine Society, American Association of Clinicai Endocrinologists, American Thyroid Association) promote a target TSH range of 1.0-1.5 mU/Iiter in patients already receiving T4 therapy 29. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt·Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

The lower end of the normal or reference range for TSH lies between 0.2 and 0.4 mU!Iiter, as indicated by a number of clinicai studies 30. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126 31. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991 ;34:77-83 32. Warren RE, Perros P, Nyirenda MJ, Frier BM.

Serum thyrotropin is a better predictor of future thyroid

dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853-7 33. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch lntern Med. 2000;160:526-34 34. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM.

Low serum thyrotropin (thyroid

stimulating hormone) in older persons without hyperthyroidism. Arch lntern Med. 1991 ;151 :165-8 35. Hershman JM, Pekary AE, Berg L, Solomon DH, Sawin CT

Serum thyrotropin and thyroid hormone leveis in

elderly and middle-aged euthyroid persons. J Am Geriatr Soe. 1993;41:823-8 36. Parle JV, Maisonneuve P, Sheppare MC, Boyle P, Franklyn JA.

Prediction of ali-cause and cardiovascular

mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:8615

The TSH reference range for an INDIVIDUAL is narrower than the reference range for a population The value of a population-based reference range is limited when the individual patient-based reference range (i. e. his personal reference range) is narrow 37. Fraser CG, Harris EK. Generation and application of data on biological variation in clinicai chemistry. Crit Rev Clin Lab Sei. 1989;27:409-37 38. Harris EK. Effects of intra- and interindividual variation on the appropriate use of normal ranges. Clin Chem. 1974;20:1535-42

The individual TSH reference ranges are remarkably narrow within a relatively small segment of the population reference range, i.e. confined to only 25% of a range of 0.3-5.0 mU!Iiter. A shift in the TSH value of the individual outside of his or her individual reference range, but still within lhe population reference range, would not be normal for that individual. For example, an individual (as in Anderson's series) with a personal range of 0.5-1.0 mU/Iiter would be at subphysiological thyroid hormone leveis at the population mean TSH of 1.5 mU/Iiter (as explained by Wartofsky 2005) 39. Andersen S, Petersen KM, Brunn NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068-72

Studies of twins have data to support that each of us has a genetically determined optimal free T4 (FT4)-TSH set point or relationship 40. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138-40

520

41. Meikle AW, Stringham JD, Woodward MG, Nelson JC. Hereditary and environmental influences on lhe variation of thyroid hormones in normal male twins. J Clin Endocrinol Metab. 1988 ; 66:588-92

A measured TSH ditference of0.75 mU!Iiter can already be significant in a patient. The NACB guideline 8 states that "lhe magnitude of difference in ...TSH values lha! would be clinically significant when monitoring a patient's response to therapy... is 0.75 mU/Iiter." Greater TSH fluctuations in a specific patient may mean that s/he becomes hypothyroid or hyperthyroid. 42. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

A serum TSH that rises in a given individual from a set point of 1.0 to 3.5 is likely to be abnormally elevated and imply early thyroid failure. A minor change in serum free T4 results in an amplified change in TSH to outside of lhe usual population-based reference range, although the free T4 is still within its own population-based reference range, because of lhe lhe log-linear relationship between TSH and free T4. In lhe case oi subclinical hypothyroidism, for example, a slight drop in free T4 results in an amplified and inverse response in TSH secretion (as explained by Wartofsky 2005) 43. Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345:260-5 44. Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44-50

There is a 3-fold difference between the average daily maximal TSH (3) and minimal TSH (1 miU/ml) 89. Brabant G, Prank K, Ranlt U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, 45. Feistner H, Hesch RD, von zur Muhlen A. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab. 1990 Feb;70(2):403-9

Conclusion: TSH reference range is too large

=>

need for narrower ranges

46. Pain RW. Simple modifications oi three routine in vitro tests of thyroid function. Clin Chem. 1976; 22(10): 1715-8 47. Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin levei: normal ranges and reference intervals are not equivalent. Thyroid. 2005 Sep;15(9):1035-9 48. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8

Other arguments that may explain why the TSH test alone is not the only test The TSH test is insufficient to diagnose ali forms of hypothyroidism, including lhe borderline forms.

The frequency of abnormal TSH values 49. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch lntern Med. 2000;160:526-34 50. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853-7 Longitudinal studies indicating a rate of progression of mild thyroid failure into overt hypothyroidism of about 5o/o per year (50% ar more in 1 O years!): they have to be treated 51. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence oi thyroid disorders in the community: a twenty-year follow-up oi lhe Whickham Survey. Clin Endocrinol (Oxf). 1995; 43:55-68 52. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in lhe elderly in lhe United Kingdom. Clin Endocrinol (Oxl). 1991;34:77-83 53. Huber G, Staub J-J, Meier C, Mitrache C, Guglielmetti M, Huber P, Braverman LE. Prospective study of lhe spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87:3221-6 54. Kabadi UM. 'Subclinical hypothyroidism:' natural course of lhe syndrome during a prolonged follow-up study. Arch lntern Med. 1993;153:957-61 The pituitary 5'-deiodinase type 2 that converts thyroxine into triiodothyronine (T3), is different than the liver and kidney 5'-deiodinase type 1 that provides the T3 for the rest of the body. This difference may explain why TSH secretion and thus serum TSH secreted by the pituitary gland may be normal, while lhe rest of lhe body may be in a thyroid deficient state.

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Agíng 67. Urban RJ. Neuroendocrinology of aging in lhe male and female. Endocrinol Metab Clin North Am. 1992;21(4): 921-31 68. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid­ stimulating hormone) in older persons without hyperthyroidism. Arch lntern Med. 1991; 151(1): 165-8

Fastíng 69. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, Nicoloff OA. Decreased serum thyrotropin induced by fasting. J Clin Endocrinol Metab. 1977; 45: 560 70. Borst GC, Osburne RC, O'Brian JT, Georges LP, Burman KD. Fasting decreases thyrotropin responsiveness to thyrotropin-releasing hormone: A potential cause of misinterpretation of thyroid function tests in lhe critically ill. J Clin Endocrinol Metab. 1983 Aug;57(2):380-3

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Schlienger JL, Sapin R, Grunenberger F, Gasser F, Pradignac A. Thyrotropin assay by chemiluminescence in lhe diagnosis of dysthyroidism with low thyrotropin and normal thyroid hormones leveis. Pathol Biol Paris. 1993; 41(5): 463-8 Spencer C, Eigen A, Shen D, Duda M, Qualls S, Weiss S, Nicoloff J. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987 Aug;33(8):1391-6

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Spencer CA, Challand GS. lnterference in a radioimmunoassay for human thyrotropin. Clin Chem 1977;23(3):

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Kahn BB, Weintraub BD, Csako G, Zweig MH. Factitious elevation o! thyrotropin in a new ultra-sensitive

584-8 assay: lmplications for lhe use o! monoclonal antibodies in 'sandwich' immuno-assay. J Clin Endocrinol Metab. 1988 Mar;66(3):526-33 110.

Kourides IA, Weintraub BD, Martorana MAL, Maloof F. Alpha subunit contamination o! human albumin preparations: lnterference in radioimmunoassay. J Clin Endocrinol Metab. 1976; 43(4): 919-23

111.

Bartlett WA, Browning MC, Jung RT. Artefactual increase in serum thyrotropin concentration caused by heterophilic antibodies with specificity for lgG o! lhe family Bouidea. Clin Chem. 1986; 32(12): 22(4-9)

112.

Csako G, Weintraub BD, Zweig MH.

The potency o! immunoglobulin antibodies in

a monoclonal

immunoradiometric assay for thyrotropin. Clin Chem. 1988 Jul;34(7):1481-3 113.

Seghers J, Schruers F, De Nayer P, Beckers C. lnterference in thyrotropin (TSH) determination: Falsely elevated TSH values in a transplanted patient. Eur J Nucl Med. 1989; 15(4): 194-6

114.

Spencer C, Eigen A, Shen D, Duda M, Quails S, Weiss S, Nicoloff J. Specificity o! sensitive assays o!

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Ealey PA, Marshall NJ, Ekins RP. Time-related thyroid stimulation by thyrotropin and thyroid-stimulating

thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987;33(8):1391-6 antibodies, as measured by lhe cytochemical section bioassay. J Clin Endocrinol Metab. 1981 ;52(3): 483-7

Doubts on the adeguateness of measurinq the serum TSH as a help to monitor a thyroid treatment ( follow-

.!:!.Pl The serum TSH test for follow-up: The risk of misinterpretation increases when monitoring the treatment of hyper- or hypothyroidism 116.

Talbot JN, Duron F, Feron R. Aubert P, Milhaud G. Thyroglobulin, thyrotropin and thyrotropin binding inhibiting immunoglobulins assayed at lhe withdrawal o! antithyroid drug therapy as predictors o! relapse of Graves' disease within one year. J Endocrinol lnvest. 1989; 12(9): 589-95

In 36-47 % of cinically euthyroid patients receiving adequate long-term thyroid therapy for hypothyroidism, an undetectable serum TSH is found 117.

Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison o! second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab 1994; 78(6): 1368-71

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Gow SM, Caldwell G, Toft AD, Seth J, Hussey AJ, Sweeting VM, Beckett GJ. Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement. J Clin Endocrinol Metab. 1987; 64(2): 364-70

After intake of thyroidhormones, the serum TSH is transitorily depressed within 60 minutes and remains low for up to 9 hours after intake 119.

Chopra U, Carlson HE, Solomon DH. Comparison of inhibitory effects of 3,5,3'-triiodothyronine (T3), thyroxine (T4), 3,3,',5'-triiodothyronine (rT3,), and 3,3'-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in lhe rat in vitro. Endocrinology. 1978;103(2):393-402

Some patents who exhibit reversion of an initially high TSH levei back into the reference range, are found to subsequently develop mild thyroid failure 120.

Calaciura F, Motta RM, Miscio G, Fichera G, Leonardi D, Carta A, Trichitta V, Tassi V, Sava L, Vigneri R. Subclinical hypothyroidism in early childhood: a frequent outcome o! transient neonatal hyperthyrotropinemia. J Clin Endocrinol Metab. 2002;87:3209-14

Supporters of the recommendations of the consensus panel promote a target TSH range of 1.o-1.5 mU/Iiter in patients already receiving T4 therapy, whereas they refuse to accept TSH leveis of 3-10 mU/Iiter as

abnormal in patients not receiving T4 therapy. 121.

Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

The lower end of the normal or reference range for TSH lies between 0.2 and 0.4 mU/Iiter, as indicated by a number of clinicai studies 122. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

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Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up oi abnormal thyrotrophin (TSH) concentrations in lhe elderly in lhe United Kingdom. Clin Endocrinol (Oxf). 1991;34:77-83

124.

Warren RE, Perros P, Nyirenda MJ, Frier BM.

Serum thyrotropin is a better predictor oi future thyroid

dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853-7

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Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch

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Hershman JM, Pekary AE, Berg L, Solornon OH, Sawin CT Serurn thyrotropin and thyroid horrnone leveis in elderly and rniddle-aged euthyroid persons. J Am Geriatr Soe. 1993;41:823-8

128.

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DISCUSSIONS ON THYROID TREATMENT

DOES THYROID TREATMENT DEFINITELY SUPPRESS THE IHYROID GLAND? No, after stopping thyroid medications, the thyroid axis recovers its initial condition in 2 to 3 weeks on the average

1.

Krugman LG, Hershman JM, Chopra IJ, Levine GA, Pekary E, Geffner DL, Chua Teco GN. Patterns off recovery oi lhe hypothalamic-pituitary-thyroid axis in patients taken oi chronic thyroid therapy. J Clin Endocrinol Metab. 1975 Jul;41 (1):70-8 0 (Fui/ recoveryback to initial serum T3, T4, TSH leveis is obtained after

a mean of 16 to 22 days, even after 28 years of treatment) 2.

Vagenakis AG, Braverman LE, Azizi F, Portinay Gl, lngbar SH. Recovery oi pituitary thyrotropic function after withdrawal oi prolonged thyroid-suppression therapy. N Engl J Med. 1975 Oct 2;293(14):681-4 ("During

exogenous hormone administration, 1311 uptake was suppressed, and serum thyrotropin concentrations before and after administration of thyrotropin-releasing hormone were undetectable. .. .. After withdrawal of long-term thyroid hormone, decreased thyrotropin reserve persisted for two to tive weeks. Detectable va/ues of serum thyrotropin (/ess than 1.2 muU per mil/iliter) and a norma/ 1311 uptake usual/y occurred concurrently in two to three weeks. Serum thyroxine concentration retumed to normal at /east four weeks after hormone withdrawal. '? 3.

Greer MA. The effect on endogenous thyroid activity oi feeding desiccated thyroid to normal human subjects. N Engl J Med. 1951 Mar 15;244(11):385-90 ("After withdrawal of thyroid therapy, thyroid function retumed to normal in most subjects within 2 weeks, although a few were depressed ofr 6-11 weeks. Thyroid function

4.

retumed as rapidly in those whose glands had been depressed by severa/ years of thyroid medication as it did for those whose glands had been depressed for only a few days.'? Mosier HD, DeGolia RC. Effect oi prolonged administration oi thyroid hormone on thyroid gland function oi euthyroid children. J Clin Endocrinol Metab. 1960 Sep;20:1296-301. ("In ali of the echildren and adolescents

7.

inc/uded in this study, thyroid function retumed to normal (as judged by clinicai signs ans by /aboratory measurements) within four months after discontinuing thyroid hormone,in spite of previous administration of suppressive doses for periods of 20 toa 125 months during years of somatic growth'j. Farquharson RF, Squires AH. lnhibition oi the secretion oi lhe thyroid gland by continued ingestion oi thyroid substance. Ir A Am Physicians. 1941;56:87 Johnston MW, Squires AH, Farquharson RF. The effect oi prolonged administration oi thyroid. Ann lntern Med. 1951 Nov;35(5):1008-22 Riggs OS, Man EB, Winkler AW. Serum iodine oi euthyroid subjects treated with desiccated thyroid. J Clin

8.

Stein RB, Nicoloff JT. Triiodothyronine withdrawal test -a test oi thyroid-pituitary adequacy. J Clin Endocrinol

5. 6.

lnvest. 1945;24:722-31 Metab. 1971 Feb;32(2}:127-9 lf the thyroid treatment is stopped because it is judged not necessary, recovery takes place

9.

Rubinoff H, Firernan BH. Testing for recovery oi thyroid function after withdrawal oi long-term suppression therapy. J Clin Epidemiol. 1989;42(5):417-20 (At 8 weeks, 30 of the 45 patients whose chart reviews did not

demonstrate a clear need for thyroid replacement., were normal)

528

MILD THYROID FAILURE: TO TREAT OR NOT TO TREAT

Arguments pro thyroid treatment of mild thyroid failure Longitudinal studies indicating a rate of progression of mild thyroid failure into overt hypothyroidism of about 5% per year 1.

(50% or more in 10 years!): they have to be treated

Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence oi thyroid disorders in lhe community: a twenty-year lollow-up oi lhe Whickham Survey. Clin Endocrinol (Oxl). 1995; 43:55-68

2.

Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and lollow-up of abnormal thyrotrophin

3.

Huber G, Staub J-J, Meier C, Mitrache C, Guglielmetti M, Huber P, Braverman LE. Prospective study oi lhe

(TSH) concentrations in lhe elderly in lhe United Kingdom. Clin Endocrinol (Oxf). 1991;34:77-83 sponlaneous course of subclinical hypolhyroidism: prognoslic value of thyrotropin, lhyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87:3221-6 4.

Kabadi UM. 'Subclinical hypothyroidism:' natural course oi lhe syndrome during a prolonged lollow-up sludy. Arch lntern Med. 1993;153:957-61

Little benefit of T4 therapy if TSH reductions are put into only the range of 3-3.5 mU/IL. Mainly studies using dosage titralion to TSH leveis

<

3.0 are associated with irnprovement in symptorns, lipid abnormalities, and

cardiovascular lunction (except lhe study by Meier and colleagues lha! showed benefit with minimal TSH reductions in lhe 3-3.5 miU/ml range) 5.

Meier C, Slaub J-J, Rolh C-8, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH­ controlled L-thyroxine therapy reduces cholesterol leveis and clinicai symploms in subclinical hypothyroidism. Am J Med. 2001;112:348-54

6.

Meier C, Staub J-J, Roth C-8, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled

L-thyroxine

therapy

reduces

cholesterol

leveis

and

clinicai

symptoms

in

subclinical

hypothyroidism: a double blind, placebo-controlled trial (Base! Thyroid Study). J Clin Endocrinol Metab. 2001; 86:4860-6 7.

Cooper OS 2001 Subclinical hypothyroidism. N Engl J Med 345:260-5

8.

Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44-50

9.

McDermott MT, Ridgway EC. Clinicai perspective: subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab. 2001; 86:4585-90

(shows benefit with mínima/ TSH reductions down to only

lhe range of 3-3.5 mU!Iiter) Studies with appropriate dosage titration to TSH leveis under 3.0 are more often associated with improvement in symptoms, lipid abnormalities, and cardiovascular function 10. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adampoulos P, Koutras DA. High serum cholesterol levels in persons with 'high-normal' TSH leveis: should one extend lhe definition of subclinical hypothyroidism. Eur J Endocrinol.1998;138:141-5 11. Ayala A, Wartofsky L 2002 The case for more aggressive screening and treatment of mild thyroid failure ("subclinical" hypothyroidism). Cleveland Clin J Med. 69:313-20 12. Faber J, Petersen L, Wiinberg N, Schifter S, Mehisen J.Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism. Thyroid. 2002; 12:319-24 13. Monzani F, DiBello V, Caraccio N, Bertini A, Giorgi O, Guisti C, Ferranni E. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Melab. 2001; 86:1110-5 14. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, Bone F, Lombardi G, Sacca L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999; 84:2064-7 15. Di Bello V, Monzani F, Giorgi O, Bertini A, Caraccio N, Valenti G, Talini E, Paterni M, Ferrannini E, Giusti C. Ultrasonic myocardial textura! analysis in subclinical hypothyroidism. J Am Soe Echocardiogr. 2000;13:832-40 16. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, Stametelopoulos S, Koutras DA. Flow-mediated, endothelium-dependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin values. Thyroid. 1997; 7:411-4 17. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Salvetti A, Ferrannini E, Monzani F. lmpaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficiai effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88:3731-7 18. Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JPJ, Heine RJ, Gans ROB. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab.86:1206-11

529

19. Krausz Y, Freedman N, Lester H, Newman JP, Barkai G, Bocher M, Chisin R, Bonne O. Regional cerebral blood flow in patients with mild hypothyroidism. J Nucl Med. 2004; 45:1712-5 20. lmaizumi M, Akahoshi M, lchimaru S, Nakashima E, Hida A, Soda M, Usa T, Ashizawa K, Yokayama N, Maeda R, Nagataki S, Eguchi K. Risk for ischemic heart disease and ali-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004;89:3365-70 21. Monzani F, Caraccio N, Kozakowa M, Dardano A, Vittone F, Virdis A, Taddei S, Palombo C, Ferrannini C. Effect oi levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double­ blind, placebo-controlled study. J Clin Endocrinol Metab. 2004;89:2099-106

Other studies in defence of treatment of mild thyroid failure: it is important to treat mild thyroid failure to avoid adverse physical and psychological consequences 22. Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, Baschieri L. Subclinical hypothyroidism: neurobehavioral features and beneficiai effect oi L-thyroxine treatment. Clin lnvestig. 1993 May;71(5):367-71 23. Tappy L, Randin JP, Schwed P, Wertheimer J, Lemarchand-Beraud T. Prevalence oi thyroid disorders in psychogeriatric inpatients. A possible relationship oi hypothyroidism with neurotic depression but not dementia. J Am Geriatr Soe. 1 987;35:526-31 24. Joffe RT, Levitt AJ 1992 Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology. 17:215-21 25. Haggerty Jr JJ, Stern RA, Mason GA, Beckwith J, Morey CE, Prange Jr AJ. Subclinical hypothyroidism: A modifiable risk factor for depression? Arn J Psychiatry. 1993;150:508-1O 26. Maneie! G, Dartigues JF, Decamps A, et ai. 1995 The PAQUID survey and correlates oi subclinical hypothyroidism in elderly community residents in lhe southwest oi France. Age Aging. 24:235-41 27. Baldini IM, Vila A, Maura MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925-35 28. Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry. 1996;40:714-25 29. Monzani F, Caraccio N, Siciliano G, Manca L, Murri L, Ferrannini E. Clinicai and biochemical features oi muscle dysfunction in subclinical hypothyroidism. J Clin Endocrinol Metab. 1997;82:3315-8 30. Monzani F, Caraccio N, Del Guerra P, Casolaro A, Ferrannini E. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficiai effect oi L-T4 replacement therapy. Clin Endocrinol. 1999;51:237-42 31. Misiunas A, Ravera HN, Faraj G, Faure E. Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995;5:283-6 32. Goulis DG, Tsimpiris N, Delaroudis S, Maltas B, Tzoiti M, Dagilas A, Avramides A. Stapedial reflex: a biological index found to be abnormal in clinicai and subclinical hypothyroidism. Thyroid. 1998 Jul;8(7):583-7 33. Beyer IW, Karmali R, DeMeester-Mirkine N, Cogan E, Fuss MJ. Serum creatine kinase leveis in overt and subclinical hypothyroidism. Thyroid 1998;8:1029-31 34. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O'Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development oi the child. N Engl J Med. 1999 Aug 19;341(8):549-55 35. Foundation for Blood Research, Scarborough, ME 04074, USA 36. Ridgway EC, Cooper OS, Walker H, Rodbard D, Maloof F. Peripheral responses to thyroid hormone belore and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1981 Dec;53(6):1238-42 37. Cooper OS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. Ann lntern Med. 1984;101:18-24 38. Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg P-A, Lindstedt G. A double-blind cross-over 12-month study oi L-thyroxine treatment oi women with 'subclinical' hypothyroidism. Clin Endocrinol. 1988;29:63-76 (Approximately one woman in four with this 'subclinical' condition wi/1 benefit from L-thyroxine treatment) 39. Bell GM, Todd WT, Forfar JC, Martyn C, Wathen CG, Gow S, Riemersma R, Toft AD. End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol (Oxl). 1985 Jan;22(1 ):83-9 40. Forfar JC, Wathen CG, Todd WT, Bell GM, Hannan WJ, Muir AL, Toft AO. Left ventricular performance in subclinical hypothyroidism. Q J Med. 1985 Dec;57(224):857-65 Foldes J, lstvanfy M, Halmagyi M, Varadi A, Gara A, Partos O. Hypothyroidism and the heart. Examination oi left ventricular function in subclinical hypothyroidism. Acta Med Hung. 1987;44:337-47 41. Kahaly GJ 2000 Cardiovascular and atherogenic aspects oi subclinical hypothyroidism. Thyroid 10:665-79 42. Arem R, Rokey R, Kiefe C, Escalante DA, Rodriquez A. Cardiac systolic and diastolic function at rest and exercise in subclinical hypothyroidism: Effect oi thyroid hormone therapy. Thyroid. 1996 ;6:397-402 43. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, Ferrannini E. Effect oi levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001 Mar;86(3):1110-5 44. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, Bone F, Lombardi G, Sacca L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999 Jun;84(6):2064-7

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45. Tanis BC, Westendorp RGJ, Smelt AHM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol. 1996;44:643-9 46. Danese MD, Ladenson PW, Meinert CL, Powe NR; Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitativa review of the literatura. J Clin Endocrinol Metab. 2000;85:2993-3001 47. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, Koutras DA. High serum cholesterol levels in persons with 'high-normal' TSH leveis: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998 Feb;138(2):141-5 48. Bindels AJ, Westendorp RG, Frolich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol leveis in middle aged men and women: a need for case­ finding? Clin Endocrinol. 1999;50:217-20 49. Bakker SJL, Ter Matten JC, Popp-Snijders C, Slaets JPJ, Heine RJ, Gans ROB. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 2001;86: 1206-11 50. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P. Flow-mediated, endothelium-dependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid. 1997;7:411-4 51. Powell J, Zadeh JA, Carter G, Greenhalgh RM, Fowler PB. Raised serum thyrotrophin in women with peripheral arterial disease. Br J Surg. 1987;74:1139-41 52. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Rodgers H, Tunbridge F, Young ET. The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid 1996 Jun;6(3):155-60 53. Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L, Carbotte R. Does treatment

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health

status

in

middle-aged

and

older

adults

with

subclinical

hypothyroidism? J Gen lntern Med. 1996 Dec;11(12):744-9 54. Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch lntern Med. 1995;155:1490-5 55. Perk M, O'Neill BJ. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol. 1997;13:273-6 56. Stockigt J. Serum thyrotropin and thyroid hormone measurements and assessment of thyroid hormone transport. In: Braverman LE, Utiger RD, eds. Werner and lngbar's the thyroid. 2000, ed 8. Philadelphia: Lippencott Williams and Wilkins; 376-92 57. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination. JAMA. 1996;276:285-92 58. McDermott MT, Haugen BR, Lezotte DC, Seggelke S, Ridgway EC. Management practices among primary care physicians and thyroid specialists in the care of hypothyroid patients. Thyroid. 2001;11:757-76 59. Zoncu S, Pigliaru F, Putzu C, Pisano L, Vargiu S, Deidda M, Mariotti S, Mercuro G. Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging. Eur J Endocrinol. 2005 Apr;152(4):527-33

("impairment of systolic ejection, a de/ay in diastolic relaxation and a decrease in lhe compliance to lhe ventricular filling... Severa/ significant correlations were found between lhe parameters and serum-free T(3) and T(4) and TSH concentrations. Data strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis. '?

Subclinical thyroid dysfunction is an abnormal serum thyroid-stimulating hormone levei (reference range: 0.45 to 4.50 iJU/mL) and free thyroxine and triiodothyronine leveis within their reference ranges 60. Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24

lmportant frequency of subclinical hypothyroidism: 61. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, 62. Young E, Bird T, Smith PA. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977 Dec;7(6):481-93 63. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch lntern Med. 2000;160:526-34 64. Hollowell J, Braverman LE, Spencer CA, Staehling N, Flanders D, Hannon H Serum TSH, T4, and thyroid antibodies in the United States population: NHANES 111. ?2nd Annual Meeting of the American Thyroid Association, Paim Beach, FL, 1999; Abstract 213 65. Guel KW, van Sluisveld IL, Grobbee DE, Docter R, de Bruyn AM, Hooykaas H, van der Merwe JP, van Hemert AM, Krenning EP, Hennemann G, et ai. The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids. Clin Endocrinol (Oxf). 1993 Sep;39(3):275-80 66. Rivolta G, Cerutti R, Colombo R, Miano G, Dionisio P, Grossi E. Prevalence of subclinical hypothyroidism in a population living in the Milan metropolitan area. J Endocrinol. lnvest. 1999;22:693-7 67. Bagchi N, Brown TR, Parish RF. Thyroid dysfunction in adults over age 55 years. A study in an urban U.S. community. Arch lntern Med. 1990;150:785-7

531

68. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging lhyroid. lncreased prevalence of elevaled serum lhyrolropin leveis in lhe elderly. JAMA. 1979;242:247-50 69. Lindeman RD, Schade DS, LaRue A, Romero LJ, Liang HC, Baumgartner RN, Koehler KM, Garry PJ. Subclinical hypolhyroidism in a bielhnic, urban communily. J Am Gerialr Soe. 1999 Jun;47(6):703-9 70. Hak AE, Pois HAP, Visser TJ, Drexhage HA, Hofman A, Witteman JCM. Subclinical hypolhyroidism is an independent risk faclor for alherosclerosis and myocardial infarclion in elderly women: The Rotterdam sludy. Ann lnlern Med. 2000;132:27Q-8 71. Rosenlhal MJ, Hunl WC, Garry PJ, Goodwin JS. Thyroid failure in lhe elderly: microsomal anlibodies as discriminanl for lherapy. JAMA. 1987 ;258:209-13 72. Wilson GR, Curry RW Jr. Subclinical lhyroid disease. Am Fam Physician. 2005 Ocl 15;72(8):1517-24 {'The prevalence of subclinical hypothyroidism is about 4 to 8.5 percent, and may be as high as 20 percent in women o/der than 60 years') lmportant risk of progression into overt hypothyrodism

73. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal lhyrolrophin (TSH) concenlralions in lhe elderly in lhe Uniled Kingdom. Clin Endocrinol (Oxf). 1991;34:77-83 74. Baslenie PA, Bonnyns M, Vanhaelsl L. Natural history of primary myxedema. Am J Med. 1985;79:91-100 75. Kabadi UM. Subclinical hypothyroidism. Natural course of the syndrome during a prolonged follow-up study. Arch lntern Med. 1993;153:957-61 76. Tunbridge WMG, Brewis M, French JM, Appleton D, Bird T, Clark F, Evered DC, Evans JG, Hall R, Smith P, Stephenson J, Young E. Natural history of auloimmune thyroiditis. Br Med J (Ciin Res Ed). 1981 Jan 24;282(6260):258-62 77. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F,Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et ai. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995 Jul;43(1):55-68 78. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am. 1997;26:189-218 79. Huber G, Mitrache C, Guglielmetti M, Huber P, Staub JJ. Predictors of overt hypothyroidism and natural course: a long-term follow-up study in impending thyroid failure. 71st Annual Meeting of the American Thyroid Association, Portland, OR, 1998; Abstract 109 lmportance of clinicai evaluation of subclinical hypothyroidism

80. Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinicai score: evaluation of patients wilh various grades of hypolhyroidism and contrais. J Clin Endocrinol Melab. 1997;82:771-6 Studies showing that it is important to treat mild glandular failure that causes other diseases such as diabetes and hypertension 81. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with

cardiovascular disease and mortality in adults: the European Prospective lnvestigation inlo Cancer in Norfolk. Ann lntern Med. 2004;141:413-20 82. Vasan AS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, Benjamin EJ, Levy D. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004 351:33-41 83. Dluhy RG, Williams GH. Aldosterone: villain or bystander? N Engl J Med. 2004;351:8-10

Arguments against thyroid treatment of mild thyroid failure

84. Chu JW, Crapo LM. Should mild hypothyroidism be treated? Am J Med. 2002;112:422-3 85. Chu JW, Crapo LM. The lreatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Melab. 2001;86:4591-9 lnitiation of levothyroxine therapy for mild thyroid failure would be inappropriate because it results in overtreatment with attendant risks of subclinical hyperthyroidism. (citic: this risk applies to a vety sma/1 fraction of the population to be treated. An equivalent risk of undertreatment of such individuais applies as we/1. 8oth results could be minimized by education of our primary care physicians about the desirable TSH target in their patients)

86. Surks Ml, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper AS, Weissman NJ. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228-38 87. Surks Ml. Commentary: subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinicai Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:586-7

532

T4 treatment does not improve clinically hypothyroid patients who have normal tests (critic: but possibly T3-T4

does) 88. Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, Mclaren EH. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ. 2001 Oct;323(7318):891-5

T4 treatment in subclinically hypothyroid patients but normal tests does not improve the patient (explanation:

The absence of clinically relevant benefits of thyroid therapy for mild thyroid failure may be due to (1) a TSH normalization that was typically described as Jowering of TSH to < 5 mU/Iiter, whereas leveis between 3 - 5 mU are probably sti/1 elevated and request higher dosage; (2) the use of thyroxine without any addition of triiodothyronine)

89. Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB, Crook M, Dore CJ, Finer N. A 6-month randomized trial of thyroxine

treatment in

women with

mild subclinical hypothyroidism.

Am J

Med.

2002;112:348-54

Thyroxine treatment does improve cholesterol levels and clinicai symptoms in subclinical hypothyroidism 90. Meier C, Staub J-J, Roth C-8, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH­ controlled L-thyroxine therapy reduces cholesterol leveis and clinicai symptoms in subclinical hypothyroidism: a

(An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in LDL cholesterol)

double blind, placebo-controlled trial (Basel Thyroid Study}. J Clin Endocrinol Metab. 2001 Oct;86:486Q-6

There is an equal concern about correct diagnosis and treatment of patients with TSH leveis that are slightly below lhe reference interval because of risks to both heart and bone 91. Parle JV, Maisonneuve P, Sheppare MC, Boyle P, Franklyn JA. Prediction of ali-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lance!. 2001;358:8615 92. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ, D'Agostino RB. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249-52 93. Stathatos N, Wartofsky L. Effects of thyroid hormone on bone. Clin Rev Bone Miner Metab. 2004;2:135-50

533

CONTROVERSY ON THE BEST THYROID TREATMENT: T4 OR T4-T3? Arguments pro treatment with T4 alone: Guidelines on T4 recommendation 1.

Brent GA, Larsen PR. Treatment of hypothyroidism. In: Braverman LE, Utiger RD, ed. Werner and lngbar's. The

2.

Utiger RD. Hypothyroidism. In DeGroot LJ et ai, eds. Endocrinology, Vol 1. 2n

3.

Mandei S J , Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann lntern Med

4.

Roti E, Braverman LE. Thyroid hormone therapy: when to use it, when to avoid it. Drug Therapy. 1994; 24(4):2-

Thyroid: A Fundamental and Clinicai Text.

ylh ed., 1996, Philadelphia,

Ravens- Lippincott Publishers d ed. Philadelphia, Pa: WB

Saunders Co, 1989;702-21 1993;119:492-502 35. Arguments pro treatment with either T4 alone, either T4 and T3 T3-T4 treatments work as good as T4 alone, but not better 5.

Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF. Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract. 2005 Jui-Aug;11(4):223-33

6.

Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003 Oct;88(10):4551-5

Arguments pro treatment with T4 and T3 combinations T3-T4 {and T3) treatments work better than T4 7. Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM. Partial substitution of thyroxine (T4) with tri­ iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. Clin Endocrinol Metab. 2005 Feb;90(2):805-12 8.

1032. Kloppenburg M, Dijkmans BA, Rasker JJ. Effect of therapy for thyroid dysfunction on musculoskeletal symptoms. Clin Rheumatol. 1993 Sep;12(3):341-5

9.

Hertoghe T, Lo Cascio A., Hertoghe J. Considerable improvement of hypothyroid symptoms with two combined T3-T4 medication in patients still symptomatic with thyroxine treatment alone. Anti-Aging Medicine, Ed. German Society of Anti-Aging Medicine-Verlag 2003- 2004; 32-43

10. Pareira VG, Haron ES, Lima-Neto N, Medeiros-Neto GA. Management of myxedema coma: report on three successfully treated cases with nasogastric or intravenous administration of triiodothyronine. J Endocrinol lnvest. 1982;5:331-4 11. Chernow B, Burman KD, Johnson DL, McGuire RA, O'Brian JT, Wartofsky L, Georges LP. T3 may be a better agent than T4 in lhe critically ili hypothyroid patient: evaluation of transpor! across the blood-brain barrier in a primate model. Crit Care Med. 1983 Feb;11(2):99-104 12. Arlot S, Debussche X, Lalau JD, Mesmacque A, Tolani M, Quichaud J, Fournier A. Myxoedema coma: response of thyroid hormones with oral and intravenous high-dose L-thyroxine treatment. lntensive Care Med. 1991;17(1):16-8 T3-T4 treatment: adding T3 to T4 results in greater improvement of clinicai symptoms and signs in hypothyroid patients 13. Benevicius R, Kazanavicius G, Zalinkovicius R, Prange AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med.1999; 340: 424-9 When T3 and T4 are both supplemented to the food simultaneously with goitrogens, a much better prevention of goiter is obtained than when solely T4 is added, even if T4 is given at doses 7 times higher those of T3-T4 treatments 14. Devlin WF, Watanabe H. Thyroxin-triiodothyronine concentrations in thryoid powders. J Pharm Sei. 1966 Apr;55(4):390-3 In humans, T4-T3 treatments reduce serum cholesterol and increase the speed of the Achilles tendon reflexes better than T4 treatments alone 15. Alley RA, Danowski TS, Robbins T JL, Weir TF, Sabeh G, and Moses CL. lndices during administration of T4 and T3 to euthyroid adults. Metabolism. 1968;17(2):97-104 A study in rats rendered hypothyroid shows that cellular euthyroidism is only obtained in the target organs of hypothyroid rats if T3 is added to the classic T4 medication

534

16. Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM. Only lhe combined treatment with thyroxine and triiodothyronine ensures euthyroidism in ali tissues of lhe thyroidectomized rat. Endocrinology. 1996 Jun;137(6):2490-502 17. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in ali tissues, as studied in thyroidectomized rats. J Clin lnvest. 1995 Dec;96(6):2828-38

Medications with T4 alone do not succeed in achieving complete cellular euthyroidism in the target organs, probably because T3 is really lhe aclive hormone 18. Asper SP Jr, Selenkow HA, and Plamondon CA. A comparaison of lhe metabolic activities of 3,5,3'­ triiodothyronine and 1-thyroxine in myxedema. Buli John Hopkins Hosp. 1953; 93: 164 19. Blackburn CM, McConahey WM, Keating FR Jr, Albert A. Calorigenic effects of single intravenous doses of 1triiodothyronine and 1-thyroxine in myxedematous persons. J Clin lnvest. 1954 Jun;33(6):819-24

T3 is much more potent than T4 20. Gross J, Pitt-Rivers R. Physiological activity of 3:5:3'-L-triiodothyronine. Lancei. 1952 Mar 22;1(12):593-4 21. Gross J, Pitt-Rivers R. 3:5:3'-triiodothyronine. 2. Physiological activity. Biochem J. 1953 Mar;53(4):652-7 Conditions that reduce the conversion of T4 to T3 such as aging, obesity, disease, stress, exercise, malnutrition, etc., reducing thereby the efficacy of a T4 alone treatment 22. Burroughs V, Shenkman L. Thyroid function in lhe elderly. Am J Med Sei. 1982, 283 (1): 8-17 23. Carter JN, Eastman CJ, Corcoran JM, and Lazarus L. lnhibitibn of conversion of thyroxine to triiodothyronine in patients with severe chronic íllness. Clin Endocrinol. 1976; 5: 587-94 24. Tulp OL and McKee TD Sr. Triiodothyronine neogenesis in lean and obese LA/N-cp rats. Biochem Biophys Res Communications. 1986; 140 (1): 134-42 25. Katzeff Hl, Selgrad C. lmpaired peripheral thyroid hormone metabolism in genetic obesity. Endocrinology. 1993; 132 (3): 989-95 26. Croxson MS and lbbertson HK. Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa. J Clin Endocrinol Metab. 1977; 44: 167-73 27. Harns ARC, Fang SH, Vagenakis AG, and Braverman LE. Effect of starvation, nutriment replacement, and hypothyroidism on in vitro hepatic T4 to T3 conversion in lhe rat. Metabolism. 1978;27(11):1680-90 28. Opstad PK, Falch D, Óktedalen O, Fonnum F, and Wergeland R.

The thyroid function in young rnen during

prolonged physical exercise and lhe effect of energy and sleep deprivation. Clin Endocrinol. 1984; 20: 657-69 29. Walfish PG. Triiodothyronine and thyroxine interrelationships in health and disease. Can Med Ass. J 1976, 115: 338-42

Toxic substances such as phenols, cadmium, mercury, etc, and rnedications such as propranolol, amiodarone and several others may interfere by stimulating or inhibiting lhe T4 to T3 conversion 30. Feyes D, Hennernann G and Visser TJ. lnhibition of iodothyronine deiodinase by phenolphtalein dyes. Fed Eur Biomed Sei. 1982; 137(1):40-4 31. Bahn AK, Mills JL, Snyder PJ, Gann PH, Houten L, Bialik O, Hollmann L, and Utiger RD. Hypothyroidism in workers exposed to polybrominated biphenyls. N Engl J Med. 1980; 302: 31-3 32. lkeda T, lto Y, Murakami I, Mokuda O, Tominaga M and Mashiba H. Conversion of T4 to T3 in pertused liver of rats with carbontetrachloride-induced liver injury. Acta Endocrinol. 1986;112: 89-92 33. Paier B, Hagmüller K, Nolli Mi, Gonzalez Pondal M, Stiegler C and Zaninovich AA. Changes induced by cadmium administration on thyroxine deiodination and sulfhydryl groups in rat liver. J Endocrinol. 1993; 138: 219-24 34. Barregãrd L, Lindstedt G, Schütz A, Sãllsten G. Endocrine function in mercury exposed chloralkali workers. Occup Envir Med. 1994; 51: 536-40

Deficiencies in hormones (T3 itself, TSH, growth hormone, insulin, melatonin, etc) and trace elements (selenium, iron, zinc, cupper, etc) partially block this essential step for thyroid function 35. Burger AG, Lamber! M, Cullen M. lnterférence de substances médicamenteuses dans la conversion de T4 en T3 et rT3 chez l'homme. Ann Endocrinol (Paris). 1981,42:461-9 36. Grussendorf M, Hüfner M. lnduction of the thyroxine to triiodothyronine converting enzyme in rat liver by thyroid hormones and analogs. Clin Chim Acta. 1977;80:61-6 37. Erickson VJ, Cavalieri RR, Rosenberg LL. Thyroxine-5'-diodinase of rat thyroid, but not that of liver, is dependent on thyrotropin. Endocrinology. 1982;111 :434-40 38. Rezvani I, DiGeorge AM, Dowshen SA, Bourdony CJ. Action of human growth hormone on extrathyroidal conversion of thyroxine to triiodothyronine in children with hypopituitarism. Pediatr Res. 1981;15:6-9

535

39. 8chrõder-Van der elst JP, Van der heide D. Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues. Diabetes. 1992;41 :147-52 40. Gavin LA, Mahon FA, Moeller M. The mechanism of impaired T3 production from T4 in diabetes. Diabetes. 1981;30:694-9 41. Hoover PA, Vaughan MK, Little JC, Reiter RJ. N-methyi-D-aspartate does not preveni effects of melatonin on lhe reproductive and thyroid axes of male 8yrian hamsters. J Endocrinology. 1992;133:51-8 42. Chanoine J-P, 8afran M, Farwell AP, Tranter P, Ekenbarger DM, Dubord 8, Alex s, Arthur JR, Beckett GJ, Braverman LE, Leonard JL. 8elenium deficiency and type 11 5'-deiodinase regulation in lhe euthyroid and hypothyroid rat: evidence of a direct effect oi thyroxine. Endocrinology. 1992;130:479-84 43. Arthur JR, Nicol F, Beckett GJ. 8elenium deficiency, thyroid hormone metabolism, and thyroid hormone deiodinases. Am J Clin Nutr 8uppl. 1993; 57:2368-98 44. Beard J, Tobin B, and Green W. Evidence for thyroid hormone deficiency in iron-delicient anemic rats. J Nutr. 1989;772-8 45. Fujimoto 8, Indo Y, Higashi A, Matsuda I, Kashiwabara N, and Nakashima I. Conversion oi thyroxine into triiodothyronine in zinc deficient rat liver. J Pediatr Gastroenterol Nutr. 1986;5:799-805 46. Olin

Kl,

Walter

RM,

and

Keen

CL.

Copper

deliciency

affects

selenoglutathione

peroxidase

and

selenodeiodinase activities and antioxidant delense in weanling rats. Am J Clin Nutr 1994;59:654-8 47. Westgren U, Ahren B, Burger A, lngemansson 8, Melander A. Eflects oi dexamethasone, desoxycorticosterone, and ACTH on serum concentrations ot thyroxine, 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine.

Acta Med

8cand. 1977;202 (1-2): 89-92 On the other hand, excesses in hormones

(glucocorticoids, ACTH, estrogens, .. .) and trace elements (iodine,

lithium, .. . ) may slow down this conversion. 48. Heyma P, Larkins RG. Glucocorticoids decrease lhe conversion oi thyroxine into 3,5,3'-triiodothyronine by isolated rat renal tubules. Clin 8cience. 1982; 62: 215-20 49. 8cammell JG, 8hiverick KT, Fregly MJ. Eflect oi chronic treatment with estrogen and thyroxine, alone and combined, on lhe rale oi deiodination oi 1-thyroxine to 3,5,3'-triiodothyronine in vitro. Pharmacology. 1986;33: 52-7 50. Aizawa T, Yamada T. Effects oi thyroid hormones, antithyroid drugs and iodide on in vitro conversion of thyroxine to triiodothyronine. Clin Exp Pharmacol Physiol. 1981; 8: 215-25 51. Voss C, 8chrober HC, Hartmann N. Einfluss von Lithium auf die in vitro-Deioderung von 1-Thyroxin in der Ratten leber. Acta Biol Med Germ. 1977; 36:1061-5 40 41 The absorption of oral T4 can be variable (50 to 73% ' ), contrasting with that of T3 that is more constant and efficient (95%) 52. Hays MT. Absorption oi oral thyroxine in man. J Clin Endocrinol Metab. 1968; 28 (6):749-56 53. 8urks Ml, 8chodlow AR, 8tock Jm, Oppenheimer JH. Determination oi iodothyronine absorption and conversion of L-thyroxine using turnover rate techniques. J Clin lnvest. 1 973; 52:809-11 54. Hays MT. Absorption oi triidothyronine in man. J Clin Endocrinol Metab. 1970; 30(5):675-6 43 44 Defects in the commercial T4 preparation · 55. Hubbard WK. FDA notice regarding levothyroxine sodium. Federal register. 1997; 62(157): 1-10 56. Peran 8, Garriga MJ, Morreale de Escobar G, Asuncion M, Peran M. lncrease in plasma thyrotropin leveis in hypothyroid patients during treatment due to a delect in the commercial preparation . J Clin Endocrinol Metab. 1997;82(10):3192-5

536

THYROID TREATMENT ANO THE HEART Claim: Thyroid hormone treatment is dangerous for lhe heart as it can cause side effects such as atrial fibrillation. Facts: Euthyroidism (normal thyroid function) is essential for lhe heart; both hypothyroidism as well as hyperthyroidism impair lhe working of lhe heart and may facilitate atrial fibrillation.

Arguments contra thvroid treatment: because of possible cardiac side effects, especially in cardiac patients Hyperthyroidism: causes tachycardia (critic: tachycardia is the result of hyperthyroidism, hypocorticism, or drinking of caffeinated beverages; avoiding these conditions by adequate treatment or abstention wi/1 preveni many cases of tachycardia) 1.

Maciel BC, Gallo L Jr, Marin Neto JA, Maciel LM, Alves ML, Paccola GM, lazigi N. The role of lhe autonomic

2.

Abadie E, Leclercq JF, Fisch A, Babalis D, Blanche PM, Passa P, Coumel P. Pathogenesis oi tachycardia in

nervous system in lhe resting tachycardia of human hyperthyroidism. Clin Sei (Lond). 1987 Feb;72(2):239-44 hyperthyroidism. Value of Holter monitoring and lhe use of a beta-blocker. Presse Med. 1985 Feb 2;14(4):197-9

Hyperthyroidism (high serum thyroid hormones) is associated with an increased risk of atrial fibrillation 3. Parmar MS. Thyrotoxic atrial librillation. Med Gen Med. 2005 Jan 4;7(1):74 (a fria/ fibrillation was seen in 15% of hyperthyroid patients) 4. Dorr M, Volzke H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol. 2005 Dec;30(4):199-216 (5.2 times more risk of atrial fibrillation in hyperthyroidism) 5. Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial librillation or flutter: a population-based study. Arch lntern Med. 2004 Aug 9-23;164(15):1675 (atrial fibrillation was observed in 8.3% of hyperthyroid patients) Hyperthyroidism is associated with an increased risk of angina pectoris 6. Gitlin MJ. L-triiodothyronine-precipitated angina and clinicai response. Biol Psychiatry. 1986 May;21(5-6):543-5 Possibility to administer a betablocker together with thyroid medication to hypothyroid patients with angina pectoris 7. Ellyin F, Fuh CY, Singh SP, Kurnar Y. Hypothyroidism with angina pectoris. A clinicai dilemma. Postgrad Med. 1986 May 15;79(7):93-8

Patients aged 40 years or older at emergency admission who present a high serum free and total T3, have an increased risk of of angina pectoris and mycocardial infarct at admission and 3 years !ater (critic: possibly due to hypocorticism that increases (the conversion of T4 into)T3??) 8. Peters A, Ehlers M, Blank B, Exler D, Falk C, Kohlrnann T, Fruehwald-Schultes B, Wellhoener P, Kerner W, Fehm HL.

Excess triiodothyronine as a risk factor oi coronary

events.

Arch

lntern Med.

2000 Jul

10;160(13):1993-9

A high serum T4 is found in patients with coronary heart disease (critic: possibly accompanied by a low serum T3, which reflects a clinicai more hypothyroid state, because of the decrease in conversion of T4 to T3 that is generally observed in the disease state) 9.

Sidorenko BA, Begliarov Ml, Titov VN, Masenko VP, Parkhimovich RM. Blood thyroid hormones in ischemic heart disease (a comparison with coronary angiographic data, severity of stenocardia and blood lipid levei)] Kardiologiia. 1981 Dec;21(12):96-101

10. Selivonenko VG, Zaika IV. The function of lhe thyroid and thyrotropic function in patients with chronic ischemic heart disease and rhythm disorders. Lik Sprava. 1998 Jan-Feb;(1):81-3

Arguments pro thyroid treatment: lhe heart needs to have thyroid hormones or heart disease appears; also lhe case for cardiac patients (but they must be treated with great caution and should receive lower thyroid doses)

Thyroid hormone leveis are positively correlated with the heart rhythm 11. Tseng KH, Walfish PG, Persaud JA, Gilbert BW. Concurrent aortic and mitral valve echocardiography permits measurement of systolic time intervals as an index of peripheral tissue thyroid lunctional status. J Clin Endocrinol Metab. 1989 Sep;69(3):633-8 A lower serum T3 (and higher serum T4) is found in heart patients with arrhythmia

537

12. Selivonenko VG, Zaika IV. The function of lhe thyroid and thyrotropic function in patients with chronic ischemic heart disease and rhy1hm disorders. Lik Sprava. 1998 Jan-Feb;(1):81-3 13. lnama G, Furlanello F, Fiorentini F, Braito G, Vergara G, Casana P. Arrhy1hmogenic implications of noniatrogenic thyroid dysfunction.

G ltal Cardiol. 1989 Apr;19(4):303-10 (Hypothyroidism in patients with

hyperkinetic ventricular arrhythmias (25%), atrial fibrillation (37.5%) and atrio-ventricular b/ock (37.5%)) 14. Vanin LN, Smetnev AS, Sokolov SF, Kotova GA, Masenko VP. Thyroid function in patients with ventricular arrhy1hmia.

Kardiologiia. 1989 Feb;29(2):64-7 (Hyperthyroidism was diagnosed in 4.8% of 21 patients with

persistent ventricular arrhythmias, and /atent hypothyroidism was diagnosed in 38.1%) 15. Vanin LN, Smetnev AS, Sokolov SF, Kotova GA, Masenko VP. Study of thyroid function in patients with paroxysmal supraventricular tachycardia. Kardiologiia. 1989 Jan;29(1): 71-4 16. Nesher G, Zion MM. Recurrent ventricular tachycardia in hypothyroidism--report of a case and review of lhe literature. Cardiology. 1988;75(4):301-6 17. Fredlund BO, Olsson SB. Long QT interval and ventricular tachycardia of "torsade de pointe" type in hypothyroidism. Acta Med Scand. 1983;213(3):231-5

Low serum T3 and T41evels are found in patients with coronary heart disease 18. Miura S, litaka M, Suzuki S, Fukasawa N, Kitahama S, Kawakami Y, Sakatsume Y, Yamanaka K, Kawasaki S, Kinoshita S, Katayama S, Shibosawa T, lshii J. Decrease in serum leveis of thyroid hormone in patients with coronary heart disease. Endocr J. 1996 Dec;43(6):657-63

A low serum free T3 in patients with coronary bypass increases the risk of postoperative atrial fibrillation (higher risk than lha! of not taking a beta-blocker) 19. Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003 Oct;24(4):487-92

Progressively lower serum T3 leveis are found in patients with ischemic heart disease form coronary stenosis to mycocardial infarct 20. Telkova IL, Tepliakov AT. Changes of thyroid hormone leveis in lhe progression of coronary artery disease. Arteriosclerosis. Klin Med (Mosk). 2004;82(4):29-34 21. Pavlou HN, Kliridis PA, Panagiotopoulos AA, Goritsas CP, Vassilakos PJ. Euthyroid sick syndrome in acute ischemic syndromes. Angiology. 2002 Nov-Dec;53(6):699-707 22. Pimenov LT, Leshchinskii LA. Thyroid hormone changes (iodothyroninemia) in patients with acute myocardial infarction, and their clinicai significance. Kardiologiia. 1984 Oct;24(10):74-7

Low serum free and total T3 (and low free T4 and high TSH) leveis are found in patients suffering from acute mycocardial infarct with poor outcome 23. Satar S, Seydaoglu G, Avci A, Sebe A, Karcioglu O, Topal M. Prognostic value of thyroid hormone leveis in acute myocardial infarction: jus! an epiphenomenon? Am Heart Hosp J. 2005 Fall;3(4):227-33 Auto-immune thyroidiits is associated with poorer heart indices 24. Zoncu S, Pigliaru F, Putzu C, Pisano L, Vargiu S, Deidda M, Mariolti S, Mercuro G. Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging. Eur J Endocrinol. 2005 Apr;152(4):527-33 (namely "impairment of systolic ejection, a delay in diastolic relaxation and a decrease in lhe compliance to lhe ventricular filling. Severa/ significant correlations were found between lhe parameters and serum-free T(3) and T(4) and TSH concentrations. Data strongly support lhe concept of a continuum spectrum of a slight thyroid fai/ure in autoimmune thyroiditis') lncreased incidence of auto-immune thyroiditis and overt hypothyroidism in men with acute mycocardial infarct, which may have contributed to lhe development of lhe disease. 25. Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003 Oct;24(4):487-92

A low serum T3 or T4 (hypothyroidism) is found in cardiac failure: 26. Khaleeli AA, Memon N. Factors affecting resolution of pericardial effusions in primary hypothyroidism: a clinicai, biochemical and echocardiographic study. Postgrad Med J. 1982 Aug;58(682):473-6 27. Reza MJ, Abbasi AS. Congestive cardiomyopathy in hypothyroidism. West J Med. 1975 Sep;123(3):228-30 28. Rays J, Wajngarten M, Gebara OC, Nussbacher A, Telles RM, Pierri H, Rosano G, Serro-Azul JB. Long-term prognostic value of triiodothyronine concentration in elderly patients with heart failure. Am J Geriatr Cardiol. 2003 Sep-Oct;12(5):293-7 ("Lower serum T3 in cardiac failure: lhe odds ratio for events was 9.8 (95% confidence interva/,2.2-43, p=0.004) for patients in lhe Jowest tertile of triiodothyronine, that is, Jower than 80 ngldL, compared with patients with leveis above 80 ng/dL') 29. Pingitore A, Landi P, Taddei MC, Ripoli A, L'Abbate A, lervasi G. Triiodothyronine leveis for risk stratification of patients with chronic heart failure. Am J Med. 2005 Feb;118(2):132-6

538

30. Klein I, Ojama K.

In: Werner & lngbar's The Thyroid, ed. Braverman LE & Utiger RD, Lippincott-Raven

Publishers, Philadelphia, 1996, 62: 799-804

A low serum free T3 index/reverse T3 ratio in chronic heart failure patients is a highly significant predictor of poor outcome 31. Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003 32. Hamilton MA, Stevenson LW, Luu M, Walden JA. Altered thyroid horrnone metabolism in advanced heart failure. J Am Coll Cardiol. 1990 Jul;16(1):91-5 33. Kozdag G, Ural D, Vural A, Agacdiken A, Kahraman G, Sahin T, Ural E, Komsuoglu B. Relation between free triiodothyronine/free thyroxine ratio, echocardiographic parameters and mortality in dilated cardiomyopathy. Eur J Heart Fail. 2005 Jan;7(1):113-8

A low serum T3 or T4 in heart patients is associated wilh an increased risk of cardiac arrest/dealh 34. Wortsman J, Premachandra BN, Chopra IJ, Murphy JE. Hypothyroxinemia in cardiac arrest. Arch Jntern Med. 1987 Feb;147(2):245-8 35. lervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L'Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003 Feb 11;1 07(5):708-13

Cardiovascular disease and mortalily is increased in hypolhyroidism (+ 70% for both) 36. Dorr M, Volzke H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol. 2005 Dec;30(4):199-216

Correclive lhyroid therapy is safe in hypothyroid palienls with common benign cardiac arrhylhmias at lhe

condi/íon that thyroid treatment is started at low doses and then gradually and prudently increased to the adequa/e dose. The treatment does not trigger an increase in arrhythmia frequency except in rare patients with baseline atrial premature beats. lt is, however, associated with an increase in basal, average and maximal heart rates. 37. Polikar R, Feld GK, Dittrich HC, Smith J, Nicod P. Effect of thyroid replacement therapy on the frequency of benign atrial and ventricular arrhy1hmias. J Am Coll Cardiol. 1989 Oct;14(4):999-1002

Thyroid lherapy correcls lhe bradycardia of hypolhyroidism 38. Yamauchi K, Takasu N, lchikawa K, Yamada T, Aizawa T. Effects of long-term treatment with thyroxine on pituitary TSH secretion and heart action in patients with hypothyroidism. Acta Endocrinol (Copenh). 1984

("T4 doses shou/d be adjusted to maintain normal ETIPEP (systolic time intervals) rather than normal serum TSH leveis'?

Oct;1 07(2):218-24

Thyroid therapy correcls lhe ventricular arrhylhmia 39. Vanin LN, Smetnev AS, Sokolov SF, Kotova GA, Masenko VP. Thyroid function in patients with ventricular

("Thyroid therapy for hypothyroidism /ed to lhe disappearance of paroxysms of ventricular tachycardia and reduced the total number and grades of ventricular extra-systoles in patients with ventricular arrhythmias; moreover, sensitivity to antiarrhythmic agents developed to replace an earlier resistance'?

arrhy1hmia. Kardiologiia. 1989 Feb;29(2):64-7

Coronary heart disease in humans: lhe improvement wilh lhyroid lreatment 40. Barnes BO. Prophylaxis of ischaemic heart-disease by thyroid therapy. Lancei. 1959 Aug 22;2:149-52 41. Holland FW 2nd, Brown PS Jr, Clark RE. Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg. 1992 Aug;54(2):301-5 42. Israel M. An effective therapeutic approach to the control of atherosclerosis illustrating harmlessness of prolonged use of thyroid hormone in coronary disease. Am J Dig Ois. 1955 June;161-8 43. Yokoyama Y, Novitzky D, Deal MT, Snow TR. Facilitated recovery of cardiac performance by triiodothyronine following a transient ischemic insult. Cardiology. 1992;81(1 ):34-45

Adequate lhyroxine replacemenl in hypothyroidism prevents coronary artery disease progression 44. Perk M, O'Neill BJ; The effect of thyroid therapy on angiographic artery disease progression . Can J Card. 1997;13(3):273-6

Desiccated thyroid therapy improves cardiac failure refractory to digitalis in humans 45. Zondek H. Myxederna Heart. Munch Med Wochenschr. 1918, 65: 1180-3 46. Khaleeli AA, Memon N. Factors affecting resolution of pericardial effusions in primary hypothyroidism: a clinicai, biochemical and echocardiographic study. Postgrad Med J. 1982 Aug;58(682):473-6

539

T3-therapy improves the outcome of open heart sugery, especially heart transplants 47. Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V. lmpact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Cardiology. 1996 Nov-Dec;87(6):509-15. 48. Novitzky D, Cooper DK, Chaffin JS, Greer AE, DeBault LE, Zuhdi N. lmproved cardiac allograft function following triiodothyronine therapy to both donor and recipient. Transplantation. 1990 Feb;49(2):311-6 Thyroid hormone therapy greatly reduces the lesions of experimental myocardial infarct in rats 49. Holland FW, Brown PS, Clark RE. Acute severe postischemic myocardial depression triiodothyronine. Ann Thorac Surg 1992 54: 301-305

reversed

by

Thyroid therapy reduces coronary artery disease and cardiac fibrosis in mice 50. Yao J, Eghbali M. Decreased collagen mRNA and regression of cardiac fibrosis in the ventricular myocardium of the tight skin mouse following thyroid hormone treatment. Cardiovasc Res. 1992 Jun;26(6):603-7 Thyroid therapy reduced the lesions of experimental cardiac arrest in dogs 51. Facktor MA, Mayor GH, Nachreiner RF, D'Aiecy LG. Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs. Resuscitation. 1993 Oct;26(2):141-62 Thyroid therapy reduced the complications of hemorrhagic shock in dogs 52. Shigematsu H, Shatney CH. The effect of triiodothyronine (T3) and reverse triiodothyronine (rT3) on canine hemorrhagic shock. Nippon Geka Gakkai Zasshi. 1988 Oct;89(10):1587-93.

THYROID THERAPY ANO BONE DENSITY Studies with association between thyroid therapy and increased loss of bone densitv Bone loss during thyroid treatment mainly occurs in HRT untreated postmenopausal women and who have a suppressed TSH, possibly being overtreated with thyroid hormones 4. Taelman P, Kaufman JM, Janssens X, Vandecauter H, Vermeulen A. Reduced forearm bone mineral content and biochemical evidence of increased bone turnover in women with euthyroid goitre treated with thyroid hormone. Clin Endocrinol (Oxf). 1990 Jul;33(1):1 07-17 5. Stall GM, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine. Ann lntern Med. 1990 Aug 15;113(4):265-9 6. Adlin EV, Maurer AH, Marks AD, Channick BJ. Bone mineral density in postmenopausal women treated with L­ 7.

thyroxine. Am J Med. 1991 Mar;90(3):360-6 Paul TL, Kerrigan J, Kelly AM, Braverman LE, Baran DT. Long-term L-thyroxine therapy is associated with decreased hip bone density in premenopausal women. JAMA. 1988;259:3137-41

Bone loss is mainly transitory only during the first year with no increased fracture incidence 8. Tremollieres F, Pouilles JM, Louvet JP, Ribot C. Transitory bone loss during substitution treatment for hypothyroidism. Results of a two year prospective study. Rev Rhum Mal Osteoartic. 1991 Dec;58(12):869-75 9. Ribot C, Tremollieres F, Pouilles JM, Louvet JP. Bone mineral density and thyroid hormone therapy. Clin Endocrinol (Oxf). 1990 Aug;33(2):143-53 Oestrogen therapy neutralizes, prevents bone loss induced by corrective thyroid therapy 10.

Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. JAMA 1994;271:1245-9

Studies where thyroid therapy does not cause or increase loss of bone density 11. Greenspan SL, Greenspan FS, Resnick NM, Block JE, Friedlander AL, Genant HK. Skeletal integrity in premenopausal and postmenopausal women receiving long-term L -thyroxine therapy Am J Med. 1991 ;91:5-14 12. Franklyn JA, Betteridge J, Daykin J, Holder R, Oates GD, Parle JV, Lilley J, Heath DA, Sheppard MC. Long-term thyroxine treatment and bone mineral density. Lance!. 1992 Jul 4;340(8810):9-13 13. Eulry F, Bauduceau B, Lechevalier D, Magnin J, Crozes P, Flageat J, Gautier D. Bone density in differentiated cancer of the thyroid gland treated by hormone-suppressive therapy. Study based on 51 cases. Rev Rhum Mal Osteoartic. 1992 Apr;59(4):247-52 14. Grant DJ, McMurdo ME, Mole PA, Paterson CR, Davies RR. Suppressed TSH leveis secondary to thyroxine replacement therapy are not associated with osteoporosis. Clin Endocrinol (Oxf). 1993 Nov;39(5):529-33. Studies where thyroid therapy improves bone formation 15. Svanberg E, Healey J, Mascarenhas D. Anabolic effects of rhiGF-1/IGFBP-3 in vivo are influenced by thyroid status. Eur J Clin lnvest. 2001 Apr;31(4):329-36

540

THYROID HORMONE DEFICIENCIES with THYROID TESTS within REFERENCE RANGE

Should individuais with symptoms and signs of thyroid deficiency but serum thyroid leveis within the normal reference range be treated with thyroid hormones?

Old view •

•

Thyroid deficiency is diagnosed upon laboratory tests with serum leveis of thyroid hormones T3 and T 4 below the lower limit of the reference range and that of the TSH above the upper limit. People with thyroid test values within lhe reference range are healthy and have no thyroid dysfunction.

Scientific view •

People who have serum leveis of thyroid hormones T3 and T4 within the reference range (situated in the lower 2/3 rds, lower half, lower third, lower forth, lower fifth or lower 10% of the reference range) and that of the TSH above lhe 0.4 have usually a significant increased risk of disease. This signifies that they suffer from a certain degree of mild thyroid failure, as this increased risk is reducible or preventable by improving thyroid hormone leveis in the upper half or upper third of the reference range and that of TSH towards the lower limit. Thus, milder degrees of thyroid failure exist with se rum leveis of thyroid hormones T3, T4 and TSH within lhe reference range.

•

•

Thyroid deficiency is diagnosed upon laboratory tests with serum leveis of the thyroid hormones below lhe average levei (halfway situated between the upper and lower limit of the reference range) and of lhe TSH above the average levei. Clinicai evaluation (checking for symptoms and physical signs of thyroid dysfunction) reflect final effects of lhe hormones in lhe target cells and are essential aids to lhe diagnosis. People with thyroid test values within lhe reference range are not necessarily healthy and may suffer from thyroid dysfunction.

I. Diagnosis of hvpothyroidism Publications that stress the importance of both clinicai and biochemical assessments in the evaluation of thyroid function 1.

3.

(No author listed). Optimal use of blood tests for assessment of thyroid function. JAMA 1993;269:2736; Thyroid. 1993;3(4):353-354 Larsen PR, Davies TF, Hay ID. Symptoms of hypothyroidism. In Williams' Textbook of endocrinology. 9th ed., WB Saunders: p. 461, table 11·22 (data from Ateans JH. The thyroid and its diseases. 2nd ed. JB Lippincott, Philadelphia 1948: 233) Wiersinga WM. Hypothyroidism and myxedema coma. 105: 1491 In Endocrinology, 4th ed., Degroot LJ,

4.

Jameson JL. Ed., 2 Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinicai score:

2.

evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol 1997;82:771-6

541

Metab.

11. The reference ranges of normalitv for the thyroid tests are too wide

and do not take into account specific individual reference ranges

A. Studies that show association of disease (markers)

with lower serum T3 leveis within the reference range

These associations form evidence suggesting that not ali T3 leveis within the reference ranges are healthy; some may be indicative of mild thyroid failure, and thus require correction with thyroid replacement

Labs: reference range

Scientific publications: tertiles, quartiles, quintiles, deciles, etc. 3.1 pg/ml

�

1.8-3.7 pg/ml

Highest tertile

310

�

�

2.8 to 3.09 pg/ml

Serum free T3 (fT3)

pg/dl

4.77 pmol/1

180-370 pg/dl

Middle tertile

280 to 309 pg/dl 4.31 to 4.76 pmol/1 <

2.77-5.69 pmoi/L

Lowest tertile

<

Auer J, et ai. Clin 2003 Cardiol. Dec;26(12):569-73

2.79 pg/ml 279 pg/dl <

4.30 pmol/1

Studies with data that indicate that

1) The healthiest serum T3 leveis may be found in the upper tertile (33%) of the reference range Study with suggestion that a healthy serum freeT3 should be in the upper two tertiles (upper 67%) of the reference range, and preferably in the upper tertile, in hemodialysis patients, otherwise, in particular in case of serum T3 in the lower tertile, there may be a higher risk of abnormal inflammatory markers (such as increases in serum interleukin-6 and C-reactive protein) markers of endothelial activation (intercellular adhesion molecule-1 [ICAM-1] and vascular cellular adhesion molecule-1 [VCAM-1]) (strong and inverse associations between free T3 and IL-6, C-reactive protein, ICAM-1, and VCAM-1) 5.

Zoccali C, Tripepi G, Cutrupi S, Pizzini P, Mallamaci F. Low triiodothyronine: a new facet of inflammation in end­ stage renal disease. J Am Soe Nephrol. 2005 Sep;16(9):2789-95. CNR-IBIM, Clinicai Epidemiology and Pathosphysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Calabria, ltaly. [email protected]

Study with suggestion that a safe serum free T3 in elderly patients with heart failure should be above 80 ng/dl (upper limit of the lower tertile of the reference range), and preferably in the upper tertile (33%), otherwise the risk of adverse cardiovascular event may be significantly higher 6.

Rays J, Wajngarten M, Gebara OC, Nussbacher A, Telles RM, Pierri H, Rosano G, Serro-Azul JB. Long-term prognostic value of triiodothyronine concentration in elderly patients with heart failure. Am J Geriatr Cardiol. 2003 Sep-Oct;12(5}:293-7. Division of Geriatric Cardiology, Heart lnstitute (lnCor), University of Sao Paulo Medicai School, Sao Paolo, Brazil

Study with suggestion that a healthy serum free T3 should be above the lower tertile (33%), and preferably in the upper tertile (33%) of the reference range in postmenopausal women, otherwise the risk of breast cancer may be highly increased 7.

Strain JJ, Bokje E, van't Veer P, Coulter J, Stewart C, Logan H, Odling-Smee W, Spence RA, Steele K. Thyroid hormones and selenium status in breast cancer. Nutr Cancer. 1997;27(1):48-52. Human Nutrition Research Group, University of Ulster, Coleraine, Northern lreland

542

Study with suggestion that a healthy serum free T3 should be equal to or above 2.8 pg/ml Oust above the lower tertile in patients who undergo coronary angiography, otherwise the risk is higher for having an increased severity of coronary artery atherosclerosis 8.

Auer J. Berent R, Weber T, Lassnig E, Eber B. Thyroid function is associated with presence and severity of coronary atherosclerosis. Clin Cardiol. 2003 Dec;26(12):569-73. Second Medicai Department, Division of Cardiology and lntensive Care, General Hospital Wels, Wels, Austria. [email protected]

Study with suggestion that a healthy serum TSH should be below 1.98 imU/L in patients with coronary artery disease, otherwise the risk of aggravation of coronary heart disease may be higher 9.

Auer J, Berent R, Weber T, Lassnig E, Eber B. Thyroid function is associated with presence and severity of coronary atherosclerosis. Clin Cardiol. 2003 Dec;26(12):569-73. Second Medicai Department, Division of Cardiology and Intensiva Care, General Hospital Wels, Wels, Austria. [email protected]

2) The healthiest serum free T3 and ratio of serum free T3/reverse T3 may be found in the upper three guartiles (75%) of the reference range Study with suggestion that a healthy serum free T3 should be above the lower quartile (25%) of the reference range in patients with end-stage renal disease, otherwise the risk of left ventricular dysfunction and left ventricular hypertrophy may be significantly increased 10. Zoccali C, Benedetto F, Mallamaci F, Tripepi G, Cutrupi S, Pizzini P, Malatino LS, Bonanno G, Seminara G. Low triiodothyronine

and

cardiomyopathy

in

patients

with

end-stage

renal

disease.

J

Hypertens.

2006

Oct;24(10):2039-46. CNR-IBIM, lnstitute of Biomedicine, Clinicai Epidemiology and Physiopathology of Renal Diseases and Hypertension & Division of Nephrology, Reggio Calabria, ltaly. [email protected]

Study with suggestion that a safe ratio of serum free T3/reverse T3 should be in the upper three quartiles (upper 75o/o)of the reference range in critically ill patients, and preferably in the upper quartile, otherwise the risk of dying may be higher 11. Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G. Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with post­ mortem tissue deiodinase activities. J Clin Endocrinol Metab. 2005 Aug;90(8):4559-65 Department of Internai Medicine, Erasmus University Medicai Center, Rotterdam, The Netherlands

3) The healthiest serum free T3 may be found at a levei of above 2.3 pq/ml (approximately the upper 4 guintilesl of the reference range 12. Evrengul H, Tanriverdi H, Enli Y, Kuru O, Seleci D, Bastemir M, Kilic A, Kaftan A, Kilic M. lnteraction of Plasma Homocysteine and Thyroid Hormone Concentrations in lhe Pathogenesis of lhe Slow Coronary

Flow

Phenomenon. Cardiology. 2006 Nov 3;108(3):186-192 Department of Cardiology, Pamukkale University Faculty of Medicine, Denizli, Turkey

4) Associations between a low serum free T3 within the reference range and pathological parameters Study with suggestion that lower serum free T3 leveis within the reference range may be associated in overweight and obese women with a higher risk of intra-abdominal adipose tissue, a risk factor for many diseases 13. Kunesova M, Hainer V, Obenberger J, Mikulova R, Parizkova J, Slaba S, Bezdickova D, Seidl Z. Adipose tissue distribution in obese females. Relationship to androgens,cortisol, growth hormone and leptin. Sb Lek. 2002;103(4):477-85. Obesity Management Centre of lhe 3rd Department of Internai Medicina, 1st Medicai Faculty of Charles University, U nemocnice 1, 128 08 Prague 2, Czech Republic. [email protected]

Study with suggestion that lower ratios of free T3/reverse T3 leveis within the reference range in patients undergoing elective cardiac surgery may be associated with a higher risk of delirium after surgery 14. van der Mas! RC, van den Broek WW, Fekkes D, Pepplinkhuizen L, Habbema JD. ls delirium after cardiac surgery related to plasma amino acids and physical condition? J Neuropsychiatry Clin Neurosci. 2000 Winter;12(1):57-63. Department of Psychiatry, Dijkzigt University Hospital Rotterdam, The Netherlands

543

Study with suggestion that lower serum free T3 leveis within the reference range in women may be associated with a higher risk of breast cancer 15. Takatani O, Okumoto T, Kosano H, Nishida M, Hiraide H, Tamakuma S. Relationship between the leveis of serum thyroid hormones or estrogen status and lhe risk of breast cancer genesis in Japanese women. Cancer Res. 1989 Jun 1;49(11):3109-12. Third Department of Internai Medicine, National Defense Medicai College, Saitama, Japan

Study with suggestion that lower serum total T3 and free T3 index leveis within the reference range in critically ill patients may be associated with a higher risk of dying 16. Maldonado LS, Murata GH, Hershman JM, Braunstein GD. Do thyroid function tests independently predict survival in the critically ili? Thyroid. 1992 Summer;2(2): 119-23. Department of Medicine, Cedars-Sinai Medicai Center, UCLA School of Medicine

Study with suggestion that serum free T3 is associated with a lower CD4+ percentage in children affected with HIV, implicating that immunity is lower at lower T3 leveis 17. Panamonta O, Kosalaraksa P, Thinkhamrop B, Kirdpon W, lngchanin C, Lumbiganon P. Endocrine function in thai children infected with human immunodeficiency virus. J Pediatr Endocrinol Metab. 2004 Jan;17(1):33-40

B. Studies that show an association of disease (markers)

with serum T4 leveis within the reference range

Evidence suggests that not ali serum T4 leveis within the reference ranges are healthy; some may be indicative of mild thyroid failure, and thus require correction with thyroid replacement.

Serum levei Free

T4

(IT4)

Labs: reference range

1O - 28 pmol/1

4.5 - 12.5 llQ/dl

Total

Scientific publications: tertiles, quartiles, quintiles, deciles, etc.

0.8 - 1.8 ng/dl

T4

Highest tertile

medium tertile

(TI4) 58-161 nmol/1

lowest tertile

8.1 to 12.51-lg/dl 104 to 161 nmol/1 6.6 to 8.0 !lg/dl 85 to 103 nmol/1

Volpato S, et ai.. 2002; Neurology. 1055-61

4.5 to 6.5 119/dl 58 to 84 nmol/1

Studies with data that indicate that 1) The healthiest serum T4 leveis may be found in the upper guartile of the reference range A study where it is suggested that a healthy serum free T4 in adults should be above the lower quartile (25%) of the reference range, preferably in the upper quartile, otherwise the risk of having metabolic syndrome and clinically features of it such as a high fasting glucose, a high blood pressure, a high serum total triglyceride, 8% had low high-density lipoprotein cholesterol, and obesity significantly increases 18. Lin SY, Wang YY, Liu PH, Lai WA, Sheu WH. Lower serum free thyroxine leveis are associated with metabolic syndrome in a Chinese population. Metabolism. 2005 Nov;54(11):1524-8. Division of Endocrinology and Metabolism, Department of Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan. [email protected]

Study with suggestion that a healthy serum free T3 should be in the upper half of the reference range in patients with Alzheimer's disease, otherwise the rish of depression may slightly increase

544

19. Stuerenburg HJ, Arlt S, Mueller-Thomsen T. Free thyroxine, cognitive decline and depression in Alzheimer's disease. Neuro Endocrinol Lett. 2006 Aug;27(4):535-7. Neurological Department, Median-Kiinik Bad Suelze, Bad Suelze, Germany. [email protected]

2) The healthiest serum T41evels may be found in the upper tertile of the reference range Studies that suggest that the healthy range for serum T4 should be equal to or above 8 IJg/dl (that's in the upper tertile of the T4 reference range) during thyroid treatment in children with infantile hypothyroidism, otherwise, at leveis less than 8 [.lg/dl (that's approximately in the lower two tertiles of the T4 reference range), the risk significantly increases of lower intellectual development with lower intelligence quotient (IQ): eman 18 points less) and the treatment may be considered inadequate 20. [No authors listed] Characteristics of infantile hypothyroidism discovered on neonatal screening. J Pediatr. 1984 Apr;104(4):539-44. Study with suggestion that a healthy serum free T4 should be situated in the upper two tertiles (66%0 of the reference range, and preferably in the upper tertile (33%), in "biochemically euthyroid" older women, otherwise, at lower serum free T4 leveis within the reference range, the risk of memory impairment may be increased (lowest tertile (4.5 to 6.5 [.lg/dl vs medium tertile (6.6 to 8.0 [.lg/dl) vs highest (best) T4 tertile (8.1 to 12.5 [.lg/dl)) 21. Volpato S, Guralnik JM, Fried LP, Remaley AT, Cappola AR, Launer LJ. Serum thyroxine levei and cognitive Laboratory of Epidemiology, decline in euthyroid older women. Neurology. 2002 Apr 9;58(7):1055-61. Demography, and Biometry, National lnstitute on Aging, National lnstitutes of Health, Bethesda, MD 20892, USA. [email protected] Study with suggestion that a healthy serum free T4 should be situated in the upper two tertiles (66%0 of the reference range, and preferably in the upper tertile (33%), in "biochemiccally euthyroid" patients, otherwise, at lower serum free T4 leveis within the reference range, an increased risk of dyslipidemia (lower total & LDL cholesterol, lower triglycerides, higher HDL cholesterol) and metabolic X syndrome) appears. 22. Roos A, Bakker SJ, Links TP, Gans RO, Wolffenbuttel BH. Thyroid function is associated with components of lhe metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab. 2007 Feb;92(2):491-6. Department of Endocrinology, University Medicai Gente r Groningen and University of Groningen, P.O. Box 30001, 9700 RB Groningen, Netherlands Study with suggestion that a healthy serum free T4 should be situated in the upper two tertiles (66%0 of the reference range, and preferably in the upper tertile (33%), in "biochemiccally euthyroid" in patients with hyperlipidemia, otherwise, at lower serum free T41evels within the reference range, the risk may be higher of having abnormal cardiovascular bio-markers 23. Jublanc C, Bruckert E, Girai P, Chapman MJ, Leenhardt L, Carreau V, Turpin G. Relationship of circulating C­ reactive protein leveis to thyroid status and cardiovascular risk in hyperlipidemic euthyroid subjects: low free thyroxine is associated with elevated hsCRP. Atherosclerosis. 2004 Jan;172(1):7-11. Department of Endocrinology, Group Hospitalier la Pitie-Salpetriere, Hopital Pitie-Salpetriere, AP-HP, 47-83 Boulevard de I'Hopital 75651, Paris Cedex 13, France. [email protected] 3) The healthiest serum T4 leveis may be found in the upper three guartiles of the reference range Study with suggestion that a healthy serum free T4 should be in the upper three quartiles (upper75 %) of the reference range in infants born before 30 weeks of gestation, otherwise, at leveis of serum free T4 in the lower quartile (25%), the risk of worse neurodevelopmental outcome at 2 and 5 years significantly increases 24. van Wassenaer AG, Briet JM, van Baar A, Smit BJ, Tamminga P, de Vijlder JJ, Kok JH. Free thyroxine leveis during lhe first weeks of life and neurodevelopmental outcome until the age of 5 years in very preterm infants. Pediatrics. 2002 Sep;110(3):534-9. Department of Neonatology, Academic Medicai Center, Emma Children's Hospital, Amsterdam, The Netherlands. [email protected] Study with suggestion that a healthy serum free T4 during the first 4 weeks after birth should be in the upper three quartiles (upper75 %) of the reference range (that's equal to or above 67.8 nmoi/L (5.3 [.!g/dl)) in premature bom infants (weighing 500 to 1500 g at birth), otherwise, at leveis of serum free T4 in lhe lower quartile (25%), the risk of white matter damage (reflected as echolucency in the cerebral white matter) significantly increases

545

25. Leviton A, Paneth N, Reuss ML, Susser M, Allred EN, Dammann O, Kuban K, Van Marter LJ, Pagano M. Hypothyroxinemia of prematurity and lhe risk of cerebral white matter damage. J Pediatr. 1999 Jun;134(6):70611. Children's Hospital, Boston, Massachusetts, USA. 4) The healthiest serum T41evels may be found in the 3'd to

sth

deciles of the reference range

26. Study with suggestion lha! lhe healthy range for serum T4 should be between lhe 3rd to 6th decile (11.9-14.6 pmol/1) within lhe reference range in patients with chronic heart failure, otherwise, at leveis higher or lower, there an increased probability of more severe degree of heart failure th The optimal free T4 leveis are within the 3'd to 6 deciles (11.9-14.6 pmol/1) compared to the low-normal, bottom 2 deciles (where lhe free T 4 leveis are :> 11.8) or the high-normal, top 4 deciles (free T 4

>

14.6 pmol/1)

27. Mayer O Jr, Cech J, Rosolova H, Pikner R, Simon J. [Association between free thyroxin concentration and degree of heart failure in patients with chronic heart insufficiency] Cas Lek Cesk. 2005;144(11):742-6. Centrum preventivni kardiologie, 11. interni klinika LF UK, Plzen. [email protected] 5) The healthiest serum T41evels may be found in the upper 90% of the reference range (above the 10th percentile)

A study with suggestion that a healthy serum free T4 in the mother during the pregnancy of healthy 10month old children (born after uncomplicated pregnancies and deliveries) should be above the lower 10% of the reference range, otherwise the risk of impaired psychomotor development for the child significantly increases 28. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf). 1999 Feb;50(2):149-55. Department of Social and Behavioural Sciences, University of Tilburg, The Netherlands.

A study with suggestion that a healthy serum T4 should be in the higher part of the reference range, and certainly above the lower 1O % of the reference range, in infants on the fifth day of life, otherwise the risk of needing intensive rescue interventions, mechanical ventilation or continuous positive airway pressure and/or treatment of neonatal seizures significantly increases for the child (inverse correlation of serum T4 on the fifth day of life with score for neonatal acute physiology) 29. Lim DJ, Herring MK, Leef KH, Getchell J, Bartoshesky LE, Paul DA. Hypothyroxinemia in mechanically ventilated term infants is associated with increased use of rescue therapies. Pediatrics. 2005 Feb;115(2):406-1 O. Department of Pediatrics Thomas Jefferson University, Philadelphia, Pennsylvania, USA

A study where it is suggested that a safe serum T4 should be above the 5.4 j.Jg/dl (which is within the reference range of 4.5-12.5 j.Jg/dl) in premature infants weighing less than 1500 grams at birth, otherwise the risk of intraventricular hemorrhage increases 30. Paul DA, Leef KH, Stefano JL, Bartoshesky L. Low serum thyroxine on initial newborn screening is associated with intraventricular hemorrhage and death in very low birth weight infants. Pediatrics. 1998 May;101(5):9037.Section of Neonatology, Departrnent of Pediatrics, Christiana Care Health System, Newark, Delaware 19718, USA 6) Low serum T4 1evels within the reference range may be associated with disease (associations between lower serum t4 leveis within the reference range and pathological parameters) Study with suggestion that lower serum free T4 leveis within the reference range may be associated in patients low in risk of developing coronary heart disease (because they have no or few established risk factors) with a higher risk of developing coronary heart disease in the next 5 to 6 years 31. Heller RF, Miller NE, Wheeler MJ, Kind PR. Coronary heart disease in 'low risk' men. Atherosclerosis. 1983 Nov;49(2): 187-93 Study with suggestion that lower serum free T4 leveis within the reference range may be associated in women with a higher risk of breast cancer ( high inverse correlation between serum free T 4 and risk of breast cancer) 32. Thomas BS, Bulbrook RD, Goodman MJ, Russell MJ, Quinlan M, Hayward JL, Takatani O. Thyroid function and lhe incidence of breast cancer in Hawaiian, British and Japanese women. nt J Cancer. 1986 Sep 15;38(3):325-9

546

Study with suggestion that lower serum free T4 leveis within the reference range in women may be associated with a higher risk of breast cancer 33. Takatani O, Okumoto T, Kosano H, Nishida M, Hiraide H, Tamakuma S. Relationship between lhe leveis oi serum thyroid hormones or estrogen status and lhe risk oi breast cancer genesis in Japanese women. Cancer Res. 1989 Jun 1;49(11):3109-12. Third Department oi Internai Medicine, National Delense Medicai College, Saitama, Japan

Study with suggestion that lower serum total and free T4 leveis within the reference range may be associated in pregnant women with a higher risk of spontaneous abortion occurring between 8 and 20 weeks of gestation 34. Ross HA, Exalto N, Kloppenborg PW, Benraad TJ. Thyroid hormone binding in early pregnancy and lhe risk oi spontaneous abortion. Eur J Obstei Gynecol Reprod Biol. 1989 Aug;32(2):129-36. Department oi Medicine, SI. Radboud University Hospital, Nijmegen, The Netherlands.

Study with suggestion that lower serum T4 leveis within the reference range may be associated in persons admitted to permanent institutional care with a higher risk of dying in the next two years 35. Tilvis RS, Visapaa J, Sorva A. Survival prognosis in geriatric patients admitted to permanent institutional care. Aging (Milano). 1992 Mar;4(1):77-84. Second Department oi Medicine, University oi Helsinki, Finland

Study with suggestion that safe serum free & total T4 leveis should be in the upper part of the reference range in burned patients, otherwise lhe risk oi dying signilicantly increases 36. Vaughan GM, Mason AD Jr, McManus WF, Pruitt BA Jr. Alterations oi mental status and thyroid hormones after thermal injury. J Clin Endocrinol Metab. 1985 Jun;60(6):1221-5

Studies with suggestion that safe serum total & free T4 leveis should be in the upper part of the reference range in patients with acute myocardial infarction, otherwise, ai decreasing leveis oi serum total & lree T4, lhe risk oi dying signilicantly increases 37. De Marinis L, Mancini A, Masala R, Torlontano M, Sandric S, Barbarino A. Evaluation oi pituitary-thyroid axis response to acute myocardial inlarction. J Endocrinol lnvest. 1985 Dec;8(6):507-11 38. Wartolsky L, Burman KD. Alterations in thyroid lunction in patients with systemic illness: the "euthyroid sick syndrome". Endocr Rev. 1982 Spring;3(2):164-217

Study with suggestion that serum free T4 is associated with a lower CD4+ percentage in children affected with HIV, implicating that immunity is lower at lower T4 leveis 39. Panamonta O, Kosalaraksa P, Thinkhamrop B, Kirdpon W, lngchanin C, Lumbiganon P. Endocrine lunction in thai children inlected with human immunodeliciency virus. J Pediatr Endocrinol Metab. 2004 Jan;17(1):33-40

C. References of studies that show association of disease (markers) with serum TSH leveis within the reference range

Evidence suggests lha! not ali TSH leveis within the relerence ranges are healthy; some may be indicative oi mild thyroid lailure, and thus require correction with thyroid replacement.

Labs: reter. range

Scientific publications: tertiles, quartiles, quintiles, deciles, etc. Upper quintile

>

Higher middle quintile

2.0- 3.6 mU/1

Middle quintile

1.0-1.99 mU/1

Lower middle quintile

0.4-0.99 mU/1

Lower quintile

<

3.6 mU/1

N,

Knudsen

Serum TSH

Ovesen 0.2-4.5 mU/ml

Laurberg

P,.

Rasmussen LB, Bülow I, Perrild H, L,

Jorgensen

T.

Sma/1

Differences in Thyroid Funclion May Be tmportanl for Body Mass lndex and lhe Occurrence of Obesily in lhe Poputation. J Clin Endocrinot Metab. 2005;90 (7):4019-24

547

0.4 mU/1

Studies with data that indicate that

1) The healthiest serum TSH leveis may be found in the lower three guartiles of the reference range Study with suggestion that a healthy serum TSH should be in the lower three quartiles (lower 75%) of the reference range in patients with major depression, as serum TSH leveis in the upper 25th percentile of the normal reference range may be associated with characteristics of a more severe form of depression such as recurrent depression (with severe major depressiva episodes), presence of somatic disease condition, suicide attempts, etc. 40. Berlin I, Payan C, Corruble E, Puech AJ. Serum thyroid-stimulating-hormone concentration as an index of severity

of

major

depression.

lnt

J

Neuropsychopharmacol.

1999

Jun;2(2):105-110

Department

of

Pharmacology, Hopital Pitie-Salpetriere, Paris, France

Study with suggestion that a healthy serum TSH should be in the lower three quartiles (lower 75%) of the reference range in depressed hospitalized patients, otherwise, in case of a serum TSH levei in the upper quartile (25%) of the reference range, there may be an increased risk of more severe form of depression and slower or impaired response to antidepressant therapy 41. Nyrnes A, 2006Berlin I, Lemoine A, Hardy P. Should major depression with 'high normal' thyroid-stimulating hormone

be

treated

preferentially

with

tricyclics?

Neuropsychobiology.

2004;50(2):144-6.

Psychiatry

Department, Bicetre Hospital, Assistance Publique-Hopitaux de Paris, PSIGIM, Paris XI University, Kremlin Bicetre, France. [email protected]

2) The healthiest serum TSH leveis may be found below the

3 mU/l

Study with suggestion that a healthy serum TSH should be below 3 mU/1 in patients with auto-immune thyroiditis, otherwise cardiac abnormalities may be found found at Doppler imaging 42. Zoncu S, Pigliaru F, Putzu C, Pisano L, Vargiu S, Deidda M, Mariotti S, Mercuro G. Cardiac function in borderline

hypothyroidism:

a study by pulsed wave tissue Doppler imaging. Eur J

Endocrinol.

2005

Apr;152(4):527-33. Department of Cardiovascular Sciences, University of Cagliari, Sardinia, ltaly

Study with suggestion that a healthy serum TSH should be below 3 mU/1 in post-partum women, otherwise the risk of having had post-partum hypothyroidism and development of recurrent hypothyroidism after treatment withdrawal in the future is high 43. Azizi F. Age as a predictor of recurrent hypothyroidism in patients with post-partum thyroid dysfunction. J Endocrinol lnvest. 2004 Dec;27(11):996-1002.

Endocrine Research Center, Shaheed Beheshti University of

Medicai Sciences, Tehran, IR lran

3) The healthiest serum TSH leveis may be found in the lower half of the reference range Study with suggestion that a healthy serum TSH should be equal to or below 2.5 miU/1 in pregnant women, or otherwise there may be a significantly increased risk of auto-immune thyroid disease (positiva for anti-thyroid peroxidase antibodies), which itself is associated with an increased risk of overt hypothyroidism. The risk increased with age. 44. Quinn FA, Gridasov GN, Vdovenko SA, Krasnova NA, Vodopianova NV, Epiphanova MA, Schulten M. Prevalence of abnormal thyroid stimulating hormone and thyroid peroxidase antibody-positive results in a population of pregnant women in the Samara region of the Russian Federation. Clin Chem Lab Med. 2005;43(11):1223-6. Abbott Laboratories, Abbott Park, IL, USA. [email protected]

Study with suggestion that a healthy serum TSH should be equal to or below 2.5 miU/1 in women undergoing in vitro fertilization, or otherwise there may be an increased risk of a lower gestational age at delivery and lower birth weight of the baby 45. Baker VL, Rone HM, Pasta DJ, Nelson HP, Gvakharia M, Adamson GD. Correlation of thyroid stimulating hormone (TSH) levei with pregnancy outcome in women undergoing in vitro fertilization. Am J Obstet Gynecol. 2006 Jun;194(6):1668-74; discussion 1674-5 Fertility Physicians of Northern California, San Jose, CA, USA. [email protected]

548

Study with suggestion that a healthy serum TSH should be equal to or below 2 for pregnant women, otherwise, in case their serum TSH is above 2, the risk to deliver a low birth weight

(< 2.5 kg) baby may double

46. ldris I, Srinivasan R, Simm A, Page RC. Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcome. Clin Endocrinol (Oxf). 2005 Nov;63(5):560-5 Department of Diabetes and Endocrinology, Nottingham City Hospital, UK. [email protected] Study with suggestion that a healthy serum TSH should be equal to or below 1.9 for pregnant women, otherwise there may be an increased risk of auto-immune thyroiditis 47. Sieiro Netto L, Medina Coeli C, Micmacher E, Mamede Da Costa S, Nazar L, Galvao D, Buescu A, Vaisman M. lnfluence of thyroid autoimmunity and maternal age on the risk of miscarriage. Am J Reprod lmmunol. 2004 Nov;52(5):312-6. Faculdade de Medicina/Servicos de Endocrinologia, HUCFF, UFRJ, Rio de Janeiro, Brazil. [email protected] Study with suggestion that a healthy serum TSH should be below 2.1 mU/1 in angina patients, or otherwise serum creatinine, Gensini's score (assigns a severity score for a stenosed vessel depending on the degree of luminal narrowing and the importance of its location), and the incidence of multiple vessel disease, may be higher 48. Yun KH, Jeong MH, Oh SK, Lee EM, Lee J, Rhee SJ, Yoo NJ, Kim NH, Ahn YK, Jeong JW. Relationship of thyroid stimulating hormone with coronary atherosclerosis in angina patients. lnt J Cardiol. 2007 Jan 11; [Epub ahead of print] Department of Cardiovascular Medicine, Wonkwang University Hospital, lksan, South Korea Study with suggestion that a healthy serum TSH should be equal or below 2 mU/1 in patients taking L­ thyroxine-replacement therapy, or otherwise higher serum homocysteine and CRP leveis may be found 49. Gursoy A, Ozduman Cin M, Kamel N, Gullu S. Which thyroid-stimulating hormone levei should be sought in hypothyroid patients under L-thyroxine replacement therapy? lnt J Clin Pract. 2006 Jun;60(6):655-9. Department of Endocrinology and Metabolic Diseases, Ankara University, School of Medicine, Ankara, Turkey. alptekingursoy@ hotmail.com Study with suggestion that a healthy serum TSH should be below 2.01 in normal individuais, or otherwise mild increases of arterial stiffness may occur 50. Dagre AG, Lekakis JP, Papaioannou TG, Papamichael CM, Koutras DA, Stamatelopoulos SF, Alevizaki M. Arterial stiffness is increased in subjects with hypothyroidism. lnt J Cardiol. 2005 Aug 3;103(1):1-6 Vascular Laboratory, Department of Clinicai Therapeutics, Alexandra University Hospital, Athens, Greece Study with suggestion that a healthy serum TSH should be below 2 mU/1 in normotensives, otherwise the risk of familial predisposition to hypertension and thus the risk of hypertension may be increased 51. Gumieniak O, Hurwitz S, Perlstein TS, Ngumezi UC, Hopkins PN, Jeunemaitre X, Williams GH. Aggregation of high-normal thyroid-stimulating hormone in hypertensive families. J Clin Endocrinol Metab. 2005 Nov;90(11 ):5985-90. Epub 2005 Aug 9. Endocrinology, Diabetes, and Hypertension Division, 221 Longwood Avenue, RFB-2, Boston, Massachusetts 02115, USA Study with suggestion that a healthy serum TSH should be below 2 mU/1 in patients with auto-immune thyroid antibodies, otherwise lhe patients may develop hypercholesterolemia (high total cholesterol >7.5 mmol/1 and a high LDL cholesterol) that can be significantly reduced by two months of a small dose of 50 J.lg/day thyroxine 52. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, Koutras DA. High serum cholesterol leveis in persons with 'high-normal' TSH leveis: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998 Feb;138(2):141-5. Department of Medicai Therapeutics and Evgenidion Hospital, Athens University School of Medicine, Greece Study with suggestion that a healthy serum TSH should be below 1.98 mU/L in patients with coronary artery disease, otherwise the risk of aggravation of coronary heart disease may be higher 53. Auer J, Berent R, Weber T, Lassnig E, Eber B. Thyroid function is associated with presence and severity of coronary atherosclerosis. Clin Cardiol. 2003 Dec;26(12):569-73. Second Medicai Department, Division oi Cardiology and lntensive Care, General Hospital Wels, Wels, Austria. [email protected]

549

Study with suggestion that a healthy serum TSH should be below 2 mU/1 in patients with auto-immune thyroiditis, or otherwise there is an increased risk of upcoming overt hypothyroidism 54. Geul KW, van Sluisveld IL, Grobbee DE, Docter R, de Bruyn AM, Hooykaas H, van der Merwe JP, van Hemert AM, Krenning EP, Hennemann G, et ai. The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids. Clin Endocrinol (Oxf). 1993 Sep;39(3):275-80. Department of Internai Medicine 111, Erasrnus University, Medicai SchooiRotterdarn, The Netherlands

4) The healthiest serum TSH leveis may be found in the lower tertile (33%) of the reference range Study with suggestion that a healthy serum TSH should be /equal to or below 1.53 mU/L diabetic patients, otherwise, if the TSH is higher, the risk may highly increase of developing overt hypothyrodism in the next years 55. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004 Oct;14(10):853-7. Department of Diabetes, Royal lnfirmary of Edinburgh, Edinburgh, United Kingdom

5) The healthiest serum TSH leveis may be found in the lower guartile (lower 25%) of the reference range Study with suggestion that a healthy serum TSH should be /in the lower quartile of the reference range in normal individuais, otherwise, if the TSH is higher, and in particular if the TSH in the upper 25% of the reference range, the risk may increase of undergoing a greater increase in body mass index over 7 years 56. Nyrnes A, Jorde R, Sundsfjord J. Serum TSH is positively associated with BMI. lnt J Obes (Lond). 2006 Jan;30(1):100-5 Department of Geriatric Medicine, University Hospital of North Norway, Tromso. [email protected]

Study with suggestion that a healthy serum TSH should be in the lower quartile ((25%) of the reference range in adult women, otherwise if the TSH is higher, and in particular if the TSH in the upper 25% of the reference range, the risk may increase of having cardiovascular abnormalities such as increased waist circumference, body mass index (BMI), glucose, triglyceride, and systolic blood pressure. 57. Waterhouse DF, Mclaughlin AM, Walsh CO, Sheehan F, O'shea D. An examination of the relationship between normal range thyrotropin and cardiovascular risk parameters: a study in healthy women. Thyroid. 2007 Mar;17(3):243-8. Department of Endocrinology and Metabolism, St. Vincent's University Hospital, Dublin, lreland

Study with suggestion that a healthy serum TSH should be in the lower quartile of the reference range in normal individuais, otherwise, if the TSH is higher, and in particular if the TSH is in the upper 25% of the reference range, the risk may increase of having higher systolic and diastolic blood pressures. Optimally, is to have a serum TSH below the 1.88 in males and 1.79 in temales 58. lqbal A, Figenschau Y, Jorde R. Blood pressure in relation to serum thyrotropin: The Tromso study. J Hum Hypertens. 2006 Dec;20(12):932-6. Department of Cardiology, University Hospital of North Norway, Tromso, Norway. [email protected]

Study with suggestion that a healthy serum TSH should be should be below 0.9 mU/L, and even below 0.4 mU/L in patients with palpable thyroid enlargement, otherwise the risk of thyroid malignancy may increase in parallel with the serum TSH levei 59. Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC, Franklyn JA. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab. 2006 Nov;91(11):4295-301 Division of Medicai Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham 815 2TH, United Kingdom. [email protected]

Study with suggestion that a healthy serum TSH should be below 0.4 mU/L in patients with palpable thyroid enlargement, otherwise, at leveis of serum TSH above the 0.4 mU/L, the risk of thyroid malignancy may increase 60. Kumar H, Daykin J, Holder R, Watkinson JC, Sheppard MC, Franklyn JA. Gender, clinicai findings, and serum thyrotropin measurements in the prediction of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and investigated by fine-needle aspiration cytology. Thyroid. 1999 Nov;9(11):1105-9. Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, United Kingdom

550

6) The healthiest serum TSH leveis may be found in the lower quintile (lower 20%) of the reference range Study with suggestion that a healthy serum TSH should be below 0.4 mU/L, otherwise lhe BMI (body mas index is increasingly higher, above lhe 24.6 61. Knudsen N, Laurberg P,. Rasmussen LB, Bülow I, Perrild H, Ovesen L, J0rgensen T. Small Ditferences in Thyroid Function May Be lmportant for Body Mass lndex and lhe Occurrence of Obesity in lhe Population. J Clin Endocrinol Metab. 2005;90 (7):4019-24

7) Adverse associations between serum TSH within the reference range and pathological parameters Study with suggestion that a higher serum TSH leveis within the reference range may be associated with increased dyslipidemia in normal individuais without known thyroid disease: increases in total serum cholesterol, LDL cholesterol, non-HDL cholesterol & and in particular triglycerides, and a (linear) decrease in HDL cholesterol (with increasing TSH) (Significant association of serum TSH with lipid parameters) The risk further

increases in men over age 50 and overweight individuais.) 62. Asvold BO, Vatten LJ, Nilsen TI, Bjoro T. The association between TSH within lhe reference range and serum lipid concentrations in a population-based study. The HUNT Study. Eur J Endocrinol. 2007 Feb;156(2):181-6 Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway

Study with suggestion that higher serum TSH leveis within the reference range in patients with insulin resistance may be associated with linear increases in LDL cholesterol and reductions in HDL cholesterol (with increasing serum TSH leveis above 1.5 MU/1) 63.

Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JP, Heine RJ, Gans RO. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 2001 Mar;86(3):1206-11. Department of Internai Medicine, University Hospital Groningen, 9700 RB Groningen. [email protected]

Study with suggestion that higher serum TSH leveis within the reference range in men may be associated with increased prostate cancer risk 64.

Lehrer S, Diamond EJ, Stone NN, Stock RG. Serum thyroid-stimulating hormone is elevated in men with Gleason 8 prostate cancer. BJU In!. 2005 Aug;96(3):328-9. Department of Radiation Oncology, Mount Sinai Medicai Center, Bronx, New York, NY 10029, USA. [email protected]

Study with suggestion that higher serum TSH leveis within the reference range in women may be associated with increased breast cancer risk (positive association of serum TSH with breast cancer risk) 65.

Thomas BS, Bulbrook RD, Goodman MJ, Russell MJ, Quinlan M, Hayward JL, Takatani O. Thyroid function and the incidence of breast cancer in Hawaiian, British and Japanese women. nt J Cancer. 1986 Sep 15;38(3):325-9

D. Studies that show for each individual the reference range for thyroid tests is different in particular for serum TSH, and constitutes a smaller part of the population reference range presented by the laboratory

The TSH reference range for an INDIVIDUAL is narrower than the reference range for a population 66.

The value of a population-based reference range is limited when lhe individual patient-based reference range (i.e. his personal reference range) is narrow

67.

Fraser CG, Harris EK. Generation and application of data on biological variation in clinicai chemistry. Cri! Rev Clin Lab Sei. 1989;27:409-37

68.

Harris EK. Effects of intra- and interindividual variation on the appropriate use of normal ranges. Clin Chem. 1974;20:1535--42

551

The individual TSH reference ranges are remarkably narrow within a relatively small segment of the population reference range, i.e. confined to only 25% of a range of 0.3-5.0 mU/Iiter. A shift in lhe TSH value of lhe individual outside of his or her individual reference range, but still within lhe population reference range, would not be normal for that individual. For example, an individual (as in Anderson's series) with a personal range of 0.5-1.0 mU/Iiter would be at subphysiological thyroid hormone leveis at lhe population mean TSH of 1.5 mU/Iiter (as explained by Wartofsky 2005) 69.

Andersen S, Petersen KM, Brunn NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1 068-72

Studies of twins have data to support that each of us has a genetically determined optimal free T4 (FT4)-TSH set point or relationship 70.

Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and

71.

Meikle AW, Stringham JD, Woodward MG, Nelson JC.

monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138-40 Hereditary and environmental influences on lhe

variation of thyroid hormones in normal male twins. J Clin Endocrinol Metab. 1988 ; 66:588-92

A measured TSH difference of 0.75 mU/Iiter can already be significant in a patient. The NACB guideline 8 states that "the magnitude of difference in ...TSH values that would be clinically significant when monitoring a patient's response to therapy... is 0.75 mU/Iiter." Greater TSH fluctuations in a specific patient may mean that s/he becomes hypothyroid or hyperthyroid. 72.

Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smy1h PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinicai Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

A serum TSH that rises in a given individual from a set point of 1.0 to 3.5 is likely to be abnormally elevated and imply early thyroid failure. A minor change in serum free T4 results in an amplified change in TSH to outside of the usual population-based reference range, although lhe free T4 is still within its own population-based reference range, because of lhe lhe log-linear relationship between TSH and free T4.

In the case of subclinical

hypothyroidism, for example, a slight drop in free T4 results in an amplified and inverse response in TSH secretion (as explained by Wartofsky 2005) 73.

Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345:26Q-5

74.

Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44-50

There is a 3-fold difference between the average daily maximal TSH (3) and minimal TSH (1 miU/ml) 75.

Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Muhlen A. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab. 1990 Feb;70(2):403-9

E. Publications on the need for narrower reference ranges for the thyroid tests:

76.

Pain RW. Simple modifications of three routine in vitro tests of thyroid function. Clin Chem. 1976; 22(10):

77.

Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin levei: normal ranges and reference intervals are not

1715-8. equivalent. Thyroid. 2005 Sep;15(9):1035-9 78.

Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8

Adaptation of the reference ranges for serum T3 and serum T4 may be indicated in certain conditions such as pregnancy 79.

Soldin OP, Hilakivi-Ciarke L, Weiderpass E, Soldin SJ. Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays. Clin Chim Acta. 2004 Nov;349(1-2):181-9

552

F. Excessive fluctuations of serum leveis of T3, T4 and TSH

Physiological serum TSH fluctuations 80.

Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Muhlen A. Physiological regulation oi circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab. 1990 Feb;70(2):403-9

(There is a 3-lold difference between the average

daily maximal TSH (3) and minimal TSH (1 miU/ml)) 81.

Brabant G, Prank K, Ranft U, Bergmann P, Schuermeyer T, Hesch RD, von zur Muhlen A. Circadian and pulsatile TSH secretion under physiological and pathophysiological conditions. Horm Metab Res Suppl. 1990;23:12-7

82.

Goichot B, Brandenberger G, Schlienger JL. Secretion oi thyrotropin during states oi wakelulness and sleep.

83.

Rao ML, Gross G, Strebel B, Halaris A, Huber G, Braunig P, Marler M. Circadian rhythm oi tryptophan,

84.

Rose SR, Nisula BC. Circadian variation oi thyrotropin in childhood. J Clin Endocrinol Metab. 1989;

85.

Scanlon MF, Weetman AP, Lewis M, Pourmand M, Rodriguez Arnao MO, Weightman DR, Hall R.

Physiological data and clinicai applications. Presse Med. 1996;25(21):980-4 serotonin, melatonin, and pituitary hormones in schizophrenia. Biol Psychiatry. 1994;1:35(3): 151-63 68(6):1086-90 Dopaminergic modulation oi circadian thyrotropin rhythms and thyroid hormone leveis in euthyroid subjects. J Clin Endocrinol Metab. 1980 Dec;51(6):1251-6 86.

Rom Bugoslavskaia ES, Shcherbakova VS. Seasonal characteristics oi the effect oi melatonin on thyroid lunction. Buli Eksp Biol Med. 1986;101(3):268-9

Variations in the biological activity of TSH 87.

Beck-Peccoz P, Persani L. Variable biological activity oi thyroid stimulating hormone. Eur J Endocrinol. 1994 Oct;131(4):331-40

88.

Maes M, Mommen K, Hendrickx D, Peeters D, D'Hondt P, Ranjan R, De Meyer F, Scharpe S. Components oi biological variation oi TSH, TI3, FT4, PRL, cortisol and testosterone in healthy volunteers. Clin Endocrinol (Oxf). 1997 May;46(5):587-98

89.

Hiromoto M, Nishikawa M, lshihara T, Yoshikawa N, Yoshimura M, Inada M. Bioactivity oi thyrotropin (TSH) in patients with central hypothyroidism: Comparison between the in vivo 3,5,3'- triiodo-thyronine response to TSH and in vitro bioactivity oi TSH. J Clin Endocrinol Metab. 1995 Apr;80(4):1124-8

Variations in serumT3 and T4 90.

Azukizawa M, Pekary AE, Hershman JM, Parker DC.

Plasma thyrotropin, thyroxine, and triiodothyronine

relationships in man. J Clin Endocrinol Metab. 1976 Sep;43(3):533-42 91.

Sawin CT, Hershman JM, Chopra IJ. The comparativa effect oi T4 and T3 on the TSH response to TRH in young adult men. J Clin Endocrinol Metab. 1977 Feb;44(2):273-8

92.

Weeke J, Gundersen HJ. Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects. Acta Endocrinol (Copenh). 1978 Dec;89(4):659-72

G. Thyroid dysfunction at cellular levei, undetectable by classical laboratory tests

93.

Tj0rve E,. Tj0rve K, Olsen JO, Senum R, Oftebro H. On the commonness and rarity oi thyroid hormone resistance: A discussion based on mechanisms oi reduced sensitivity in peripheral tissues. Med Hypotheses. 2007 Mar 23; (PDF, ahead of print; lt is argued that the acquired form of RTH, caused by endogenous and

exogenous sources, may indeed be more common than the congenital, as in insulin resistance. /f acquired resistance to thyroid hormone exists, then it may not be picked up by blood assays of thyroid hormone and TSH. An appropriate test to assess thyroid hormone action in peripheral tissues is therefore greatly desired.) Studies that show that the maximal nuclear binding capacity for T3 declines already at middle age (31-60 years) persons and for T4 at older age (61-90years) compared to young persons (16-30 years) in mononuclear blood cells 94.

Kvetny J. Nuclear thyroxine and triiodothyronine binding in mononucear cells and dependence oi age. Horm Metabol Res. 1985; 17 (1): 35-8)

553

Study that shows that in abrupt adrenal failure (by stopping glucocorticoid medication) the affinity of T3 nuclear receptors declines by more than 50 % after two days 95.

De Nayer P, Dozin B, Vandeput Y, Bottazzo FC, Crabbe J. Altered interaction between triiodothyroinine and its nuclear receptors in absence of cortisol: a proposed mechanism for increased TSH secretion in corticossteroid deficiency states. J Clin lnvest 1987; 17(2): 106-10

Study that shows that in obesity the affinity of T4 nuclear receptors I slower than in normal weight persons 96.

Kvetny J. Nuclear thyroxine receptors and cellular metabolism of thyroxine in obese subjects before and after fasting Horm. Res. 1985;21 (1 ):60-5. ( The

maximal specific binding capacity for T4 was decreased in fed obese subjects compared to normal weight persons)

Studies that show that in the cells there may be lower thyroid activity in older persons, despite apparently adequate serum T3 leveis, because the levei of reverse T3, a cellular antagonist of the active thyroid hormone T3, is increased in older persons 97.

Szabolcs I, Weber M, Kovacs Z, lrsy G, Goth M, Halasz T, Szilagyi G. The possible reason for serum 3,3'5'­ (reverse) triiodothyronine increase in old people. Acta Med Acad Sei Hung. 1982;39(1-2): 11-7

98.

Smeulers J, Visser TJ, Burger AK, Docter R, Hennemann G. Decreased triiodothyronine (T3) production in constant reverse T3 production in advanced age. Ned Tijdschr Geneeskd. 1979 Jan 6;123(1):12-5

H. Thyroid treatment of biochemical "euthyroid" patients.

Studies with no effect of thvroid treatment on clinically hypothyroid, but biochemically euthyroid patients

100 IJg/day of Thyroxine was no more effective than placebo in improving cognitiva function and psychological wellbeing in patients with symptoms of hypothyroidism although serum free T3 increased in patients taking thyroxine. Thyroid function tests remained within the reference range 99.

Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, Mclaren EH. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. Br Med J. 2001 ;323: 91-5 Department of Biochemistry, Stobhill Hospital, Glasgow G21 3UW. [email protected]

Successively increasing the dose of thyroxine with 25, 50 and 75 IJg/day in women with primary hypothyroidism treated with thyroxine brought the serum TSH from a baseline serum TSH 0.1-4.8 mU/Iiter down to a mean of 2.8, 1.0, and 0.3 mU/Iiter respectively, but had no significant effects on well-being, symptoms, quality of life, or cognitive function and provided no significant treatment preference. These data do not support the suggestion that the target TSH range for the treatment of primary hypothyroidism should differ from the general laboratory range. 100.

Walsh JP, Ward LC, Burke V, Bhagat Cl, Shiels L, Henley D, Gillett MJ, Gilbert R, Tanner M, Stuckey BG. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms,

well­

being, or quality of life: results of a double-blind, randomized clinicai trial. J Clin Endocrinol Metab. 2006 Jul;91(7):2624-30. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia. [email protected]

(Critic: could be due to the patients' need for additional T3 in

lhe treatments) Studies that may support that there is a need to increase the dosage of thyroid treatment in thyroid treated patients who are biochemically euthyroid Studies that show little benefit of thyroxine therapy if TSH reductions are only put into the range of 3-3.5 mU/IL. Mainly studies using dosage titration to TSH leveis < 3.0 are associated with improvement in symptoms, lipid abnormalities, and cardiovascular function (except the study by Meier and colleagues that showed benefit with rninimal TSH reductions in the 3-3.5 miU/ml range)

554

101.

Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled

L-thyroxine

therapy reduces cholesterol leveis and clinicai

symptoms

in subclinical

hypothyroidism. Am J Med. 2001;112:348-54 102.

Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled

L-thyroxine therapy

reduces cholesterol leveis

and

clinicai

symptoms

in

subclinical

hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001; 103.

86:486Q-6 Cooper DS 2001 Subclinical hypothyroidism. N Engl J Med 345:26D-5

104.

Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44-50

105.

McDermott MT, Ridgway EC.

Clinicai perspective: subclinical hypothyroidism is mild thyroid failure and

should be treated. J Clin Endocrinol Metab. 2001; 86:4585-90

{Shows benefit with minimal TSH reductions

down to only the range of 3-3.5 mU/Iiter) Study that shows the persistence of impairment in psychological well-being and increased symptoms of hypothyroidism in hypothyroid patients treated with L-T4 alone, despite normal TSH leveis

106.

Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Psychological well-being in patients on 'adequate' doses of L-thyroxine: results of a large, controlled community-based questionnaire study. Clin Endocrinol (Oxf). 2002;57:577-85 (large, controlled, community-based study

Studies with beneficiai effect of thyroid treatment on clinically patients

hypothyroid. but biochemically euthyroid

In some of lhe double-blind placebo-controlled studies comparing treatment with levothyroxine alone with combinations of levothyroxine plus liothyronine in hypothyroid patients, the patients preferred levothyroxine plus

liothyronine combinations, possibly indicating that lhe researchers were no! investigating lhe rigtht psychoiogical and physical parameters in lhe studies where they concluded to no significant effects of adding T4 to lhe patients with serum TSH within lhe reference range 107.

Benevicius R, Kazanavicius G, Zalinkovicius R, Prange AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med.1999; 340: 424-9 (double-biind placebo­

108.

Hertoghe T, Lo Cascio A., Hertoghe J. Considerable improvement of hypothyroid symptoms with two

controlled study) combined T3-T4 medication in patients still symptomatic with thyroxine treatment alone. Anti-Aging Medicine (Ed. German Society of Anti-Aging Medicine-Veriag 2003) 2004; 32-43 (open study) 109.

Escobar-Morreale HF, Botella-Carretero Jl, Escobar dei Rey F, Morreale de Escobar G. REViEW: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab. 2005 Aug;90(8):4946-54. Epub 2005 May 31. Department of Endocrinology, Hospital Ramon y Cajal, Madrid, Spain (double-blind placebo-controlled study)

Studies with appropriate dosage titration to TSH leveis under 3.0 are more often associated with improvement in symptoms, lipid abnormalities, and cardiovascular function 11O.

Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adampoulos P, Koutras DA. High serum choiesterol leveis in persons with 'high-normal' TSH leveis: should one extend lhe definition of subclinical hypothyroidism. Eur J Endocrinol. 1998; 138:141-5

111.

Ayala A, Wartofsky L 2002 The case for more aggressive screening and treatment of mild thyroid failure

112.

("subclinical" hypothyroidism). Cleveiand Clin J Med. 69:313-20 Faber J, Petersen L, Wiinberg N, Schifler S, Mehisen J. Hemodynamic changes after levothyroxine treatment

113.

Monzani F, DiBello V, Caraccio N, Bertini A, Giorgi D, Guisti C, Ferranni E. Effect of levothyroxine on cardiac

in subclinical hypothyroidism. Thyroid. 2002; 12:319-24 function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001; 86:111D-5 114.

Biondi B, Fazio S, Paimieri EA, Carella C, Panza N, Cittadini A, Bone F, Lombardi G, Sacca L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999; 84:2064-7

115.

Di Bello V, Monzani F, Giorgi D, Bertini A, Caraccio N, Valenti G, Talini E, Paterni M, Ferrannini E, Giusti C.

116.

Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, Stametelopoulos S, Koutras

Ultrasonic myocardial textura! analysis in subclinical hypothyroidism. J Am Soe Echocardiogr. 2000;13:832-40 DA. Fiow-mediated, endothelium-dependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin values. Thyroid. 1997; 7:411-4 117.

Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Salvetti A, Ferrannini E, Monzani F. impaired

endothelium-dependent

vasodilatation

in

subclinical

ievothyroxine therapy. J Clin Endocrinoi Metab. 2003;88:3731-7

555

hypothyroidism:

beneficiai

effect

of

118.

119. 120.

121.

Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JPJ, Heine RJ, Gans ROB. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 86:1206-11 Krausz Y, Freedman N, Lester H, Newman JP, Barkai G, Bocher M, Chisin R, Bonne O. Regional cerebral blood flow in patients with mild hypothyroidism. J Nucl Med. 2004; 45:1712-5 lmaizumi M, Akahoshi M, lchimaru S, Nakashima E, Hida A, Soda M, Usa T, Ashizawa K, Yokayama N, Maeda R, Nagataki S, Eguchi K. Risk for ischemic heart disease and ali-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004;89:3365-70 Monzani F, Caraccio N, Kozakowa M, Dardano A, Vittone F, Virdis A, Taddei S, Palombo C, Ferrannini C. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004;89:2099-106

Studies with beneficiai effects thyroxine treatment of biochemically euthyroid patients with thyroid hyperplasia. nodules ancl/or goiter Necessity to treat "harmless" biochemically "euthyroid" goiters in puberty with thyroxine because of: lipid abnormalities (higher average lipid values etc.), sign of disturbed efficacy of thyroid hormones 122.

Ronnefarth G, Kauf E, Deschner F, Forberger M. [Euthyroid goiter in puberty--a harmless illness?] Klin Padiatr. 1996 Mar-Apr;208(2):77-82. Universitats-Kinderklinik Jena

Studies where thyroxine was an effective and well-tolerated treatment of euthyroid nodules and goitre 123.

Karges B, Muche R, Knerr I, Ertelt W, Wiesel T, Hub R, Neu A, Klinghammer A, Aufschild J, Rapp A, Schirbel A, Boehm BO, Debatin KM, Heinze E, Karges W. Levothyroxine in euthyroid autoimmune thyroiditis and type 1 diabetes: a randomized, controlled trial. J Clin Endocrinol Metab. 2007 May;92(5):1647-52. Division of Pediatric Endocrinology and Diabetes, University Children's Hospitai,University of Ulm, Eythstrasse 24, D89075 Ulm, Germany. [email protected] (T4 treatment (1.3 microglkg daily, 24 months) to

biochemical/y euthyroid children and adolescents with type 1 diabetes and positive thyroid peroxidase antibodies, thyroglobulin antibodies, or both, reduced thyroid volume , but had no effect on thyroid function and serum autoantibody compared to diabetic contrais, T41evels) 124.

Peters H, Hackel D, Schleusener H. Treatment of euthyroid struma. Comparable volume reduction with 400 micrograms iodine, 100 micrograms levothyroxine combined with 100 micrograms iodine or individually dosed levothyroxine. Med Klin (Munich). 1997 Feb15;92(2):63-7 (1/:Jd volume reduction with T4 treatment)

125.

Svensson J, Ericsson UB, Nilsson P, Olsson C, Jonsson B, Lindberg B, lvarsson SA. Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis. J Clin Endocrinol Metab. 2006 May;91(5):1729-34.Department of Pediatrics, Malmõ University Hospital, Lund University, SE-205 02 Malmõ, Sweden. [email protected]

126.

Güllü S, Gürses MA, Ba�kal N, Uysal AR, Kamel AN, Erdogan G. Suppressive therapy with levothyroxine for euthyroid diffuse and nodular goiter. Endocr J. 1999 Feb;46(1):221-6. Department of Endocrinology and Metabolic Diseases, Ankara University Medicai School, Turkey (The mean decrease of thyroid volume at six

months was about 20% in patients with diffuse goiter; a reduction of 50% or more in volume was detected in 31% of the patients. 54% of the patients showed a 10-49% decrease in nodule volume.) 127.

Hegedüs L, Hansen JM, Feldt-Rasmussen U, Hansen BM, Heier-Madsen M. lnfluence of thyroxine treatment on thyroid size and anti-thyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf). 1991 Sep;35(3):235-8. Department of Internai Medicine and Endocrinology F, Herlev Hospital, Denmark (32 %decrease of thyroid volume in 24 months of thyroxine therapy)

128.

Lima N, Knobel M, Cavaliere H, Sztejnsznajd C, Tomimori E, Medeiros-Neto G. Levothyroxine suppressive therapy is partially effective in treating patients with benign, solid thyroid nodules and multinodular goiters. Thyroid. 1997 Oct;7(5):691-7 Department of Medicine, University of Sao Paulo Medicai School, Brazil (200

J.lg/day of levothyroxine for 12 months to euthyroid subjects with a benign, solitary, predominantly solid nodule: 37.1% patients with single, solid nodules had 50% or more regression of the nodular volume (responders), 20.3% patients had more than 20%, but /ess than 49.9% reduction of nodular volume (partia/ responders), nonresponders were 42.5%) 129. Diacinti D, Salabê GB, Olivieri A, D'Erasmo E, Tomei E, Lotz-Salabê H, De Martinis C. Efficacy of L-thyroxine (L-T4) therapy on lhe volume of lhe thyroid gland and nodules in patients with euthyroid nodular goiter. Minerva Med. 1992 Nov;83(11):745-51. lstituto di Clinica Medica 11, Università di Roma, La Sapienza (the

mean decrease of thyroid volume at nine months was 25% with thyroxine treatment)

556

Publication where thyroxin therapy is proposed in young euthyroid (with normal serum TSH) patients with small, diffuse goiter 130.

Hermus AR, Huysmans DA. Diagnosis and therapy of patients with euthyroid goiter. Ned Tijdschr Geneeskd. 2000 Aug 19;144(34):1623-7

Study where thyroxine treatment to euthyroid subjects in suppressive or replacement doses was not efficient to reduce nodule or goiter size 131.

Celani MF.Levothyroxine suppressive therapy in lhe medicai management of nontoxic benign multinodular goiter. Exp Clin Endocrinol. 1993;101(5):326-32 Department of Medicine, Castelfranco Emilia Hospital, Modena, ltaly

Studies with beneficiai effects thyroxine treatment of biochemically euthyroid patients with auto-immune disease Studies where thyroxine treatment to biochemically euthyroid patients with treated (drug-normalized) Graves' disease) reduced the production of thyroid antobodies 132.

133.

Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab. 1990 Sep;71(3):661-9. lstituto di Endocrinologia, Università di Pisa, ltaly (reduced antibodies to TSH receptors and lhe frequency of recurrence of hyperthyroidism) Hashizume K, lchikawa K, Sakurai A, Suzuki S, Takeda T, Kobayashi M, Miyamoto T, Arai M, Nagasawa T. Administration of thyroxine in treated Graves' disease. Effects on lhe levei of antibodies to thyroid-stimulating hormone receptors and on lhe risk of recurrence of hyperthyroidism. N Engl J Med. 1991 Apr 4;324(14):94753 (reduced anti-thyroid peroxidase antibodies)

Studies where thyroxine treatment to biochemically "euthyroid" patients with Hashimoto's thyroiditis reduced the leveis of thyroid antibodies 134.

135.

Aksoy DY, Kerimoglu U, Okur H, Canpinar H, Karaagaoglu E, Yetgin S, Kansu E, Gedik O. Effects of prophylactic thyroid hormone replacement in euthyroid Hashimoto's thyroiditis. Endocr J. 2005 Jun;52(3):33743. Section of Endocrinology and Metabolism, Department of Internai Medicine, Hacettepe University, Ankara, Turkey {15 months of L-thyroxine treatment, there was a significant increase in free T4 and a significant decrease in TSH and anti-thyroglobulin and anti-thyroid peroxidase antibody leveis; conclusion: prophylactic thyroid hormone therapy can be used in patients with Hashimoto's thyroiditis even if they are euthyroid) Rieu M, Richard A, Rosilio M, Laplanche S, Ropion V, Fombeur JP, Berrod JL. Effects of thyroid status on thyroid autoimmunity expression in euthyroid and hypothyroid patients with Hashimoto's thyroiditis. Clin Endocrinol (Oxf). 1994 Apr;40(4):529-35 Department of Endocrinology, Saint-Michel Hospital, Paris, France.

136.

137.

138.

(12 months of L-thyroxine treatment reduces TSH-receptor antibodies and thyroid peroxidase antibodies in patients with euthyroid or hypothyroid goitrous Hashimoto's thyroiditis, and increased again after L-thyrxoine withdrawal) Chiovato L, Marcocci C, Mariotti S, Mori A, Pinchera A. L-thyroxine therapy induces a fali of thyroid microsomal and thyroglobulin antibodies in idiopathic myxedema and in hypothyroid, but not in euthyroid Hashimoto's thyroiditis. J Endocrinol lnvest. 1986 Aug;9(4):299-305 Padberg S, Heller K, Usadel KH, Schumm-Draeger PM. One-year prophylactic treatment of euthyroid Hashimoto's thyroiditis patients with levothyroxine: is there a benefit? Thyroid. 2001 Mar;11(3):249-55. Medica Clinic I, Endocrinology, Center of Internai Medicine, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany Rink T, Schroth HJ, Holle LH, Garth H. Effect of iodine and thyroid hormones in lhe induction and therapy ofHashimoto's thyroiditis] Nuklearmedizin. 1999;38(5):144-9. Abteilung fÃV..r Nuklearmedizin, Stadtkrankenhaus Hanau, Deutschland. [email protected] (thyroxine treatment is able to reduce the TgAb and lhe TPOAb leveis even in euthyroid patients with Hashimoto's thyroiditis)

Studies where thyroxine treatment to biochemically "euthyroid" patients with Hashimoto's thyroiditis did not significantly reduced the leveis of anti-thyroid peroxidase antibodies 139.

Hegedüs L, Hansen JM, Feldt-Rasmussen U, Hansen BM, H0ier-Madsen M. lnfluence of thyroxine treatment on thyroid size and anti-thyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf). 1991 Sep;35(3):235-8. Department of Internai Medicine and Endocrinology F, Herlev Hospital, Denmark (no significant change of anti-thyroid peroxidase antibodies after 24 months of thyroxine)

557

I. Transitory T3-hyperthyroidism or intolerance due to the presence of other hormone deficiencies

A. lntolerance to thyroid treatment because of adrenal deficiency

lntolerance to thyroid treatment because of adrenal deficiency 140.

Shaikh

MG,

Lewis

P,

Kirk

JM.

Thyroxine

unmasks

Addison's

disease.

Acta

Paediatr.

2004

Dec;93(12):1663-5. Department of Endocrinology, Birmingham Children's Hospital, Birmingham, United Kingdom. [email protected] 141.

Graves L, Klein RM, Walling AD. Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome. South Med J. 2003 Aug;96(8):824-7. Division of Metabolism, Endocrinology and Genetics, Department of Internai Medicine, University of Kansas Medicai Center, Kansas City, Kansas 66160, USA. [email protected]

142.

Rey L, Bulliard C, Pralong F, Waeber G. Adrenal insufficiency caused by treatment with levothyroxine. Schweiz Rundsch Med Prax. 2001 Nov 29;90(48):2103-8.Département de Médecine Interne, Centre Hospitalier Universitaire Vaudois, Lausanne

143.

Olukoga A, Horsman G, Stewart F. Lessons to be learned: a case study approach: severe hyponatraemia induced by primary hypothyroidism and associated with possible increased hepatic sensitivity to thyroxine replacement. J R Soe Health. 1999 Jun;119(2):117-20

144.

Rey L, Bulliard C, Pralong F, Waeber G. Adrenal insufficiency caused by treatment with levothyroxine] Schweiz Rundsch Med Prax. 2001 Nov 29;90(48):2103-8. Centre Hospitalier Universitaire Vaudois, Lausanne

145.

Miell J, Wassif W, McGregor A, Butler J, Ross R. Life-threatening hypercalcaemia in association with Addisonian crisis. Postgrad Med J. 1991 Aug;67(790):770-2. Department of Medicine, King's College Hospital School of Medicine, London, UK

146.

Davis J, Sheppard M. Acute adrenal crisis precipitated by thyroxine. BMJ. 1986;292:1595 Hosp. Pract. (Off. Ed.). 1986 May 15;21(5):132, 134

147.

Banitt PF, Munson AK. Addisonian crisis after thyroid replacement. Hosp. Pract. (Off. Ed.). 1986 May

148.

Murray JS, Jayarajasingh R, Perros P. Deterioration of symptoms after start of thyroid hormone

15;21(5):132, 134 replacement. BMJ. 2001 August 11; 323(7308): 332-333. Freeman Hospital, High Heaton, Newcastle upon Tyne, UK 149.

Osman A, Leslie P. Adrenal insufficiency should be excluded before thyroxine replacement is started. BMJ 1996;313:427

lncrease in serum T3 in hypocorticism 150.

Comtois R, Hebert J, Soucy JP. lncrease in T3 leveis during hypocorticism in patients with chronic secondary adrenocortical insufficiency. Acta Endocrinol. 1992 Apr;126(4):319-24. Department of Medicine, Notre-Dame Hospital, University of Montreal, Quebec, Canada

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Excessive thyroid hormone leveis after lowering the cortisol leveis through treatment of Cushing's syndrome 152.

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Haraguchi K, Hiramatsu K, Onaya T. Transient thyrotoxicosis after unilateral adrenalectomy in two patients with Cushing's syndrome. Endocrinol Jpn. 1984 Oct;31(5):577-82

155.

Morita H, lsaji M, Mune T, Daido H, lsomura Y, Sarui H, Tanahashi T, Takeda N, lshizuka T, Yasuda K. Transient

Graves

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2002 Japan.

Glucocorticoids reduces the conversion of T4 into T3, reducing thereby thyroid activity 156.

Re RN, Kourides IA, Ridgeway EC, Weintraub BD, Maloof F. The effect of glucocorticoid administation on

157.

Heyma P, Larkins RG. Glucocorticoids decrease the conversion of thyroxine into 3,5,3'-triiodothyronine by

human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab. 1976; 43:338-46 isolated rat renal tubules. Clin Science. 1982; 62: 215-20 158.

Banos C, Tako J, Salamon F,

Gyorgyi S,

Czikkely R. Effect of ACTH-stimulated glucocorticoid

hypersecretion on lhe serum concentrations of thyroxine-binding globulin, thyroxine, triiodothyronine, reverse triiodothyronine and on lhe TSH-response to TRH. Acta Med Acad Sei Hung. 1979;36(4):381-94 159.

Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite effects of dexamethasone on serum concentrations of 3,3',5'-triiodothyronine (reverse T3) and 3,3'5-triiodothyronine (T3). J Clin Endocrinol Metab. 1975 Nov;41(5):911-20

160.

Jennings AS, Ferguson DC. Effect of dexamethasone on triiodothyronine production in lhe perfused rat liver

161.

Cavalieri RR, Castle JN, McMahon FA. Effects of dexamethasone on kinetics and distribution of

162.

Yamamoto M, Saito S, Kaise K, Kaise N, Yoshida K, Yoshinaga K. Changes in thyroid hormones by

and kidney. Endocrinology.1984 Jan;114(1):31-6 triiodothyronine in lhe rat. Endocrinology. 1984 Jan;114(1):215-21 treatment with aspirin and prednisolone in subacute thyroiditis with hyperthyroidism. Tohoku J Exp Med. 1979 Jan;127(1):85-95 163.

Westgren

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desoxycorticosterone, and ACTH on serum concentrations of thyroxine, 3,5,3'-triiodothyronine and 3,3',5'­ triiodothyronine. Acta Med Scand. 1977;202(1-2):89-92

Glucocorticoids reduce more the T3 than the T4 in the treatment of hyperthyroidism 164.

Williams DE, Chopra IJ, Orgiazzi J, Solomon OH. Acute effects of corticosteroids on thyroid activity in Graves' disease. J Clin Endocrinol Metab. 1975 Aug;41(2):354-61

Glucocorticoids reduce the secretion of TSH, possibly reducing thereby thyroid active 165.

Re RN, Kourides IA, Ridgeway EC, Weintraub BD, Maloof F. The effect of glucocorticoid administation on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab. 1976; 43:338-46

B. lntolerance to thyroid treatment because of estroqen deficiency

Higher thyroid hormone leveis (especially higher serum T3) in estrogen deficiency states such as in the postmenopause, improvement with estrogen therapy 166.

Custro N, Scafidi V. Mild hyperthyroidism with inappropriate secretion of TSH in postmenopausal women. Acta Endocrinol (Copenh). 1986 Feb;111(2):204-8

167.

Wasyluk H, Chrabalowski Z, Doroszewski J, Hartwig W. Menopause and hyperthyroidism. Pol Arch Med Wewn. 1976 Nov;56(5):439-44

168.

Lederer J. Estrogen therapy of hyperthyroidism after castration or menopause; remate results. Ann Endocrinol (Paris). 1950;11(5):459-70

169.

Schoutens A, Laurent E, Markowicz E, Lisart J, De Maertelaer V. Serum triiodothyronine, bone turnover, and bone mass changes in euthyroid pre- and postmenopausal women.

Calei! Tissue lnt. 1991

Aug;49(2):95-100. Department of Nuclear Medicine, HA'pital Erasme-Free University of Brussels, Belgium. 170.

Schoutens A, Laurent E, Markowicz E, Lisart J, De Maertelaer V. Serum triiodothyronine, bone turnover, and bone mass changes in euthyroid pre- and postmenopausal women. Calei! Tissue In!. 1991 Aug;49(2):95-100. Department of Nuclear Medicine, Hôpital Erasme-Free University of Brussels, Belgium (In postmenopausal women, serum iT3 corrected for thyroid binding globulin (TBG) (T3c) was higher in those receiving no estrogen replacement therapy.)

Estrogens reduce the conversion of T4 into T3, reducing thereby thyroid activity 171.

EI-Etreby MF, Graf KJ, Gunzel P, Neumann F. Evaluation of effects of sexual steroids on lhe hypothalamic­ pituitary system of animais and man. Arch Toxicol Suppl. 1979;2:11-39

172.

Scammell JG, Shiverick KT, Fregly MJ. Effect of chronic treatment with estrogen and thyroxine, alone and combined, on lhe rale of deiodination of L-thyroxine to 3,5,3'-triiodothyronine in vitro. Pharmacology. 1986;33(1):52-7

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Vandorpe G, Kuhn ER. Estradiol-17 beta silastic implants in female Rana ridibunda depress thyroid hormone concentrations in plasma and lhe in vitro 5'-monodeiodination activity of kidney homogenates. Gen Comp Endocrinol. 1989 Dec;76(3):341-5. Laboratory of Comparative Endocrinology, Catholic University of Leuven, Belgium

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Cyr DG, MacLatchy DL, Eales JG. The influence of short-term 17 beta-estradiol treatment on plasma T3 leveis and in vitro hepatic T4 5'-monodeiodinase activity in immature rainbow trout, Salmo gairdneri. Gen Comp Endocrinol. 1988 Mar;69(3):431-8. Department of Zoology, University of Manitoba, Winnipeg, Canada.

175.

Chan V, Besser GM, Landon J. Effects of oestrogen on urinary thyrosine excretion. Br Med J. 1972 Dec

176.

Lemarchand-Beraud T. lnfluence of estrogens on pituitary responsiveness to LHRH and TRH in human.

23;4(5842):699-701 Reymond M, Berthier C. Ann Endocrinol Paris. 1977; 38(6): 379-82

Estrogens increase serum TBG and reduce the conversion of T4 into T3, reducing thereby thyroid activity 177.

Wiegratz I, Kutschera E, Lee JH, Moore C, Mellinger U, Winkler UH, Kuhl H. Effect of four oral contraceptives on thyroid hormones, adrenal and blood pressure parameters.

Contraception.

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Selenkow HA. Remission oi hyperthyroidism and oral contraceptive therapy. [Answer to question]. JAMA. 1984 Nov 2;252(17):2463

C. Other factors Other factors or conditions that may reduce the conversion of T4 into T3 (stress, acute exercise, perinatal period, posttraumatic stress disorder cold, nephritic syndrome, meals (n particular carbohydrate feeding), malathion (pesticide in food), and treatments with various supplements such as

selenium, zinc (controversial),

vitamin A, iodine, glutathione, growth hormone, IGF-1, TRH, etc. 179.

Turakulov laKh, Burikhanov RB, Patkhitdinov PP, Myslitskaia AI. Effect oi immobilization stress on lhe levei oi thyroid hormone secretion Probl Endokrinol (Mosk). 1993 Sep-Oct;39(5):47-8.

180.

Kellner K, Hecht K, Marek H, Aquino AM. Behavior oi thyroid hormones, corticosterone, adrenocorticotropic hormone and insulin in lhe plasma oi lhe rat under stress conditions. Z Gesamte lnn Med. 1980 May 15;35(10):418-21 (an immobilization!hypokinase stress produced a decrease of the T4 and an increase of the T3)

181.

Opstad PK, Falch O, Oktedalen O, Fonnum F, Wergeland R. The thyroid function in young men during prolonged exercise and lhe effect oi energy and sleep deprivation. Clin Endocrinol (Oxf). 1984 Jun;20(6):657-69 (initial increase of T4 to T3 conversion with prolonged exercise, but if chronic followed by a reduced conversion of T4 to T3)

182.

Klein AH, Oddie TH, Fisher DA. Effect oi parturition on serum iodothyronine concentrations in fetal sheep.

183.

Mason J, Southwick S, Yehuda R, Wang S, Riney S, Bremner O, Johnson O, Lubin H, Blake O, Zhou G.

Endocrinology. 1978 Oct; 103(4):1453-7 (increase in perinatal period of serum T3) Elevation oi se rum free triiodothyronine, total triiodothyronine, thyroxine-binding globulin, and total thyroxine leveis in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1994 Aug;51(8):629-41. National Center for Posttraumatic Stress Disorder, Veterans Affairs Medicai Center, West Haven, Conn 184.

Sawhney RC, Malhotra AS, Nair CS, Bajaj AC, Rajan KC, Pai K, Prasad R, Basu M. Thyroid function during a prolonged stay in Antarctica. Eur J Appl Physiol Occup Physiol. 1995;72(1-2):127-33. Defence lnstitute oi Physiology and Allied Sciences, Delhi Cantt, lndia

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Konno N. Comparison between the thyrotropin response to thyrotropin-releasing hormone in summer and that in winter in normal subjects. Endocrinol Jpn. 1978 Dec;25(6):635-9 (slight elevation of serum T3 concentration in winter but not in serum T4 leve/)

186.

Scammell JG, Sarney CC, Fregly MJ. Proposed mechanism for increased thyroxine deiodination in cold­ acclimated rats. J Appl Physiol. 1981 Nov;51(5):1157-61 (The rates of hepatic and renal deiodination of T4 to T3 in rats exposed to 4 degree C for 20 days were 297 and 222% higher, respectively, than contrai)

187.

Glass AR, Vigersky RA, Rajatanavin R, Pardridge W, Smallridge RC, Wartofsky L, Burman KD. Low serum thyroxine and high serum triiodothyronine in nephrotic rats: etiology and implications for bioavailability of protein-bound hormone. Endocrinology. 1984 May;114(5):1745-53

188.

Glick Z, Wu SY, Lupien J, Reggio R, Bray GA, Fisher DA. Meal-induced brown fat thermogenesis and thyroid hormone metabolism in rats. Am J Physiol. 1985 Nov;249(5 Pt 1):E519-24.

189.

Glade MJ, Reimers TJ. Effects oi dietary energy supply on serum thyroxine, tri-iodothyronine and insulin concentrations in young horses. J Endocrinol. 1985 Jan;104(1):93-8

190.

Gavin LA, Moeller M, McMahon FA, Castle JN, Gulli R, Cavalieri RR. Carbohydrate feeding increases total body and specific tissue 3,5,3'-triiodothyronine neogenesis in the rat. Endocrinology. 1988 Aug;123(2):107581. Department oi Medicine, Veterans' Administration Medicai Center, San Francisco, California 94121.

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191.

Yadav AK, Singh TP. Effect of pesticide on circulating thyroid hormone leveis in lhe freshwater catfish, Heteropneustes fossilis (Bioch). Environ Res. 1986 Feb;39(1):136-42 (Malathion, an organophosphorus,

seems to increase the plasma T3/evel, probably by increasing the T4 to T3conversion) 192.

Napolitano G, Bonomini M, Bomba G, Bucci I, Todisco V, Albertazzi A, Monaco F. Thyroid function and plasma selenium in chronic uremic patients on hemodialysis treatment. Biol Trace Elem Res. 1996 Dec;55(3):221-30. Chair of Endocrinology, University G. D'Annunzio, Chieti, ltaly

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Kauf E, Dawczynski H, Jahreis G, Janitzky E, Winnefeld K. Sodium selenite therapy and thyroid-hormone status in cystic fibrosis and congenital hypothyroidism. Biol Trace Elem Res. 1994 Mar;40(3):247-53. Childrens Hospital, Friedrich-Schiller-University, Jena, Germany

194.

Chen MO, Lin WH, Lin PY, Wang JJ, Tsou CT. lnvestigation on lhe relationships among blood zinc, copper, insulin and thyroid hormones in non-insulin dependent diabetes mellitus and obesity. Zhonghua Yi Xue Za Zhi (Taipei). 1991 Dec;48(6):431-8. Department of Medicine, Taichung Veterans General Hospital, Taiwan, Republic of China (8/ood zinc concentration was inversely re/ated to T3 leve/ in diabetics and obese

individuais) 195.

Morley JE, Melmed S, Reed A, Kasson BG, Levin SR, Pekary AE, Hershman JM. Effect of vitamin A on lhe hypothalamo-pituitary-thyroid axis. Am J Physiol. 1980 Feb;238(2):E174-9 (In vitro, vitaminA enhanced T4

to T3conversion in hepatic homogenates). 196.

Okamura K, Taurog A, Krulich L. Elevation of serum 3,5,3'-triiodothyronine al')d thyroxine leveis in rats fed Remington diets; opposing effects of nutritional deficiency and iodine Endocrinology. 1981 Apr;108(4):124756. deficiency (iodine increases T4 to T3conversion)

197.

Ozawa Y, Shimizu T, Shishiba Y. Effect of sulfhydryl reagents on lhe conversion of thyroxine to 3,5,3'­ triiodothyronine: direct action on thyroxine molecules. Endocrinology. 1982 Jan;110(1):241-5 (reduced

glutathione markedly enhanced subsequent T3generation from T4 by the homogenate) 198.

Gomez Saez JM, Gomez Arnaiz N, Soler Ramon J. Changes in lhe lipid profile and thyroid function in adult patients with hypopituitarism after substitutive treatrnent with growth hormone. Med Clin (Sare). 1999 Dec 11;113(20):775-6

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Wolthers T, Groftne T, Moller N, Christiansen JS, Orskov H, Weeke J, Jorgensen JO. Calorigenic effects of growth hormone: lhe role of thyroid hormones. J Clin Endocrinol Metab. 1996 Apr;81(4):1416-9. Medicai Department M, Aarhus University Hospital, Denmark

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Sacco V, Maioli A, Citro G, Galasso R, Vinci ML, Zampino A. Effect of treatment with biosynthetic GH on thyroid function in patients with an isolated deficiency of GH] Minerva Endocrinol. 1992 Jan-Mar;17(1):1320. Divisione di Endocrinologia, Ospedale San Carlo, Potenza

201.

Jorgensen JO, Moller J, Laursen T, Orskov H, Christiansen JS, Weeke J. Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose­ dependent manner and suppresses circadian thyrotrophin leveis: studies in GH-deficient adults. Clin Endocrinol (Oxf). 1994 Nov;41(5):609-14. Medicai Department M (Endocrinology and Diabetes), Aarhus Kommunehospital, Denmark

202.

Hussain MA, Schmitz O, Jorgensen JO, Christiansen JS, Weeke J, Schmid C, Froesch ER. lnsulin-like growth factor I alters peripheral thyroid hormone metabolism in humans: comparison with growth hormone. Eur J Endocrinol. 1996 May;134(5):563-7. Division of Endocrinology and Metabolism, University Hospital of Zurich, Switzerland

203.

Campos-Barros A, Kohler R, Muller F, Eravci M, Meinhold H, Wesemann W, Baumgartner A.The influence of sleep deprivation on thyroid hormone metabolism in rat frontal cortex. Neurosci Lett. 1993 Nov 12;162(12):145-8. Department of Nuclear Medicine (Radiochemistry), Universitãtsklinikum Steglitz, Berlin, FRG.

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Pirazzoli P, Cacciari E, Mandini M, Sganga T, Capelli M, Cicognani A, Gualandi S. Growth and thyroid function in children treated with growth hormone. J Pediatr. 1992 Aug;121(2):210-3. First Pediatric Clinic, University of Bologna, ltaly

205.

Moller J, Jorgensen JO, Moller N, Christiansen JS, Weeke J. Effects of growth hormone administration on fuel oxidation and thyroid function in normal man. Metabolism.

1992 Ju1;41(7):728-31. University

Department of Internai Medicine and Endocrinology, Aarhus Kommunehospital, Denmark. 206.

Peeters R, Buys N, Vanmontfort D, Van lsterdael J, Decuypere E, Kuhn ER. Preferential release of tri­ iodothyronine following stimulation by thyrotrophin or thyrotrophin-releasing hormone in sheep of different ages. J Endocrinol. 1992 Jan;132(1):93-100. Laboratory for Physiology of Domestic Animais, Catholic University of Leuven, Belgium

207.

Valenta LJ, Eisenberg H, Ascher MS, Elias AN. Response of thyroid hormones in peripheral and thyroid venous blood to TRH administration in man. Horm Res. 1983;17(2):78-83

561

Chapter seven:

Calcitonin

Senescence is associated with a decline of serum calcitonin 1.

Bueht E, Rong H, Sjoberg HE, Sjostedt U, Granberg B, Torring O. Serum ealeitonin forms and eoneentrations in young and elderly healthy females. Calei! Tissue In!. 1995 Jan;56(1):32-7

2.

Pedrazzoni M, Mantovani M, Ciotti G, Girasole G, Pioli G, Palummeri E. Caleitonin leveis in normal women of various ages evaluated with a new sensitive radioimmunoassay. Horm Metab Res. 1988 Feb;20(2):118-9

3.

Tsai CL, Pu HF, Wang PS, Liu TK. Coneentration of plasma ealeium in response to human ealeitonin in female rats during aging. J Gerontol. 1992 Mar;47(2):B45-7

4.

Tsai CL, Wong TY, Tsai SC, Lau CP, Chen YZ, Hwang GS, Wang PS. Age-related differences in lhe hypocaleemie effeet of ealeitonin and ealeium exeretion in female rats. Chin J Physiol. 1991;34(4):455-62

Thyroidectomy is associated with calcitonin deficiency 5.

Cappelli C, Cottarelli C, Cumetti D, Agosti B, Gandossi E, Rizzoni D, Agabiti Rasei E. Bone density and mineral metabolism in ealeitonin-defieieney patients. Minerva Endoerinol. 2004 Mar;29(1):1-10 (Undetectable leveis of calcitonin in patients with total thyroidectomy)

6.

Mirzaei S, Krotla G, Knoll P, Koriska K, Kõhn H. Possible effeet of ealeitonin defieieney on bane mass after subtotal thyroideetomy. Aeta Med Austriaea. 1999;26(1):29-31

7.

MeDermott MT, Kidd GS,

Blue P,

Ghaed V,

Hofeldt FD.

Redueed bane mineral eontent in

totally

thyroideetomized patients: possible effeet of ealeitonin defieieney. J Clin Endoerinol Metab. 1983 May;56(5):9369 8.

Sehneider P, Berger P, Kruse K, Bõrner W. Effeet of ealeitonin defieieney on bane density and bane turnover in totally thyroideetomized patients. J Endoerinol lnvest. 1991 Dee;14(11):935-42

Radioactive iodine treatment is associated with calcitonin deficiency 9.

Tzanela M, Thalassinos NC, Nikou A, Georgiadis G, Philokiprou D. Effeet of 1311 treatment on lhe ealeitonin response to ealeium infusion in hyperthyroid patients. Clin Endoerinol (Oxf). 1993 Jan;38(1):25-8

A calcitonin gene anomaly may trigger a mechanism of senescence Free radicais: Caleitonin reduees superoxide anion formation by osteoelasts 10. Datta HK, Manning P, Rathod H, MeNeil CJ. Effeet of ealeitonin, elevated ealeium and extraeellular matriees on superoxide anion produetion by rat osteoclasts. Exp Physiol. 1995 Sep;80{5):713-9

Poor gene polymorphisms: A poor ealcitonin gene polymorphism may promete lhe development of osteoporosis and lhe oeeurrenee of hip or vertebral fraetures 11. Braga V, Sangalli A, Malerba G, Mottes M, Mirandola S, Gatti D, Rossini M, Zamboni M, Adami S. Relationship among VDR (Bsml and Fokl), COLIA1, and CTR polymorphisms with bane mass, bone turnover markers, and sex hormones in men. Calei! Tissue lnt. 2002 Jun;70(6):457-62

Calcitonin and age-related diseases Migraine: prevention with calcitonin treatment 12. Gennari C, Chieriehetti MS, Gonnelli S, Vibelli C, Montagnani M, Piolini M. Migraine prophylaxis with salmon caleitonin: a eross-over double-blind, plaeebo-eontrolled study. Headaehe. 1986 Jan;26(1):13-6 13. Mieieli G, Cavallini A, Martignoni E, Covelli V, Faeehinetti F, Nappi G. Effeetiveness of salmon ealeitonin nasal spray preparation in migraine treatment. Headaehe. 1988 Apr;28(3):196-200 14. Patti F, Seapagnini U, Nieoletti F, Prato A, Millia C, Clementi G. Caleitonin and migraine. Headaehe. 1986 Apr;26(4):172-4 (30 patients in a crossover placebo study) 15. Brady SI, Kaufman K, Hart LL. Caleitonin in migraine. DICP. 1991;25:1185-6

Platelet aggregation in vitro and in vivo: the inhibition with calcitonin 16. Pogliani EM, Corghi E, Ortolani S, Girardello R, Vigo PL, Polli IE. Effeets of poreine ealeitonin on human platelet funetion. Biomed Pharmaeother. 1984;38(2):97-101

562

Obesity: the improvement with calcitonin treatment 17. Chelikani PK, Haver AC, Reidelberger RD. Effects of intermittent intraperitoneal infusion of salmon calcitonin on food intake and adiposity in obese rats. Am J Physiol Regul lntegr Comp Physiol. 2007 Nov;293(5):R1798-808

Osteoarthritis: the improvement with calcitonin treatment 18. Karsdal MA, Byrjalsen I, Henriksen K, Riis BJ, Lau EM, Arnold M, Christiansen C. The effect of oral salrnon calcitonin delivered with 5-CNAC on bane and cartilage degradation in osteoarthritic patients: a 14-day randomized study. Osteoarthritis Cartilage. 201O Feb;18(2):150-9 19. Manicourt DH, Azria M, Mindeholm L, Thonar EJ, Devogelaer JP. Oral salmon calcitonin reduces Lequesne's algofunctional index scores and decreases urinary and serum leveis of biomarkers of joint metabolism in knee

(1 mg per day of oral salmon calcitonin reduces pain and functional disability in patients with knee osteoarthritis) 20. Bagger YZ, Tankó LB, Alexandersen P, Karsdal MA, Olson M, Mindeholm L, Azria M, Christiansen C. Oral salmon calcitonin induced suppression of urinary collagen type li degradation in postmenopausal women: a new potential treatment ofosteoarthritis. Bane. 2005 Sep;37(3):425-30 21. Zhang Y, Wang W, Zhang L. Effect of calcitonin on articular cartilage of osteoarthritis. Zhongguo Xiu Fu Chong osteoarthritis. Arthritis Rheum. 2006 Oct;54(10):3205-11

Jian Wai Ke Za Zhi. 2008 Nov;22(11):1393-5 22. Papaioannou NA, Triantafillopoulos IK, Khaldi L, Krallis N, Galanos A, Lyritis GP. Effect of calcitonin in early and late stages of experimentally induced osteoarthritis. A histomorphometric study. Osteoarthritis Cartilage. 2007 Apr;15(4):386-95 23. Manicourt DH, Altman RD, Williams JM, Devogelaer JP, Druetz-Van Egeren A, Lenz ME, Pietryla D, Thonar EJ. Treatment with calcitonin suppresses the responses of bane, cartilage, and synovium in lhe early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions. Arthritis Rheurn. 1999 Jun;42(6):1159-67 24. Sondergaard BC, Oestergaard 8, Christiansen C, Tankó LB, Karsdal MA. The effect of oral calcitonin on cartilage turnover and surface erosion in an ovariectomized rat model. Arthritis Rheum. 2007 Aug;56(8):2674-8

Rheumatoid arthritis: the improvement with calcitonin treatment 25. Aida

8,

Okawa-Takatsuji

M,

Aotsuka

8,

Shimoji

K,

Yokohari

R.

Calcitonin

inhibits

production

of

immunoglobulins, rheumatoid factor and interleukin-1 by mononuclear cells from patients with rheumatoid

("84% of calcitonin-treated patients who complained arthralgia experienced a gradual joint pain relief) 26. Mancini L, Paui-Ciark MJ, Rosignoli G, Hannon R, Martin JE, Macintyre I, Perretti M. Calcitonin and prednisolone display antagonistic actions on bane and have synergistic effects in experimental arthritis. Am J Pathol. 2007 Mar;170(3):1018-27 arthritis. Ann Rheum Ois. 1994 Apr;53(4):247-9

Join pain: the relief with calcitonin treatment 27. Janke A, Badurski J, Stasiewicz J, Sajewicz I, Namiot Z. Calcitonin versus cimetidine or De-Nol in gastric ulcer treatment. An endoscopically controlled trial. Dtsch Z Verdau Stoffwechselkr. 1988;48(5):239-43 (In the

calcitonin group a gradual joint pain relief was observed in

84% of patients who complained arthra/gia)

Osteoporosis and osteopenia: the association with lower calcitonin leveis 28. Foresta C, Scanelli G, Zanatta GP, Busnardo B, Scandellari C. Reduced calcitonin reserve in young hypogonadic osteoporotic men. Horm Metab Res. 1987 Jun;19(6):275-7 29. Melton LJ 3rd, Ardila E, Crowson CS, O'Fallon WM, Khosla S.

Fractures following thyroidectomy in women: a

population-based cohort study. Bane. 2000 Nov;27(5):695-700 30. Chuchalin AG, Suleimanov SSh, Gasanov SG, Grigor'ev AI, Shmushkovich Bl. Study of calcitonin and parathyroid hormone in patients with bronchial asthma with steroid-induced osteoporosis. Probl Endokrinol (Mosk). 1983 Sep-Oct;29(5):19-20 31. Cappelli C, Cottarelli C, Cumetti D, Agosti B, Gandossi E, Rizzoni D, Agabiti Rasei E. Bane density and mineral 2004 Mar;29(1):1-10 ("Calcitonin was undetectable in thyroidectomized patients, while the mean value was 7. 1 +1-3.2 pg/ml in the contrai group. At bone ultrasonography 50% of patients showed osteopenia, while only one subject showed osteopenia in the contrai group")

metabolism in calcitonin-deficiency patients. Minerva Endocrinol.

32.

Osteoporosis and osteopenia: the improvement with calcitonin treatment 33. Karsdal MA, Byrjalsen I, Riis BJ, Christiansen C. lnvestigation of the diurnal variation in bane resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin. BMC Clin Pharmacol. 2008 Dec 4;8:12

563

34. Wang SX, Li H. Salmon calcitonin in prevention of osteoporosis in maintenance dialysis patients. Chin Med J (Engl). 2008 Jul 20;121(14):1280-4 35. Wang SX, Li H.

Effects of salmon calcitonin in treatment of osteoporosis in patients undergoing dialysis.

Zhonghua Yi Xue Za Zhi. 2008 Feb 5;88(6):387-90 36. Knopp JA, Diner BM, Blitz M, Lyritis GP, Rowe BH. Calcitonin for treating acute pain of osteoporotic vertebral compression

fractures:

a

systematic

review

of

randomized,

controlled

trials.

Osteoporos

lnt.

2005

Oct;16(10):1281-90 37. lshida Y, Kawai S. Comparativa efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am J Med. 2004 Oct 15;117(8):549-55 38. Flicker L, Hopper JL, Larkins RG, Lichtenstein M, Buirski G, Wark JD. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporos lnt. 1997;7(1):29-35 39. Kotaniemi A, Piirainen H, Paimela L, Leirisalo-Repo M, Uoti-Reilama K, Lahdentausta P, Ruotsalainen P, Kataja M, Vaisanen E, Kurki P. ls continuous intranasal salmon calcitonin effective in treating axial bone loss in patients with aclive rheumatoid arthritis receiving low dose glucocorticoid therapy? J Rheumatol. 1996 Nov;23(11):18759 40. Kung AW, Yeung SS. Prevention of bone loss induced by thyroxine suppressive therapy in postmenopausal women: the effect of calcium and calcitonin. J Clin Endocrinol Metab. 1996 Mar;81(3):1232-6 41. Abbiati G, Arrigoni M, Frignani S, Longoni A, Bartucci F, Castiglioni C. Effect of salmon calcitonin on deoxypyridinoline (Dpyr) urinary excretion in healthy volunteers. Calcif Tissue lnt. 1994 Nov;55(5):346-8 42. Mango D, Ricci S, Manna P, Natili G, Deii'Acqua S. Preventiva treatment of cortical bone loss with salmon nasal calcitonin in early postmenopausal women. Minerva Endocrinol. 1993 Sep;18(3):115-21 43. Overgaard K, Hansen MA, Jensen SB, Christiansen C. Effect of salcatonin intranasally on bone mass and fracture rates in established osteoporosis: A dose-response study. Br Med J. 1992; 305, 556-61 44. Chuchalin AG, Baranova IA, Berova MM. An intranasal method of administration of calcitrin to steroid-dependent patients with bronchial asthma. Klin Med (Mosk). 1991 Sep;69(9):24-6 45. Montemurro L, Schiraldi G, Fraioli P, Tosi G, Riboldi A, Rizzato G. Prevention of corticosteroid-induced osteoporosis with salmon calcitonin in sarcoid patients. Calcif Tissue lnt. 1991 Aug;49(2):71-6 46. Zara C, Perotti F, Ferraro R, Lauri A, Saviotti C, Montrasio MG, Caprotti M, Polatti F. Treatment of ovariectomized patients with intramuscular and nasal-spray synthetic calcitonin. Minerva Endocrinol. 1989 Jan­ Mar;14(1):53-6 47. Maclntyre I, Whitehead Ml, Banks LM, Stevenson JC, Wimalwansa SJ, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lance! 1988;1:900-2 48. Okayasu T, Masuda T, Hashimoto M, Tanabe T. Clinicai study of a synthetic calcitonin derivativa (elcatonin) in patients with metastatic bone tumors. Gan To Kagaku Ryoho. 1987 Sep;14(9):2703-9 49. Mazzuoli G, Passeri M, Gennari C, Minisola S, Antonelli R, Valtorta C, Palummeri E, Cervellin F, Gonelli S, Francini G. Effects of salmon calcitonin in postmenopausal osteoporosis: A controlled double-blind clinicai study. Calcif. Tissue lnt. 1986;38:3-8 50. Tanko LB, Bagger YZ, Alexandersen P, Devogelaer JP, Reginster JY, Chick R, Olson M, Benmammar H, Mindeholm L, Azria M, Christiansen C Safety and efficacy of a novel salmon calcitonin (sCT) technology-based oral formulation in healthy postmenopausal women: acute and 3-month effects on biomarkers of bone turnover. J Bone Miner Res. 2004 Sep;19(9):1531-8

Vertebral fractures: the improvement with calcitonin treatment 51. lshida Y, Kawai S. Comparativa efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am J Med. 2004 Oct 15;117(8):549-55 52. Rico H, Revilla M, Hernandez ER, Villa LF, Alvarez de Buergo M. Total and regional bone mineral content and fracture rate in postmenopausal osteoporosis treated with salmon calcitonin: a prospectiva study. Calcif Tissue lnt. 1995 Mar;56(3):181-5 ('The calcitonin-treated group had a 6.4 times less in incidence of vertebral fractures,

and a 60% reduction in the number of new fractures, while the group receiving only calcium had a 45% increase'?

Paget's disease: the improvement with calcitonin treatment 53. Gonzalez D, Vega E, Ghiringhelli G, Mautalen C. Comparison of the acute effect of the intranasal and intramuscular administration of salmon calcitonin in Paget's disease. Calcif Tissue lnt. 1987 Dec;41(6):313-5 54. Pontiroli AE, Pajetta E, Calderara A, Alberetto M, Pozza G, Manganelli V, Resmini G, Tessari L, Maresca V. lntranasal and intramuscular human calcitonin in female osteoporosis and in Paget's disease of bones: a pilot study. J Endocrinol lnvest. 1991 Jan;14(1):47-51 55. Chapuy MC, Meunier P, Terrier M, David L, Vignon G. Short-term biological effects of synthetic salmon calcitonin in Paget's disease. lnfluence of posology. Pathol Biol (Paris). 1975 May;23(5):349-59

564

Hyperparathyroidism: the improvement with calcitonin treatment 56. Stone MD, Marshall DH, Hosking DJ, Garcia-Himmelstine C, White DA, Worth HG. Comparison of /ow-dose intramuscular

and

intravenous

salcatonin

in

lhe

treatment

of

primary

hyperparathyroidism.

Bone.

1992; 13(3):265-71 57. Torring O, Bucht E, Sjostedt U, Sjoberg HE. Sa/mon ca/citonin treatment by nasal spray in primary hyperparathyroidism. Bone. 1991;12{5):311-6.

Pain (vertebral fractures, Paget's disease, metastatic bone disease): the improvement with calcitonin treatment 58. B/au LA, Hoehns JD. Analgesic efficacy of calcitonin for vertebral fracture pain. Ann Pharmacother. 2003 Apr;37(4):564-70 59. Lyritis GP, Tsakalakos N, Magiasis B, Karachalios T, Yiatzides A, Tsekoura M. Analgesic effect of salmon calcitonin in osteoporotic vertebral fractures: a double-blind placebo-controlled clinicai study. Calei! Tissue lnt. 1991 Dec;49(6):369-72 60. Th. Garofalidis Research Centre, University of Athens, KAT Hospital, Kifissia, GreecePontiroli AE, Pajetta E, Scaglia L, Rubinacci A, Resmini G, Arrigoni M, Pozza G. Analgesic effect of intranasa/ and intramuscular salmon calcitonin in post-menopausal osteoporosis: a double-blind, double-p/acebo study. Aging {Milano). 1994 Dec;6(6):459-63 61. /saia GC, Di Stefano M, Sciolla A, Mussetta M, Vassellatti D. Synthetic salmon calcitonin suppositories for lhe short-term treatment of involutive osteoporosis. Minerva Med. 1995 Mar;86{3):101-4

(A statistical/y significant

decrease of pain, .. bane mineral density at lumbar spine showed an increase'j 62. Sasaki F, Uchino J, Haia Y, Saio Y, Konno T, Okuno T, Ohira S, Taguchi K, Fuzisawa J, Oku T. Clinicai study of ee/ calcitonin for relief of pain from metastatic bone lesions. Gan To Kagaku Ryoho. 1991 Mar;18{3):437-42

("Calcitonin was effective on 55.6% of patients to reduce severe bane pain, but did not decrease the amount of analgesics in most patients'? 63. Okayasu T, Masuda T, Hashimoto M, Tanabe T. Clinicai study of a synthetic calcitonin derivative (elcatonin) in patients with metastatic bone tumors. Gan To Kagaku Ryoho. 1987 Sep;14(9):2703-9 64. Miseria S, Torresi U, Piga A, Tummarello D, Belleggia C, Caputi CA, Cellerino R. Analgesia with epidural calcitonin in cancer patients. Tumori. 1989 Apr 30;75{2):183-4 65. Pontiroli AE, Pajetta E, Calderara A, Alberetto M, Pozza G, Manganelli V, Resmini G, Tessari L, Maresca V. lntranasa/ and intramuscu/ar human calcitonin in lema/e osteoporosis and in Paget's disease of bones: a pilo! study. J Endocrinol lnvest. 1991 Jan;14(1):47-51 66. Pun KK, Chan LW. Analgesic effect of intranasal sa/mon calcitonin in lhe treatment of osteoporotic vertebral fractures. C/in Ther. 1989 Mar-Apr;11(2):205-9. 67. Matsumoto T, Nagata N, Horikoshi N, Adachi I, Ohashi Y, Ogata E. Comparative study of incadronate and elcatonin in patients with malignancy-associated hypercalcaemia. J lnt Med Res. 2002 May-Jun;30(3):230-43

Calcitonin Diagnosis Serum calcitonin 68. Zhan Z, Meng X, Chen L, Zhou X, Liu S. The setting up of human serum calcitonin radioimmunoassay and its clinicai Application. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1997 Jun;19(3):236-40 69. Emmertsen K, Marqversen J, Jensen FT, Hansen HH. Radioimmunoassay of calcitonin in unextracted human serum: a sensitive method. Scand J C/in Lab lnvest. 1982 Nov;42(7):539-44 70. Suzuki H. Calcitonin leveis in normal individuais with new highly sensitive chemiluminescent enzyme immunoassay. J C/in Lab Anal. 1998;12{4):218-22. 71. Stepan JJ, Zikan V. Calcitonin /oad test to assess lhe efficacy of sa/mon calcitonin. Clin Chim Acta. 2003 Oct;336(1-2):49-55 72. lsmailov SI, Piulatova NR. Postoperative ca/citonin study in medullary thyroid carcinoma. Endocr Relat Cancer. 2004 Jun;11(2):357-63 73. Karanikas G, Moameni A, Poetzi C, Zettinig G, Kaserer K, Bieglmayer C, Niederle B, Dudczak R, Pirich C. Frequency and relevance of elevated calcitonin leveis in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects. J Clin Endocrinol Metab. 2004 Feb;89(2):515-9 74. Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, lacconi P, Baso/o F, Pinchera A, Pacini F. /mpact of routine measurement of serum calcitonin on lhe diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders.

J Clin Endocrinol Metab. 2004

Jan;89(1):163-8 75. Bojunga

J,

Dragan

C,

Schumm-Draeger

PM,

Usadel

KH,

Kusterer

K.

Circulating

calcitonin

and

carcinoembryonic antigen m-RNA detected by RT-PCR as tumour markers in medullary thyroid carcinoma. Br J Cancer. 2001 Nov 16;85{10):1546-50

565

Corrective calcitonin therapy 76. Siminoski K, Josse RG. Prevention and management of osteoporosis: consensus statements from lhe Scientific Advisory Board of lhe Osteoporosis Society of Canada. 9. Calcitonin in lhe treatment of osteoporosis. CMAJ. 1996 Oct 1;155(7):962-5

Calcitonin medications lntramuscular calcitonin 77. Chen P, Lai JM, Deng JF, Lu SB, Ku H. Relative bioavailability of salmon calcitonin given intramuscularly. Zhonghua Yi Xue Za Zhi (Taipei). 2000 Aug;63(8):619-27

Subcutaneous calcitonin 78. O'Doherty DP, Bickerstaff DR, McCioskey EV, Atkins R, Hamdy NA, Kanis JA. A comparison of lhe acute effects of subcutaneous and intranasal calcitonin. Clin Sei (Lond). 1990 Feb;78(2):215-9

lntranasal calcitonin 79. Thamsborg G. Effect of nasal salmon calcitonin on calcium and bane metabolism. Dan Med Buli. 1999 Apr;46(2):118-26 (real, but madest efficacy af nasal calcitanin an bane density, even at 200 IU/day) 80. Reginster JY, Denis D, Albert A, Franchimont P. Assessment of lhe biological effectiveness of nasal synthetic salmon calcitonin (SSCT) by comparison with intramuscular (i.m.) or placebo injection in normal subjects. Bane Miner. 1987 Apr;2(2):133-40

Experimental forros: Oral calcitonin 76. Chin CM, Gutierrez M, Still JG, Kosutic G. Pharmacokinetics of modified oral calcitonin product in healthy volunteers. Pharmacotherapy. 2004 Aug;24(8):994-1 001 77. Martins S, Silva AC, Ferreira DC, Souto EB. lmproving oral absorption of Salmon calcitonin by trimyristin lipid nanoparticles. J Biomed Nanotechnol. 2009 Feb;5(1):76-83 78. Lee HE, Lee MJ, Park CR, Kim AY, Chun KH, Hwang HJ, Oh DH, Jean SO, Kang JS, Jung TS, Choi GJ, Lee S. Preparation and characterization of salmon calcitonin-sodium triphosphate ionic complex for oral delivery. J Contrai Release. 2010 Apr 19;143(2):251-7 79. Karsdal MA, Byrjalsen I, Henriksen K, Riis BJ, Christiansen C. lnvestigations of inter- and intraindividual relationships between exposure to oral salmon calcitonin and a surrogate marker of pharmacodynamic efficacy. Eur J Clin Pharmacol. 2010 Jan;66(1):29-37 80. Karsdal MA, Byrjalsen I, Azria M, Arnold M, Choi L, Riis BJ, Christiansen C. lnfluence of food intake on lhe bioavailability and efficacy of oral calcitonin. Br J Clin Pharmacol. 2009 Apr;67(4):413-20 81. Karsdal MA, Byrjalsen I, Henriksen K, Riis BJ, Christiansen C. A pharmacokinetic and pharmacodynamic comparison of synthetic and recombinant oral salmon calcitonin. J Clin Pharmacol. 2009 Feb;49(2):229-34 82. Karsdal MA, Byrjalsen I, Riis BJ, Christiansen C. lnvestigation of lhe diurnal variation in bone resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin. BMC Clin Pharmacol. 2008 Dec 4;8:12 83. Karsdal MA, Byrjalsen I, Riis BJ, Christiansen C. Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: lhe effect of water and timing of meal intake on oral delivery of Salmon Calcitonin. BMC Clin Pharmacol. 2008 Sep 9;8:5 84. Buclin T, Gosma Rocha! M, Burckhardt P, Azria M, Attinger M. Bioavailability and biological efficacy of a new oral formulation of salmon calcitonin in healthy volunteers. J Bane Miner Res. 2002 Aug;17(8):1478-85

Rectal calcitonin 81. Fiare CE, Fiorito S, Foti R, Motta M, lncognito C, Grasso G. Evaluation of lhe biological activity of unmodified synthetic eel calcitonin rectal capsules. Comparison with intramuscular administration and placebo. In! J Clin Pharmacol Res. 1992;12(4):185-9 82. Buclin T, Randin JP, Jacquet AF, Azria M, Attinger M, Gomez F, Burckhardt P. The effect of rectal and nasal administration of salmon calcitonin in normal subjects. Calcif Tissue In!. 1987 Nov;41(5):252-8 ('1he peaks being high and short after rectal administration, low but more sustained after nasal application") 83. !saia GC, Di Stefano M, Sciolla A, Mussetta M, Vassellatti D. Synthetic salmon calcitonin suppositories for lhe short-term treatment of involutive osteoporosis. Minerva Med. 1995 Mar;86(3):101-4

Calcitonin treatment: efficacy/potency of calcitonin medications 84. Gennari C, Gonnelli S, Agnusdei D, Civitelli R. Biological activity of different calcitonins in men. Exp Gerontol. 1990;25(3-4):339-47 (the patency arder salman ca/citanin (CT) greater than human CT greater than amina­ suberic acid derivative af ee/ CT')

566

85. Ponliroli AE, Pajetta E, Scaglia L, Rubinacci A, Resmini G, Arrigoni M, Pozza G. Analgesic effecl of inlranasal and inlramuscular salmon calcilonin in posl-menopausal osleoporosis: a double-blind, double-placebo sludy. Aging (Milano). 1994 Dec;6(6):459-63. 86. Abbiali G, Arrigoni M, Frignani S, Longoni A, Bartucci F, Casliglioni C. Effecl of salmon calcilonin on deoxypyridinoline (Dpyr) urinary excrelion in heallhy volunleers. Calei! Tissue lnt. 1994 Nov;55(5):346-8('a

dose of 50 lU I.M. of salmon calcitonin reduces resorption, with a bane gain in lhe first 24 hours calculated as 9.4 mg!IU"- that's about 1 gram a day for a IM injection of 100 lU per day'} Calcitonin treatment: dosage 87. O'Doherty DP, Bickerslaff DR, McCioskey EV, Atkins R, Hamdy NA, Kanis JA. A comparison of lhe acute effecls of subculaneous and inlranasal calcilonin. Clin Sei (Lond). 1990 Feb;78(2):215-9

(400 units of calcitonin administered as a nasal spray induced effects qualitatively similar to those seen with subcutaneous calcitonin, with an efficacy equivalent to approximately 30 units of subcutaneous calcitonin)

88. Schlemmer A, Ravn P, Hassager C, Chrisliansen C. Morning or evening administralion of nasal calcilonin? Effects on biochemical markers of bane turnover. Bane. 1997 Jan;20(1):63-7

("the present study does not indica/e that neither evening nor twice-daily administra/íon is superior to moming administration'?

Calcitonin treatment interferences - associations 89. Flicker L, Hopper JL, Larkins RG, Lichtenstein M, Buirski G, Wark JD. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporos lnt. 1997;7(1):29-35

(Separately administered lhe

medications increase bane density, combined they neutralize each other!) 90. Reginster JY, Deroisy R, Fontaine MA, Franchimont P. lnfluence of estrogen replacement therapy on endogenous calcitonin production rales. Gynecol Endocrinol. 1992 Mar;6(1 ):65-71.

Calcitonin treatment: safety, side effects, complications 91. Gennari C, Gonnelli S, Agnusdei D, Civitelli R. Biological aclivity of differenl calcilonins in men. Exp Gerontol. 1990;25(3-4):339-47

("the mos! constant side effect is flushing, and the frequency arder of side effects is human calcitonin (CT) greater than sa/mon calcitonin, greater than the amino-suberic acid derivative of ee/ calcitonin'?

92. Reginster JY, Franchimont P. Side effects of synthelic salmon calcitonin given by intranasal spray compared with inlramuscular injection. Clin Exp Rheumatol. 1985 Apr-Jun;3(2):155-7 93. Horst-Sikorska W, Ruszkowska J, Kosowicz J. Comparison of calcitonin tolerance after intramuscular or intranasal dministration in treatment for postmenopausal osteoporosis.Przegl Lek. 1996;53(1):9-11

("Calcitonin in intramuscular or subcutaneous injections led to severa/ side effects, /ike nausea, vomiting, abdominal pains, skin rush, headaches, dropping blood pressure, symptoms of bronchial spasm; patients receiving calcitonin in nasal spray did not manifest any severe side effects')

94. Porcel SL, Cumplido JA, de la Hoz B, Cuevas M, Losada E. Anaphylaxis to calcitonin. Allergol lmmunopathol (Madr). 2000 Jui-Aug;28(4):243-5 95. Tagliaro F, Dorizzi R, Luisetto G. Effect of antibodies to calcitonin on lhe pharmacokinetics and lhe pharmacodynamics of the hormone. Horm Metab Res. 1995

Jan;27(1):31-4('presence of antibodies to eel

calcitonin does not represent a negative event in the therapy'} 96. Bessette L, Carette S, Fosse! AH, Lew RA. A placebo controlled crossover trial of subculaneous salmon calcitonin in the treatment of patients with fibromyalgia. Scand J Rheumatol. 1998;27(2):112-6

('The principal

side effect observed with salmon calcitonin was nausea ")

Follow-up of calcitonin treatment Measurement of the reduction in caleium 97. Casao E, Elosegui LM, lbanez MA, Vidal MO, Cervera P, Escanero JF. Short- and long-term effects of calcitonin and calcium administration on bloodcalcium, magnesium and inorganic phosphorus in post menopausa! osteoporosis. J Trace Elem Med Biol. 1995 Oct;9(3):181-4

(A decrease in the total and ionic Ca was observed immediately (short-term) and after three months of calcitonin treatment (/ong term))

Measurement of the degree of suppression by calcitonin of bone resorption urinary markers of bone resorption: urinary deoxypyridino/ine [DPD], type I cross-linked N-telopeptide [NTX], and type I cross-/inked C­

telopeptide [CTX] 98. Hodsman AB, Fraher LJ, Ostbye T, Adachi JD, Steer BM. An evaluation of severa! biochemical markers for bane formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis. J Clin lnvest. 1993 Mar;91(3):1138-48

567

99. Gur A, Colpan L, Cevik R, Nas K, Jale Sarac A. Comparison of zinc excrelion and biochemical markers of bone remodelling in lhe assessmenl of lhe effecls of alendronale and calcilonin on bone in poslmenopausal osleoporosis. Clin Biochem. 2005 Jan;38(1):66-72 100.Tanko LB, Bagger YZ, Alexandersen P, Devogelaer JP, Reginsler JY, Chick R, Olson M, Benmammar H, Mindeholm L, Azria M, Christiansen C Safety and efficacy of a novel salmon calcitonin (sCT) technology-based oral lormulation in healthy poslmenopausal women: acute and 3-month ellecls on biomarkers oi bone turnover. J Bone Miner Res. 2004 Sep;19(9):1531-8 101.Trovas GP, Lyrilis GP, Galanos A, Raptou P, Constanlelou E. A randomized lrial oi nasal spray salrnon calcitonin in men wilh idiopathic osteoporosis: effects on bone mineral densily and bone markers. J Bone Miner Res. 2002 Mar;17(3):521-7.

TOPICS OE DISCUSSION

NO INHIBITION OF ENDOGENOUS CALCITONIN SECREIION BY INTRANASAL ANO INTRAMUSCULAR CALCITONIN 102.Reginster JY, Denis D, Albert A, Franchimonl P. Assessment oi lhe biological ellectiveness oi nasal synthelic salmon calcitonin (SSCT) by comparison wilh inlramuscular (i.m.) or placebo injeclion in normal subjects. Bone Miner. 1987 Apr;2(2):133-40

568

Chapter eight:

Parathormone

Senescence is associated with unfavorable changes of the calcium-parathormone axis Senescence is associated with telomere shortening in parathyroid tissue 1. Kammori M, Nakamura K, Kawahara M, Mimura Y, Kaminishi M, Takubo K. Telomere shortening with aging in human thyroid and parathyroid tissue. Exp Gerontol. 2002 Apr;37(4):513-21 Senescence is associated with lower serum leveis of parathormone in hemodialysis and bedridden patients 2.

3.

Mehrotra R, Supasyndh O, Berman N, Kaysen G, Hurst L, Leonardi M, Das D, Kopple JD. Age-related decline in serum parathyroid hormone in maintenance hemodialysis patients is independent of inflammation and dietary nutrient intake. J Ren Nutr. 2004 Jul;14(3):134-42 Bjõrkman MP, Sorva AJ, Risteli J, Tilvis RS. Low parathyroid hormone leveis in bedridden geriatric patients with vitamin D deficiency. J Am Geriatr Soe. 2009 Jun;57(6):1045-50

Senescence is associated with higher serum leveis of parathormone 4.

5.

6.

7. 8.

Vieth R, Ladak Y, Walfish PG. Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin D. J Clin Endocrinol Metab. 2003 Jan;88(1):185-91 McKane WR, Khosla S, Egan KS, Robins SP, Burritt MF, Riggs BL. Role of calcium intake in modulating age­ related increases in parathyroid function and bone resorption. J Clin Endocrinol Metab. 1996 May;81(5):1699703 Chan EL, Lau E, Shek CC, MacDonald D, Woo J, Leung PC, Swaminathan R. Age-related changes in bone density, serum parathyroid hormone, calcium absorption and other indices of bone metabolism in Chinese women. Clin Endocrinol (Oxf). 1992 Apr;36(4):375-81 Endres DB, Morgan CH, Garry PJ, Omdahl JL. Age-related changes in serum immunoreactive parathyroid hormone and its biological action in healthy men and women. J Clin Endocrinol Metab. 1987 Oct;65(4):724-31 Marcus R, Madvig P, Young G. Age-related changes in parathyroid hormone and parathyroid hormone action in normal humans. J Clin Endocrinol Metab. 1984 Feb;58(2):223-30

Senescence is associated with a progressively (and excessively) higher secretion of parathyroid hormone in response to lower serum calcium leveis 9.

Portale AA, Lonergan ET, Tanney DM, Halloran BP. Aging alters calcium regulation of serum concentration of parathyroid hormone in healthy men. Am J Physiol. 1997 Jan;272(1 Pt 1):E139-46

Senescence is associated with a need for progressively higher serum vitamin 03 leveis and intake to reduce serum parathormone leveis 10. Vieth R, Ladak Y, Walfish PG. Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin D. J Clin Endocrinol Metab. 2003 Jan;88(1):185-91 (PTH leveis of the elderly who had 25(0H)D concentrations greater than 100 nmol/liter matched PTH of younger adults having 25(0H)D concentrations near 70 nmol/liter) 11. Bjõrkman M, Sorva A, Tilvis R. Responses of parathyroid hormone to vitamin D supplementation: a systematic review of clinicai trials. Arch Gerontol Geriatr. 2009 Mar-Apr;48(2):160-6 12. Bjõrkman M, Sorva A, Risteli J, Tilvis R. Vitamin D supplementation has minor effects on parathyroid hormone and bone turnover markers in vitamin D-deficient bedridden older patients. Age Ageing. 2008 Jan;37(1):25-31 High caleium intake (2.4 g/day vs 0.8 g/day) neutralizes the age-related increase in serum parathormone 13. McKane WR, Khosla S, Egan KS, Robins SP, Burritt MF, Riggs BL. Role of calcium intake in modulating age­ related increases in parathyroid function and bone resorption. J Clin Endocrinol Metab. 1996 May;81(5):1699703 14. Kennel KA, Riggs BL, Achenbach SJ, Oberg AL, Khosla S. Role of parathyroid hormone in mediating age­ related changes in bone resorption in men. Osteoporos lnt. 2003 Aug;14(8):631-6

Genetic parathormone abnormalities may trigger senescence Poor gene polymorphisms: A poor parathyroid hormone gene polymporphism may be associated with higher cardiovascular mortality, secondary hyperparathyroidism and higher or slower bone density loss with age 15. Tsujimoto Y, Tabata T, lnoue T, Tahara H, Shoji T, Shinohara K, lnaba M, Nishizawa Y. Effects of parathyroid hormone gene polymorphism on cardiovascular mortality. Clin Calcium. 2005 Sep;15 Suppl 1:106-9

569

16. Gohda T, Shou I, Fukui M, Funabiki K, Horikoshi S, Shirato I, Tomino Y. Parathyroid hormone gene polymorphism

and

secondary hyperparathyroidism

in

hemodialysis

patients.

Am

J

Kidney

Ois.

2002

Jun;39(6):1255-60 17. Gong G, Johnson ML, Barger-Lux MJ, Heaney RP. Association of bone dimensions with a parathyroid hormone gene polymorphism in women. Osteoporos lnt. 1999;9(4):307-11

Parathormone and psychic well-being Lower quality of life and fatigue: the improvement with parathormone treatment 18. Langdahl BL, Rajzbaum G, Jakob F, Karras D, Ljunggren O, Lems WF, Fahrleitner-Pammer A, Walsh JB, Barker C, Kutahov A, Marin F. Reduction in fracture rate and back pain and increased quality of life in postmenopausal women treated with teriparatide: 18-month data from the European Forsteo Observational Study (EFOS). Calei! Tissue lnt. 2009 Dec;85(6):484-93 19. Lau AN, Ali SH, Sawka AM, Thabane L, Papaioannou A, Gafni A, Adachi JD. lmprovement in health-related quality of life in osteoporosis patients treated with teriparatide. BMC Musculoskelet Disord. 2008 Nov 7;9:151 20. Maugeri D, Russo E, Luca S, Leotta C, Mamazza G, Sorace R, Rizzotto M, Manuele S, Fiare V, Taverna G, Castiglia B, Calitro M. Changes of the quality-of-life under the treatment of severe senile osteoporosis with teriparatide. Arch Gerontol Geriatr. 2009 Jui-Aug;49(1):35-8

Parathormone and physical appearance Sarcopenia: the association with excessive parathormone leveis 21. Visser M, Deeg DJ, Lips P; Longitudinal Aging Study Arnsterdam. Low vitamin D and high parathyroid hormone leveis as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab. 2003 Dec;88(12):5766-72

Obesity, higher fat mass: the association with excessive parathormone leveis 22. Rejnmark L, Vestergaard P, Brot C, Mosekilde L. Parathyroid response to vitamin D insufficiency: relations to bone, body composition and to lifestyle characteristics. Clin Endocrinol (Oxf). 2008 Jul;69(1):29-35.

Parathormone and age-related diseases Mild hypercholesterolemia: the association with excessive parathormone leveis 23. Zanos S, Mitsopoulos E, Sakellariou G. Parathyroid hormone leveis, calcium-channel blockers, and the dyslipidemia of nondiabetic hemodialysis patients. Ren Fail. 2005;27(2):163-9.

Arterial hypertension: the association with excessive parathormone leveis 24. Hjelmesaeth J, Hofso D, Aasheim ET, Jenssen T, Moan J, Hager H, Roislien J, Bollerslev J. Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a cross-sectional study. Cardiovasc Diabetol. 2009 Feb 3;8:7

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Obesily: the improvement with IGF-1 treatmenl 134.Thompson JL, Butterfield GE, Gylfadottir UK, Yesavage J, Marcus R, Hintz RL, Pearman A, Hoffman AR. Effects oi human growth hormone, insulin-like growth factor I, and diel and exercise on body composition oi obese postmenopausal women. : J Clin Endocrinol Metab. 1998 May;83(5):1477-84 135.Laron Z, Anin S, Klipper-Aurbach Y, Klinger B. Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism. Lance!. 1992 May 23;339(8804):1258-61 136.Hayes VY, Urban RJ, Jiang J, Mareei! TJ, Helgeson K, Mauras N. Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects. J Clin Endocrinol Metab. 2001 May;86(5):2211-9

Diabetes: lhe associalion wilh lower IGF-1 leveis 137.Sesti G, Sciacqua A, Scozzafava A, Vatrano M, Angotti E, Ruberto C, Santillo E, Parlato G, Perticone F. Effects oi growth hormone and insulin-like growth factor-1 on cardiac hypertrophy oi hyperlensive patients. J Hypertens. 2007 Feb;25(2):471-7 138.Rasmussen MH, Hvidberg A, Juul A, Main KM, Gotfredsen A, Skakkebaek NE, Hilsted J, Skakkebae NE. Massive weight loss restares 24-hour growth hormone release profiles and serum insulin-like growth factor-1 leveis in obese subjects. J Clin Endocrinol Metab. 1995 Apr;80(4):1407-15 139.Rasmussen MH, Frystyk J, Andersen T, Breum L, Christiansen JS, Hilsted J. The impact oi obesity, fal distribution, and energy restriction on insulin-like growth factor-1 (IGF-1), IGF-binding protein-3, insulin, and growth hormone. Metabolism. 1994 Mar;43(3):315-9 140.Poulos JE, Leggett-Frazier N, Khazanie P, Long S, Sportsman R, MacDonald K, Caro JF. Circulating insulin-like growth factor I concentrations in clinically severe obese patients with and without NIDDM in response to weight loss. Horm Metab Res. 1994 Oct;26(10):478-80

Diabetes: lhe improvemenl with IGF-1 treatment 141.Guier HP, Zapf J, Froesch ER. Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adulls. N Engl J Med. 1987 Jul 16;317(3):137-4 142.Bianda TL, Hussain MA, Keller A, Glatz Y, Schmitz O, Christiansen JS, Alberti KG, Froesch ER. lnsulin-like growth factor-1 in man enhances lipid mobilization and oxidalion induced by a growth hormone pulse. Diabetologia. 1996 Aug;39(8):961-9 143.Kerr D, Tamborlane WV, Rife F, Sherwin RS. Effect oi insulin-like growth factor-1 on lhe responses to and recognition oi hypoglycemia in humans. A comparison with insulin. J Clin lnvest. 1993 Jan;91(1):141-7 144.Vaccarello MA, Diamond FB Jr, Guevara-Aguirre J, Rosenbloom AL, Fielder PJ, Gargosky S, Cohen P, Wilson K, Rosenfeld RG. Hormonal and metabolic effects and pharmacokinetics of recombinant insulin-like growth factor-1 in growth hormone receptor deficiency/Laron syndrome. J Clin Endocrinol Metab. 1993 Jul;77(1):273-80 145.Liu F, Yu M, Zhu Q. Recombinant human IGF-1 prevents type 1 diabetes in female non-obese diabetic mice. Zhonghua Yu Fang Yi Xue Za Zhi. 2000 Sep;34(5):281-3

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Fibromyalgia: the association with lower IGF-1 leveis 146.Samborski W, Stratz T, Schochat T, Mennet P, Müller W. Biochemical changes in fibromyalgia. Z Rheumatol. 1996 May-Jun;55(3):168-73 147.Tander B, Atmaca A, Aliyazicioglu Y, Canturk F. Serum ghrelin leveis but no! GH, IGF-1 and IGFBP-31evels are altered in patients with fibromyalgia syndrome. Joint Bone Spine. 2007 Oc\;74(5):477-81 Rheumatism: the association with lower IGF-1 leveis 148.Lis K. lnsulin-like growth factor 1 and growth hormone as the markers oi osteoarthritis. Chir Narzadow Ruchu Ortop Pol. 2008 Jan-Feb;73(1):49-52 149.Eihassan AM, Adem A, Suliman IA, Mustafa A, Lindgren JU. Prolactin, growth hormone, and IGF-1 in ankles and plasma oi adjuvant arthritic rats. Scand J Rheumatol. 1999;28(6):368-73 Rheumatism: the improvement with IGF-1 treatment 150.Melikoglu MA, Karatay S, Senel K, Akcay F. Association between dynamic exercise therapy and IGF-1 and IGFBP-3 concentrations in lhe patients with rheumatoid arthritis. Rheumatol lnt. 2006 Feb;26(4):309-13 151.Rogachefsky RA, Dean DO, Howell OS, Altman RD. Treatment oi canine osteoarthritis with insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate. Osteoarthritis Cartilage. 1993 Apr;1(2):105-14 Osteoporosis: the association with lower IGF-1 leveis 152.Liu JM, Zhao HY, Ning G, Chen Y, Zhang LZ, Sun LH, Zhao YJ, Xu MY, Chen JL. IGF-1 as an early marker for low bone mass or osteoporosis in premenopausal and postmenopausal women. J Bone Miner Metab. 2008;26(2):159-64 153.Reed BY, Zerwekh JE, Sakhaee K, Breslau NA, Gottschalk F, Pak CY. Serum IGF 1 is low and correlated with osteoblastic surface in idiopathic osteoporosis. J Bone Miner Res. 1995 Aug;10(8):1218-24 154.Ljunghall S, Johansson AG, Burman P, Kampe O, Lindh E, Karlsson FA. Low plasma leveis oi insulin-like growth factor 1 (IGF-1) in male patients with idiopathic osteoporosis. J lntern Med. 1992 Jul;232(1):59-64 155.Aii O, Shim M, Fowler E, Cohen P, Oppenheim W. Spinal bone mineral density, IGF-1 and IGFBP-3 in children with cerebral palsy. Horm Res. 2007;68(6):316-20 Osteoporosis: the improvement with IGF-1 treatment 156.Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith O. Circulating leveis oi IGF-1 directly regulate bone growth and density. J Clin lnvest. 2002 Sep;110(6):771-81 157.Stabnov L, Kasukawa Y, Guo R, Amaar Y, Wergedal JE, Baylink DJ, Mohan S. Effect of insulin-like growth factor-1 (IGF-1) plus alendronate on bone density during puberty in IGF-1-deficient MIDI mice. Bone. 2002 Jun;30(6):909-16 Cancer: the association with lower IGF-1 hormone leveis 158.Lónn S, lnskip PD, Pollak MN, Weinstein SJ, Virtamo J, Albanes O. Glioma risk in relation to serum leveis oi insulin-like growth factors. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):844-6 159.Agurs-Collins T, Adams-Campbell LL, Kim KS, Cullen KJ.Ins ulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women. Cancer Detect Prev. 2000;24(3):199-206 160.Fuhrman B, Barba M, Schünemann HJ, Hurd T, Quattrin T, Cartagena R, Carruba G, Muti P. Basal growth hormone concentrations in blood and lhe risk for prostate cancer: a case-control study. Prostate. 2005 Jul 1;64(2):109-15 161.Woodson K, Tangrea JA, Pollak M, Copeland TO, Taylor PR, Virtamo J, Albanes O. Serum insulin-like growth factor 1: tumor marker or etiologic factor? A prospective study oi prostate cancer among Finnish men. Cancer Res. 2003 Jul 15;63(14):3991-4 162.Palmqvist R, Hallmans G, Rinaldi S, Biessy C, Stenling R, Riboli E, Kaaks R. Plasma insulin-like growth factor 1, insulin-like growth factor binding protein 3, and risk oi colorectal cancer: a prospective study in northern Sweden. Gut. 2002 May;50(5):642-6 163.Lónn S, lnskip PD, Pollak MN, Weinstein SJ, Virtamo J, Albanes O. Glioma risk in relation to serum leveis of insulin-like growth factors. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):844-6 164.Stolzenberg-Solomon RZ, Limburg P, Pollak M, Taylor PR, Virtamo J, Albanes O. lnsulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer

in male smokers. Cancer Epidemiol Biomarkers Prev.

2004 Mar;13(3):438-44 165.Schaffer A, Koushik A, Trottier H, Duarte-Franco E, Mansour N, Arseneau J, Provencher O, Gilbert L, Gotlieb W, Ferenczy A, Coutiée F, Pollak MN, Franco EL; Biomarkers oi Cervical Cancer Risk Study Team . lnsulin-like growth factor-1 and risk oi high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):716-22

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166.Serrano ML, Romero A, Cendales R, SÃi nchez-GÃ3mez M, Bravo MM. Serum leveis of insulin-like growth factor-1 and -11 and insulin-like growth factor binding protein 3 in women with squamous intraepithelial lesions and cervical cancer. Biomedica. 2006 Jun;26(2):258-68 167.Chen C, Lewis SK, Voigt L, Fitzpatrick A, Plymate SR, Weiss NS. Prostate carcinoma incidence in relation to prediagnostic circulating leveis oi insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin. Cancer. 2005 Jan 1 ;103(1):76-84 168.Palmqvist R, Hallmans G, Rinaldi S, Biessy C, Stenling R, Riboli E, Kaaks R. Plasma insulin-like growth factor 1, insulin-like growth facto r binding protein 3, and risk of colorectal cancer: a prospective study in northern Sweden. Gut. 2002 May;50(5):642-6 Longevity: the association with lower IGF-1 leveis 169.Guirnarães SM, Lima EQ, Cipullo JP, Lobo SM, Burdmann EA. Low insulin-like growth factor-1 and hypocholesterolemia as mortality predictors in acute kidney injury in the intensive care unit. Crit Care Med. 2008 Dec;36(12):3165-70 170.Arai Y, Takayama M, Gondo Y, lnagaki H, Yarnarnura K, Nakazawa S, Kojirna T, Ebihara Y, Shimizu K, Masui Y, Kitagawa K, Takebayashi T, Hirose N. Adipose endocrine function, insulin-like growth factor-1 axis, and exceptional survival beyond 100 years of age. J Gerontol A Biol Sei Med Sei. 2008 Nov;63(11):1209-18 171.Brugts MP, van den Beld AW, Hofland LJ, van der Wansern K, van Koetsveld PM, Frystyk J, Lamberts SW, Janssen JA. Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality. J Clin Endocrinol Metab. 2008 Jul;93(7):2515-22 172.Petretta M, Colao A, Sardu C, Scopacasa F, Marzullo P, Pivonello R, Fontanella L, de Caterina M, de Sirnone A, Bonaduce D. NT-proBNP, IGF-1 and survival in patients with chronic heart failure. Growth Horrn IGF Res. 2007 Aug;17(4):288-96 173.Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in rnen with chronic heart failure: prevalence and detrimental irnpact on survival. Circulation. 2006 Oct 24; 114(17): 1829-37 174.Rasmuson T, Grankvist K, Jacobsen J, Olsson T, Ljungberg B. Serurn insulin-like growth factor-1 is an independent predictor of prognosis in patients with renal cell carcinoma. Acta Oncol. 2004;43(8):744-8 175.Denti L, Annoni V, Cattadori E, Salvagnini MA, Visioli S, Merli MF, Corradi F, Ceresini G, Valenti G, Hoffrnan AR, Ceda GP. lnsulin-like growth factor 1 as a predictor of ischernic stroke outcorne in the elderly. Am J Med. 2004 Sep 1;117(5):312-7 176.0nenli-Mungan N, Yildizdas D, Yapicioglu H, Topaloglu AK, Yüksel B, Ozer G. Growth hormone and insulin-like growth factor 1 leveis and their relation to survival in children with bacterial sepsis and septic shock. J Paediatr Child Health. 2004 Apr;40(4):221-6 177.Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D. The prospective association of serum insulin-like growth factor I (IGF-1) and IGF-binding protein-1 leveis with ali cause and cardiovascular disease rnortality in older adults: lhe Rancho Bernardo Study. J Clin Endocrinol Metab. 2004 Jan;89(1):114-20 178.Vasan RS, Sullivan LM, D'Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D, Wilson PW. Serum insulin­ like growth factor I and risk for heart failure in elderly individuais without a previous myocardial infarction: the Framingharn Heart Study. Ann lntern Med. 2003 Oct 21;139(8):642-8 179.Roubenoff R, Parise H, Payette HA, Abad LW, D'Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB. Cy1okines, insulin-like growth factor 1, sarcopenia, and mortality in very old cornmunity-dwelling rnen and wornen: lhe Framingham Heart Study. Arn J Med. 2003 Oct 15;115(6):429-35 180.Roubenoff R, Parise H, Payette HA, Abad LW, D'Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB. Cy1okines, insulin-like growth factor 1, sarcopenia, and rnortality in very old community-dwelling men and women: the Framingham Heart Study. Arn J Med. 2003 Oct 15;115(6):429-35 181.Ruiz-Torres A, Soares de Melo Kirzner M. Ageing and longevity are related to growth hormone/insulin-like growth factor-1 secretion. Gerontology. 2002 Nov-Dec;48(6):401-7 182.Fernández-Reyes MJ, Alvarez-Ude F, Sánchez R, Mon C, lglesias P, Díez JJ, Vázquez A. lnflamrnation and malnutrition as predictors of mortality in patients on hernodialysis. J Nephrol. 2002 Mar-Apr;15(2):136-43 183.Caregaro L, Alberino F, Arnodio P, Merkel C, Angeli P, Plebani M, Bolognesi M, Gatta A. Nutritional and prognostic significance of insulin-like growth factor 1 in patients with liver cirrhosis. Nutrition. 1997 Mar;13(3):185-90. Longevity: the improvement with IGF-1 treatment 184.Serose A, Salrnon A, Fiszman MY, Frornes Y. Short-term treatrnent using insulin-like growth factor-1 (IGF-1) improves life expectancy of the delta-sarcoglycan deficient hamster. J Gene Med. 2006 Aug;8(8):1048-55

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IGF-1 Diagnosis: Clinicai findings of IGF-1 deficiency 185.Ying YQ, Wei H, Cao LZ, Lu JJ, Luo XP. Clinicai features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family. Zhongguo Dang Dai Er Ke Za Zhi. 2007 Aug;9(4):335-8 186.Yang C, Chen JY, Lai CC, Lin HC, Yeh GC, Hsu HH. Clinicai, biochemical and molecular investigations of three Taiwanese children with Laron syndrome. J Pediatr Endocrinol Metab. 2004 Feb;17(2):165-71 187.Laron Z, Klinger B. Laron syndrome: clinicai features, molecular pathology and treatment. Horm Res. 1994;42(45):198-202 188.Savage MO, Blum WF, Ranke MB, Postei-Vinay MC, Cotterill AM, Hall K, Chatelain PG, Preece MA, Rosenfeld RG. Clinicai features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab. 1993 Dec;77(6):1465-71 189.Rosenbloom AL, Savage MO, Blum WF, Guevara-Aguirre J, Rosenfeld RG. Clinicai and biochemical characteristics

of

growth hormone receptor

deficiency

(Laron

syndrome). Acta

Paediatr Suppl.

1992

Sep;383:121-4 190.Guevara-Aguirre J, Rosenbloom AL, Vaccarello MA, Fielder PJ, de la Vega A, Diamond FB Jr, Rosenfeld RG. Growth hormone receptor deficiency (Laron syndrome): clinicai and genetic characteristics. Acta Paediatr Scand Suppl. 1991;377:96-103 191.Meyer S, lpek M, Keth A, Minnemann T, von Mach MA, Weise A, lttner JR, Nawroth PP, Plóckinger U, Stalla GK, Tuschy U, Weber MM, Kann PH; German KIMS Board; German KIMS Pharmacogenetics Study Group. Short stature and decreased insulin-like growth factor I (IGF-1)/growth hormone (GH)-ratio in an adult GH­ deficient patient pointing to additional partia! GH insensitivity due to a R179C mutation of lhe growth hormone receptor. Growth Horm IGF Res. 2007 Aug;17(4):307-14

Serum IGF-1 tests 192.Anckaert E, Schiettecatte J, Vanbesien J, Smitz J, Velkeniers B, De Schepper J. Variability among tive different commercial IGF-1 immunoassays in conditions of childhood-onset GH deficiency and GH therapy. Acta Clin Belg. 2006 Nov-Dec;61(6):335-9 193.Granada ML, Ulied A, Casanueva FF, Pico A, Lucas T, Torres E, Sanmartí A. Serum IGF-1 measured by four different immunoassays in patients with adult GH deficiency or acromegaly and in a contrai population. Clin Endocrinol (Oxf). 2008 Jun;68(6):942-50 194.Milani D, Carmichael JD, Welkowitz J, Ferris S, Reitz RE, Danoff A, Kleinberg DL. Variability and reliability of single serum IGF-1 measurements: impact on determining predictability of risk ratios in disease development. J Clin Endocrinol Metab. 2004 May;89(5):2271-4 195.Rosenfeld RG, Buckway C, Selva K, Pratt KL, Guevara-Aguirre J. lnsulin-like growth factor (IGF) parameters and tools for efficacy: lhe IGF-1 generation test in children. Horm Res. 2004;62 Suppl 1:37-43

Corrective IGF-1 Therapy IGF-1 medications: mecasermin 196.Mecasermin rinfabate: insulin-like growth factor-1/insulin-like growth factor

binding protein-3, mecaserimin

rinfibate, rhiGF-1/rhiGFBP-3. Drugs R D. 2005;6(2):120-7 197.Fintini D, Brufani C, Cappa M. Profile of mecasermin for lhe long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag. 2009 Jun;5(3):553-9 198.Williams RM, McDonald A, O'Savage M, Dunger DB. Mecasermin rinfabate: rhiGF-1/rhiGFBP-3 complex: iPLEX. Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):311-24 199.Kemp SF, Fowlkes JL, Thrailkill KM. Efficacy and safety of mecasermin rinfabate. Expert Opin Biol Ther. 2006 May;6(5):533-8 200.Kemp SF. lnsulin-like growth factor-1 deficiency in children with growth hormone insensitivity: current and future treatment options. BioDrugs. 2009;23(3):155-63

Administration of IGF-1 partially reduceds growth hormone release to GHRH 201.Maccario M, Tassone F, Gianotti L, Lanfranco F, Grottoli S, Arvat E, Muller EE, Ghigo E. Effects of recombinant human insulin-like growth factor I administration on the growth hormone response to GH-releasing hormone in obesity. J Clin Endocrinol Metab. 2001 Jan;86(1):167-71 (a low rh/GF-1 dose inhibits the somatotroph

responsiveness to GHRH in obese as we/1 as in normal subjects, indicating that somatotroph sensitivity to the inhibitory effect ot rh/GF-1 is preserved in obesity)

584

Hormones that next to growth hormone increase the production and/or serum levei of IGF-1

/nsulin: 202.Siawik M, Schories M, Busse Grawitz A, Reincke M, Petersen KG. Treatment with insulin glargine does not suppress serum IGF-1. Diabet Med. 2006 Jul;23(7):814·7

Thyroid hormones: 203.Bena G, Rapa A, Beccardo G, Silvestre L, Chiorboli E. IGF-1 and IGFBP in cengenital and acquired hypethyreidism after leng-term replacement treatment. Minerva Endocrinel. 1999 Jun;24(2):51-5 204.Bena G, Rapa A, Boccarde G, Silvestre L, Chiorboli E. IGF-1 and IGFBP-3 in cengenital and acquired hypothyreidism a!ter leng-term replacement treatment. Panminerva Med. 1998 Jun;40(2):103-6 Factors that reduce the production and/or serum leveis of IGF-1: antihypertensives 205.Jalil JE, Ebensperger R, Meléndez J, Acevede E, Sapag-Hagar M, Genzález-Jara F, Gálvez A, Pérez-Montes V, Lavandere S. Elfects ef antihypertensive treatment en cardiac IGF-1 during preventien of ventricular hypertrephy in the rat. Life Sei. 1999;64(18):1603-12 206.Díez J, Laviades C. lnsulin-like grewth facter-1 and cardiac mass in essential hypertensien: comparative elfects of captopril, lisinepril and quinapril. J Hypertens Suppl. 1994 Jui;12(4):S31-6 Studies that suggest that associating IGF-1 to GH treatment provides better results than either treatment alone 207.Thompsen JL, Butterfield GE, Gylfadottir UK, Yesavage J, Marcus R, Hintz RL, Pearman A, Holfman AR. Elfects ef human growth hermene, insulin-like growth factor I, and diet and exercise en bedy cemposition of obese postmenopausal wemen. : J Clin Endocrinel Metab. 1998 May;83(5):1477-84 (The largesl weighl lass was abserved in lhe GH plus /GF-1 graup) 208.Dubuis JM, Deal C, Tsagaroulis P, Clark RG, Van Vliet G. Elfects of 14-day infusions of grewth hormene and/or insulin-like growth facter I on the obesity of growing Zucker rats. Endocrinelogy. 1996 Jul;137(7):2799-806 (In grawing genelically abese rals the cambinatian af /GF-1 and GH reduces inguinal tal beller lhan eilher afane)) 209.Ciark RG, Mortensen DL, Carlsson LM, Carlsson B, Carmignac D, Robinson IC. The obese growth hormone (GH)-deficient dwarf rat: bedy fat responses to patterned delivery of GH and insulin-like growth factor-1. Endecrinology. 1996 May;137(5):1904-12 (In rats wilh abesily induced by a high tal diel lhe cambinatian af /GF-

1 and GH reduces weight better lhan eilher trealment afane) 210.Mendenhall CL, Roselle GA, Gartside P, Grossman CJ. Effects of recombinant human insulin-like growth factor1 and recombinant human growth hermene en anabolism and immunity in calorie-restricted alceholic rats. Alcohol Clin Exp Res. 1997 Feb;21(1):1-10 IGF-1 treatment: side effects, complications 211.Rosenbloem AL. Mecasermin (recombinant human insulin-like growth factor 1). Adv Ther. 2009 Jan;26(1 ):40-54 212.Torjusen E, Calderon J, Rivkees SA. Anaphylactic reaction to recombinant insulin-like growth factor-1. J Pediatr Endocrinol Metab. 2008 Apr;21(4):381-4

585

IGF-1 and/or GROWTH HORMONE DEFICIENCIES with SERUM IGF-1 LEVELS within the REFERENCE RANGE: TO TREAT OR NOT TO TREAT?

Should individuais with symptoms and signs of growth hormone and/or IGF-1 deficiencies, but serum IGF-1 leveis within the normal reference range for their age, be treated with growth hormone andlor IGF-1?

Old view IGF-1 deficiency is diagnosed upon laboratory tests with serum IGF-1 leveis below lhe lower limil of lhe reference range. People wilh a serum IGF-11evel wilhin lhe reference range of their age group are healthy and have no IGF-1 deficiency. Scientific view Milder degrees of GH/IGF-1 deficiency exist with serum leveis of IGF-1 within the reference range. People who have serum leveis of IGF-1 within lhe reference range (situaled in lhe lower lhree quarters, lower two thirds, lower half, lower lhird, lower forth, lower fifth or lower 10% of lhe reference range) have a significanl increased risk of various types of disease and death. This suggesls that lhey suffer from a degree of IGF-1 failure, as lhe increased risk may be reduced or prevenled by increasing IGF-1 leveis in lhe upper two thirds, upper half, upper third or upper quarter of lhe reference range lhrough trealment wilh growth hormone or IGF-1 or bolh. IGF-1 deficiency may be diagnosed upon laboralory lests with serum leveis of IGF-1 below lhe average levei (lhe IGF-1 levei halfway situated belween lhe upper and lower limit of lhe reference range). The clinicai evaluation (checking for symptoms and physical signs of IGF-1 deficiency or sufficiency, which reflect lhe final effects of IGF-1 in lhe largel cells is an essenlial aid to lhe diagnosis. •

People with a serum IGF-1 levei within lhe reference range are not necessarily heallhy and may suffer from IGF-

1 dysfunction and safely benefit from IGF-1 treatment

S tudies that show that individuais who are at or below the 901h percentile of serum

IGF-1 or growth hormone

leveis have an increased risk of disease or dying: Mos! studies that show an inverse association between /GF-1 leveis and lhe risk of disease/dying belong to this group Higher risk of dying 1.

Fernández-Reyes MJ, Alvarez-Ude F, Sánchez R, Mon C, lglesias P, Díez JJ, Vázquez A. lnflammation and malnutrition as predictors of mortality in patients on hemodialysis. J Nephrol. 2002 Mar-Apr;15(2):136-43. Servicio de Nefrología, H. General, Segovia, Spain. [email protected] (Significant inverse association of

2.

serum /GF-1 and mortality

=>

increased mortality in hemodialysis patients at /ower serum /GF-1 leveis)

Petretta M, Colao A, Sardu C, Scopacasa F, Marzullo P, Pivonello R, Fontanella L, de Caterina M, de Simone A, Bonaduce D. NT-proBNP, IGF-1 and survival in patients with chronic heart failure. Growth Horm IGF Res. 2007 Aug;17(4):288-96. Department of Internai Medicine, Cardiology, Heart and lmmunological Sciences, Section of Internai Medicine, University of Naples Federico 11, ltaly. (Significant inverse association of serum IGF-1 and mortality

=>

higher mortality in chronic heart failure patients at /ower serum /GF-1, especially at /ower /GF-1/GH

ratio leveis) 3.

Denti L, Annoni V, Cattadori E, Salvagnini MA, Visioli S, Merli MF, Corradi F, Ceresini G, Valenti G, Hoffman AR,

Ceda GP. lnsulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. Am J Med. 2004

Sep 1 ;117(5):312-7. Department of Internai Medicine and Biomedical Sciences, Section of Geriatrics, Universily

of Parma, Parma, ltaly. (/GF-1 leveis and lhe ratio IGF-1/IGF-BP-3 (The bioavailable IGF-1) was inverse/y related to increased mortality and other forms of poor outcome in stroke patients at 3 and 6 months after stroke:

4.

for each 20-ng/mL increase of /GF-1 lhe risk of poor outcome (mainly death) decreased by 30%) Roubenoff R, Parise H, Payette HA, Abad LW, D'Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: lhe Framingham Heart Study. Am J Med. 2003 Oct 15;115(6):429-35. United States Department of Agriculture Jean Mayer Human Nutrition Research Cenler on Aging at Tufts University, Boston, Massachusetts, USA. [email protected] (higher /GF-1 /eve/s were inverse/y associated with reduced mortality during lhe next 2 years in very o/d men and women aged 72 to 92 years at baseline)

586

Higher risk of dyslipidemia Higher triglycerides in hea/thy men and women aged 55-80 years 5.

Janssen JA, Stolk RP, Pois HA, Grobbee DE, Lamberts SW. Serum totai iGF-1, free IGF-1, and IGFB-1 leveis in an elderly population: relation to cardiovascular risk factors and disease. Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):277-82. Department of Internai Medicine 111, Erasmus University, Rotterdam, The Netherlands. (The

serum leveis of free /GF-1 were inverse/y related to higher serum triglycerides in healthy men and women aged 55-80 years) Higher risk of atherosclerosis (atherosclerotic plaques, increased carotid ntima media thickness) in healthy men and women aged 55-80 years

6.

Janssen JA, Stolk RP, Pois HA, Grobbee DE, Lamberts SW. Serum totai iGF-1, free IGF-1, and IGFB-1 leveis in an elderly population: relation to cardiovascular risk factors and disease. Arterioscler Thrornb Vasc Biol. 1998 Feb;18(2):277-82. Department of Internai Medicine 111, Erasmus University, Rotterdam, The Netherlands. (The

serum leveis of free /GF-1 were inversely related to a higher risk of atherosclerotic plaques in lhe carotid arteries in healthy men and women aged 55-80 years) In GH-deficient and normal persons 7.

Leonsson M, Hulthe J, Johannsson G, Wiklund O, Wikstrand J, Bengtsson BA, Oscarsson J. lncreased lnterleukin-6 leveis in pituitary-deficient patients are independently related to their carotid intirna-rnedia thickness. Clin Endocrinol (Oxf). 2003 Aug;59(2):242-50. Research Centre for Endocrinology and Metabolism, University Hospital, GÃ1lteborg, Sweden. [email protected] (Significant inverse association of serum IGF-1 and atherosclerosis => Higher intima media thickness of common carotid artery in GH-deficient and normal persons at /ower serum /GF-1 leveis ) Sahlgrenska

In elder/y subjects 8.

Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, ldei T, lguchi T. Relationship between serum insulin-like growth factor-1 leveis and Alzheimer's disease and vascular dementia. J Am Geriatr Soe. 2005 Oct;53(10):174853.

Department

of

Biochemistry,

Showa

University

School

of

Medicine,

Tokyo,

Japan.

[email protected] (Serum IGF-1 concentrations had a significant inverse correlation with carotid

intima media thickness in Japanese elderly subjects) Higher CRP in metabolic syndrome patients 9.

Efstratiadis G, Tsiaousis G, Athyros VG, Karagianni D, Pavlitou-Tsiontsi A, Giannakou-Darda A, Manes C. Total serum insulin-like growth factor-1 and C-reactive protein in metabolic syndrome with or without diabetes. Angiology. 2006 May-Jun;57(3):303-11. Department of Nephrology, Hospital, Thessaloniki, Greece. [email protected]

Aristotelian University,

Hippocration

(CRP leveis showed a significant negative correlation with

total serum /GF-1 in normal adults and subjects with metabo/ic syndrome or type 2 diabetes mellitus, suggesting a close relationship with cardiovascu/ar disease. The corre/ation between high CRP and low total /GF-1 might indica/e that an increase in CRP leveis may we/1 be a key factor for the reduction in /GF-1 concentrations) In women with hypopituitarism 10. Sesmilo G, Miller KK, Hayden O, Klibanski A. lnflarnmatory cardiovascular risk markers in women with hypopituitarism. J Clin Endocrinol Metab. 2001 Dec;86(12):5774-81. Neuroendocrine Uni!, Massachusetts General Hospital and Harvard Medicai School, Boston, Massachusetts 02114, USA.

with /GF-1 (P

=

(CRP correlated negative/y

0.010))

lncreased carotid arterial intima media thickness in elderly men 11. van den Beld AW, Bois ML, Janssen JA, Pois HA, Lamberts SW, Grobbee DE. Endogenous hormones and carotid atherosclerosis in elderly men. : Am J Epidemiol. 2003 Jan 1;157(1):25-31. Department of Internai Medicine, Erasmus University Medicai Center Rotterdam, Rotterdam, The Netherlands. [email protected] (Serum free IGF-1 was inversely related to intima-media thickness in e/derly men)

587

Higher blood pressure in healthy subjects and chronic kidney failure patients 12. Aitman TJ, Palmer RG, Loftus J, Ansell BM, Royston JP, Teale JD, Clayton RN. Serum IGF-IIevels and growth failure in juvenile chronic arthritis. Clin Exp Rheumatol. 1989 Sep-Oct;7(5):557-61. Clinicai Research Centre, Harrow, Middlesex, U.K. (Significant inverse association of serum /GF-1 and b/ood pressure

=>

at lower serum

/GF-1 leveis, there are higher risks of high systolic blood pressure in healthy subjects and chronic kidney failure patients and of higher diastolic blood pressure in chronic kidney failure patients (the association is independent of age, but not of BMJ)) Higher risk of angina pectoris or myocardial infarction in healthy men and women aged 55-80 years 13. Janssen JA, Stolk RP, Pois HA, Grobbee DE, Lamberts SW. Serum totai iGF-1, free IGF-1, and IGFB-1 leveis in an elderly population: relation to cardiovascular risk factors and disease. Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):277-82. Department o! Internai Medicine 111, Erasmus University, Rotterdarn, The Netherlands. {The serum leveis of free /GF-1 were inversely related a higher risk of history of angina pectoris or of a myocardial infarction on the ECG in healthy men and women aged 55-80 years) lncreased severity of heart failure in chronic heart failure patients 14. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental irnpact on survival. Circulation. 2006 Oct 24;114(17):1829-37. Cardiology Department, Military Hospital, ui. Weigla 5, 50981 Wroclaw, Poland. [email protected] Worse TNM (tumor-node-metastasis) stage in breast cancer patients 15. Agurs-Collins T, Adarns-Campbell LL, Kim KS, Cullen KJ.Ins ulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women. Cancer Detect Prev. 2000;24(3):199-206. Howard University Cancer Center, Division o! Epidemiology and Cancer Contrai, Washington, DC 20012, USA. (Significant inverse association of serum /GF-1 and cancer stage: higher TNM (tumor-node-metastasis) stage at lower serum IGF-1 in breast cancer patients, despite a higher serum /GF-1 in BC patients) Hyperglycemia in patients with the metabolic syndrome 16. Maison P, Balkau B, Souberbielle JC, Cunin P, Vol S, Macquin-Mavier I, Eschwege E; D. E. S. I. R. Study Group. Evidence for distinct effects o! GH and IGF-1 in the metabolic syndrome. Diabet Med. 2007 Sep;24(9):1012-8. Service de Pharmacologie Clinique, AP-HP, Hôpital Henri Mondar, Université Paris XII, Créteil, France. [email protected] .(Serum /GF-1 showed a negative correlation with the /g/ucose factor. In women, GH showed a strong negative correlation with the obesitylg/ucose factor) Diabetes in type 1 diabetic patients 17. Dills DG, Moss SE, Klein R, Klein BE, Davis M. ls insulin-like growth factor I associated with diabetic retinopathy? Diabetes. 1990 Feb;39(2):191-5. Department o! Medicine, University o! Wisconsin School of Medicine, Madison 53792. (Significant inverse association of serum IGF-1 and diabetes in a /arge population­ based study of 682 early-onset (diagnosed before 30 yr of age) adult insulin-taking diabetic subjects significant negative correlations between /GF-1 leveis and age (P glycosylated hemogtobin (P < 0.05))

<

0.0001), duration of disease (P

<

0.0001), and

Pregnancy-induced diabetes in pregnant women 18. Qiu C, Vadachkoria S, Meryman L, Frederick 10, Williams MA. Maternal plasma concentrations o! IGF-1, IGFBP-1, and C-peptide in early pregnancy and subsequent risk o! gestational diabetes mellitus. Am J Obstet Gynecol. 2005 Nov;193(5):1691-7. Center for Perinatal Studies, Swedish Medicai Center, Seattle, WA 98122, USA. [email protected] (Free /GF-1 were inverse/y associated with gestational diabetes mellitus risk) Higher body mass index, weight In normal boys 19. Martha PM, Gorman KM, Blizzard RM, Rogai AD, Veldhuis JD. Endogenous growth hormone secretion and clearance rales in normal boys, as determined by deconvolution analysis: relationship to age, pubertal status,

588

and body mass. J Clin Endocrinol Metab. 1992 Feb;74(2):336-44. Department oi Pediatrics, University of Virgínia Health Sciences Center, CharlottesviiiE;. (Higher body mass index in normal boys at various stages of

puberty and young adulthood (7-27 yrs) at /ower 24-h serum GH and serum /GF-1. The 24-h GH secretion rate varied inversely with the subjects' body mass index SD score (r P < 0.01), suggesting that differences in body mass, even within the normal range, contribute to the wide variability in daily GH secretion rates among normally growing children.) In adults 20. Henderson KD, Goran Ml, Kolonel LN, Henderson BE, Le Marchand L. Ethnic disparity in the relationship between obesity and plasma insulin-like growth factors: the multiethnic cohort. Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2298-302. Keck School oi Medicine, University oi Southern California, Los Angeles, California 90033-0800, USA. [email protected] (Plasma IGF-1 leveis declined with increasing BMI most

dramatically in Latinos and Japanese the adjusted least-squares mean /GF-1/eve/s in ng/mL for BMI 29.99, and >Or=30 were 184.6, 147.7, and 132.7)

<

25, 25 to

Greater number of metabolic syndrome features 21. Efstratiadis G, Tsiaousis G, Athyros VG, Karagianni D, Pavlitou-Tsiontsi A, Gíannakou-Darda A, Manes C. Total serum insulin-like growth factor-1 and C-reactive protein in metabolic syndrome with or without diabetes. Angiology. 2006 May-Jun;57(3):303-11. Department oi Nephrology, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece. [email protected] (Higher metabolic syndrome features at /ower total serum

/GF-1 a/most linear re/ationship with the number of metabolic syndrome components) Obesity

22. Maison P, Balkau B, Souberbielle JC, Cunin P, Vol S, Macquin-Mavier I, Eschwege E; D. E. S. I. R. Study Group. Evidence for distinct effects of GH and IGF-1 in the metabolic syndrome. Diabet Med. 2007 Sep;24(9):1012-8. Service de Pharmacologie Clinique, AP-HP, Hôpital Henri Mondor, Université Paris XII, Créteil, France. [email protected] (Serum /GF-1showed a negative correlation with obesity)

Higher visceral fat mass 23. Marin P, Kvist H, Lindstedt G, Sjõstrõm L, Bjõrntorp P. Low concentrations of insulin-like growth factor-1 in abdominal obesity. In! J Obes Relat Metab Disord. 1993 Feb;17(2):83-9. Department of Medicine I, Sahlgren's Hospital, University of Gõteborg, Sweden. (/GF-1 was negative/y correlated with visceral fat mass (r 0.40), =

independently of subcutaneous and total fat mass) Lower immunity in children affected with HIV 24. Panamonta O, Kosalaraksa P, Thinkhamrop B, Kirdpon W, lngchanin C, Lumbiganon P. Endocrine function in thai children infected with human immunodeficiency vírus. J Pediatr Endocrinol Metab. 2004 Jan;17(1):33-40. (A

lower serum /GF-1 is associated with a lower CD4+ percentage in children affected with HIV, implicating that immunity is lower at /ower /GF-1 leveis) Lower stature in children with arthritis 25. Aitman TJ, Palmer RG, Loftus J, Ansell BM, Royston JP, Teale JD, Clayton RN. Serum IGF-IIevels and growth failure in juvenile chronic arthritis. Clin Exp Rheumatol. 1989 Sep-Oct;7(5):557-61. Clinicai Research Centre, Harrow, Míddlesex, U.K. (Height was significantly correlated with serum IGF-1 leveis (rs 0.49; p 0.008); =

height velocity was significantly, although less strongly corre/ated with /GF-f fevels (rs

=

0.41; p

=

=

0.027))

Lower bone mineral density (femoral neck) in pre- and postmenopausal women with endogenous subclinical hyperthyroidism

26. Fõldes J, Lakatos P, ZsadÃjnyi J, HorvÃjth C. Decreased serum IGF-1 and dehydroepiandrosterone sulphate may be risk factors for the development of reduced bone mass in postmenopausal women with endogenous subclinical hyperthyroídism. Eur J Endocrinol. 1997 Mar;136(3):277-81. First Department of Medicine, Semmelweis University, Budapest, Hungary. (Serum IGF-1/eve/s correlated with BMD (femoral neck, P < 0.05)

in pre- and postmenopausa/ women with endogenous subclinical hyperthyroidism)

589

Osteoporotic bone fractures in postmenopausal women 27. Gamero P, Sornay-Rendu E, Delmas PD. Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women. Lance!. 2000 Mar 11;355(9207):898-9. (Decreased serum concentrations of IGF-1

were strongly associated with an increased risk of osteoporotic fractures independently of bane-mineral density) Higher risk of cognitive decline in healthy elderly men 28. Kalmijn S, Janssen JA, Pois HA, Lamberts SW, Breteler MM. A prospective study on circulating insulin-like growth factor I (IGF-1), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab. 2000 Dec;85(12):4551-5. Departments of Epidemiology and Biostatistics, Erasmus Medicai Center Rotterdam, 3000 DR Rotterdam, The Netherlands. (Higher risk of cognitive decline in chronical/y institutionalized healthy e/derly

men at lower total serum IGF-1 and total serum /GF-11/GFBP-3 ratio) Dementia, delirium in elderly patients 29. Abbasi AA, Drinka PJ, Mattson DE, Rudman D. Low circulating leveis of insulin-like growth factors and testosterone in chronically institutionalized elderly men. J Am Geriatr Soe. 1993 Sep;41(9):975-82. Department of Medicine, Medicai College oi Wisconsin, Milwaukee. (Higher risk of dementia in chronically institutionalized

elderly men at /ower serum /GF-1 /eve/s) 30. Wilson K, Broadhurst C, Diver M, Jackson M, Mottram P. Plasma insulin growth lactor-1 and incident delirium in older people. lnt J Geriatr Psychiatry. 2005 Feb;20(2):154-9. Elderly Mental Health Academic Unit, University oi

(+22% higher risk of for incident delirium in elderly patients aged 75 & over admitted to an acute medica/ ward at /ower total serum IGF-1 - a protective cytokine released by brain cel/s in response to insu/t)

Liverpool, Liverpool, UK. [email protected]

Rectal cancer in men and women 31. Palmqvist R, Hallmans G, Rinaldi S, Biessy C, Stenling R, Riboli E, Kaaks R. Plasma insulin-like growth factor 1, insulin-like growth lactor binding protein 3, and risk oi colorectal cancer: a prospective study in northern Sweden. Gut. 2002 May;50(5):642-6. Department of Medicai Biosciences, Pathology, UmeÃ)j( University, SE-901 87 Umeã,Sweden. (Rectal cancer risk was inversely related to leveis of IGF-1 (Ors 1.00, 0.45, 0.33, 0.33; p=0.09)

in men andwomen who developed cancers of the co/on or rectum and matched contrais) Studies that show that subjects who are at or below the 901h percentile of serum growth hormone leveis have an increased risk of disease or dying: this includes most studies that show an inverse association between GH leveis and the risk of the following diseases: Higher body mass index, insulin and obesity markers in adolescent boys and girls

32. Molero-Conejo E, Morales LM, Fernà i ndez V, Raleigh X, Casanova A, Connell L, GÃ3mnez ME, Ryder E, Campos G. Serum insulin, leptin and growth hormone leveis are associated with body mass index and obesity

index in adolescents. Arch Latinoam Nutr. 2006 Mar;56(1):29-35. Instituto de lnvestigaciones CIÃnicas Dr. Américo Negrette,

SecciÃ3n de BioquÃmica, Facultad de Medicina.

Universidad dei Zulia, Maracaibo,

Venezuela (Higher body mass index and obesity index in adolescent boys and girls (13-18 years) at /ower serum

growth hormone. lnsulin and obesity markers were negatively associated with growth hormone leve/) Obesity and hyperglycemia 33. Maison P, Balkau B, Souberbielle JC, Cunin P, Vol S, Macquin-Mavier I, Eschwãge E; the D. E. S. I. R. Study Group . Evidence for distinct effects oi GH and IGF-1 in lhe metabolic syndrome. Diabet Med. 2007 2007 Sep;24(9):1012-8 Service de Pharmacologie Clinique, and Unité de Recherche Clinique, AP-HP, Hôpital Henri Mondor, Université ParisXII, Créteil, France .(Serum GH showed a strong negative correlation with the

obesity!glucose factor)

Studies that show that subjects who are at or below the 67'h percentile (in the lower two tertilesl of serum IGF-1 leveis have an increased risk of the following disease Metabolic X syndrome in middle-aged men with a lamily history oi type 2 diabetes 34. Tong PC, Ho CS, Yeung VT, Ng MC, So WY, Ozaki R, Ko GT, Ma RC, Poon E, Chan NN, Lam CW, Chan JC. Association of testosterone, insulin-like growth lactor-1, and C-reactive protein with metabolic syndrome in

590

Chinese middle-aged men with a family history of type 2 diabetes. J Clin Dec;90(12):6418-23.

Department of Medicine and Therapeutics,

Endocrinol

Metab.

2005

School of Public Health, The Chinese

University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong. [email protected]

(Clinicai

characteristics,frequency of metabolic X syndrome increased,with declining tertiles of IGF-1 in Chinese middle­

aged men with a family history of type 2 diabetes aged 39.1)

Studies that show that subjects who are at or below the 801h percentile (in the lower four quintiles) of serum IGF-1 leveis have an increased risk of dying lschemic heart disease mortality in older adults 35. Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D. The prospective association of serum insulin-like growth factor I (IGF-1) and IGF-binding protein-1 leveis with ali cause and cardiovascular disease mortality in older adults: lhe Rancho Bernardo Study. J Clin Endocrinol Metab. 2004 Jan;89(1):114-20. Department of Family and Preventive Medicine, University of California-San Diego School of Medicine, La Jolla, California 92093-0607.(/ncreasing ischemic heart disease mortality across decreasing IGF-1 quintiles in o/der adults 633 men and 552 nonestrogen-using postmenopausal women, aged 51-98 yr (mean, 74 year); The relative risk of ischemic heart disease mortality was 38% higher for every 40 nglml (1 SO) decrease in JGF-1.)

Studies that show that subjects who are at or below the 801h percentile (in the lower four guintilesl of serum growth hormone leveis have an increased risk of the following disease: Prostate cancer 36. Fuhrman B, Barba M, Schünemann HJ, Hurd T, Quattrin T, Cartagena R, Carruba G, Muti P. Basal growth hormone concentrations in blood and lhe risk for prostate cancer: a case-control study. Prostate. 2005 Jul 1;64(2):109-15. Department of Social and Preventive Medicine, University ai Buffalo, State University of New York, Buffalo, NY 14214, USA. (Jncreasing prostate cancer risk across decreasing GH quintiles in men, aged 4585 years )

Studies that show that subjects who are at or below the 751h percentile (in the lower three guartiles) of serum IGF-1 leveis have an increased risk of the following diseases: Arterial hypertension in normal men and women aged 30 to 62 years 37. Hunt KJ, Lukanova A, Rinaldi S, Lundin E, Nora! T, Palmqvist R, Stattin P, Riboli E, Hallmans G, Kaaks R. A potential inverse association between insulin-like growth factor I and hypertension in a cross-sectional study. Ann Epidemiol. 2006 Jul;16(7):563-71. Division of Clinicai Epidemiology, University of Texas Health Science Center, San Antonio, TX, USA. (There was a stepwise inverse graded association between increasing /GF-1 quartile and hypertension: the risk of (especially diastolic) hypertension in normal men and women aged 30 to 62 years in the lower quartile was two-fold higher than in the optimal upper quartile)

lschemic heart disease, especially in subjects with an IGF-1 in lhe lower quartile and IGF-BP-3 in lhe upper quartile 38. Juul A, Scheike T, Davidsen M, Gyllenborg J, JÃ,rgensen T. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002 Aug 20;106(8):939-44. [email protected]

Department

(A

of

Growth

and

Reproduction,

Rigshospitalet,

Copenhagen,

Denmark.

high-risk population with Jow /GF-1 and high /GFBP-3 leveis was tound that had a

significantly and markedly 4-fo/d higher risk of ischemic heart disease (lHO) compared with the index group. Subjects in the low /GF-1 quartile had a significantly higher risk of lHO during the 15-year tollow-up period, with a relative risk) of 1.94 (95 of lHO compared with the high IGF-1 quartile group. Conversely, Individuais in the high /GFBP-3 quartile group had an adjusted RR of 2.16 of having lHO.)

Hyperglycemia in normal men and women aged 30 to 62 years 39. Hunt KJ, Lukanova A, Rinaldi S, Lundin E, Nora! T, Palmqvist R, Stattin P, Riboli E, Hallmans G, Kaaks R. A potential inverse association between insulin-like growth factor I and hypertension in a cross-sectional study. Ann Epidemiol. 2006 Jul;16(7):563-71. Division of Clinicai Epidemiology, University of Texas Health Science Center, San Antonio, TX, USA. (There was a stepwise inverse graded association between increasing IGF-1 quartile 2h- glucose levei in normal men and women aged 30 to 62 years)

591

Studies that show that subjects who are below the median (50th percentile) of serum IGF-1 leveis have an increased risk of dying or of the following diseases: Higher risk of dying in kidney cancer patients 40. Rasmuson T, Grankvist K, Jacobsen J, Olsson T, Ljungberg B. Serum insulin-like growth factor-1 is an independent predictor of prognosis in patients with renal cell carcinoma. Acta Oncol. 2004;43(8):744-8. Department

of

Radiation

Sciences,

Oncology,

Umea

University,

Umea

Sweden.

[email protected] (Higher mortality in renal ce/1 carcinoma patients at lower 50 % of serum /GF-1leveis) 41. Caregaro L, Alberino F, Amodio P, Merkel C, Angeli P, Plebani M, Bolognesi M, Gatta A. Nutritional and prognostic significance of insulin-like

growth

factor 1

in patients

with liver cirrhosis. Nutrition.

1997

Mar;13(3):185-90. Department of Clinicai and Experimental Medicine, University of Padua, ltaly. (Lower 3-year survival in patients with cirrhosis below lhe median (50th percentile)

Higher risk of cognitive decline 42. Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, ldei T, lguchi T. Relationship between serum insulin-like growth factor-1 leveis and Alzheimer's disease and vascular dementia. J Am Geriatr Soe. 2005 Oct;53(10):174853.

Department

of

Biochemistry,

Showa

University

School

of

Medicine,

Tokyo,

Japan.

[email protected] (Lower Mini-Mental State Examination scores with IGF-1/eve/s of 140 ng/mL ar /ess (50% percentile) versus those with /GF-1leveis greater than 140 nglmL)

Higher risk of risk of heart failure in elderly persons 43. Vasan RS, Sullivan LM, D'Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D, Wilson PW. Serum insulin­ like growth factor I and risk for heart failure in elderly individuais without a previous myocardial infarction: the Framingham Heart Study. Ann lntern Med. 2003 Oct 21;139(8):642-8. National Heart, Lung, and Blood lnstitute's Framingham Heart Study, Framingham, Massachusetts 01702-5803, USA. (Two-fold higher risk of heart failure in elderly men and women (mean age 78yrs) atar below 140 ng/ml (median value); There was a 2 7% decrease in risk for heart fai/ure for evety 1standard deviation increment in log IGF-1)

Higher visceral fat mass 44. Marin P, Kvist H, Lindstedt G, Sjõstrõm L, Bjõrntorp P. Low concentrations of insulin-like growth factor-1 in abdominal obesity. lnt J Obes Relat Metab Disord. 1993 Feb;17(2):83-9. Department of Medicine I, Sahlgren's Hospital, University of Gõteborg, Sweden (Víscera/ fat mass, systolic blood pressure and triglycerides were significantly higher (P < 0.05) in the group with low (87 f.lg/1) /GF-1 values, compared to those with high (126 f.lg/1) IGF-1 values, divided after lhe median value)

Studies that show that subjects who are at or below the 33th percentile (in the lower tertile) of serum IGF-1 leveis have an increased risk of disease lncreased risk of glioma in normal men aged 50-69 45. Lõnn S, lnskip PD, Pollak MN, Weinstein SJ, Virtamo J, Albanes D. Glioma risk in relation to serum leveis of insulin-like growth factors. Cancer Epidemia! Biomarkers Prev. 2007 Apr;16(4):844-6. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer lnstitute, Room 7053, 6120 Executive Boulevard, Bethesda, MD 20892-7238, USA. [email protected] (3 -fold higher risk of glioma in normal men aged 50-69 yrs who are in lhe /owest tertile of serum IGF-1 compared to the upper 2 tertiles)

Pancreatic cancer in male smokers aged >50-69 yrs 46. Stolzenberg-Solornon RZ, Limburg P, Pollak M, Taylor PR, Virtamo J, Albanes D. lnsulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer

in male smokers. Cancer Epidemia! Biomarkers Prev.

2004 Mar;13(3):438-44. Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer lnstitute, Bethesda, MD, USA. [email protected] (Nonsignificantly -3 7% lower risk of pancreatic cancer in mate smokers aged >50-69 yrs when highest compared to lowest tertile ( P = O. 17))

592

Endometrial cancer in postmenopausal women 47. Lacey JV Jr, Potischman N, Madigan MP, Berman ML, Mortel R, Twiggs LB, Barrett RJ, Wilbanks GD, Lurain JR, Fillmore CM, Sherman ME, Brinton LA. lnsulin-like growth factors, insulin-like growth factor-binding proteins, and endometrial cancer in postmenopausal women: results from a U.S. case-contrai study. Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):607-12. Division of Cancer Epidemiology and Genetics, National Cancer lnstitute,

6120 Executive Boulevard,

MSC

7234,

Rockville,

MO

20852-7234,

USA.

[email protected]

(Nonsignificantly -37% lower risk of endometria/ cancer in postmenopausal women ) for the highest tertile versus the lowest tertile of serum IGF-1 leveis)

Studies that show that subjects who are at or below the 25th percentile (in the lower guartile) of serum IGF-1 leveis have an increased risk of the following disease Prostate cancer 48. Woodson K, Tangrea JA, Pollak M, Copeland TD, Taylor PR, Virtamo J, Albanes D. Serum insulin-like growth lactor 1: tumor marker or etiologic lactor? A prospective study oi prostate cancer among Finnish men. Cancer Res. 2003 Jul 15;63(14):3991-4. Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer lnstitute, Bethesda, Maryland 20892, USA. [email protected] (The risk of prostate cancer for men in the 2nd, 3rd, & 4th (upper) quartiles was Jower than that in men with serum /GF-1 in the 1st (Jowest) quartile of distribution: non sign doubling, of the risk of prostate cancer in men for the fourth versus the first quartile of serum IGF-1. Serum IGF-1, but not IGFBP-3, increased significantly over time in cases (18% increase) but not

contrais (4% decrease; P

=

0.02))

49. Chen C, Lewis SK, Voigt L, Fitzpatrick A, Plymate SR, Weiss NS. Prostate carcinoma incidence in relation to

prediagnostic circulating leveis oi insulin-like growth lactor I, insulin-like growth factor binding protein 3, and

insulin. Cancer. 2005 Jan 1;103(1):76-84. Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. [email protected] (+30 to 50% higher

risk of prostate cancer in men in the lower quartile of serum IGF-1 versus the 3 upper quartiles) Human papilloma virus infection and cervical cancer in women 50. Schaffer A, Koushik A, Trottier H, Duarte-Franco E, Mansour N, Arseneau J, Provencher D, Gilbert L, Gotlieb W, Ferenczy A, Coutlée F, Pollak MN, Franco EL; Biomarkers of Cervical Cancer Risk Study Team. lnsulin-like growth factor-1 and risk oi high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):716-22. Department oi Epidemiology and Biostatistics, McGill University, Montréal, Québec, Canada.

(Reduced risk of HGC/N for increasing leveis of /GF-1, with an -60% /ower risk for lhe highest quartile relative to lhe lowest quartile of /GF-1. 5-fo/d higher risk of being positive for human papilloma virus infection HPV-16 or HPV-18 and 2,5 times higher risk of high-grade cervical intraepithelial neoplasia. Cervical cancer, which is also of epithelial origin, has been shown to overexpress receptors for IGF-1) 51. Serrano ML, Romero A, Cendales R, Sánchez-Gómez M, Bravo MM. Serum leveis oi insulin-like growth lactor-1 and -11 and insulin-like growth lactor binding protein 3 in women with squamous intraepithelial lesions and cervical cancer. Biomedica. 2006 Jun;26(2):258-68. Grupo de lnvestigación en Biología del Cancer, Instituto Nacional de Cancerología, Bogota D.C., Colombia. [email protected] (Women in the highest quartile of IGF-1 and IGF-1:/GFBP-3 molar ratio were at an 80% (OR 0.2, 95% C! [0.06-0.61}) and a 77% (OR 0.23, 95% C! [O. 07-0.73]) lower risk of cervical cancer, respectively, compared with women in lhe corresponding =

=

reference category) Studies that show that subjects who are at or below the 10th percentile of serum IGF-1 leveis have a higher risk of dying Higher risk of dying 52. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart lailure: prevalence and detrimental impact on survival. Circulation. 2006 Oct 24;114(17):1829-37. Cardiology Department, Military Hospital, ui. Weigla 5, 50981 Wroclaw, Poland. [email protected] (Higher risk of dying in men with chronic heart fai/ure in ali age categories (median age: 63 years )

593

Studies with lower IGF-1 receptors in disease states, suggesting that lhe patients are resistant to IGF-1 and that lhe lack of IGF-1 effects may contribute to lhe disease

Markedly lower IGF-1 receptor leveis in breast cancer tissue 53. Voskuil DW, Bosma A, Vrieling A, Rookus MA, van 't Veer LJ. lnsulin-like growth factor (IGF)-system mRNA quantities in normal and tumor breast tissue of women with sporadic and familial breast cancer risk. Breast Cancer Res Treat. 2004 Apr;84(3):225-33. Division of Experimental Therapy, The Netherlands Cancer lnstitute, The Netherlands. (The number of /GF-1 receptors is -61% lower in human breast cancer tissue, -72% lower in

sporadic breast cancer and -26% lower in familial breast cancer) Lower IGF-1 receptor leveis in vascular tissue of obese mice and rats 54. lmrie H, Abbas A, Viswambharan H, Rajwani A, Cubbon RM, Gage M, Kahn M, Ezzat VA, Duncan ER, Grant PJ, Ajjan R, Wheatcroft SB, Kearney MT. Vascular lnsulin-like growth factor-1 resistance and diet-induced obesity. (IGF-1 or insulin-like growth factor1: Endocrinology. 2009 Oct;150(10):4575-82 55. Walsh MF, Ali SS, Sowers JR. Vascular insulin/insulin-like growth factor-1 resistance in female obese Zucker rats. Metabolism. 2001 May;50(5):607-12

Studies with CUTOFF leveis for serum IGF-1 below which there is an increased risk of disease A number of studies show that individuais with serum IGF-1 leveis within lhe normal (reference range), but at or below a precise cutoff serum levei may be at a higher risk of developing a disease. The first table below presents lhe IGF-1 reference range.

Reference ranges for serum IGF- 1 Age

(llg/1 =ng/ml)

Age

Males

Females

17-248

17-248

6 - 8 years

88-474

9- 11 years 12 -15 years

9 months

-

5 years

Reference ranges for serum IGF-1 (llg/1 =ng/ml)

Males

Females

16-24 years

182-780

182-780

88-474

25-39 years

114-492

114-492

110-565

117-771

40-54 years

90-360

90-360

202-957

261-1096

55-98 years

71-290

71-290

Note: Data from Quest diagnostics, edition 2002; The free /GF contributes to less than 1% of ali serum IGF-1.

594

The second table presents the threshold or cutoff leveis of serum IGF-1, below which the risk of disease has been reported to significantly increase.

Thresholds or cutoff leveis of serum total IGF-1 leveis for disease within the reference range The cutoff levei

CUTOFF levei of

Morbidity BELOW

is

Serum IGF-1

the cutoff levei

prematurity

Hellstrõm A, Engstrõm E, Hard AL, Albertsson-Wikland K, Carlsson B,

(retinopathy, bronchopulmon.

Niklasson A, Lõfqvist C, Svensson E, Holm S, Ewald U, Holmstrõm G,

dy splasia, intraventricular hemorrhage, OR necrotizing enterocolitis))and esp. retinopathy of prematurity

Smith LE. Postnatal serum insulinlike growth factor I deficiency is associated with retinopathy of prematurity and other

Morbidity of

WITHIN lhe IGF-1 reference range of 9 month- to 5 year-old

33

(lg/1 (ng/ml)

4.3

nmol/1

children

Lower cognition

140

(lg/1

Heart failure

Hyper-glycemia, 152

19.9

(lg/1

nmol/1

complications of premature birth. Pediatrics. 2003 Nov;112(5):1 01620 Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, ldei T, lguchi T. Relationship between serum insulin-like growth factor-1 leveis and Alzheimer's disease and vascular dementia. J Am Geriatr Soe. 2005 Oct;5�1 0):1748-53

Comment

Serum IGF-1 < or 33 (lg/1 at 33 wks

=

postmenstrual age is associated with 2.2-fold more moribitiy morbidity of prematurity (retinopathy, bronchopulmon. dysplasia, intraventricular hemorrhage, OR necrotizing enterocolitis)

Elderly subjects

Vasan RS, Sullivan LM, D'Agostino RB, Roubenoff R, Harris T, Sawyer

18.3 nmol/1

WITHIN the IGF-1 reference range of ali age categories

Publication

glucose intolerance

and

type 2diabetes

DB, Levy D, Wilson PW. Serum insulin-like growth factor I and risk for heart failure in elderly individuais without a previous myocardial infarction: lhe Framingham Heart Study. Ann lntern Med. 2003 Oct 21 ;139(8):642-8

Patients with IGF-1 levei at or above the median value (140 (lg/L) had half the risk for heart failure

Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Circulating concentrations of insulin-like growth factor-1 and development of glucose intolerance: a prospective

-50% less risk of glucose impaired tolerance or type-2 diabetes in normal men and women

observational study. Lance!. 2002 May 18;359(9319):1740-5.

aged 45-65 years with IGF-1 above 152 ng/ml

Thresholds or cutoff leveis of serum free IGF-1 for disease within the reference range The cutoff levei is

WITHIN the rei. range for free serum IGF-1

CUTOFF levei of Serum serum free IGF-1 below

0.95

(lg/1

0.10 nmol/1

Morbidity BELOW the cutoff levei

Gestational diabetes in pregnant women

Publication

Comment

Qiu C, Vadachkoria S, Meryman L, Frederick 10, Williams MA. Maternal plasma concentrations of IGF-1, IGFBP-1, and C-peptide in early pregnancy and subsequent risk of gestational diabetes mellitus. Am J Obstet Gynecol. 2005 Nov;193(5):1691-7

Women with free IG > ar 1.08 ng/mL h a - 69% lower risk diabe gestational (CI 0.12-0.75) women having ser IGF-1 < 0.80 ng/mL

Note: /GF-1 concentrations, conversion factor: 111gll= O. 131 nmo//1

595

=

DOES IGF-1 CAUSECANCEB?

Common information: Many studies show association between cancer and serum IGF-1 leveis Eacts: Most studies on other forms of cancer than breast cancer show no association or the opposite (that higher leveis of IGF-1 are associated with a lower risk of cancer (inverse associations)) In breast cancer and others cancers a higher IGF-1 may not be cause but a consequence of the cancer, reflecting a state of (cancer) tissue resistance to IGF-1 caused by a sharp reduction in the number of cellular receptors for IGF-1 (as reported in breast cancer tissues a local production by tumor tissue (as reported for rodent prostate cancer tissue) Human studies reporting lower serum IGE-1 leveis in cancer Lower serum !GE-1 in glioma Lõnn S, lnskip PD, Pollak MN, Weinstein SJ, Virtamo J, Albanes D. Glioma risk in relation to serum leveis of insulin-like growth factors. Cancer Epidemia! Biomarkers Prev. 2007 Apr;16(4):844-6

1.

Lower serum IGE-1 in prostate cancer 2. Agurs-Collins T, Adams-Campbell LL, Kim KS, Cullen KJ.Ins ulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women. Cancer Detect Prev. 2000;24(3):199-206 3. Fuhrman B, Barba M, Schünemann HJ, Hurd T, Quattrin T, Cartagena R, Carruba G, Muti P. Basal growth hormone concentrations in blood and the risk for prostate cancer: a case-contrai study. Prostate. 2005 Jul 1;64(2):109-15 4. Woodson K, Tangrea JA, Pollak M, Copeland TD, Taylor PR, Virtamo J, Albanes D. Serum insulin-like growth factor 1: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. Cancer Res. 2003 Jul 15;63(14):3991-4 5. Chen C, Lewis SK, Voigt L, Fitzpatrick A, Plymate SR, Weiss NS. Prostate carcinoma incidence in relation to prediagnostic circulating leveis of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin. Cancer. 2005 Jan 1;1 03(1):76-84 Lower serum IGE-1 in colorectal cancer 6. Palmqvist R, Hallmans G, Rinaldi S, Biessy C, Stenling R, Riboli E, Kaaks R. Plasma insulin-like growth factor 1, insulin-like growth factor binding protein 3, and risk of colorectal cancer: a prospective study in northern Sweden. Gut. 2002 May;50(5):642-6 Lower serum IGE-1 in pancreatic cancer 7. Stolzenberg-Solomon RZ, Limburg P, Pollak M, Taylor PR, Virtamo J, Albanes D. lnsulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer in male smokers. Cancer Epidemia! Biomarkers Prev. 2004 Mar;13(3):438-44 Lower serum IGE-1 in cervical cancer 8. Schaffer A, Koushik A, Trottier H, Duarte-Franco E, Mansour N, Arseneau J, Provencher D, Gilbert L, Gotlieb W, Ferenczy A, Coutiée F, Pollak MN, Franco EL; Biomarkers of Cervical Cancer Risk Study Team . lnsulin­

9.

like growth factor-1 and risk of high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):716-22 Serrano ML, Romero A, Cendales R, SÃi nchez-GÃ3mez M, Bravo MM. Serum leveis of insulin-like growth factor-1 and -11 and insulin-like growth factor binding protein 3 in women with squamous intraepithelial lesions and cervical cancer. Biomedica. 2006 Jun;26(2):258-68

Human study reporting lower IGE-1 leveis in lprostatel cancer tissue 1O.

11.

Téllez Martínez-Fornés M, Balsa J, Maganto Pavón E, Jiménez Cidre M, Burgos Revilla FJ. [lnsulin growth factor I (IGF-1) in normal, hyperplastic, and tumor prostatic tissue]. Actas Urol Esp. 1996 May;20(5):409-13 (Nonsignificant lower presence of /GF-1 in prostate cancer tissue ( confirmed in ali

tissues (6.02 +1- 1.42) than in normal (9.62 +1- 5.81) or hyperplastic tissue (8.32 +1- 7.81 ng/mg protein))

596

Animal studies when IGF-1 is shown to be secreted by cancer tissue, suggesting that IGF-1 is not a cause but a consequence of cancer Prostate cancer DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Boi DK, Beltrán L, Moats S, Ramirez A, Jorcano J, Conti C .. Deregulated expression of IGF-1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sei USA 2000; 97: 3455-60 13. Kaplan PJ, Mohan S, Cohen P, Foster BA, Greenberg NM. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res. 1999 May 1 ;59(9):2203-9. IGF axis and prostate cancer: lessons from transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res 1999; 59: 2203-9 12.

Human study showing that there is no seasonal variation in IGF-1 leveis in breast cancer patients 14.

Holdaway IM, Mason BH, Gibbs EE, Rajasoorya C, Lethaby A, Hopkins KD, Evans MC, Lim T, Schooler B. Seasonal variation in the secretion of mammotrophic hormones in normal women and women with previous breast cancer. Breast Cancer Res Treat 1997 Jan;42(1):15-22 (Contra/women had significantly higher /GF-1 leveis in summer compared to winter. In contrast, BC women had no significant seasonal difference in /GF-1 concentrations)

Human study reporting greater malignancy of breast cancer in women with low IGF-1 leveis 15.

Agurs-Collins T, Adams-Campbell LL, Kim KS, Cullen KJ.Ins ulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women. Cancer Detect Prev. 2000;24(3):199-206. (Significant inverse association of serum /GF-1 and cancer stage: higher TNM (tumor-node-metastasis))

Human study reporting a lower number of IGF-1 receptors in cancer, suggesting the lack of IGF-1 effects may contribute to the disease Markedly lower number of IGF-1 receptors in breast cancer tissue, suggesting an I GF-1 resistance (similar to insulin resistance) 16. Voskuil DW, Bosma A, Vrieling A, Rookus MA, van 't Veer LJ. lnsulin-like growth factor (IGF)-system mRNA quantities in normal and tumor breast tissue of women with sporadic and familial breast cancer risk. Breast Cancer Res Treat. 2004 Apr;84(3):225-33 (The number of /GF-1 receptors is -61% lower in human breast cancer tissue, -72% lower in sporadic breast cancer and -26% lower in família/breast cancer) 17. Nardon E, Buda I, Stanta G, Buratti E, Fonda M, Cattin L. lnsulin-like growth factor system gene expression in women with type 2 diabetesand breast cancer. J Clin Pathol. 2003 Aug;56(8):599-604. (Suggested higher risk of breast cancer at low norma/leveis of gene expression of IGF-1 and /GF-1 receptor in women)

Human studies reportinq hiqher serum IGF-1 leveis in cancer Higher IGF-1 leveis in lung cancer Wang H, Wan YX, Zhang QK. Significance and expression of insulin-like growth factor 1 and IGF binding protein 3 in serum of patients with lung cancer. AiZheng. 2004 Jun;23(6):710-4

18.

Higher IGF-1 leveis in gastric cancer 19. Franciosi CM, Piacentini MG, Conti M, Romano F, Musco F, Caprotti R, Rovelli F, Uggeri F. IGF-1 and IGF1 BP3 in gastric adenocarcinoma. Preliminary study. Hepatogastroenterology. 2003 Jan-Feb;50(49):297-300 Higher IGF-1 leveis in breast cancer: several studies, including: 20. Bruning PF, Van Doorn J, Bonfrêr JM, Van Noord PA, Korse CM, Linders TC, Hart AA. lnsulin-like growth­ factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer. lnt J Cancer. 1995 Jul 28;62(3):266-70 (The IGF-1//GFBP-3 ratio was a significam breast-cancer risk factor) Li BD, Khosravi MJ, Berkel HJ, Diamandi A, Dayton MA, Smith M, Yu H. Free insulin-like growth factor-1 and 21. breast cancer risk. lnt J Cancer 2001 Mar 1;91(5):736-9 (The odds ratios for breast cancer patients having high plasma /GF-1:? median) after adjusting for menopausa/ status and /GFBP-3 were 2.00 (p :> 0.376) for totai/GF-1 and 6.31 (p :>0.047) for free /GF-1. 22.

A high ratio of IGF-1 to IGFBP-3 was also associated with breast

cancer (p < 0.05)) Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B Speizer FE, Pollak M. Circulating concentrations of insulin-like growth factor-1 and risk of breast cancer. Lance! 1998 May 9;351(9113):1393-6 lnt J Cancer 1998 Jun 10;76(6):787-90 (A positive relation between circulating /GF-1 concentration and risk of breast cancer was found among premenopausal but not postmenopausal women)

597

23.

Bohlke

K,

Cramer

DW,

Trichopoulos D,

Mantzoros

CS.

lnsulin-like

growth

lactor-1

in

relation to

premenopausal duelai carcinoma in situ oi the breast. Epidemiology 1998 Sep;9(5):570-3 (Women in lhe highest two tertiles of IGF-1 and lhe lowest tertile of /GFBP-3 were at notably higher risk than women in lhe lowest tertile of /GF-1 and lhe highest two tertiles of IGFBP-3 (odds ratio = 3.7; 95% C/=

1.1-12.2)

In acromegaly the incidence of cancer other than gastrointestinal cancer does not seem to be increased 24.

Cohen P, Clemmons DR, Rosenleld RG. Does the GH-IGF axis play a role in cancer pathogenesis? Growth Horm IGF Res. 2000 Dec;10(6):297-305.Department oi Pediatrics, Mattel Children's Hospital, UCLA, Los Angeles, CA 90095-1752, USA. hassy@ mednet.ucla.edu

lncreased incidence of oesophagus, stomach and colon cancer 25.

Ron E, Gridley G, Hrubec Z, Page W, Arara S, Fraumeni JF Jr. Acromegaly and gastrointestinal cancer. Cancer. 1991 Oct 15;68(8):1673-7. National Cancer lnstitute, Bethesda, Maryland

26.

Ma J, Pollak MN, et ai. Prospecftive study oi colorectal cancer risk in men and plasma leveis oi IGF-1 and IGF-BP-3. J Natl Cancer lnst. 1999; 91: 620-625

High leveis in prostate cancer t 27.

Peng L, Tang S, Xie J, Luo T, Dai B.

Quantitative analysis oi IGF-1 and its application in the diagnosis oi

prostate cancer. Hua Xi Yi Ke Da Xue Xue Bao. 2002 Jan;33(1):137

Human studies reporting no association of serum IGF-1 leveis with cancer: many studies, including Prostate cancer 28.

Weiss JM, Huang WY, Rinaldi S, Fears TR, Chatterjee N, Chia D, Crawford ED, Kaaks R, Hayes RB. IGF-1 and IGFBP-3: Risk oi prostate cancer among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. lnt J Cancer. 2007 Nov 15;121(10):2267-73

Colorectal cancer 29.

Probst-Hensch NM, Yuan JM, Stanczyk FZ, Gao YT, Ross RK, Yu MC. IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort oi Chinese men in Shanghai. Br J Cancer. 2001 Nov 30;85(11):1695-9

Breast cancer 30.

Del Giudice ME, Fantus IG, Ezzat S, McKeown-Eyssen G, Page D, Goodwin PJ. lnsulin and related lactors in premenopausal breast cancer risk. Breast Cancer Res Treat

1998 Jan;47(2):111-20 (No statistically

significant differences between breast cancer patients and controls for IGF-1 and IGFBP-1

leveis in

premenopausal women) 31.

Kajdaniuk D, Marek B. lnfluence oi adjuvant chemotherapy with cyclophosphamide methotrexate and 5fluorouracil on plasma insulin-like growth lactor-1 and chosen hormones in breast cancer pre-menopausal patients. J Clin Pharm Ther

2000 Feb;25(1):67-72 (Plasma /GF-1 concentration

prior to treatment did not differ significantly from that of hea/thy women)

598

in breast cancer patients

Chapter ten: Cortisol

and glucocorticoids

Senescence is associated with a moderate decline of the adrenal-cortisol axis 1.

Derouet H, Lehmann J, Stamm B, Lühl C, Rõmer O, Georg T, lsenberg E, Gebhardt T, Stoeckle M. Age dependent secretion of LH and ACTH in healthy men and patients with erectile dysfunction. Eur Urol. 2002 Feb;41(2):144-53 (The serum cortisol level declines with age in men)

2.

Ferrari E, Arcaini A, Gornati R, Pelanconi L, Cravello L, Fioravanti M, Solerte SB, Magri F.Pineal and pituitary­ adrenocortical function in physiological aging and in senile dementia. Exp Gerontol. 2000 Dec;35(9-10):1239-

3.

4. 5. 6.

50 Magri F, Terenzi F, Ricciardi T, Fioravanti M, Solerte SB, Stabile M, Balza G, Gandini C, Villa M, Ferrari E. Association between changes in adrenal secretion and cerebral morphometric correlatas in normal aging and senile dementia. Dement Geriatr Cogn Disord. 2000 Mar-Apr;11(2):90-9 Jensen HK, Blichert- Toft M. Serum corticotrophin, plasma cortisol and urinary secretion of 17 -ketogenic steroids in lhe elderly (age group 66-94 years). Acta Endocrinol (Copenh). 1971;66:25 Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone leveis in middle­ aged men: results oi lhe Massachusetts Male Aging Study. J Clin Endocrinol Metab. 1991 Nov;73(5):1016-25 Ferrari E, Cravello L, Muzzoni B, Casarotti O, Paltro M, Solerte SB, Fioravanti M, Cuzzoni G, Pontiggia B, Magri F. Age-related changes of lhe hypothalamic- pituitary-adrenal axis: pathophysiological correlates. Eur J Endocrinol. 2001 Apr;144(4):319-29

7.

Drafta O, Schindler AE, Stroe E, Neacsu E. Age-related changes of plasma steroids in normal adult males. J Steroid Biochem. 1982 Dec;17(6):683-7 ("The age related changes of plasma steroids in elderly men, were

8.

Lupien S, Lecours AR, Schwartz G, Sharma S, Hauger RL, Meaney MJ, Nair NP. Longitudinal study of basal cortisol leveis in healthy elderly subjects:evidence for subgroups. Neurobiol Aging. 1996 Jan-Feb;17(1):95105

9.

Zietz B, Hrach S, Scholmerich J, Straub RH. Differential age-related changes of hypothalamus - pituitary adrenal axis hormones in healthy women and men - role of interleukin 6. Exp Clin Endocrinol Diabetes. 2001;109(2):93-101 Sharma M, Palacios-Bois J, Schwartz G, lskandar H, Thakur M, Quirion R, Nair NP. Circadian rhythms oi melatonin and cortisol in aging. Biol Psychiatry. 1989 Feb 1;25(3):305-19

suggestive of decreased cortisol secretion'?

10. 10.

Romanoff LP, Morris CW, Welch P, Rodriguez RM, Pincus G. The metabolism of cortisoi4-C14 in young and elderly men. 1. Secretion rale of cortisol and daily excretion of tetrahydrocortisol, allotetrahydrocortisol, tetrahydrocortisone, and cortalone (20 alpha and 20 beta). J Clin Endocrinol Metab 1961 Nov;21 :1413-25

11.

Samuels LT. Factors affecting lhe metabolism and distribution oi cortisol as measured by leveis of 17 hydroxycorticosteroids in blood. Cancer. 1957 Jui-Aug;10(4):746-51

12.

West CO, Brown H, Simmons EL, Carter DB, Kumagai LF, Engelbert EL. Adrenocortical function and cortisol metabolism in old age. J Clin Endocrinol Metab; 1961;21:1197-207

13.

Weykamp CW, Penders TJ, Schmidt NA, Borburgh AJ, van de Calseyde JF, Wolthers BJ. Steroid profile for urine: reference values. Clin Chem. 1989 Dec;35(12):2281-4 Rasmuson S, Andrew R, Nasman B, Seckl JR, Walker BR, Olsson T. lncreased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer's disease. Biol P�ychiatry. 2001 Mar 15;49(6):547-52

14.

Senescence is associated with a lowering of glucocorticoid (cellular) receptors with senescence 15. 16. 17. 18. 19. 20. 21.

Timiras PS. Steroid-secreting endocrines: adrenal, ovary, testis. 111. The Adrena Cortex: 28-35, in Hormones and aging, 1995, Timiras PS, Quay WD, Vernadakis A., CRC Press, Boca Raton -New York Armanini O, Scali M, Vittadello G, Ribecco M, Zampollo V, Pratesi C, Orlandini E,Zovato S, Zennaro CM, Karbowiak I.Corticosteroid receptors and aging. J Steroid Biochem Moi Biol. 1993 Apr;45(1-3):191-4. Armanini O, Karbowiak I, Scali M, Orlandini E, Zampollo V, Vittadello G. Corticosteroid receptors and lymphocyte subsets in mononuclear leukocytes in aging. Am J Physiol. 1992 Apr;262(4 Pt 1):E464-6 Sharrna R, Timiras PS. Glucocorticoid receptors, stress and aging. in Regulation of neuroendocrine agingng, Everitt AV & Walton JR, Eds. Karger, Basel, 1988, 98 Roth GS. Age-related changes in specific glucocorticoid binding by steroid-responsive tissues of rats. Endocrinology. 1974 Jan;94(1):82-90 Latham KR, Finch CE. Hepatic glucocorticoid binders in mature and senescent C57BU6J male mice. Endocrinology. 1976 Jun;98(6):1480-9 Sharma R, Timiras PS. Age-dependent regulation of glucocorticoid receptors in lhe liver of male rats. Biochim Biophys Acta. 1987 Sep 14;930(2):237-43

599

lncreasingly greater imbalance of the anabolic/catabolic hormonal balance with senescence 20. Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of slress and aging: lhe glucocorticoid cascade hypothesis. Endocr Rev. 1986 Aug;7(3):284-301 21. Valenti G. Neuroendocrine hypothesis of aging: lhe role of corticoadrenal sleroids. : J Endocrinol lnvest. 2004;27(6 Suppl):62-3 22. Debigare R, Marquis K, Cote CH, Tremblay RR, Michaud A, LeBianc P, Maltais F. Catabolic/anabolic balance and muscle wasting in patients with COPO. Chest. 2003 Ju1;124(1):83-9 Senescence can be associated with a higher serum cortisol in the evening and at night, and phase advance of cortisol rhythm 23. Vgonlzas AN, Zoumakis M, Bixler EO, Lin HM, Prolo P, Vela-Bueno A, Kales A, Chrousos GP. lmpaired night-time sleep in healthy old versus young adults is associated with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications. J Clin Endocrinol Metab. 2003 May;88(5):2087-95 24. Sherman B, Wysham C, Pfohl B. Age-related changes in the circadian rhythm of plasma cortisol in man. J Clin Endocrinol Metab. 1985 Sep;61(3):439-43 Cortisol treatment may oppose and cortisol deficiency may trigger several mechanisms of senescence Excessive free radical formation: glucocorticoids may increase antioxidant activity 25. Shuto M, Higuchi K, Sugiyama C, Yoneyama M, Kuramoto N, Nagashima R, Kawada K, Ogita K. Endogenous and exogenous glucocorticoids preveni trimethyltin from causing neuronal degeneration of lhe mouse brain in vivo: involvement of oxidative stress palhways. J Pharmacol Sei. 2009 Aug;110(4):424-36 26. Gavan N, Maibach H. Effect of topical corticosteroids on lhe activity of superoxide dismutase in human skin in vitro. Skin Pharmacol. 1997;10(5-6):309-13 lmbalanced apoptosis: cortisol and corticosterone may inhibit undesirable apotosis 27.

Chen QM, Alexander D, Sun H, Xie L, Lin Y, Terrand J, Morrissy S, Purdom S. Corticosteroids inhibit cell death induced by Doxorubicin in cardiomyocytes: induction of antiapoptosis, antioxidant, and detoxification genes. Moi Pharmacol. 2005 Jun;67(6):1861-73

lmmune deficiency: cortisol may stimulate lhe immune system 28. 29. 30. 31. 32. 33. 34. 35.

15.

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("Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 1.5 mg/d (0.75 mgld for fluticasone propionate), although there is a considerable degree of interindividual susceptibility'J

analysis. Arch lntern Med. 1999 May 10;159(9):941-55

Efficacy of low doses of gluccorticoids is greater than high doses 276.

Williamson DR, Lapointe M. The hypotha/amic-pituitary-adrenal axis and low-dose glucocorticoids in the

("Aithough high-dose glucocorticoids have not positively affected clinicai outcome, sma/1 trials in which low-dose glucocorticoids were administered to patients with septic shock and relative adrenal insufficiency have shown decreased mortality")

treatment of septic shock. Pharmacotherapy. 2003 Apr;23(4):514-25

277.

Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on

('The efficacy of steroids on septic shock: depends on the lower dose: benefit at low doses and increasing harm at higher doses and longe r courses'J

survival and shock during sepsis depends on the dose. Ann lntern Med. 2004 Jul 6;141(1):47-56.

Frequency of glucocorticoid treatment use 278.

Gallant C, Kenny P. Oral glucocorticoids and their complications. A review. J Am Acad Dermatol. 1986

(prescribed to over 7% of hospitafized patients. Of this group, some 17% may experience adverse effects)

Feb;14(2 Pt 1):161-77

lmportance to add anabolic hormone supplementation to glucocorticoid treatment: to assure a good anabo/ic­ DHEA or other I catabolic-cortisol balance: for more information read the references on association of other hormones in one of the following sections on cortisol and bane density 279.

Ferrari E, Cravello L, Muzzoni B, Casarotti D, Paltro M, Solerte SB, Fioravanti M, Cuzzoni G, Pontiggia B, Magri F. Age-related changes of lhe hypothalamic-pituitary-adrenal axis: pathophysiological corre/ates. Eur J Endocrinol. 2001 Apr;144(4):319-29

Glucocorticoid treatment: interferences 280.

Frey BM, Frey FJ. Clinicai pharmacokinetics of prednisone and prednisolone. C/in Pharmacokinet. 1990 Aug;19(2):126-46

281.

Gambertoglio JG, Amend WJ Jr, Benet LZ.

Pharmacokinetics and bioavailability of prednisone and

prednisolone in healthy volunteers and patients: a review. J Pharmacokinet Biopharm. 1980 Feb;8(1):1-52

611

282.

Abernethy DR, Greenblatt DJ. Drug disposition in obese humans. An update. Clin Pharrnacokinet. 1986 May­

283.

Jun;11 (3):199-213 (the volume of distribution is in obese persons moderately increased for prednisolone) Geri H, Rohde W, Biering H, Schulz N, Lochs H. Food-dependent Cushing syndrome of long standing with mild clinicai features Dtsch Med Wochenschr. 2000 Dec 22;125(51-52):1565-8.

Glucocorticoid treatment: safety, side effects, complications

Relative safety of low doses of glucocorticoids 284.

da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Ines LB, de Koning EJ, Buttgereit F, Cutolo M, Capell H, Rau R, Bijlsma JW. Low-dose glucocorticoid therapy in rheumatoid arthritis. A review on safety: published evidence and prospectiva trial data. Ann Rheum Dis. 2005 Published Online First: 17 August 2005 (" ..in the available literature on low-dose glucocorticoid therapy very little of the commonly held beliefs about the incidence, prevalence and impact (of adverse effects) of glucocorticoids proved to be supported by clear scientific evidence .... randomized controlled clinicai trials ... showed that the incidence, severity and impact of adverse effects of low dose glucocorticoid therapy in rheumatoid arthritis trials are modest, and often not statistical/y different to those of placebo. Conclusions: Probably many of the we/1 known adverse effects of

285. 286.

287.

glucocorticoids are predominantly associated with high dose treatment. '? Strand V, Simon LS. Low dose glucocorticoids in early rheumatoid arthritis. Clin Exp Rheumatol. 2003 Sep­ Oct;21(5 Suppl 31):8186-90 ("low dose glucocorticoid therapy (e.g. <ar= 5 mg prednisone per day)'J McConnell EM, Bell PM, Hadden DR, McCance DR, Sheridan B, Atkinson AB. Prevalence of diabetes and impaired glucose tolerance in adult hypopituitarism on low dose oral hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 2001 May;54(5):593-9 Glenn Haugeberg, MD, PhD; Anders Strand; Tore K. Kvien, MD, PhD; John R. Kirwan, MD Reduced Loss of Hand Bone Density With Prednisolone in Early Rheumatoid Arthritis. Results From a Randomized Placebo­ Controlled Trial. Arch lntern Med. 2005;165:1293-7

Aggravation ot salt loss, correctable by addition of tludrocortisone 288. Bey-Omar F, Feit JP, Forest MG, David M. Aggravation of sal! loss due to hydrocortisone in lhe first days of treatment of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. Pediatria. 1983 Mar;38(2):77-86

Allergy reactions due to the excipients in drugs (succinate salt, sulphites, carboxy-methyl-cel/ulose, ..) 289. Ventura MT, Muratore L, Calogiuri GF, Dagnello M, Buquicchio R, Nicoletti A, Altamura M, Sabba C, Tursi A. Allergic and pseudoallergic reactions induced by glucocorticoids: a review. Curr Pharm Des. 2003;9(24):195664 Adverse effects of higher doses of glucocorticodis 290.

291. 292. 293. 294.

Gallant C, Kenny P. Oral glucocorticoids and their complications. A review. J Am Acad Dermatol. 1986 Feb;14(2 Pt 1):161-77 (prescribed to over 7% of hospitalized patients. Of this group, some 17% may experience adverse effects) dei Rincon I, O'Leary DH, Haas RW, Escalante A. Effect of glucocorticoids on lhe arteries in rheumatoid arthritis. Arthritis Rheum. 2004 Dec;50(12):3813-22 Gubba EM, Netherton CM, Herbert J. Endangerment of the brain by glucocorticoids: experimental and clinicai evidence. J Neurocytol. 2000 May-Jun;29(5-6):439-49. Sholter DE, Armstrong PW. Adverse effects of corticosteroids on lhe cardiovascular system. Can J Cardiol. 2000 Apr;16(4):505-11 Allen DB. Growth suppression by Sep;25(3):699-717

glucocorticoid therapy.

Endocrinol Metab Clin

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Glucocorticoid treatment: follow-up

295.

Jerjes WK, Cleare AJ, Wood PJ, Taylor NF. Assessment of subtle changes in glucocorticoid negative feedback using prednisolone: Comparison of salivary free cortisol and urinary cortisol metabolites as endpoints. Clin Chim Acta. 2006 Feb;364(1-2):279-86

612

TOPICS OE D!SCUSS!ON:

CORTISOL OR GLUCOCORTICOID TREATMENT ANO ADRENAL SUPPRESSION lntroduction: the normal daily cortisol (= hydrocortisone) production In sedentary conditions, women make 20 mg/day of cortisol (hydrocortisone), men make 30 mg/day, amounts that correspond to an oral hydrocortisone treatment of 35-40 mg/day in women and 50-60 mg/day in men for patients who need a total replacement dose, as about 50-60 % of oral hydrocortisone gets effectively absorbed from the gut into the blood stream. .Giucocortiocoid treatments: may inhibit or even suppress the cortisol production by the adrenal glands depending upon the dose! 1) Subreplacement doses Very low hydrocortisone- 5 to 15 mg per day- do not reduce the pituitary-adrenal axis, even not in CFS patients who are more sensitive to such a suppression. Jnsulin stress tests do not show any degree of suppression of endogenous adrenal function (ACTH or cortisol) with 5 to 10 mg per day of hydrocortisone. 1. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP, Chrousos G, Gold PW. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991;73(6) :1224-34 2. Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999 Feb 6;353(9151):455-8 (double blind placebo study with low-dose (5 mg or 10 mg daily) hydrocortisone or placebo for 1 month; "lnsulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone'j

On the contrary, an increased adrenal responsiveness to CRH stimulation in patients has been shown under this low dose of hydrocortisone 3. Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, O'Keane V. Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. J Clin Endocrinol Metab 2001 Aug;86(8):3545-54 ("ímprovement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.'J Low hydrocortisone - from 20 mg /day of hydrocortisone to a maximum of 40- 60 mg/day depending on the degree of cortisol deficiency: at these doses a significant, but partia!, moderate and temporary suppression of adrenal cortisol secretion occurs. 4. Swartz SL, Dluhy RG. Corticosteroids: clinicai pharmacology and therapeutic use. Drugs. 1978 Sep;16(3):23855 Normal low hydrocortisone - 25 to 35 mg per day: leads to a 20 to 35 % decrease in endogenous ACTH and cortisol production in chronic fatigue patients, who have an enhanced negative feedback on the pituitary levei. After stopping, it may take severa! days to severa! weeks to recover the previous adrenocortical status. McKenzie R, O'Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, Garcia-Borreguero D, Blackwelder W, 5. Straus SE. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998 Sep 23-30;280(12):1061-6 ("some suppression of adrenal glucocorticoid responsiveness was documented in 12 patients on 30 who received hydrocortisone compared to nane in the placebo group'J 6. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP, Chrousos G, Gold PW. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991;73(6):1224-34 5 mg/day of prednisone inhibit in general only during the first 12 hours the cortisol production with the only consistent inhibition (-41 to -47 %) 9 hours after of intake Jerjes WK, Cleare AJ, Wood PJ, Taylor NF. Assessment of subtle changes in glucocorticoid negative 7. feedback using prednisolone: Comparison of salivary free cortisol and urinary cortisol metabolites as endpoints. Clin Chim Acta. 2006 Feb;364(1-2):279-86 ("Prednisone at midnight (Oh) caused a partia/ inhibition of urine cortisol metabolites that began at 0600 and ceased after 1800; Suppression of salivary cortisol was only consistently seen at 0900: mean suppression was 41+1-5% in males and 47+/-9% in females'j

613

Use of exogenous synthetic glucocortiocoids by inhalation reduces the 30 minutes post-awakening cortisol leveis (mildly for inhaled use, up to -60 % for systemic use at high doses, but no inhibitory effect on cortisol leveis 12 h atter 8.

Masharani U, Shiboski S, Eisner MO, Katz PP, Janson SL, Granger DA, Blanc PD. lmpact of exogenous glucocorticoid

use

on

salivary

cortisol

measurements

among

adults

with

asthma

and

rhinitis.

Psychoneuroendocrinology. 2005 Sep;30(8):744-52

2) Total replacement doses:

40 -60 mg per day ; suppress more, but no! totally, adrenal cortisol secretion.

3) Suprareplacement or supraphysioloqical doses: more than 15 mg per day of oral prednisone ( 60 mg/day =

or more of oral hydrocortisone) are above lhe physiologica/ range. lt takes 5 days to 12 months to fully recover lhe initial adrenal axis depending upon lhe dose and lhe length of use of lhe overdose. Any person who has received a g/ucocorticoid in a dose equivalent to 20 to 30 mglday of prednisone for more than 5 days shou/d be suspected of having hypothalamic-pituitary suppression 9.

Axelrod L. Glucocorticoid therapy. Medicine (Baltimore). 1976 Jan;55(1):39-65

10.

Axelrod L.

Glucocorticoids.

In Kelley WN, Harris ED Jr, Ruddy S,

Sledge CB (esd); Textbook of

Rheumatology, ed 4. Philadelphia: Saunders, 1993 11.

Daly JR, Fletcher MR, Glass D, Chambers DJ, Bitensky L, Chayen J. Comparison of effects of long-term corticotrophin and corticosteroid treatment on responses of plasma growth hormone, ACTH, and corticosteroid to hypoglycaemia. Br Med J. 1974 Jun 8;2(918):521-4.

12.

Graber AL, Ney RL, Nicholson WE, lsland DP, Liddle GW. Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids. J Clin Endocrinol Metab. 1965 Jan;25:11-6

13.

Streck WF, Lockwood OH. Pituitary adrenal recovery following short-term suppression with corticosteroids. Am J Med. 1979 Jun;66(6):910-4 (-50 % reduction of pituitary-adrenal axis after 5 days of 50 mg/day

prednisone, fui/ recovery in 5 days after stopping lhe 5-day treatment) 14.

Spitzer SA, Kaufman H, Koplovitz A, Topilsky M, Blum I. Beclomethasone dipropionate and chronic asthma. The effect of long-term aerosol administration on lhe hypothalamic-pituitary-adrenal axis after substitution for oral therapy with corticosteroids. Chest. 1976 Jul;70(1 ):38-42. (Beclomethasone dipropionate aerosol therapy

permitted in patients who had previously received prolonged treatment with corticosteroids with various degrees of adrenal suppression to achieve a/mos/ complete recovery of adrenal function withín a period of síx months ín mos! patíents; treatment with beclomethasone dípropíonate did not affect lhe hypothalamic-pituítary­ adrenal axis in other asthmatic patients who had not received prolonged cortícosteroíd therapy) 15.

Westerhof L, van Ditmars MJ, Kinderen PJ der, Thijssen JH, Schwarz F. Recovery of adrenocortical function during long-term treatment with corticosteroids. Br Med J. 1970 Nov 28;4(734):534-7

16.

Westerhof L, Van Ditmars MJ, Der Kinderen PJ, Thijssen JH, Schwarz F. Recovery of adrenocortical function during long-term treatment with corticosteroids. Br Med J. 1972 Apr 22;2(807):195-7

Suprareplacemenl/pharmacological doses in severe criticai illnesses, high doses may be used but these doses usually suppress adrenal function. After long-term use of very high doses lhe adrenal cortex secretions may almost totally be suppressed. To completely block endogenous production minimal doses of 15 mg per day of prednisolone or 75 or more of hydrocortisone ar necessary, but in some patients much higher doses have to be reached before completely blocking lhe adrenal glands. Without externai stimulation, it can take an average of eight to twelve months to fully recover lhe initial adrenal axis as have been shown in patients who had removal of adrenal tumors that were hypersecreting cortisol.

Pharmacological doses are doses above 7.5 mg/day of prednisone 17.

Hermus AR, Zelissen PM. Diagnosis and therapy of patients with adrenocortical insufficiency. Ned Tijdschr Geneeskd 1998 Apr 25;142(17):944-9 (Patíents wíth prímary adrenocortica/ insuffícíencv need substítution not

onlv wíth glucocorticoids but a/so with mineralocortícoids. When pharmacologícal amounts of glucocortícoíds

(> 7.5 mg prednisone daíly) are used for 3 weeks or /onger, a clínically relevant suppression of lhe pituítary­ adrenal axís ís possíble, and thís may persíst for one year after discontinuing lhe use of g/ucocortícoíds)

lt is important to note that even in the case high doses (from 20 to 50 mg/d) of a synthetic derivative as prednisone (apparently more suppressive than the natural one), the inhibition of the corticotrope axis is temporary and partial 18.

Bartelink AK, van Deuren M, Hermus AR, Gemke RJ, Thijs LG. Corticosteroid administration for critically ill

19.

Kuperman H, Damiani D, Chrousos GP, Dichtchekenian V, Manna TO, Filho VO, Setian N. Evaluation of lhe

patients. Ned Tijdschr Geneeskd. 2001 Sep 8;145(36):1725-9 hypothalamic-pituitary-adrenal axis in children with leukaemia before and after 6 weeks of high-dose glucocorticoid therapy. J Clin Endocrinol Metab. 2001 Jul;86(7):2993-6.

614

20.

Wenning GK, Wielholler H, Schnauder G, Muller PH, Kandulh S, Renn W. Recovery of lhe hypolhalamic­ piluilary-adrenal axis from suppression byshort-lerm, high-dose inlravenous prednisolone lherapy in palienls wilh MS. Acla Neural Scand. 1994 Apr;89(4):270-3.

21.

Moore GE, Hoenig M. Duralion of piluilary and adrenocortical suppression after long-lerm adminislralion of anli-inflammalory doses of prednisone in dogs. Am J Vel Res. 1992 May;53(5):716-20.

22.

Rubens R. Corticoid lherapy: how? Buli Soe Belge Ophlalmol. 1990;236:45-55.

23.

Karilzky D, von Pelrykowski W, Bohlayer R, Zeisel H. Recovery of hypolhalamic-piluilary-adrenocortical axis

24.

Slreck WF, Lockwood DH. Piluilary adrenal recovery following short-lerm suppression wilh corticosleroids.

afier high-dose dexamelhasone lrealment. Dlsch Med Wochenschr. 1980 Aug 1;105(31):1086-9. Am J Med. 1979 Jun;66(6):910-4

Recovery from adrenal suppression with ACTH-depot injections: In case of adrenal suppression, ACTH injections can restimulate and activate the adrenal cortex, acce/erating adrenal recovery. Keleslimur F, Akgun A, Gunay O. A comparison belween short synaclhen lesl and depol synaclhen lesl in lhe evalualion of cortisol reserve of adrenal gland in normal subjecls. J Endocrinol lnvest. 1995 Dec;18(11 ):823-6 26. Oberger E, Thoren M, Engslrom I. Long-lerm lrealmenl wilh corticosleroids/ACTH in aslhmalic children. 11.

25.

Hypolhalamic-piluilary-adrenal funclion. Acla Paedialr Scand. 1986 Jan;75(1):164-71 27.

Hugh-Jones P, Pearson RS, Boolh M. Telracosaclrin for lhe managemenl of aslhmalic palienls after long­ lerm corticosleroids. Thorax. 1975 Aug;30(4):426-9

28.

Oblulowicz K, Glowacka A. Synaclhen-depol lrealmenl during wilhdrawal of long-lerm corticolherapy in palienls wilh aslhma. Pol Tyg Lek. 1974 Apr 1;29(13):519-22

615

GLUCOCORTICOIDS ANO BONE DENSITY 1.

Strand V, Simon LS. Low dose glucocorticoids in early rheumatoid arthritis. Clin Exp Rheumatol. 2003 Sep­ Oct;21(5 Suppl 31):8186-90 (In this study it is "suggested that with appropriate monitoring and carefu/

concomitant prophylactic therapy to prevent osteoporosis, adjunctive therapy using Jow dose g/ucocorticoids ... may be a reasonable treatment plan for select patients'? Studies with adverse effects of glucocortioid treatment on bone densitv: Study where persons with higher peak serum levei of cortisol after ACTH stimulation have an increased bone density loss 2. Reynolds RM, Dennison EM, Walker BR, Syddall HE, Wood PJ, Andrew R, Phillips DI, Cooper C. Cortisol seeretion and rate of bone loss in a population-based eohort of elderly men and women. Calei! Tissue lnt. 2005 Sep;77(3):134-8 (increased Jumbar spine bane /oss in men, reduced femoral neck bane density in

women) Studies where the use of glucocortioids was associated with a reduction of bone density (Critics: the treatments were not counterbalanced by a supplement of anabolic hormones such as DHEA, androgen or tema/e harmone or calcitonin therapy) 3.

Saito JK, Davis JW, Wasnieh RD, Ross PD. Users of low-dose glueoeortieoids have increased bone loss rales: a longitudinal study. Calei! Tissue lnt. 1995 Aug;57(2):115-9 ("The most common dose was equivalent

to 5 mg!day of prednisone; fewer than 15% of users had taken doses equivalent to 10 mg/day or more':· Critics: the treatment was not counterbalanced by a supp/ement of anabolic hormones; patients were o/d : a mean of 64 yrs for women and 68 yrs for men, an age where the decline in anabolic hormones is important, Jeaving the body unprotected against any supplement of a catabalic hormone) 4.

5.

Krogsgaard MR, Thamsborg G, Lund B.[Bone loss during low dose glueocortieoid treatment in patients with polymyalgia rheumatiea. A double-blind, prospeetive eomparison between prednisolone and deflazaeort. Ugeskr Laeger. 1997 Jul 21;159(30):4641-4 MeKenzie R, Reynolds JC, O'Fallon A, Dale J, Deloria M, Blackwelder W, Straus SE. Deereased bone mineral density during low dose glueocortieoid administration in a randomized, placebo eontrolled trial. J Rheumatol. 2000 Sep;27(9):2222-6 ("a dose of 25 to 35 mg/day (equivalent to abaut 7.5 mg prednisone/day) for 12 weeks (causes) a mean decrease in bane mineral density from baseline of the lateral spine of -2.0% and a mean

change of the anteroposterior spine of -0.8% compared to placebo + 1.0% and +0.2%'; Critic: above 4 mg/day of prednisolone or 20 mg!day of hydrocortisone us, the bane density decreases unless a supplement of anabolic hormones is added) 6.

Sambrook PN, Eisman JA, Champion GD, Poeock NA. Sex hormone status and osteoporosis in postmenopausal women with rheumatoid arthritis. Arthritis Rheum. 1988 Aug;31(8):973-8 (8.2 mg of

prednisone a/one causes reduces significant/y the bane density of the lumbar spine, not of the femoral neck) 7.

Buckley LM, Leib ES, Cartularo KS, Vaeek PM, Cooper SM. Effects of low dose cortieosteroids on the bone mineral density of patients with rheumatoid arthritis. J Rheumatol. 1995 Jun;22(6):1055-9 (5-7 mg/day significantly reduces solely the bane density of the Jumbar spine, not of the femoral neck, while 1-4 mglday

8.

Lipworth BJ. Systemic adverse effects of inhaled eorticosteroid therapy: A systematie review and meta­

prednisone does not effect bane density of the lumbar spine, nor of the femoral neck) analysis. Arch lntern Med 1999 May 10;159(9):941-55 (Jnhaled corticosteroids in doses above 1.5 mg!d (0.75

mg!d for fluticasone propionate) may be associated with a significant reduction in bane density, although the risk for osteoporosis may be obviated by post-menopausal estrogen replacement therapy) Studies with no effect of glucocortioid treatment on bone density: studies with up to 58 months of treatment and 6 mg/day of methyprednisolone 9.

10.

Contreras LN, Rizzo L, Gomez RM, Zanehetta JR, Rossi MA, Kral M, Masini AM, Bruno OD. Long-term low­ dose glucocorticoid therapy in hyperandrogenized women: utility and effects on bone mineral eontent and hypothalamie-pituitary-adrenoeortieal funetion. Horm Res. 1991;35(3-4):142-5 ('1reatment with 1-6 mg oral evening doses of 16 beta methylprednisone for 12-58 months: absence of quantitative bane mass reduetion and normal corticotrope reserve were observed even after 58 months of daily steroid administration'? van Everdingen AA, Siewertsz van Reeserna DR, Jaeobs JW, Bijlsma JW. Low-dose glueocorticoids in early rheumatoid arthritis: diseordant effeets on bone mineral density and fraetures? Clin Exp Rheumatol. 2003 Mar­ Apr;21(2):155-60 (No significant effect on bane density, but a non significant increase in vertebral fractures)

616

1-4 mg/day of prednisone does not effect the bone density of the lumbar spine or femoral neck), while 5-7 mg/day reduces significantly solely the bone density of the lumbar spine, not of the femoral neck 11.

Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Effects of low dose corticosteroids on lhe bone mineral density of patients with rheumatoid arthritis. J Rheumatol. 1995 Jun;22(6):1055-9

A risk of bone loss may be avoided with a substitution dosage of 20 mg or even 15 mg hydrocortisone per day 12.

Wichers M, Springer W, Bidlingmaier F, Klingmuller D. How hydrocortisone substitution influences the quality of life and the bane metabolism of patients with secondary hypocortisolism. Eur J Clin lnvest 2000 Dec;30 Suppl 3:55-7

Studies with beneficiai effect of glucocortioid treatment on bones Beneficiai effect of prednisolone on bone density in rheumatoid arthritis Haugeberg G, Strand A; Kvien TK, Kirwan JR. Reduced loss of hand bane density with prednisolone in early rheumatoid arthritis. Results from a randomized placebo-controlled trial. Arch lntern Med.2005;165:1293-7

13.

Beneficiai effect of cortisol against bone resortion in vitro Krieger NS, Frick KK, Bushinsky DA. Cortisol inhibits acid-induced bone resorption in vitro. J Am Soe Nephrol. 2002 Oct;13(10):2534-9 15. Sandberg AL, Raisz LG, Wahl LM, Simmons HA. Enhancement of complement-mediated prostaglandin synthesis and bane resorption by arachidonic acid and inhibition by cortisol. Prostaglandins Leukot Med. 1982 14.

May;8(5):419-27 16.

Atkins D, Peacock M. A comparison of the effects of the calcitonins, steroid hormones and thyroid hormones on the response of bane to parathyroid hormone in tissue culture. J Endocrinol. 1975 Mar;64(3):573-83

(cortisol at high doses blocks the increase in bane resorption of parathyroid hormone) 1t is important to join treatments with anabolic hormones that counterbalance any adverse effects of glucocorticoid treatment

With calcitonin Kotaniemi A, Piirainen H, Paimela L, Leirisalo-Repo M, Uoti-Reilama K, Lahdentausta P, Ruotsalainen P, Kataja M, Vaisanen E, Kurki P. ls continuous intranasal salmon calcitonin effective in treating axial bane loss in patients with active rheumatoid arthritis receiving low dose glucocorticoid therapy? J Rheumatol. 1996 Nov;23(11):1875-9 (calcitonin-users increased in bane density, while the non-calcitonin users decreased in

17.

bane density) 18.

Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Pocock N, Eisman J. Prevention of corticosteroid bane loss. Osteoporos lnt. 1993;3 Suppl 1 :141-3.

19.

Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Pocock N, Eisman J. Prevention of corticosteroid osteoporosis. A comparison of calcium, calcitriol, and calcitonin. N Engl J Med. 1993 Jun 17;328(24):1747-52

20.

Kapetanakis El, Antonopoulos AS, Antoniou TA, Theodoraki KA, Zarkalis DA, Sfirakis PD, Chilidou DA, Alivizatos PA. Effect of long-term calcitonin administration on steroid-induced osteoporosis after cardiac transplantation. J Heart Lung Transplant. 2005 May;24(5):526-32.

21.

Cappio F, Colombo MD, Caputo R. of salmon calcitonin nasal spray in the prevention of corticosteroid-induced osteoporosis in bullous diseases. G ltal Dermatol Venereol. 1990 Dec;125(12):LXI-LXIV

With female hormone replacement Sambrook P, Birmingham J, Champion D, Kelly P, Kempler S, Freund J, Eisman J. Postmenopausal bane loss in rheumatoid arthritis: effect of estrogens and androgens. J Rheumatol. 1992 Mar;19(3):357-61. (tema/e

22.

HRT was efficient to block any excess bane /oss that 7.5mglday of prednisolone caused in the HRT-untreated patients during 0.9 yrs) With GH 23.

Kovacs G, Fine RN, Worgall S, Schaefer F, Hunziker EB, Skottner-Lindun A, Mehls O. Growth hormone prevents steroid-induced growth depression in health and uremia. Kidney lnt. 1991 Dec;40(6):1032-40.

24.

Giustina A, Bussi AR, Jacobello C, Wehrenberg WB. Effects of recombinant human growth hormone (GH) on bone and intermediary metabolism in patients receiving chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone. J Clin Endocrinol Metab. 1995 Jan;80(1):122-9. (In

patients receiving chronic glucocorticoid treatment, GH administration may significantly antagonize severa/ side-effects of long term glucocorticoid administration, such as protein wasting, osteoporosis, and hyperlipidemia, and T-helper/T-suppressor ce/1 ratio)

617

25.

Oehri M, Ninnis R, Girard J, Frey FJ, Keller U. Effecls of growth hormone and IGF-1 on glucocorticoid-induced prolein calabolism in humans. Am J Physiol. 1996 Apr;270(4 Pl 1):E552-8.

(GH blocked the catabolic effects

of g/ucocorticoids on protein metabolism)

With vitamin D 26.

Schachl E. Ralionale for lrealmenl of involulional osleoporosis in women and for prevenlion and lrealmenl of corticosleroid-induced osleoporosis wilh alfacalcidol. Calcif Tissue In!. 1999 Ocl;65(4):317-27

27.

Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Pocock N, Eisman J. Prevenlion of corticosleroid bone loss. Osleoporos In!. 1993;3 Suppl 1:141-3.

With biphosphonates 28.

Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderolh DH, Adami S, Eusebio RA, Devogelaer JP. Efficacy and safely of daily risedronate in lhe lrealmenl of corticosleroid-induced osleoporosis in men and women: a randomized Iria!. European Corticosleroid-lnduced Osteoporosis Trealmenl Sludy. J Bone Miner Res. 2000 Jun;15(6):1006-13

29.

Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M, Zizic TM, Wallach S, Sewell KL, Lukert BP, Axelrod DW, Chines AA. Risedronale lherapy prevenls corticosleroid-induced bone loss: a lwelve-monlh, mullicenler,

randomized,

double-blind,

placebo-conlrolled, parallel-group sludy.

Arthrilis Rheum.

1999

Nov;42(11):2309-18 30.

Jenkins EA, Walker-Bone KE, Wood A, McCrae FC, Cooper C, Cawley Ml. The prevenlion of corticosleroid­ induced bone loss wilh intermittenl cyclical elidronale. Scand J Rheumalol. 1999;28(3):152-6

31.

Homik JE, Cranney A, Shea B, Tugwell P, Wells G, Adachi JD, Suarez-Aimazor ME. A metaanalysis on lhe use of bisphosphonates in corticosteroid induced osteoporosis. J Rheumatol. 1999 May;26(5):1148-57

32.

Roux C, Oriente P, Laan R, Hughes RA, lttner J, Goemaere S, Di Munno O, Pouilles JM, Horlait S, Cortei B. Randomized trial of effect of cyclical etidronate in lhe prevenlion of corticosleroid-induced bone loss. Ciblos Sludy Group. J Clin Endocrinol Melab. 1998 Apr;83(4):1128-33

With sodium floride 33.

Lems WF, Jacobs WG, Bijlsma JW, Croone A, Haanen HC, Houben HH, Gerrils Ml, van Rijn HJ. Effect of sodium fluoride on lhe prevenlion of corticosleroid-induced osleoporosis. Osleoporos In!. 1997;7(6):575-82

Exercise 34.

Brailh RW, Mills RM, Welsch MA, Keller JW, Pollock ML. Resislance exercise lraining restares bone mineral densily in heart lransplant recipienls. J Am Coll Cardiol. 1996 Nov 15;28(6):1471-7

35.

(6 months of resistance exercise, consisting of low back exercise that iso/ates the /umbar spine and a regimen of variable resistance exercises, restares BMD toward pretransplantation leveis.)

Only very few patients on glucocorticoids (average dose 10 mg/day) follow an adjuvant therapy for prevention of osteoporosis (vit. D, hormone replacement) 36.

Hougardy DM, Pelerson GM, Bleasel MD, Randall CT. ls enough attenlion being given to lhe adverse effecls of corticosteroid lherapy? J Clin Pharm Ther. 2000 Jun;25(3):227-34 (Only 21% of ali patients on oral

37.

corticosteroids and 31% of those who had been taking oral corticosteroids for at /east one year were receiving medication for osteoporosis prevention, and only 15% of women over 45 years of age and on oral corticosteroid therapy were taking hormone replacement therapy) Buckley LM, Marquez M, Feezor R, Ruffin DM, Benson LL. Prevenlion of corticosleroid-induced osleoporosis: resulls of a palienl survey. Arthritis Rheum. 1999 Aug;42(8):1736-9 ("29 % reported having a bone density test, 29% were taking calcium supp/ements, and 45% were receiving vitamin O. 40 % of postmenopausal (PMP) women were receiving HRT and 14%, bisphosphonate treatment. 42 % of PMP women were receiving no preventive treatment. '?

618

MEMORY LOSS ANO ALZHEIMER'S DISEASE: DOUBTS ON GLUCOCORTICOID USE? Arguments against the use of glucocorticoids in case of memorv loss The worsening of the memory or neurons necessary for memory with cortisol or other glucocorticoid treatment 120. Chen H, Sun S, Mei Y, Liu C, Liu A, Tong E. The effect of beta-amyloid on neurons and the influence of glucocorticoid and age on such effect. J Huazhong Univ Sei Technolog Med Sei.2002;22(3):250-2 121. Keenan PA, Jacobson MW, Soleymani RM, Mayes MD, Stress ME, Yaldoo DT. The effect on memory of chronic prednisone treatment in patients with systemic disease. Neurology.1996 Dec;47(6):1396-402. Data that glucocorticoid treatment has no effects, adverse or beneficiai, in case of memory loss No effect of glucocorticoids in Alzhiemer's disease 122. Aisen PS, Davis KL, Berg JD, Schafer K, Campbell K, Thomas RG, Weiner MF, Farlow MR, Sano M, Grundman M, Thal LJ.A randomized controlled trial of prednisone in Alzheimer's disease.Alzheimer's Disease Cooperativa Study.Neurology. 2000 Feb 8;54(3):588-93. Arguments that glucocorticoid treatment may be beneficiai in case of memory loss Reduced glucocorticoid response in Alzheimer's disease 123.

Linder J, Nolgard P, Nasman B, Back O, Uddhammar A, Olsson T. Decreased peripheral glucocorticoid sensitivity in Alzheimer's disease. Gerontology. 1993;39(4):200-6

Lower glucocorticoid receptor leveis in Alzheimer's disease 124.

Armanini D, Vecchio F, Basso A, Milone FF, Simoncini M, Fiore C, Mattarello MJ, Sartorato P, Karbowiak I. Alzheimer's

disease:

pathophysiological

implications

of

measurement

oi

plasma

cortisol,

plasma

dehydroepiandrosterone sullate, and lymphocytic corticosteroid receptors.Endocrine. 2003 Nov;22(2): 113Memory loss: correlation with lower cortisol leveis 296.

Souza-Talarico JN, Chaves EC, Lupien SJ, Nitrini R, Caramelli P. Relationship Between Cortisol Leveis and Memory Performance may be Modulated by the Presence or Absence oi Cognitiva lmpairment: Evidence lrom Healthy Elderly, Mild Cognitiva lmpairment and Alzheimer's Disease Subjects. Alzheimers Ois. 201O Jan;19(3):839-48 (Cortisof levels were associaled wilh better memory performance in heaflhy elderly, bul nol

in palienls wilh memory impairmenl} 297.

Preuss D, Schools D, Woll OT. Associations between endogenous cortisol leveis and emotional memory in

298.

Nater UM, Moor C, Okere U, Stallkamp R, Martin M, Ehlert U, Kliegel M. Performance on a declarativa

young women: inlluence oi encoding instructions. Stress.2009;12(5):379-87 memory task is better in high than low cortisol responders to psychosocial stress. Psychoneuroendocrinology. 2007 Jul;32(6):758-63 299. McCormick CM, Lewis E, Somley B, Kahan TA. Individual differences in cortisol leveis and performance on a test oi executiva lunction in men and women. Physiol Behav. 2007 May 16;91(1):87-94

( Higher cortiso/ «

leveis ai lhe beginning of lhe lesl session were associaled wilh more errors in women on lhe WCST and fewer errors in men'j 300. Smeets T, Otgaar H, Candel I, Woll OT. True or lalse? Memory is differentially affected by stress-induced cortisol elevations and sympathetic activity at consolidation and retrieval. . Psychoneuroendocrinology. 2008 Nov;33(10):1378-86 301. Andreano JM, Arjomandi H, Cahill L. Menstrual cycle modulation oi the relationship between cortisol and long­ term memory. Psychoneuroendocrinology. 2008 Jul;33(6):874-82 302. Schwabe L, Bohringer A, Chatterjee M, Schachinger H. Effects oi pre-learning stress on memory for neutral, positive and negativa words: Different roles oi cortisol and autonomic arousal. Neurobiol Learn Mem. 2008 Ju1;90(1 ):44-53 303. Nater UM, Moor C, Okere U, Stallkamp R, Martin M, Ehlert U, Kliegel M. Performance on a declarativa memory task is better in high than low cortisol responders to psychosocial stress. Psychoneuroendocrinology. 2007 Jul;32(6):758-63 304.

Abercrombie HC, Speck NS, Monticelli RM. Endogenous cortisol elevations are related to memory lacilitation only in individuais who are emotionally aroused.. Psychoneuroendocrinology.2006 Feb;31(2):187-96

305.

Nakayama Y, Takahashi T, Radlord MH. Cortisol leveis and prospectiva and retrospectiva memory in humans.Neuro Endocrinol Lett. 2005 Oct;26(5):599-602

619

Memory improvement for stressful events or avoidance reactions with glucocorticoid treatment 306.

Yehuda R, Harvey PD, Buchsbaum M, Tischler L, Schmeidler J. Enhanced effects of cortisol administration on episodic

and

working

memory

in

aging

veterans

with

PTSD.

Neuropsychopharmacology.

2007

Dec;32(12):2581-91 307.

Kuhlmann S, Wolf OT. Arousal and cortisol interact in modulating memory consolidation in healthy young men. Behav Neurosci. 2006 Feb;120(1):217-23

308.

Peeters BW, Broekkamp CL.

lnvolvement of corticosteroids in lhe processing of stressful life-events. A

possible implication for lhe development of depression. J Steroid Biochem Moi Biol. 1994 Jun;49(4-6):417-27 309.

Sandi C, Rose SP, Mileusnic R, Lancashire C. Corticosterone facilitates long-term memory formation via enhanced glycoprotein synthesis. Neuroscience. 1995 Dec;69(4):1087-93

310.

Roozendaal B, Carmi O, McGaugh JL. Adrenocortical suppression blocks lhe memory-enhancing effects of amphetamine and epinephrine. Proc NatlAcad Sei USA. 1996 Feb 20;93(4):1429-33.

311.

Roozendaal B, McGaugh JL. The memory-modulatory effects of glucocorticoids depend on an intact stria terminalis. Brain Res. 1996 Feb 19;709(2):243-50

312.

Roozendaal B, McGaugh JL. Amygdaloid nuclei lesions differentially affect glucocorticoid-induced memory enhancement in an inhibitory avoidance task. Neurobiol Learn Mem. 1996 Jan;65(1):1-8

Anecdotal report on dementia reversed with glucocorticoid treatment 313.

Basavaraju N, Phillips SL. Cortisol deficient state. A cause of reversible cognitiva impairrnent and delirium in lhe elderly.J Am Geriatr Soe. 1989 Jan;37(1):49-51

620

CORTISOL DEFICIENCY with SERUM CORTISOL LABORATORY TESTS within the REFERENCE RANGE: TO TREAT OR NOT TO TREAT?

Should individuais with symptoms and signs of cortisol deficiency, but serum cortisol levels within the normal reference range, be treated with hydrocortisone or one of its glucocorticoid derivatives?

Common view:

The reference range: the upper and lower limits oi the reference range oi a cortisol laboratory discriminate between adrenal disease and adrenal health (below the lower limit = adrenal cortex deliciency, within: healthy adrenals, above = adrenal cortex excess). •

The health range: is considered to correspond to the reference range (as is oflen the case for most other laboratory tests too, except for the cholesterol tests where reference ranges have been adapted}. Treatment: only patients with leveis below the lower limit of the reference range are considered candidates for hydrocortisone or glucocorticoid supplementation.

Scientific research view: •

Reference range: In laboratory tests, the reference range is usually not a health range, but a statistical range that contains by definition for a hormone levei such as cortisol for example the leveis of 95% of the patient population that goes to the laboratory, while 2.5 % of patients will have a levei below the range and 2.5 % above the range. lf for a test a whole population is hormone deficient (the estradiol test for postmenopausal women for example), there will still be a reference range with 95% of the population having leveis within the reference range.

Health ranges: Research is aimed at finding which leveis of a hormone such as cortisol is associated with disease, leveis that may indicate a deficiency of the hormone, or an excess. To discriminate between healthy and deficient or excessive hormone leveis scientists may use: SEGMENTS of the patient population: In this case, the hormone (cortisol) leveis of much larger parts of o the population are compared with one another: the upper half (50 %) of (hormone) leveis found in a patient population is compared with the lower half of (hormone) leveis, or the upper tertile (33.3%) of leveis with the lower tertile, or most oflen the upper quartile (25%) of leveis with the lower quartile. More rarely, the upper quintile (20%), sextile (sixth} or decile (10%) of leveis is compared with the lower quintile, sextile or decile of leveis. Often patients are reported to be healthy when their hormone levei is in the upper decile, sextile, quintile, quartile, tertile, half of the leveis found in other people. They are found to be sick or to have an increased risk of disease when their (hormone) levei is in the corresponding lower segment of the population. The health rangeis thus the upper segment oi leveis found in the population that is studied. Values be/owthis segment, in particular belonging to the lowest

o

o

segment of (hormone) leveis, are considered to form the range linked with an increased risk of disease. For catabolic hormones such as cortisol and thyroid hormones, sometimes a U-shaped distribution of hormone leveis is seen with both extremities -the upper and lower segments of the population - being related to a greater incidence of pathology, while the middle quintiles, quartiles or tertile are linked to health. CUT-OFF LEVELS. In many investigations where sick people are compared to healthy persons the average levei of a hormone is found to be significantly lower in patients with disease than in healthy contrais. When the difference between the two groups is large enough, cut-off leveis can be determined by calculating the mean levei between the higher (mean) healthy levei and the lower (mean) pathological levei. The cut-off levei may determine a border or limit between hormone healthy leveis and leveis with increased risk of disease. Leveis of hormones such as cortisol that are above the cut­ off levei are considered to be in the healthy range, while those beneath it are considered deficient. LINEAR RELATIONSHIPS, which may be found between the levei of a hormone such as cortisol and the risk of a disease. Finding an inverse relationship or association of a hormone levei such as that of cortisol with a disease means that the higher the hormone levei is the less risk there is for the patient to have the disease. In other words, a person has then the greatest chances to be healthy and not have the disease when his levei is among the highest leveis found in the population. Theoretically, it is better for a patient to be in the highest 1 % leveis of a population than any value below it. A specific health range does not necessarily exist here, but rather a health target try to be at the higher leveis oi the laboratory test.

Treatment: Who should be treated with small safe daily doses of hydrocortisone or a glucocorticoid derivative? Patients with signs and symptoms of cortisol deficiency and whose cortisol leveis of cortisol are situated below

621

lhe lower limit of lhe reference range or borderline low within this range, situated in a lower segment (lower half, tertile, quartile, .. ) of lhe population leveis, or below a cut-off value.

Out of caution, we recommend no! to

overtreat patients with hydrocortisone, but rather to aim at putting cortisol leveis in lhe middle tertile of lhe population leveis as at least one study showed lha! cortisol leveis within lhe middle tertile were lhe less linked to disease (depression, reter to Bremmer MA, 2007). In acute or severe disease, higher doses of cortisol or one of its derivatives may transiently be necessary to overcome the disease.

Studies with healthy range of serum cortisol leveis above the 901h percentile of serum cortisol levels- Below this limit, the risk of disease, dysfunction or dying is increased: Most studies that show an inverse association between cortisol leveis and the risk of disease/dysfunctionldying ar a direct association with petformance belong to this group In these investigations, lhe serum leveis of cortisol were found to be increasingly healthier at progressively higher leveis within lhe reference range or even, in case of disease, above lhe upper reference limit. Thus, at increasingly higher cortisol levels, there is progressively:

Less morbidity and mortality in children with severe meningococcal disease 1.

De Kleijn ED, Joosten KF, Van Rijn B, Westerterp M, De Groot R, Hokken-Koelega AC, Hazelzet JA. Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome

(> 3x lower serum cortiso/ leveis in non-survivors than in survivors; > 15x higher serum ACTH in children who died than in survivors. lnverse associations between The median cortisoi:ACTH ratio and disease severity. The ratio

in children with severe meningococcal disease. Pediatr lnfect Dis J. 2002 Apr;21(4):330-6

progressively decreased depending on the disease severity categories) Higher leveis of alertness during wakefulness as reflected in the waking EEG beta activity in healthy human subjects 2.

Chapotot

F,

Gronfier

C,

Jouny

C,

Muzet

A,

Brandenberger

G.

Cortisol

secretion

is

related

to

electroencephalographic alertness in human subjects during day1ime wakefulness. J Clin Endocrinol Metab. 1998 Dec;83(12):4263-8

Less fatigue and depression scores in victims of mobbing with adjustment disorders 3.

Rocco A, Martocchia A, Frugoni P, Baldini R, Sani G, Di Simone Di Giuseppe B, Vairano A, Girardi P, Monaco E, Tatarelli R, Falaschi P. lnverse correlation between morning plasma cortisol levels and MMPI psychasthenia and depression scale scores in victims of mobbing with adjustment disorders. Neuro Endocrinol Lett. 2007 Oct;28(5):610-3 (The serum cortiso/ was significantly and negatively related to psychasthenia and depression)

More extraversion, less neuroticism 4.

LeBianc J, Ducharme MB. lnfluence of personality traits on plasma leveis of cortisol and cholesterol. Physiol Behav. 2005 Apr 13;84(5):677-80. (Extraversion was positively correlated to plasma leveis of cortisol and

cholestero/ while the correlation was negative for neuroticism) Less severe psychopathic traits in violent male offenders 5.

Holi M, Auvinen-Lintunen L, Lindberg N, Tani P, Virkkunen M. lnverse correlation between severity of psychopathic traits and serum cortisol leveis in young adult violent male offenders. Psychopathology. 2006;39(2):102-4.

Better retrospective memory performance for neutra! words 6.

Nakayama Y, Takahashi T, Radford MH. Cortisol levels and prospective and retrospective memory in humans. Neuro Endocrinol Lett. 2005 Oct;26(5):599-602 (Significant positive association between sa/ivary cortiso/ levels

and retrospective memory petformance for neutra/ words) Better memory in individuais who are emotionally aroused 7.

Abercrombie HC, Speck NS, Monticelli RM. Endogenous cortisol elevations are related to memory facilitation only in individuais who are emotionally aroused. Psychoneuroendocrinology. 2006 Feb;31(2):187-96

622

lncreased memory for emotionally arousing pictures obtained with focused attention or arousal in young women 8.

Preuss D, Schoofs D, Woll OT. Associations between endogenous cortisol leveis and emotional memory in young women: inlluence oi encoding instructions. Stress. 2009;12(5):379-87.Department oi Cognitive Psychology, Ruhr-University Bochum, Bochum, Germany. (positive correlation between basal salivary cortisol

leveis and memory for emotionally arousing pictures obtained with focussed attention or arousal (intentional not incidental memory formation) Less pathogenic hyperphosphorylated tau-proteins in patients with Alzheimer's disease 9.

Laske C, Stransky E, Fritsche A, Eschweiler GW, Leyhe T. lnverse association oi cortisol serum leveis with T­ tau, P-tau 181 and P-tau 231 peptide leveis and T-tau/Abeta 1-42 ratios in CSF in patients with mild Alzheimer's disease dementia. Eur Arch Psychiatry Clin Neurosci. 2009 Mar;259(2):80-5 (cortisol serum leveis were

significantly inversely correlated with T-tau, P-tau 181 and P-tau 231 protein leveis and T-tau/Abeta 1-42 ratios) Less severity of dementia in women with depression and primary degenerative dementia 1O. Bilikiewicz A, Bidzan L. [Dependence on serum cortisol level or the severity oi intellectual impairment in primary degenerative dementias] Psychiatr Pol. 1990 Jan-Feb;24(1):2-7 (A negative correlation between cortiso/level

and severity of dementia among female patients with depression was found) Better erectile function in men with sexual dysfunction 11. Kobori Y, Koh E, Sugimoto K, lzumi K, Narimoto K, Maeda Y, Konaka H, Mizokami A, Matsushita T, lwamoto T, Namiki M.The relationship oi serum and salivary cortisol leveis to male sexual dyslunction as measured by the lnternational lndex oi Erectile Function. lnt J lmpot Res. 2009 Jui-Aug;21(4):207-12 (Cortisol levels showed

significant inverse correlations with a portion of the 1/EF score) Lower body mass index in men 12. Stolk RP, Lamberts SW, de Jong FH, Pois HA, Grobbee DE. Gender differences in the associations between cortisol and insulin in healthy subjects. J Endocrinol. 1996 May;149(2):313-8 (In men, an inverse association between early morning lree cortisol serum levei and body mass index was observed) Studies with healthy range of serum cortisol levels in the upper quartile (highest 25%) of leveis In patients with an acute myocardial infarct: 13. Reynolds RM, Walker BR, Haw S, Newby DE, Mackay DF, Cobbe SM, Pell AC, Fischbacher C, Pringle S, Murdoch D, Dunn F, Oldroyd K, Macintyre P, Oorourke B, Pell JP. Low serum cortisol predicts early death after acute myocardial inlarction. Crit Care Med. 2010 Mar;38(3):973-975 (A low serum cortisol in the bottom quartile

increases by 9x the risk of early death after acute myocardial infarction)

Studies with the healthy range for serum cortisol corresponding to the middle tertile (33.3%) of leveis ("U­ shape distribution") 14. Bremmer MA, Deeg DJ, Beekman AT, Penninx BW, Lips P, Hoogendijk WJ. Major depression in late lile is associated with both hypo- and hypercortisolemia. Biol Psychiatry. 2007 Sep 1;62(5):479-86 (lncreased risks of

depression at serum cortisol levels in the bottom tertile for females, patients with joint diseases and smokers, or at serum leveis in the upper tertile for men, elderly patients, patients with cognitive impairment, patients using anti-inflammatory medications)

623

Studies where the healthy range of (baseline) serum cortisol leveis was reported to be situated above a cut­ off levei within the reference range or even above it in case of severe disease (reference range for children in intensive care uni!: 65-2110 nmoi/L (2.5- 76 �g/dl) cfr Bone et ai. Pediatrics. 2002;110:563--9; adults: 140-700 nmol/, 5 - 25 �g/dl)

Thresholds or cutoff leveis of serum total cortisol levels for disease within the reference range The cutoff levei is

CUTOFF levei of Serum Cortisol

7 �g/dl

193 nmol/1

Within lhe reference ranges of children and adults for serum total cortisol

Above lhe adult reference range

Morbidity at or BELOW the cutoff levei Adrenal (cortisol) deficiency in critically ill children Adrenal (cortisol) deficiency in

9 �g/dl

248 nmol/1

children with septic shock; higher risk of (catecholamine-

Publication

Menon K, Clarson C. Adrenal function in pediatric criticai illness. Pediatr Cri! Care Med. 2002;3:112-6

Pizarro CF, Troster EJ, Damiani D, Carcillo JA. Absolute and relative adrenal insufficiency in children with septic shock. Cri! Care Med. 2005;33:855-9

Commen

In children with criticai illness

In children with septic shock

resistant) shock

14.4 �g/dl

27 �g/dl

400 nmol/1

750 nmol/1

Adrenal (cortisol) deficiency in children with meningococcal disease

Higher mortality

Bone M, Diver M, Selby A, Sharples A, Addison M, Clayton P. Assessment of adrenal function in lhe initial phase of meningococcal disease. Pediatrics. 2002;110:563-9 (lnappropriate adrenal stress responses {lnsufficient cortisol secretion as response to ACTH stimulation in infants with serum cortisol below 400 nmol/1) Joosten KF, de Kleijn ED, Westerterp M, de Hoog M, Eijck FC, Hop WCJ, et ai. Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab. 2000;85:3746-53

624

In children with sepsis

Chapter eleven:

DHEA

Senescence is associated with a decline of the adrenai·DHEA axis Senescence is associated with a decline in adrenal androgen leveis Martinez Jabaloyas JM, Queipo Zaragoza A, Ferrandis Cortes C, Queipo Zaragoza JA, Gil Salom M, Chuan 1. Nuez P. Changes in sexual hormones in a male population over 50 years of age. Frequency of low testosterone leveis and risk factors. Actas Urol Esp. 2008 Jun;32(6):603-1O 2. Debing E, Peeters E, Duque! W, Poppe K, Velkeniers B, Van den Brande P. Endogenous sex hormone leveis in postmenopausal women undergoing carotid artery endarterectomy. Eur J Endocrinol. 2007 Jun;156(6):68793 Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, Blackman MR, Metter EJ. Relationship between 3. androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab. 2006 Feb;290(2):E234-42 (DHEAS was correlated negatively with age) 4. Fukui M, Kitagawa Y, Nakamura N, Kadono M, Yoshida M, Hirata C, Wada K, Hasegawa G, Yoshikawa T. Serum dehydroepiandrosterone sulfate concentration and carotid atherosclerosis in men with type 2 diabetes. Atherosclerosis. 2005 Aug;181(2):339-44 (A negative correlation was found between serum DHEA-S concentration and age (P < 0.0001)) Bernini GP, Sgro' M, Moretti A, Argenio GF, Barlascini CO, Cristofani R, Salvetti A. Endogenous androgens 5. and carotid intimai-mediai thickness in women. J Clin Endocrinol Metab. 1999 Jun;84(6):2008-12 Morley JE, Kaiser F, Raum WJ, Perry HM 3rd, Flood JF, Jensen J, Silver AJ, Roberts E. Potentially predictive 6. and manipulable blood serum correlates of aging in lhe healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and lhe ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sei U S A. 1997 Jul 8;94(14):7537-42 7. Birkenhãger-Gillesse EG, Derksen J, Lagaay AM. Dehydroepiandrosterone sulphate (DHEAS) in the oldest old, aged 85 and over. Ann N Y Acad Sei. 1994 May 31 ;719:543-52 (DHEAS leveis decreased fourfold 8.

2. 3.

4. 5.

between the young adults and those aged 85 and over. In men this decrease continued after the age of 85) Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 1984;59(3):551-5 Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H. Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab. 1992;75(4):1002-4 Labrie F, Belanger A, Cusan L, Gomez JL, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 1997 Aug;82(8):2396-402 Nafziger AN, Bowlin SJ, Jenkins PL, Pearson TA. Longitudinal changes in dehydroepiandrosterone concentrations in men and women. J Lab Clin Med. 1998 Apr;131(4):316-23 Gapstur SM, Gann PH, Kopp P, Colangelo L, Longcope C, Liu K. Serum androgen concentrations in young men: a longitudinal analysis of associations with age, obesity, and race. The CAROlA male hormone study. Cancer Epidemiol Biomarkers Prev. 2002 Oct;11(10 Pt 1}:1041-7

The anabolic/catabolic hormone balance becomes increasingly inadequate with senescence Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: lhe glucocorticoid cascade 6. hypothesis. Endocr Rev. 1986 Aug;7(3):284-301 7. Valenti G. Neuroendocrine hypothesis of aging: lhe role of corticoadrenal steroids. J Endocrinol lnvest. 2004;27(6 Suppl):62-3 Debigare R, Marquis K, Cote CH, Tremblay RR, Michaud A, LeBianc P, Maltais F. Catabolic/anabolic balance 8. and muscle wasting in patients with COPO. Chest. 2003 Jul;124(1):83-9 Senescence is associated with alterations of the circadian cycle of serum DHEA sulphate: a reduced amplitude up to a disappearance of lhe circadian rhythm Del Ponte A, Di Monte MG, Graziani D, Guagnano MT, Menduni P, Vitullo F, Sensi S. Changes in plasma 9. DHEAS circadian rhythm in elderly men. Prog Clin Biol Res. 1990;341A:791-6 Nicolau GY, Haus E, Lakatua DJ, Bogdan C, Sackett-Lundeen L, Popescu M, Berg H, Petrescu E, Robu E. 10. Circadian and circannual variations of FSH, LH, testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and 17-hydroxy progesterone (17 OH-Prog) in elderly men and women. Endocrinologie. 1985 Oct-Dec;23(4}:22346

625

DHEA treatment may oppose and DHEA deficiency may trigger several mechanisms of senescence Excessive free radical formation: DHEA has antioxidant aetivity 11. lwasaki Y, Asai M, Yoshida M, Nigawara T, Kambayashi M, Nakashima N. Dehydroepiandrosterone-sulfate inhibits nuclear factor-kappaB-dependent transcription in hepatocytes, possibly through antioxidant effect. J Clin Endoerinol Metab. 2004 Jul;89(7):3449-54 Bekesi G, Kakues R, Varbiro S, Racz K, Sprintz D, Feher J, Szekaes B. In vitro effeets of different steroid 12.

13.

hormones on superoxide anion production of human neutrophil granuloeytes. Steroids. 2000 Dec;65(12):88994 Bednarek-Tupikowska G, Gosk I, Szuba A, Bohdanowiez-Pawlak A, Kosowska B, Bidzinska B, Milewicz A. lnfluence of dehydroepiandrosterone on platelet aggregation, superoxide dismutase activity and serum lipid peroxide concentrations in rabbits with induced hypercholesterolemia. Med Sei Monit. 2000;6(1 ):40-5

Advanced glycation end products 14. Brignardello E, Runzo C, Aragno M, Catalano MG, Cassader M, Perin PC, Boccuzzi G. Dehydroepiandrosterone administration eounteraets oxidative imbalance and advanced glycation end product formation in type 2 diabetic patients. Diabetes Care. 2007 Nov;30(11 ):2922-7 lmmune deficiency: lmmune deficiency: the association with lower DHEA leveis 15. Martínez-Taboada V, Bartolomé MJ, Amado JA, Blanco R, García-Unzueta MT, Rodríguez-Valverde V, López-Hoyos M. Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of lhe hypothalamic-pituitary-adrenal axis. Mech Ageing Dev. 2002 Sep;123(11):1477-86 Doldi N, Belvisi L, Bassan M, Fusi FM, Ferrari A. Premature ovarian failure: steroid synthesis and 16. 17. 18.

19.

20.

21. 22.

23. 24.

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Lovas K, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison's disease. Clin Endocrinol (Oxf). 2002 May;56(5):581-8 ('Patients with Addison's disease under replacement therapy with

cortisone acetate and fludrocortisone have reduced general health perception and vitality, and increased fatigue. Female patients reported reduced physical function, which might be due to adrenal androgen depletion. .. markedly reduced subjective health status and working ability inmany others. Thus, there might be potential for further refinement of replacement therapy'') 339.

Devogelaer JP, Crabbe J, Nagant de Deuxchaisnes C. Bone mineral density in Addison's disease: evidence for an effect of adrenal androgens on bone mass. Br Med J (Ciin Res Ed). 1987 Mar 28;294(6575):798-800

("indicates that adrenal androgens may be essential for the maintenance of bane mass in postmenopausal women with Addison's disease'') DHEA treatment: interferences

340. 341.

Salek FS, Bigos KL, Kroboth PD. The influence of hormones and pharmaceutical agents on DHEA and DHEA­ S concentrations: a review of clinicai studies. J Clin Pharmacol. 2002 Mar;42(3):247-66 Swinkels LM, Meulenberg PM, Ross HA, Benraad TJ. Salivary and plasma free testosterone and androstenedione leveis in women using oral contraceptivas containing desogestrel or levonorgestrel. Ann Clin Biochem. 1988 Jul;25 ( Pt 4):354-9.

DHEA treatment: safety, minimal side effects

342.

343. 344.

Munarriz R, Talakoub L, Flaherty E, Gioia M, Hoag L, Kim NN, Traish A, Goldstein I, Guay A, Spark R. Androgen replacement therapy with dehydroepiandrosterone for androgen insufficiency and female sexual dysfunction: androgen and questionnaire results. J Sex Marital Ther. 2002;28 Suppl 1:165-73 Rommler A. Adrenopause and dehydroepiandrosterone: pharmacological therapy versus replacement therapy Gynakol Geburtshilfliche Rundsch. 2003 Apr;43(2):79-90 Ritter RH, Cryar AK, Hermans MR. Oral androstenedione-induced impotence and severe oligospermia. Fertil Steril. 2005 Jul;84(1):217

DHEA treatment: follow-up

345. 346.

347.

348.

349.

Bosy TZ, Moore KA, Poklis A. The effect of oral dehydroepiandrosterone (DHEA) on the urine testosterone/epitestosterone (T/E) ratio in human male volunteers. J Anal Toxicol. 1998 Oct;22(6):455-9 Dehennin L, Ferry M, Lafarge P, Peres G, Lafarge JP. Oral administration of dehydroepiandrosterone to healthy men: alteration of the urinary androgen profile and consequences for the detection of abuse in sport by gas chromatography-mass spectrometry. Steroids. 1998 Feb;63(2):80-7 Percheron G, Hogrel JY, Denot-Ledunois S, Fayet G, Forette F, Baulieu EE, Fardeau M, Marini JF; Double­ blind placebo-controlled trial. Effect of 1-year oral administration of dehydroepiandrosterone to 60- to 80-year­ old individuais on muscle function and cross-sectional area: a double-blind placebo-controlled trial. Arch lntern Med. 2003 Mar 24;163(6):720-7 Leder BZ, Leblanc KM, Longcope C, Lee H, Catlin DH, Finkelstein JS. Effects of oral androstenedione administration on serum testosterone and estradiol leveis in postmenopausal women. J Clin Endocrinol Metab. 2002 Dec;87(12):5449-54 Leder BZ, Longcope C, Catlin DH, Ahrens B, Schoenfeld DA, Finkelstein JS. Oral androstenedione administration and serum testosterone concentrations in young men. JAMA. 2000 Feb 9;283(6):779-82

642

IOPICS OF DISCUSSION/

DHEA TREATMENT ANO ADRENAL SUPPRESSION: very weak negative feedback mechanism A treatment with DHEA at physiological does not or poorly inhibit the hypothalamic-pituitary-adrenal axis 1. Stomati M, Monteleone P, Casarosa E, Quirici B, Puccetti S, Bernardi E,Genazzani AD, Rovati L, Luisi M, Genazzani AR. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol 2000 Oct;14(5):342-63 2.

Meno-Tetang GM, Blum RA, Schwartz KE, Jusko WJ. Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women.J Clin Pharmacol 2001 Nov;41(11):1195-205

3.

Barnhart KT, Ereeman E, Grisso JA, Rader DJ, Sammel M, Kapoor S, Nestler JE. The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. J Clin Endocrinol Metab 1999 Nov;84(11):3896-902

(Lntake of

50 mglday of DHEA reduces serum cortisol by 13.2 % less)

DHEA ANO PROSTATE CANCER Eear: DHEA could promote or aggravate hormone dependent cancers, because of its transformation into sex hormones. The effect could be more important in treatment of long duration or at high doses. Eacts: In humans, studies show no significant effect of DHEA on prostate cancer. In mos! animal studies a protective effect of DHEA on prostate cancer is observed. The more the DHEA dose is increased, the more potent the anti­ cancer effect of DHEA is.

Arguments pro DHEA use 1.

Algarte-Genin M, Cussenot O, Costa P. Prevention of prostate cancer by androgens: experimental paradox or clinicai reality. Eur Urol. 2004 Sep;46(3):285-94

Lower serum DHEA and DHEA sulfate leveis have been found in men with prostate cancer 2.

Comstock GW, Gordon GB, Hsing AW. The relationship of serum dehydroepiandrosterone and its sulfate to subsequent cancer of lhe prostate. Cancer Epidemiol Biomarkers Prev. 1993 May-Jun;2(3):219-21

3.

Stahl F, Schnorr D, Pilz C, Dorner G. Dehydroepiandrosterone (DHEA) leveis in patients with prostatic cancer, heart diseases and under surgery stress. Exp Clin Endocrinol. 1992;99(2):68-70

Lower prostate tissue leveis of DHEA and androstenedione are found in recurrent prostate cancer compared to the leveis in benign prostate hypertrophy 4. Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004 Jan 15;10(2):440-8

The serum DHEA sulfate is inversely related with the serum PSA: a high DHEAs is related to a low PSA 5. Ponholzer A, Pias E, Schatzl G, Jungwirth A, Madersbacher S; Austrian Society of Urology. Association of DHEA-S and estradiol serum leveis to symptoms of aging men. Aging Male. 2002 Dec;5(4):233-8

With age, the serum DHEA sulfate progressively declines, while the incidence of human prostate cancer gradually and almost exponentially increases 6.

Labrie F, Luu-The V, Belanger A, Un SX, Simard J, Pelletier G, Labrie C. ls dehydroepiandrosterone a hormone? J Endocrinol. 2005 Nov;187(2):169-96

7.

Data from the Surveillance, Epidemiology, and End Results (SEER) Program Staff. Section 111: lncidence. In: Cancer statistics review 1973-1986. Bethesda, MD: NIH;1989;111.45

DHEA treatment reduces the development of transplants of human prostate cancer in animais 8.

van Weerden WM, van Kreuningen A, Elissen NM, de Jong FH, van Steenbrugge GJ, Schroder FH. Effect of adrenal androgens on the transplantable human prostate tumor. Endocrinology. 1992; 131(6): 2909-13

643

DHEA treatment inhibits prostate cancer promoted by testosterone and estradiol in rats Christov KT, Moon RC, Lantvit DD, Boone CW, Kelloff GJ, Steele VE, Lubet RA, Pezzuto JM. Prostate 9. intraepithelial neoplasia in Noble rats, a potential intermediate endpoint for chemoprevention studies. Eur J Cancer. 2004 Jun;40(9):1404-11 DHEA treatment reduces the frequency and severity of carcinogen (MNU, N-methyi-N-nitrosurea)-induced prostate cancer from -33 to -60 %, whatever the moment of administration of the carcinogen (one week

before, or 20 or 40 weeks after) 10.

11.

Rao KV, Johnson WD, Bosland MC, Lubet RA, Steele VE, Kelloff GJ, McCormick DL. Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone. Cancer Res. 1999;59(13):3084-9 McCormick DL, Rao KV. Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat. Eur Urol. 1999;35(5-6):464-7

DHEA treatment of rats predisposed to develop endocrine testicular Leydig cell tumors inhibits tumor development Rao MS, Subbarao V, Yeldandi AV, Reddy JK. lnhibition of spontaneous testicular Leydig cell tumor 12. development in F-344 rats by dehydroepiandrosterone. Cancer Lett. 1992 ;65(2):123-6. No effect of DHEA on the prostate: Studies that show that the effect of DHEA on human prostate cancer is neutra! Healthy men have a levei of DHEA (sulfate} equal to that of men with benign prostate hyperplasia or prostate cancer, even adjusted to age Schatzl G, Reiter WJ, Thurridl T, Waldmuller J, Roden M, Soregi S, Madersbacher S. Endocrine patterns in 13. patients with benign and malignant prostatic diseases. Prostate. 2000 Aug;44(3):219-24 14. 15. 16. 17.

Bartsch W, Kozak I, Gorenflos P, Becker H, Voigt KD. Concentrations of 3 �-ydroxy androgens in epithelium and strorna of benign hyperplastic and normal human prostate. Prostate. 1986;8(1):3-10 Comstock GW, Gordon GB, Hsing AW. The relationship of serum dehydroepiandrosterone and its sulfate to subsequent cancer of the prostate. Cancer Epidemiol Biomarkers Prev. 1993;2(3):219-21 Stahl F, Schnorr D, Pilz C, Domer G. Dehydroepiandrosterone (DHEA) leveis in patients with prostatic cancer, heart diseases and under surgery stress. Exp Clin Endocrinol. 1992;99(2):68-70 Oesterling JE, Epstein Jl, Walsh PC.The inability of adrenal androgens to stimulate the adult human prostate: an autopsy evaluation of men with hypogonadotropic hypogonadism and panhypopituitarism. J Urol. 1986;136(5):1030-4

The levei of DHEA in the prostate is 6-7 times that in the plasma, but the levei in benign hypertrophic prostates does not differ from that in normal prostates 18.

Bartsch W, Kozak I, Gorenflos P, Becker H, Voigt KD. Concentrations of 3 �-hydroxy androgens in epithelium and stroma of benign hyperplastic and normal human prostate. Prostate. 1986;8(1):3-10

The serum DHEA sulfate levei does not influence the PSA, no significant association Schatzl G, Reiter WJ, Thurridl T, Waldmuller J, Roden M, Soregi S, Madersbacher S. Endocrine pattems in 19. patients with benign and malignant prostatic diseases. Prostate. 2000 Aug;44(3):219-24 Schatzl G, Brossner C, Schmid S, Kugler W, Roehrich M, Treu T, Szalay A, Djavan B, Schmidbauer CP, 20. Soregi S, Madersbacher S. Endocrine status in elderly men with lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary tract function. The Prostate Study Group of the Austrian Society of Urology. Urology. 2000;55(3):397-402 The prostate of men with normal adrenal glands but with no testicular function throughout life (hypogonadotropic hypogonadism or prepubertal castration) is at autopsy atrophic, while that of men with normal adrenal glands and normal testes is enlarged and shows some degree of benign prostatic hyperplasia Oesterling JE, Epstein Jl, Walsh PC. The inability of adrenal androgens to stimulate the adult human prostate: 21. an autopsy evaluation oi men with hypogonadotropic hypogonadism and panhypopituitarism. J Urol. 1986 Nov;136(5):1030-4 DHEA treatment does not increase PSA, nor at a physiologic (50 mg/day; Reiter et ai.), nor at a supraphysiologicdose (100 mg/day; Wallace et ai., Sun et ai.) Reiter WJ, Pycha A, Schatzl G, Pokomy A, Gruber DM, Huber JC, Marberger M. Dehydroepiandrosterone in 22. the treatment oi erectile dyslunction: a prospective, double-blind, randomized, placebo-controlled study. Urology. 1999;53(3):590-4; discussion 594-5 Wallace MB, Lim J, Cutler A, Bucci L. Effects of dehydroepiandrosterone vs androstenedione supplementation 23. in men. Med Sei Sports Exerc. 1999 Dec;31(12):1788-92

644

24.

Sun Y, Mao M, Sun L, Feng Y, Yang J, Shen P. Treatment of dehydroepiandrosterone sulfate. Chin Med J (Engl). 2002 Mar;115(3):402-4

osteoporosis

in

men

using

DHEA treatment at physiologic dose (50 mg/day) does not increase the prostate volume, nor the urinary residual volume 25. Reiter WJ, Pycha A, Schatzl G, Pokomy A, Gruber DM, Huber JC, Marberger M. Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study. Urology. 1999;53(3):590-4 DHEA treatment in vitro has no influence on the growth of prostate stromal cells 26. Le H, Arnold JT, McFann KK, Blackman MR. Dihydrotestosterone and testosterone, but not DHEA or estradiol, differentially modulate IGF-1, IGFBP-2 and IGFBP-3 gene and protein expression in primary cuHures of human prostatic stromal cells. Am J Physiol Endocrinol Metab. 2005 published online Dec 20 Arguments contra DHEA use DHEA administered to castrated rats stimulated the development of an implanted prostate cancer. (critíc: but to obtain an adverse effect rats must first be castrated. Castrated rats have a lower risk of implanted prostate cancer development. DHEA administration normalized the risk of prostate cancer and brought it up to the leve/ of non castrated rats, not above) 27. Schiller CO, Schneider MR, Hartmann H, Graf AH, Klocker H, Bartsch G. Growth-stimulating effect of adrenal androgens on the R3327 Dunning prostatic carcinoma. Urol Res 1991;19(1):7-13 Anecdotal report 149. Jones JA, Nguyen A, Straub M, Leidich RB, Veech RL, Wolf S. Use of DHEA in a patient with advanced prostate cancer: a case report and review. Urology. 1997 Nov;50(5):784-8

645

DHEA and BREAST CANCER Fear: DHEA could promete or aggravate hormone dependent cancers such as breast cancer, because of its transformation into sex hormones. The effect could be more important in treatment of long duration or at high doses. Facts: In premenopausal women high leveis of DHEA are associated with a low risk of breast cancer. Two studies in HRT untreated postmenopausal women show lhe opposite, namely that a high levei of DHEA sulfate is associated with an increased risk of breast cancer. This confirms lhe finding that DHEA inhibits lhe proliferation of breast cancer cells in vitro in lhe presence of oestradiol, but stimulates it in the absence of estradiol. Postmenopausal women should therefore get female hormone replacement when they receive corrective DHEA therapy. In lhe majority of animal studies a protective effect of DHEA on breast cancer is observed. The higher lhe dose of DHEA, lhe greater lhe anti-cancer effect.

Arguments PRO DHEA use: DHEA may protect premenopausal women and HRT treated postmenopausal women against breast cancer

HUMAN STUDIES Studies with associations between low leveis of DHEA sulfate and an increased risk of breast cancer Rose DP, Stauber P, Thiel A, Crowley JJ, Milbrath JR. Plasma DHEAs, Androstenedione and cortisol, and 1. urinary free cortisol excretion in breast cancer.Europ J Cancer. 1977; 13: 43-7 2. Gomes P, Cassanas G, Halberg F, Hermida R, Robel P, Baulieu EE, Lakatua D, Haus E. Taux sanguin de la DHEA-S et risque de cancer du sein. C R Acad Sei 111. 1988;306(7):261-4 3. Brownsey B, Cameron EH, Griffiths K, Gleave EN, Forres! AP, Campbell H.. Plasma dehydroepiandrosterone sulphate leveis in patients with benign and malignant breast disease., Eur J Cancer. 1972;8(1):131-7 4. Wang DY, Bulbrook RD, Herian M, Hayward JL. Studies on lhe sulphate esters of dehydroepiandrosterone and androsterone in lhe blood of women with breast cancer. Eur J Cancer. 1974;10(8):477-82 Studies with associations between low urinary leveis of DHEA metabolites and an increased risk of breast cancer 5. 6. 7. 8.

Cameron EH, Griffiths K, Gleave E, Stewart HJ, Forres! AP, Campbell H., Benign and malignant breast disease in South Wales: a study of urinary steroids., Br Med J. 1970;4(738):768-71 Bulbrook RD, Hayward JL, Spicer CC, Thomas BS. Abnormal excretion of urinary steroids by women with early breast cancer.Lancei. 1962; 1238-40 Tominaga T, Tei N, Kitamura M, Taguchi T, Kudo Y. Urinary excretion of steroids by Japanese women with breast cancer. Gann 1975 Jun;66(3):305-10 Hindy I, Prajda N, Tapolcsanyi L, Sellei C, Eckhardt S. lnvestigation of 17-ketosteriod excretion in mastopathia and premenopausal breast cancer. Arch Geschwulstforsch 1975;45(5):453-6

Studies with an association between low urinary leveis of DHEA metabolites and aggravation/progression of breast cancer 9. Tominaga T, Tei N, Kitamura M, Taguchi T, Kudo Y. Urinary excretion of steroids by Japanese women with breast cancer. Gann 1975 Jun;66(3):305-1O 10. Hindy I, Prajda N, Tapolcsanyi L, Sellei C, Eckhardt S. lnvestigation of 17-ketosteriod excretion in mastopathia and premenopausal breast cancer. Arch Geschwulstforsch 1975;45(5):453-6 Studies where the DHEA and DHEA sulfate leveis are significantly lower inside the breast cancer tumours compared to healthy breast tissues of control patients 11. Thijssen JH, van Landeghem AA, Poortman J. Uptake and concentration of steroid hormones in mammary tissues. Ann N Y Acad Sei.1986;464:106-16. Studies where low leveis of DHEA sulfate were found in female patients with advanced cancer (with metastases) compared to the levei found in women with loco-regional cancer 12. Lissoni P, Rovelli F, Giani L, Mandala M, Meregalli S, Barni S, Confalonieri G, Bonfanti A. Dehydroepiandrosterone sulfate (DHEAS) secretion in early and advanced solid neoplasms: selective deficiency in metastatic disease.lnt J Biol Markers. 1998;13(3):154-7 With age the levei of DHEA sulfate gradually declines, while at the same time the incidence of breast cancer quickly increases, phenomena that plead against lhe implication of DHEA in lhe genesis of breast cancer, and rather for lhe implication of DHEA deficiency as a factor in favor of breast cancer 13. Labrie F, Luu-The V, Belanger A, Lin SX, Simard J, Pelletier G, Labrie C. ls dehydroepiandrosterone a hormone? J Endocrinol. 2005 Nov;187(2):169-96

646

14.

Cutler SY, Young JL. Third National Cancer Survey: incidence data. Washington DC: National Cancer lnstitute Monograph; 1975; vol. 41

A law serum levei af DHEA has been abserved in ather cancers in wamen: avarian cancer, metastasized avarian cancer, the adult type af acute T cell leukemia, metastasized cancer 15.

Cuzick J, Bulstrode JC, Stratton I, Thomas BS, Bulbrook RD, Hayward JL. A prospective study of urinary

16.

Heinonen PK, Koivula T, Pystynen P. Decreased serum levei of dehydroepiandrosterone sulfate in

androgen leveis and ovarian cancer. lnt J Cancer 1983 Dec 15;32(6):723-6 postmenopausal women with ovarian cancer. Gynecol Obste! lnvest 1987;23(4):271-4 17.

Blaakaer J, Hogdall CK, Hording U, Bennett P, Toftager-Larsen K, Daugaard S,Bock J. Hormonal factors and prognosis in epithelial ovarian cancer: a multivariate analysis. Eur J Obste! Gynecol Reprod Biol 1993

18.

Uozumi K, Uematsu T, Otsuka M, Nakano S, Takatsuka Y, lwahashi M, Hanada S, Arima T. Serum

Sep;51(1):21-7 dehydroepiandrosterone and DHEA-sulfate in patients with adult T-cell leukemia and human T-lymphotropic virus type I carriers.Am J Hematol 1996;53(3):165-8 19.

Lissoni

P,

Rovelli

F,

Giani

L,

Mandala

M,

Meregalli

S,

Barni

S,

Confalonieri

G,

Bonfanti

A.

Dehydroepiandrosterone sulfate (DHEAS) secretion in early and advanced solid neoplasms: selective deficiency in metastatic disease. lnt J Biol Markers. 1998;13(3):154-7 ANIMAL STUDIES : DHEA patently reduces the incidence and develapment af breast cancer in rats that keep their avaries (The effect is proportional to lhe dose (the cancer incidence can be up to less than 10 % of normal mice not treated with DHEA!!) 20.

Li S, Yan X, Belanger A, Labrie F. Prevention by dehydroepiandrosterone of lhe development of mammary carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in lhe rat. Breast Cancer Res Treat. 1994;29(2):203-17.

21.

Lubet RA, Gordon GB, Prough RA, Lei XD, You M, Wang Y, Grubbs CJ. Steele VE, Kelloff GJ, Thomas CF, Moon

RD.

Modulation

of

methylnitrosourea-induced

breast

cancer

in

Sprague

Dawley

rats

by

dehydroepiandrosterone: dose-dependent inhibition, effects of limited exposure, effects on peroxisomal enzymes, and lack of effects on leveis of Ha-Ras mutations. Cancer Res 1998;58(5):921-6 22.

Luo S, Labrie C, Belanger A, Labrie F. Effect of dehydroepiandrosterone on bone mass, serum lipids, and dimethylbenz(a)anthracene-induced mammary carcinoma in lhe rat. Endocrinology 1997 Aug;138(8):3387-94

23.

Luo S, Sourla A, Labrie C, Belanger A, Labrie F. Combined effects of dehydroepiandrosterone and EM-800 on bone mass, serum lipids, and the development of dimethylbenz(A)anthracene-induced mammary carcinoma in lhe rat. Endocrinology 1997;138(10):4435-44

24.

Ratko TA, Detrisac CJ, Mehta RG, Kelloff GJ, Moon RC. lnhibition of rat mammary gland chemical carcinogenesis by dietary dehydroepiandrosterone or a fluorinated analogue of dehydroepiandrosterone. Cancer Res. 1991 ;51(2):481-6

25.

McCormick DL, Rao KV, Johnson WD, Bowman-Gram TA, Steele VE, Lubet RA, Kellof GJ. "Exceptional chemopreventive activity of low-dose dehydroepiandrosterone in the rat mammary gland." Cancer Res. 1996 Apr 15;56(8):1724-6.

26.

Gatto

V,

Aragno

M,

Gallo

M,

Tamagno

E,

Martini

A,

Di

Monaco

M,

Brignardello

E,

Boccuzzi

G.Dehydroepiandrosterone inhibits the growth of DMBA-induced rat mammary carcinoma via the androgen receptor. Oncol Rep. 1998 Jan-Feb;5(1):241-3 27.

Boccuzzi G, Aragno M, Brignardello E, Tamagno E, Conti G, Di Monaco M, Racca S, Danni O, Di Carlo F. Opposite effects of dehydroepiandrosterone on the growth of 7, 12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Anticancer Res. 1992 Sep-Oct;12(5): 1479-83

28.

Spinola PG, Marchetti B, Labrie F. Adrenal steroids stimulate growth and progesterone receptor leveis in rat uterus and DMBA-induced mammary tumors. Breast Cancer Res Treat. 1986;8(3):241-8

DHEA treatment reduces the incidence and develapment af breast cancer in mice that keep their avaries 29.

Green JE, Shibata MA, Shibata E, Moon RC, Anver MR, Kelloff G, Lubet R. 2-difluoromethylornithine and dehydroepiandrosterone inhibit mammary tumor progression but not mammary or prostate tumor initiation in C3(1)/SV40 T/t-antigen transgenic mice. Cancer Res. 2001 Oct 15;61(20):7449-55

The leveis af DHEA that pratect radents against breast cancer are the same than the physiagical leveis faund in premenapausal wamen 30.

Li S, Yan X, Belanger A, Labrie F. Prevention by dehydroepiandrosterone of the development of mammary carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in the rat. Breast Cancer Res Treat. 1994;29(2):203-17

647

DHEA protection is possible on condition that the ovaries remain 31.

32.

Boccuzzi G, Aragno M, Brignardello E, Tamagno E, Conti G, Di Monaco M, Racca S, Danni O, Di Carlo F. Opposile effects of dehydroepiandrosterone on lhe growth of 7, 12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Anticancer Res 1992 Sep-Oct;12(5):1479-83 Spinola PG, Marchetti B, Labrie F. Adrenal steroids stimulate growth and progesterone receptor leveis in rat uterus and DMBA-induced mammary tumors. Breast Cancer Res Treat. 1986;8(3):241-8

DHEA treatment may facilitate the development of breast cancer induced by carcinogens at the condition that the ovaries are previously removed, and thus major estrogen deficiency is created. These data should incite MD's not to prescribe DHEA to postmenopausal women without addition of female horrnone replacement. 33.

34. 35.

Boccuzzi G, Aragno M, Brignardello E, Tamagno E, Conti G, Di Monaco M, Racca S, Danni O, Di Carlo F. Opposite effects of dehydroepiandrosterone on the growth of 7, 12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Anticancer Res. 1992 Sep-Oct;12(5):1479-83 Spinola PG, Marchetti B, Labrie F. Adrenal steroids stimulate growth and progesterone receptor leveis in rat uterus and DMBA-induced mammary tumors. Breast Cancer Res Treat. 1986;8(3):241-8 lnano H, lshii-Ohba H, Suzuki K, Yamanouchi H, Onoda M, Wakabayashi Chemoprevention by dietary dehydroepiandrosterone against promotion/progression phase of radiation-induced mammary tumorigenesis in rats. J Steroid Biochem Moi Biol. 1995 Jul;54(1-2):47-53

DHEA treatment protects animais from breast cancer caused by intensive radiation 36.

Schwarlz AG. lnhibition of spontaneous breast cancer forrnation in female C3H(Avy/a) mice by long-terrn treatment with dehydroepiandrosterone. Cancer Res. 1979;39(3):1129-32

DHEA treatment significantly prevents spontaneous breast cancer development in mice predisposed to breast cancer 37. Couillard S, Labrie C, Belanger A, Candas B, Pouliot F, Labrie F. Effect of dehydroepiandrosterone and the antiestrogen EM-800 on growth of human ZR-75-1 breast cancer xenografts. J Natl Cancer lnst 1998 May 20;90(10):772-8 38.

Labrie F, Luu-The V, Labrie C, Simard J.DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 2001 Jul;22(3):185-212 (Labrie, one of the top­ researchers in DHEA suggests after severa/ years of research in animais and humans that DHEA is free of breast and uterin cancer risk)

DHEA treatment can significantly inhibit the development of human breast cancer transplants in mice 39.

Pashko LL, Schwarlz AG, Abou-Gharbia M, Swem D. lnhibilion of DNA synthesis in mouse epidermis and breast epithelium by dehydroepiandrosterone and related steroids. Carcinogenesis 1981;2(8):717-21

DHEA treatment can be beneficiai for many other cancers, in animais: uterin, prostate, testiscular, pancreas, thyroid, liver (at low doses) 40.

Rao AR. lnhibitory action of dehydroepiandrosterone on methylcholanthrene-inducedcarcinogenesis in lhe uterine cervix of mouse. Cancer Lett 1989 Apr;45(1):1-5

41. 42.

43.

44.

van Weerden WM, van Kreuningen A, Elissen NM, de Jong FH, van Steenbrugge GJ, Schroder FH. Effect of adrenal androgens on the transplantable human prostate tumor. Endocrinology. 1992; 131(6): 2909-13 Christov KT, Moon RC, Lantvit DD, Boone CW, Kelloff GJ, Steele VE, Lubet RA, Pezzuto JM. Prostate intraepithelial neoplasia in Noble rats, a potential interrnediate endpoint for chemoprevention studies. Eur J Cancer. 2004 Jun;40(9):1404-11 Rao KV, Johnson WD, Bosland MC, Lubet RA, Steele VE, Kelloff GJ, McCorrnick DL Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone. Cancer Res. 1999;59(13):3084-9 McCorrnick DL, Rao KV. Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat. Eur Urol. 1999;35(5-6):464-7

45.

Rao MS, Subbarao V, Yeldandi AV, Reddy JK. lnhibition of spontaneous testicular Leydig cell tumor development in F-344 rats by dehydroepiandrosterone. Cancer Lett. 1992 ;65(2):123-6

46.

Muscarella P, Soros LG, Fisher WE, Rink C, Melvin WS. Oral dehydroepiandrosterone inhibils the growth of

47.

Ghinea E, Dumilriu L, Stefanovici G, Pop A, Damian A, Handoca A, Stanciu R. Protein content and thyroid

human pancreatic cancer in nude mice. J Surg Res. 1998;79(2):154-7 horrnone

release

in

vitro

by

differentiated

thyroid

cancer

cells

in

the

presence

of

estradiol,

dehydroepiandrosterone, polypeptidic horrnones and pesticides. Endocrinologie. 1988;26(3):165-71

48.

Moore MA, Thamavit W, Tsuda H, Sato K, lchihara A, lto N. Modifying influence of dehydroepiandrosterone on lhe development of dihydroxy-di-n-propylnitrosamine-initiated lesions in the thyroid, lung and liver of F344 rats Carcinogenesis 1986 Feb;7(2):311-6

648

49.

Garcea R, Daino L, Pascale R, Frassetto S, Cozzolino P, Ruggiu ME, Feo F. lnhibilion by dehydroepiandrosterone of liver preneoplastic toei formation in rats after initiation-selection in experimental carcinogenesis. Toxicol Pathol 1987;15{2):164-9

50.

Weber E, Moore MA, Bannasch P.Phenotypic modulation of hepatocarcinogenesis and reduction in N­ nitrosomorpholine-induced hemangiosarcoma and adrenal lesion development in Sprague-Dawley rats by dehydroepiandrosterone. Carcinogenesis 1988 Jul;9(7):1191-5

51.

Moore MA,

Weber E,

Thomton

M,

Bannasch. Sex-dependent, tissue-specific opposing

effects of

dehydroepiandrosterone on initiation and modulation stages of liver and lung carcinogenesis induced by dihydroxy-di-n-propylnitrosamine in F344 rats. Carcinogenesis 1988 Aug;9(8):1507-9 52.

Thomton M, Moore MA, lto N. Modifying influence of dehydroepiandrosterone or butylated hydroxytoluene treatment on initiation and development stages of azaserine-induced acinar pancreatic preneoplastic lesions in the rat. Carcinogenesis 1989 Feb;10(2):407-10

53.

Símile M, Pascale RM, De Miglio MR, Nufris A, Daino L, Seddaiu MA, Muroni MR, Rao KN, Feo F. lnhibition by dehydroepiandrosterone of growth and progression of persistent liver nodules in experimental rat liver carcinogenesis. lnt J Cancer 1995 Jul 17;62(2):210-5

No effect of DHEA on the breast cancer risk in premenopausal women and HRT treated postmenopausal

!!2m!ID. Studies with no significant association between DHEA leveis and breast cancer 54. Zumoff B, Levin J, Rosenfeld RS, Markham M, Strain GW, Fukushima DK. Abnormal 24-hr mean plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer. Cancer Res 1981 Sep;41(9 Pt 1):3360-3 55. Read GF, Wilson DW, Campbell FC, Holliday HW, Blamey RW, Griffiths K. Salivary cortisol and dehydroepiandrosterone sulphate leveis in postmenopausal women with primary breast cancer. Eur J Cancer Clin Oncol 1983 Apr;19(4):477-83 Studies with no significant associations between the urinary leveis of DHEA metabolites and the risk of breast cancers 56. Juricskay S, Szabo I, Kett K. Urinary steroids at time of surgery in postmenopausal women with breast cancer. Breast Cancer Res Treat. 1997;44(1):83-9 Arguments contra DHEA use in untreated postmenopausal women: DHEA may increase the risk in postmenopausal women without HRT Two studies with report of an association between high leveis of DHEA and an increased risk of breast cancer in (HRT) untreated postmenopausal women 57. Zumoff B, Levin J, Rosenfeld RS, Markham M, Strain GW, Fukushima DK. Abnormal 24-hr mean plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer. Cancer Res 1981 Sep;41 (9 Pt 1):3360-3 58. Gordon GB, Bush TL, Helzlsouer KJ, Miller SR, Comstock GW. Relationship of serum leveis of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing postmenopausal breast cancer. Cancer Res 1990 Jul 1;50(13):3859-62 Apparently, women need to have ali their deficiencies corrected, including female hormones in order to benefit from the breast cancer protective actions of DHEA 59. Stoll BA. Dietary supplements of dehydroepiandrosterone in relation to breast cancer risk. Eur J Clin Nutr. 1999;53(10):771-5 In vitro and in vivo studies where DHEA treatment inhibited the proliferation of breast cancer (cells) in presence of estradiol in vitro, but if estrogens are withdrawn (estrogen deficiency) DHEA stimulated the proliferation of the breast cancer cells 60. Boccu zzi G, Aragno M, Brignardello E, Tamagno E, Conti G, Di Monaco M, Racca S, Danni O, Di Carlo F. Opposite effects of dehydroepiandrosterone on lhe growlh of 7, 12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Anticancer Res. 1992 Sep-Oct;12(5):1479-83. 61. Boccuzzi G, Brignardello E, di Monaco M, Forte C, Leonardi L, Pizzini A. lnfluence of dehydroepiandrosterone and 5-en-androstene-3 beta, 17 beta-diol on lhe growlh of MCF-7 human breast cancer cells induced by 17 beta-estradiol. Anticancer Res. 1992 May-Jun;12{3):799-803

649

DHEA DEFICIENCIES with SERUM ANDROGEN LEVELS within the REFERENCE RANGE: TO TREAT OR NOT TO TREAT?

Should men and women with symptoms and signs of DHEA deficiency, but serum DHEA leveis within the normal reference range for their age, be treated with DHEA?

Scientific publications support the view that Milder degrees of DHEA deficiency exist in people with leveis within the reference range. lndeed, researeh shows that individuais with DHEA sulphate or DHEA metabolite leveis within lhe relerenee range (situated in lhe lower three quarters, lower two thirds, lower hall, lower third, lower lorth, lower lilth or lower 10% oi lhe relerenee range) have a signilicant inereased risk oi various types oi disease and a higher risk oi death. These associations suggest that they suffer lrom a degree oi adrenal androgen lailure, as lhe inereased risk may be redueible or preventable by inereasing DHEA sullate or DHEA metabolite leveis in lhe upper two thirds, upper hall, upper third or upper quarter oi lhe relerenee range through supplementation with DHEA. •

People with DHEA sulphate or DHEA metabolite leveis within the lower segments of the reference range are no! neeessarily healthy, may suffer lrom DHEA delieieney and safely benefit from DHEA supplementation

Studies that show that subjects who are at or below the 90th percentile of serum DHEA sulfate leveis have an increased risk of disease, dysfunction or death: this concerns most studies that show an inverse association between DHEA leveis and the risk of pathology Trend to higher cardiovascular mortality in disabled older women 1.

Cappola AR, Xue QL, Walston JD, Leng SX, Ferrucci L, Guralnik J, Fried LP. DHEAS leveis and mortality in disabled older women: lhe Women's Health and Aging Study I. J Gerontol A Biol Sei Med Sei. 2006 Sep;61 (9):957-62

Lower vitality in premenopausal women 2. 3.

Bell RJ, Donath S, Davison SL, Davis SR. Endogenous androgen leveis and well-being: differences between premenopausal and postmenopausal women. Menopause. 2006 Jan-Feb;13(1):65-71. The Jean Hailes Foundation, Monash University, Clayton Viciaria, Australia. [email protected] (For premenopausal women, leveis of DHEA sulfate were independently and positively associated with the domain score for vitality)

Lower functional status and lower self-reported health in women 4.

Santoro N, et ai. Correlates oi cireulating androgens in mid-lile women: lhe study oi women's health across lhe nation. J Clin Endocrinol Metab. 2005 Aug;90(8):4836-45 (Serum DHEA sulfate was modestly associated with functional status and self-reported health)

Higher physical disability and more depressive symptoms in wome 5.

Haren MT, Malmstrom TK, Banks WA, Patrick P, Miller DK, Morley JE. Lower serum DHEAS leveis are associated with a higher degree oi physical disability and depressive symptoms in middle-aged to older Alrican American women. Maturitas. 2007 Aug 20;57(4):347-60 Division oi Geriatric Medicine, Saint Louis University School oi Medicine, SI. Louis, MO 63104, USA. [email protected] (Lower DHEAS leveis were independently associated with both higher IADL seores (indicating a higher degree of physical disability) and higher CESD scores (indicating a higher degree of clinically relevant depressive symptoms))

Lower HDL cholesterol in premenopausal women 6.

Bednarek-Tupikowska G, Tworowska-Bardziríska U, Tupikowski K, Bohdanowicz-Pawlak A, Szymczak J, Kubicka E, Skoczyríska A, Milewicz A. The correlations between endogenous dehydroepiandrosterone sulfate

650

and some atherosclerosis risk factors in premenopausal women. Med Sei Monit. 2008 Jan;14(1):CR37-41. Department of Endocrinology, Diabetology, and lsotope Treatment, Medicai University of Wroclaw, Wroclaw, Poland. [email protected] (In premenopausal women a significant positive correlation (p<0.05) between serum DHEA-S levei and the serum concentrations of: HDL(2)-C and HDL(2)-C/HDL{3)-C)

lncreased risk of premature atherosclerosis 7.

Savastano S, Valentino R, Belfiore A, De Luca N, de Alteriis A, Orio F Jr, Palomba S, Villani AM, Falconi C, Lupoli G, Lombardi G. Early carotid atherosclerosis in normotensive severe obese premenopausal women with low DHEA(S). J Endocrinol lnvest. 2003 Mar;26(3):236-43.

8.

Department of Molecular and Clinicai Endocrinology and Oncology, University"Federico 11" Medicai School, Naples, ltaly. [email protected] (Carotid intima/ media thickness was strongly negatively correlated with DHEA(S) (p < 0.001) in severely obese premenopausal women) 9. Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, Blackman MA, Metter EJ. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab. 2006 Feb;290(2):E234-42 (The DHEA su/fate levei was correlated negatively with age, pulse pressure, and stiffness index (each P < 0.01), but trend to significancey atter further adjustments) 10. Eller NH, Netterstmm B, Allerup P. Progression in intima media thickness--the significance of hormonal biomarkers of chronic stress. Psychoneuroendocrinology. 2005 Sep;30(8):715-23. (DHEAS was borderline significantly and negatively associated with progression in intima media thickness) 11. Fukui M, Kitagawa Y, Nakamura N, Kadono M, Yoshida M, Hirata C, Wada K, Hasegawa G, Yoshikawa T. Serum dehydroepiandrosterone sulfate concentration and carotid atherosclerosis in men with type 2 diabetes. Atherosclerosis. 2005 Aug;181(2):339-44 (Negative correlations were found between DHEA-S concentration and intima media thickness (P < 0.0001) and between DHEA-S concentration and plaque score (, P < 0.0001))

Higher risk of metabolic syndrome in men with low serum DHEASa 12. Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw YT. Endogenous sex hormones and metabolic syndrome in aging men.J Clin Endocrinol Metab. 2005 May;90(5):2618-23 (In men an inverse relationship is found: one standard deviation increase of serum DHEA-S corresponding to -24% less risk of metabolic syndrome (OR = 0.76; 95% C/, 0.56-1.02) In nonsmoking men 13. Blouin K, Després JP, Couillard C, Tremblay A, Prud'homme O, Bouchard C, Tchemof A. Contribution of age and declining androgen leveis to features of the metabolic syndrome in men. Metabolism.2005 Aug;54(8):103440. Molecular Endocrinology and Oncology Research Center, Lavai University Medicai Research Center, Quebec, Canada G1V 4G2. {The % frequency of men characterized by 3 or more features of the metabolic syndrome increased with decreasing DHEA sulphate)

Higher body mass index, total body fat, visceral fat, subcutaneous fat in premenopausal obese women 14. Pergola G, Zamboni M, Sciaraffia M, Turcato E, Pannacciulli N, Armellini F, Giorgino F, Perrini S, Bosello O, Giorgino R. Body fat accumulation is possibly responsible for lower dehydroepiandrosterone circulating leveis in premenopausal obese women. De lnt J Obes Relat Metab Disord.1996 Dec;20(12):1105-10.1nstitute of Medicai Clinic, Endocrinology and Metabolic Diseases, School of Medicine, University of Bari, Policlinco di Bari, ltaly (DHEA was negatively associated with BMI ( P < 0.05), total body fat, total body fat volume, víscera/ adipose tissue area and subcutaneous adipose tissue area (p < 0.05) in premenopausal obese women)

Higher body mass index and hip circumference in young women 15. AI-Harithy RN. Dehydroepiandrosterone sulfate leveis in women.Relationships with body mass index, insulin and glucose leveis. Saudi Med J. 2003 Aug;24(8):837-41 (DHEA-S leveis are negative/y related with BMI and hip circumference in young women (p=0.03))

Higher serum insulin and glucose leveis in nondiabetic men 16. Haffner SM, Valdez RA, Mykkãnen L, Stem MP, Katz MS. Decreased testosterone and dehydroepiandrosterone sullate concentrations are associated with increased insulin and glucose concentrations in nondiabetic men. Metabolism. 1994 May;43(5):599-603. 17. Department of Medicine, University of Texas Health Science Center, San Antonio 78284.(DHEA-S04 was significantly and inversely associated with insu/in and glucose concentrations)

651

Higher glycosylated haemoglobin 18. Yamauchi A, Takei I, Kasuga A, Kitamura Y, Ohashi N, Nakano S, Takayama S, Nakamoto S, Katsukawa F, Saruta T. Depression of dehydroepiandrosterone in Japanese diabetic men-comparison between non-insulin­ dependent diabetes mellitus and impaired glucose tolerance. Eur J Endocrinol. 1996 Jul;135(1):101-4 (HbA1C was independently negatively related to both DHEA and DHEA-S)

Higher risk of diabetes rnellitus in men 19. Kameda W, Daimon M, Oizumi T, Jimbu Y, Kimura M, Hirata A, Yamaguchi H, Ohnuma H, lgarashi M,

Tominaga M, Kato T. Association of decrease in serum dehydroepiandrosterone sulfate leveis with lhe progression to type 2 diabetes in men of a Japanese population: lhe Funagata Study. (A significant association

between decreasing serum DHEAS leveis and the progression to diabetes mellitus was found in men with a +41% increased risk of progression to diabetes mellitus per O. 1 log ng/mL of DGHEA suffate, independently from age, height, and 2h plasma glucose in men)

lncreased amyloid beta peptide 40 leveis, palhogenic factor of Alzeimer's disease, in older men with subjective memory loss or demenlia 20. Gillett MJ, Martins RN, Clamette RM, Chubb SA, Bruce DG, Yeap BB. Relationship between testosterone, sex

hormone binding globulin and plasma amyloid beta peptide 40 in o/der men with subjective memory loss or dementia. J Afzheimers Ois. 2003;5(4):267-9. Westem Australia, Australia (lnverse, near significant, association

between low serum DHEAs and higher leveis of serum amyloid beta peptd i e 40)

Higher risk of cataract in poslmenopausal women 21. Defay R, Pinchinat S, Lumbroso S, Sultan C, Papoz L, Delcourt C; The POLA study group. Relato i nships between hormonal status and cataract in French postmenopausal women: the POLA study. Ann Epidemia/. 2003 Oct;13(9):638-44 (A significant -21% /ower risk of cataract at higher leveis of DHEA sulphate leveis)

Lower bone mineral density at the femoral neck in poslmenopausal women with subclinical hyperthyroidism

22. Fõldes J, Lakalos P, ZsadÃi nyi J, HorvÃilh C. Decreased serum IGF-1 and dehydroepiandroslerone sulphale may be risk factors for lhe developmenl of reduced bone mass in postmenopausal women with endogenous subclinical hyperthyroidism. Eur J Endocrinol. 1997 Mar;136(3):277-81. Firsl Departmenl of Medicine, Semmelweis University, Budapest, Hungary (Serum DHEAS leveis coffelated with the bone mineral density at the femoral neck (P < 0.05) in pre- and postmenopausal women with endogenous subclinical hyperthyroidism)

Higher risk for aggressive prostate cancer in men 23. Severi G, Morris HA, Maclnnis RJ, English DA, TIIIey W, Hopper JL, Boyle P, Giles GG. Circulaling steroid honnones and lhe risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):86-91 (A significantly -37% and -49% lower risk for aggressive prostate cancer for a doubling of serum DHEA sulphate and androstenedione, respective!YJ

Higher HIV RNA leveis in HIV-positive men 24. Ferrando SJ, Rabkin JG, Poretsky L Dehydroepiandrosterone sulfate and testosterone: relation to HIV illness stage and progression over one year. J Acquir lmmune Defic Syndr. 1999 Oct 1;22(2):146-54. Department of Psychiatry, ComeU University Medicai College, New York, New York, USA (Baseline DHEAS below the laboratory reference range (96 1Jg/dl} was associated with history of opportunistic infections and malignancies (adjusted odds ratio [OR], 4.4; 95% C/: 1.9-10.4) and with incidence of these complications or death over 1 year (adjusted OR, 2.6))

Studies that show that subjects who are at or below the 25111 percentile (in the lower guartile) of serum DHEA sulfate leveis have an increased risk of disease or dysfunction lncreased risk of sexual dysfunction in women in lhe lower quartile of serum DHEA, DHEAs and androstenedione, which can improve with DHEA lherapy 25. Mino D, Munarriz R, Talakoub L, Fiaherty E, Gioia M, Hoag L, Kim NN, Traish A, Goldstein I, Guay A, Spark R. Androgen replacement therapy with dehydroepiandrosterone for androgen insufficiency and female sexual

652

dysfunction: androgen and questionnaire resuHs. J Sex Marital Ther. 2002;28 Suppl 1:165-73. (DHEA and DHEA-S values either below or in lhe lower quartile of the physiologic range are found in women with sexual dysfunction} ( Lower HDL cholesterol and higher LDL cholesterol levei, higher % fat and total adipose mass, lower lean body mass % and lean body mass in men aged 60 or over 26. Abbasi A, Duthie EH Jr, Sheldahl L, Wilson C, Sasse E, Rudman I, Mattson DE. Assoeiation of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community-dwelling older men and women. J Am Geriatr Soe. 1998 Mar;46(3):263-73. Department of Medicine, Medicai College of Wisconsin, and Veterans Affairs Medicai Center, Milwaukee, USA (Men, 60 years of age and o/der, in lhe highest quartile of serum DHEAS leveis compared to men in lhe /owest quartile had lower % fat and total adipose mass and increased Jean body mass %, lean body mass, HDL, and lower low density lipoprotein (LDL} cholesterol level)

Studies that show that subjects who are at or below the 1001 perçentile of serum DHEA suHate leveis have an increased risk of dysfunction or dying Higher risk of low sexual responsiveness in normal women 27. Davis SR, Davison SL, Donath S, Bell RJ. Circulating androgen leveis and self-reported sexual function in women. JAMA. 2005 Jul 6;294(1):91-6 (Associations of low serum DHEA sulfate < 10th percentile for the age group with 3.9 to 6.6-fo/d greater risk of low sexual responsiveness in women aged 18 years or o/der, and additionally low sexual desire and low sexual arousal in women aged 18 to 44 years:} lncreased mortality in chronic heart failure patients 28. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006 Oct 24;114(17):1829-37. Cardiology Department, Military Hospital, ui. Weigla 5, 50981 Wroelaw, Poland. [email protected] Studies that show that below cutoff leveis of serum DHEA sulphate increased risks of disease and/ordying are found

Thresholds or cutoff leveis of DHEA suHate in the serum for disease or mortallty within the age-related reference range CUT-OFF levei of serum DHEA suHate

1.09

40

(J.mol/l

(J.g/dl

Morbidity BELOW the cutoff levei Adreno-cortical adenoma in patients with Cushing's svndrome

1.15

42

(J.mol/l*

(J.g/dl*

1.37

50

(J.mol/l*

IJ.g/dr

Publication Ashcraft MW, Van Herle AJ, Vener SL, Geffner DL Serum cortisol leveis in Cushing's syndrome after low- and high-dose dexamethasone suppression. Ann lntem Med. 1982 Jul;97(1):21-6.

Rheumatoid arthritis in postmeno-pausal women

Sambrook PN, Eisman JA, Champion GD, Pocock NA. Sex hormone status andosteoporosis in postmenopausal women rheumatoid with arthritis. Arthritis Rheum. 1988 Aug;31(8):973-8

Depression in postmeno-pausal women

Barrett-Connor E, von Mühlen D, Laughlin GA, Kripke A. Endogenous leveis of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study. J Am Geriatr Soe. 1999 Jun;47(6):685-91

653

Comment A baseline DHEA sulfate value less than 0.4 microgram/ml indicated patients with an adrenocorticol adenoma DHEAS is significanly different between postmenopausal women with rheumatoid arthritis and normal postmenopausal women : median 0.3 (J.moles/1 vs 2.0 Postmenopausal women (aged

50 to 90 years) with depression had lower DHEAS leveis compared with nondepressed women (1.17 vs 1.57 (J.moVL; P .01; calculated cut-off 1.37 (J.mol/l (Ref.range for postm. women > 50 yrs: ().21o (J.g/dl) =

=

Thresholds or cutoff leveis of DHEA sulfate in the serum for disease or mortality within the agHelated reference range CUT-QFF levei of serum DHEA sulfate

Morbidity BELOWthe

Publication

Comment

cutoff levei

Cirrhotic men and women have more than 3 to 5 x lower levei than normal controls. Higher mortality 54.5 1.48 (Oider people withlow DHEAS in elderly IJ.mol/l j.l.g/dl persons (<54.5 IJ.g/dL) have +64% i risk of dying compared to elderly higher DHEAS) A significantly lower DHEA-S Capra F, Casaril M, Stanzial AM, Gabrielli in cirrhotic patients compared GB, Marsilli R, Ferrari S, Corrocher R. with healthy controls, both 60 Cirrhosis [Plasma dehydroepiandrosterone sulfate males (451.7 SD 440.3 ng/ml 1.63 in women and urine steroid excretion in hepatic VS 1438.3 SD 604.8, p < IJ.mol/l* j.l.g/dl* cirrhosis]. Recenti Prog Med. 1989 0.001) and females (225.5 SD Jan;80(1):4-8 152.6 ng/ml vs 974.0 SD 405.7, p < 0.001). Franz C, Watson D, Longcope C. Estrone In cirrhotic men the mean sulfate dehydroepiandrosterone DHEAS values were 0.12 and Cirrhosis 78,5 2.13 sulfate concentrations in normal subjects IJ.g/ml, significantly lower than IJ.mol/l* IJ.g/dl* in men and men with cirrhosis. Steroids. 1979 the normal values of 1.45 Nov;34(5):563-73 IJ.g/ml in normal men A significantly lower DHEA-S Capra F, Casaril M, Stanzial AM, Gabrielli in cirrhotic patients compared GB, Marsilli R, Ferrari S, Corrocher R. with healthy controls, both Cirrhosis 2.55 [Plasma dehydroepiandrosterone sulfate males (451.7 SD 440.3 ng/ml 93.9 IJ.mol/l* j.l.g/dl* in men and urine steroid excretion in hepatic vs 1438.3 SD 604.8, p < cirrhosis]. Recenti Prog Med. 1989 0.001) and females (225.5 SD 152.6 ng/ml vs 974.0 SD Jan;80(1):4-8 405.7, p < 0.001) (Plasma DHEAS and the Armanini D, Vecchio F, Basso A, Milone were ratio DHEAS/cortisol FF, Simoncini M, Fiore C, Mattarello MJ, Alzheimer's in sign.lower Sartorato P, Karbowiak I. Alzheimer's than in disease patients 2.66 Alzheimer's disease: pathophysiological implications 98 median controls (DHEAS: IJ.g/dl* Disease of measurement of plasma cortisol, IJ.mol/l* 1.81, range 0.21-3.69 vs 3.51, plasma dehydroepiandrosterone sulfate, 1.35-9.07 IJ.moi/L; DHEAS/ and lymphocytic corticosteroid receptors. cortisol: 2.04, range 0.3-5.8 vs Endocrine. 2003 Nov;22(2):113-8 6.8, range 2.7-24 I; p<0.001_ll_ Intima media thickness and Fukui M, Kitagawa Y, Nakamura N, plaque score were significantly Kadono M, Yoshida M, Hirata C, Wada K, greater in patients with lower Higher intimaHasegawa G, Yoshikawa T. Serum concentrations of DHEA-S media thickness dehydroepiandrosterone sulfate (<1000 ng/ml) than in patients in men with type concentration and carotid atherosclerosis with higher plasma DHEA-S 2 diabetic type in men with 2 diabetes. (1.07mm versus 0.91 mm, P < 0.0001, and 5.5 versus 3.1, P 2.71 100 Atherosclerosis. 2005 Aug;181(2):339-44 IJ.g/dl IJ.mol/l < 0.0001, respectively). Fukui M, Ose H, Kitagawa Y, Yamazaki M, Hasegawa G, Yoshikawa T, Nakamura Arterial Pulse wave velocity was N. Relationship between low serum stiffness significantly greater in patients endogenous androgen concentrations and in men with type with lower concentrations of arterial stiffness in men with type 2 2 diabetes DHEA·S (<1000 ng/mL) diabetes mellitus. Metabolism. 2007 mellitus Sep;56(9):1167-73 Note: * Calculated cutoff: in cases marked with and * the cutoff levei was not provided by the author(s), but was calculated as the median levei between the lower median levei of patients with disease and the higher median value of healthv aoe-matched controls. Glei DA, Goldman N. Dehydroepiandrosterone sulfate (DHEAS) and risk for mortality among older Taiwanese. Ann Epidemiol. 2006 Jul;16(7):510-5.

654

Studies of diseases or dysfunctions that are associated with lower DHEA leveis within the reference range, suggesting that lhe lower leveis might contribute to lhe development lhe disease or lhe dysfunction Negative psychic symptoms like loss of pleasure in leasure activities, cynism, hostility in men 29. Fava M, Littman A, Lamon-Fava S, Milani R, Shera D, Maclaughlin R, Cassem E, Leal A, Marchio B, Bolognesi E, et ai. Psychological, behavioral and biochemical risk factors for coronary artery disease among American and ltalian male corporate managers. Am J Cardiol. 1992 Dec 1 ;70(18):1412-6 (Significantly more cynicism and

hostility, and less enjoyment in leisure activitiesin men with lower DHEA sulfate leveis) Depression in perimenopausal women 30. Schmidt PJ, Murphy JH, Haq N, Danaceau MA, SI Clair L. Basal plasma hormone leveis in depressed perimenopausal women. Psychoneuroendocrinology. 2002 Nov;27(8):907-20. NIMH, Building 10, Room 3N-238, 10 Center Drive MSC 1276, Bethesda, MD 20892-1276, USA. [email protected] (Significantly lower

morning plasma dehydroepiandrosterone (DHEA) and its sulphated metabolite DHEA-S (but not cortisol) leveis in the depressed women compared to the non-depressed comparison group) Depression 31. Osran H, Reis! C, Chen CC, Lifrak ET, Chicz-DeMet A, Parker LN. Adrenal androgens and cortisol in major depression. Am J Psychiatry. 1993 May;150(5):806-9 (Disappearance of the normal healthy circadian vara i tion of DHEA) Decreased sexual function in women 32. Gracia CR, Freeman EW, Sammel MD, Lin H, Mogul M. Hormones and sexuality during transition to menopause. Obstei Gynecol. 2007 Apr;109(4):831-40. Department of Obstetrics/Gynecology, Center for Clinicai Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. [email protected] Erectile dysfunction in men 33. Ahn TY, Park JK, Lee SW, Hong JH, Park NC, Kim JJ, Park K, Park H, Hyun JS. Prevalence and risk factors for erectile dysfunction in Korean men: results of an epidemiological study.: J Sex Med. 2007 Sep;4(5):1269-76. Department of Urology, University of Ulsan College of Medicine, Asan Medicai Center, Seoul, Korea (Leveis of serum DHEA su/fate were significantly different between the ED and non-ED groups) Non insulin- dependent diabetes mellitus and impaired glucose tolerance in men 34. Yamauchi A, Takei I, Kasuga A, Kitamura Y, Ohashi N, Nakano S, Takayama S, Nakamoto S, Katsukawa F,

Saruta T. Depression of dehydroepiandrosterone in Japanese diabetic men--comparison between non-insulin­ dependent diabetes mellitus and impaired glucose tolerance. Eur J Endocrinol. 1996 Jul;135(1):101-4 (Serum

concentrations of DHEA and DHEA-S in the NIDDM group were significantly lower than in the IGT group and 9.7 nmol/1 vs 3.4 and 4.9 mumolll, respective/y; p < 0.01)

655

(7.8

ANDROSTENEDIONE DEFICIENCY with SERUM ANDROSTENEDIONE LEVELS within lhe REFERENCE RANGE: to TREAT or NOT to TREAT?

Studies lhat show disease and mortality to be associated with androstenedione leveis within lhe (laboratory) reference range in women

Studies that show lhat women who are at or below the 90111 percentile of serum androstenedione leveis have an increased risk of disease: this concems most studies that show an inverse association between androstenedione leveis and the risk of disease

Lower HDL and higher triglycerides in perimenopausal women aged 50-59 years 1.

Khatibi A, Agardh CD, Shakir YA, Nerbrand C, Nyberg P, Lidfeldl J, Samsioe G. Could androgens protect middle-aged women from cardiovascular events? A population-based study of Swedish women: The Wornen's Health in lhe Lund Area (WHILA) Study. Clirnacteric. 2007 Oct;10(5):386-92. Departrnent of Clinicai Sciences in Lund, Lund University, and Departrnent of Gynecology and Obstetrics, Lund University Hospital, Sweden. (Androstenedione leveis were positively associated with HDL cholesterol (fJ
lncreased carotid intimai-mediai lhickness in postmenopausal wornen

2.

3.

Bernini GP, Moretti A, Sgró M, Argenio GF, Barlascini CO, Cristofani R, Salvetti A. lnfluence of endogenous androgens on carotid wall in postrnenopausal wornen. Menopausa. 2001 Jan-Feb;8(1):43-50. Dipartirnento di Medicina Interna, University of Pisa, ltaly. (Serum androstenedione were negatively associated with severa/ carotid intimai-media/ thickness measures) Debing E, Peeters E, Duque! W, Poppe K, Velkeniers B, Van den Brande P. Endogenous sex hormone leveis in postmenopausal wornen undergoing carotid artery endarterectomy. Eur J Endocrinol. 2007 Jun;156(6):687-93 (Significant inverse relationship between serum androstenedione (P 0.028) leveis with the presence of severe atherosclerosis of interna/ carotid artery) =

lncreased risk of aggressive prostate cancer in men 4.

Severi G, Morris HA, Maclnnis RJ, English DR, Tilley W, Hopper JL, Boyle P, Giles GG. Circulating steroid hormones and lhe risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):86-91. Cancer Epidemiology Centre, The Cancer Council Victoria, University of Melbourne, Melbourne, Australia. [email protected] (The hazard ratio [HR; 95% confidence interval (95% Cl)] for aggressive cancer almost halved for a doubling of the concentration of androstenedione (HR, 0.51; 95% C/, 0.31-0.83))

lncreased risk of advanced prostate cancer in men with prostate cancer 5.

Travis RC, Key TJ, Allen NE, Appleby PN, Roddam AW, Rinaldi S, Egevad L, Gann PH, Rohrmann S, Linseisen J, Pischon T, Boeing H, Johnsen NF, Tjenneland A, Overvad K, Kiemeney L, Bueno-de-Mesquita HB, Bingham S, Khaw KT, Tumino R, Sieri S, Vineis P, Palli D, Quirós JR, Ardanaz E, Chirlaque MD, Larraiiaga N, Gonzalez C, Sanchez MJ, Trichopoulou A, Bikou C, Trichopoulos D, Stattin P, Jenab M, Ferrari P, Slimani N, Riboli E,

Kaaks R. Serum androgens and prostate cancer among 643 cases and 643 controls in lhe European Prospectiva lnvestigation into Cancer and Nutrition.: In! J Cancer. 2007 Sep 15;121(6):1331-8. Cancer Research UK Epidemiology Uni!, University of Oxford, Oxford, United Kingdom. [email protected] (A significant inverse association of androstenedione concentration and risk for advanced prostate cancer) Studies lhat show lhat women who are at or below lhe 25111 percentile (in the lower guartile) of serum androstenedione leveis have an increased risk of the following dysfunction lncreased risk of sexual dysfunction in women 6.

Mino D, Munarriz R, Talakoub L, Flaherty E, Gioia M, Hoag L, Kim NN, Traish A, Goldstein I, Guay A, Spark R. Androgen replacement therapy with dehydroepiandrosterone for androgen insufficiency and female sexual dysfunction: androgen and questionnaire results. J Sex Marital Ther. 2002;28 Suppl 1:165-73. (Androstenedione va/ues were either below or in the /ower quarti/e of the physiologic range are found in women with sexual dysfunction)

656

chapter twelve:

Pregnenolone

Senescence is associated with a decline of the adrenal-cortisol axis Senescence is associated with a progressiva decline in pregnenolone leveis, especially in women 1.

Meloun M, Hill M, Vceláková-Havlíková H. Minimizing lhe effects oi multicollinearity in lhe polynomial regression oi age relationships and sex differences in serum leveis oi pregnenolone sulfate in healthy subjects. Clin Chem Lab Med. 2009;47(4):464-70 (In women, a significant maximum was found around the 30th year followed by a rapid decline, while the maximum in men was achieved almost 10 years earfier and changes were minor up to the 60th year.

Preanenolone and psychic well-being Fatigue and work performance: the improvement with pregnenolone 2. 3. 4. 5.

Pincus G, Hoagland H. Effects on industrial production oi lhe administration oi 5 pregnenolone to lactor workers, I. Psychosom Med. 1945;7:342-6 Pincus G, Hoagland H, Wilson CH, Fay NJ. Effects on industrial production oi lhe administration oi 5pregnenolone to lactory workers, 11. Psychosom Med.1945-7-347-352 Pincus G, Hoagland H. Effects oi administered pregnenolone on latigyuing psychomotor performance.J Aviai Med.1944;15:98-115,135

Anxiety: the association with lower pregnenolone leveis Ritsner M, Maayan R, Gibel A, Weizman A. Differences in blood pregnenolone and dehydroepiandrosterone 6. leveis between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol. 2007 Apr;17(5):358-

65 7. 8. 9.

Heydari B, Le Melledo JM. Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med. 2002 Jul;32(5):929-33 Semeniuk T, Jhangri GS, Le Melledo JM. Neuroactive steroid leveis in patients with generalized anxiety disorder. J Neuropsychiatry Clin Neurosci.2001 Summer;13(3):396-8 Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, Usala L, Purdy RH, Biggio G. Social isolation­ induced decreases in both lhe abundance oi neuroactive steroids and GABA(A) receptor lunction in rat brain. J Neurochem. 2000 Aug;75(2):732-40

Anxiety: the improvement with pregnenolone treatment Reddy DS, Kulkami SK. Neurosteroid coadministration prevents development oi tolerance and augments 10. recovery lrom benzodiazepine withdrawal anxiety and hyperactivity in mice. Methods Find Exp Clin 11. 12. 13.

Pharmacol. 1997 Jui-Aug;19(6):395-405 Reddy DS, Kulkami SK. Differential anxiolytic effects oi neurosteroids in lhe mirrored chamber behavior test in mice. Brain Res. 1997 Mar 28;752(1-2):61-71 Jorge JC, Gonzalez L, Fortis A, Cruz ND. Sex-specilic modulation oi anxiety and locomotion after neonatal exposure to pregnenolone sulfate. Physiol Behav.2005 Jan 17;83(5):779-86 Melchior CL, Ritzmann RF. Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on lhe plus-maze. Pharmacol Biochem Behav. 1994 Aug;48(4):893-7

Memory loss and Alzheimer's disease: the association with lower pregnenolone leveis Weiii-Engerer S, David JP, Sazdovitch V, Uere P, Eychenne B, Pianos A, Schumacher M, Delacourte A, 14. Baulieu EE, Akwa Y. Neurosteroid quantification in human brain regions: comparison between Alzheimer's and nondemented patients.J Clin Endocrinol Metab. 2002 Nov;87(11):5138-43 15. Baulieu EE. The decrease in lhe hippocampus oi lhe neurosteroid pregnenolone sulfate is involved in memory deficit in lhe aged animal.C R Acad Sei 111. 1998 Feb-Mar;321(2-3):223-7 16. Vallee M, Mayo W, Damaudery M, Corpechot C, Young J, Koehl M, Le Moal M, Baulieu EE, Robel P, Simon H. Neurosteroids: deficient cognitiva performance in aged rats depends on low pregnenolone sulfate leveis in lhe hippocampus.Proc NaH Acad Sei USA. 1997 Dec 23;94(26):14865-70

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Memory loss: the improvement with pregnenolone treatment 17. Martín-García E, Paliares M. The neurosteroid pregnenolone sulfate neutralized the learning impairment induced by intrahippocampal nicotine in alcohol-drinking rats. Neuroscience. 2005;136(4):11 09-19 18. Darnaudery M, Paliares M, Piazza PV, Le Moal M, Mayo W. The neurosteroid pregnenolone sulfate infused into the mediai septum nucleus increases hippocampal acetylcholine and spatial memory in rats. Brain Res. 2002 Oct 4;951(2):237-42 19. Vallee M, Shen W, Heinrichs SC, Zorumski CF, Covey DF, Koob GF, Purdy RH. Steroid structure and pharmacological properties determine the anti-amnesic effects of pregnenolone sulphate in the passive avoidance task in rats. Eur J Neurosci. 2001 Dec;14(12):2003-1O 20. Vallee M, Mayo W, Le Moal M. Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging. Brain Res Brain Res Rev 2001 Nov;37(1-3):301-312 21. Mayo W, Le Moal M, Abrous DN. Pregnenolone sulfate and aging of cognitive functions: behavioral, neurochemical, and morphological investigations. Horm Behav. 2001Sep;40(2):215-7 Ladurelle N, Eychenne B, Denton D, Blair-West J, Schumacher M, Robel P, Baulieu E. Prolonged 22. intracerebroventricular infusion of neurosteroids affects cognitive performances in the mouse. Brain Res. 2000 Mar 10;858(2):371-9 23. Darnaudery M, Koehl M, Piazza PV, Le Moal M, Mayo W. Pregnenolone sulfate increases hippocampal acetylcholine release and spatial recognition. Brain Res. 2000 Jan 3;852(1):173-9 24. Darnaudery M, Bouyer JJ, Paliares M, Le Moal M, Mayo W. The promnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats. Brain Res. 1999 Feb 13;818(2):492-8 25. Paliares M, Darnaudery M, Day J, Le Moal M, Mayo W. The neurosteroid pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory. Neuroscience. 1998 Dec;87(3):551-8 26. Meziane H, Mathis C, PaulSM, U ngerer A. The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task. Psychopharmacology (Berl). 1996 Aug;126(4 ):323-30 27. Melchior CL, Ritzmann RF. Neurosteroids block the memory-impairing effects of ethanol in mice. Pharmacol Biochem Behav. 1996 Jan;53(1):51-6 28. Flood JF, Morley JE, Roberts E. Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures: the amygdala is by lar the most sensitive. Proc Natl AcadSei USA. 1995 Nov 7;92(23):10806-10 Mathis C, Paul SM, Crawley JN. The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced 29. 30. 31.

deficits in a passive avoidance memory task. Psychopharmacology (Berl). 1994 Oct;116(2):201-6 Flood JF, Morley JE, Roberts E. Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl AcadSei USA. 1992 Mar 1;89(5):1567-71 lrwin RP, Maragakis NJ, Rogawski MA, Purdy RH, Farb DH, PaulSM. Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons. Neurosci Lett. 1992 Jul 6;141(1):30-4 4

Alzheimer's disease/amyloid beta toxicity: the improvement with pregnenolone treatment in vitro 32.

Akan P, KizildagS, Ormen M, GeneS, Oktem MA, Fadiloglu M. Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not. Chem Biol lnteract. 2009 Jan 15;177(1):6570

Attention deficit: the improvement with pregnenolone treatment 33. Morley JE, Kaiser F, Raum WJ, Perry HM 3rd, Flood JF, Jensen J,Silver AJ, Roberts E. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl AcadSei USA. 1997 Jul 8;94(14):7537-42 Schizophrenia: the associations with low pregnenolone leveis 34.

Ritsner M, Maayan R, Gibel A, Weizman A. Differences in blood pregnenolone and dehydroepiandrosterone leveis between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol. 2007 Apr;17(5):35865

Negative symptoms of schizophrenia: the improvement with pregnenolone treatment 35. Marx CE, Keefe AS, Buchanan RW, Hamer RM, Kilts JD, Bradford DW,Strauss JL, Naylor JC, Payne VM, Lieberman JA,Savitz AJ, Leimone LA, Dunn L, Porcu P, Morrow AL,Shampine LJ. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology. 2009 Jul;34(8):1885-903

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Pain: reduction with pregnenolone in animais 36.

Chen SC, Liu BC, Chen CW, Wu FS.. lntradermal pregnenolone sulfate attenuates capsaicin-induced nociception in rats. Biochem Biophys Res Commun. 2006 Oct 20;349(2):626-33.

Sleep disorder: The improvement with pregnenolone treatment Darnaudery M, Bouyer JJ, Paliares M, Le Moal M, Mayo W. The prornnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats. Brain Res. 1999 Feb 13;818(2):492-8

37.

Preqnenolone and aqe-related diseases Reumatoid arthritis: the association with lower pregnenolone leveis Hedman M, Nilsson E, de la Torre B. Low blood and synovial fluid leveis of sulpho-conjugated steroids in rheurnatoid arthritis. Clin Exp Rheurnatol. 1992 Jan-Feb;10(1 ):25-30

38.

Rheumatism: the improvement with pregnenolone Freeman H, Pincus G, Bachrach S, Johnson CW, McCabe GE, MacGilpin HH Jr. Oral steroid medication in rheumatoid arthritis. J Clin Endocrinol Metab. 1950 Dec;10(12):1523-32 Freeman H, Pincus G. Oral steroid administration in rheumatoid arthritis. J Clin Endocrinol Metab. 1950 40. Jul;10(7):824 41. McGavack TH. ACTH, cortisone and pregnenolone in arthritis and allied diseases. Geriatrics. 1952 Mar­ 39.

Apr;7(2):99-108 42.

Mendell

HE,

Skelton

JM,

Moyer

JH.

An

evaluation

of

pregnenolone

and

a

combination

of

desoxycorticosterone acetate-sodium ascorbate in lhe treatment of arthritis. Am Pract Dig Treat. 1952 Oct;3(10):818-23 43.

Schaposnik F, Gutierrez A. lnefficacy of pregnenolone in maintaining remission obtained with cortisone in rheumatoid arthritis.Prensa Med Argent. 1952 May 16;39(20):1049-51

44.

Bastenie PA, Franken L, Callebaut C. Effects of pregnenolone on rheumatoid arthritis and rheumatic fever. Brux Med. 1950 Apr 30;30(18):945-54

Corrective preqnenolone treatment: Oral pregnenolone 45.

McGavack TH, Chevalley J, Weissberg J. The use of delta 5-pregnenolone in various clinicai disorders. J Clin Endocrinol Metab. 1951 Jun;11(6):559-77.

46.

McGavack TH, Chevalley J, Weissberg J. Studies with pregnenolone. 2. Clinicai applications. J Clin Endocrinol Metab. 1950 Jul;10(7):841-2

47.

Henderson E, Weinberg M, Wright WA. Pregnenolone. Endocr Rev. 1950;10:455-74

Pregnenolone treatment: Side effects 48.

Tyler ET, Payne S, Kirsch. Pregenenolone in male infertility. West J Surg. 1943;56459-63

659

chapter thirteen:

Aldosterone

Senescence is associated with a decline of the adrenal-aldosterone axis Senescence is associated with reductions of aldosterone leveis 1.

2. 3.

Weidmann P, de Chatel R, Schiffmann A, Bachmann E, Beretta-Piccoli C, Reubi FC, Ziegler WH, Vetter W. lnterrelations between age and plasma renin, aldosterone and cortisol, urinary catecholamines, and the body sodium/volume state in normal man. Klin Wochenschr. 1977 Aug 1;55(15):725-33 Hegstad R, Brown RD, Jiang NS, Kao P, Weinshilboum RM, Strong C, Wisgerhof M. Aging and aldosterone. Am J Med. 1983 Mar;74(3):442-8 Mulkerrin E, Epstein FH, Clark BA. Aldosterone responses to hyperkalemia in healthy elderly humans. J Am Soe Nephrol. 1995 Nov;6(5):1459-62 ("Advancing age is characterized by relative hypoaldosteronism in the basal state as we/1 as in response to hyperkalemia. This may contribute to an increased susceptibility to hyperkalemia if other potassium regulatory systems fail. ) Bauer JH. Age-related changes in the renin-aldosterone system. Physiological effects and clinicai implications. Drugs Aging. 1993 May-Jun;3(3):238-45 ("plasma aldosterone leveis are highest in the newbom, and lowest in "

4.

5.

the elderly population") Naka T, Ogihara T, Hata T, Maruyama A, Mikami H, Nakamaru M, Gotoh S, Masuo K, Ohde H, lwanaga K, Kumahara Y. The effect of aging on urinary kallikrein excretion in norrnotensive subjects and in patients with essential hypertension. J Clin Endocrinol Metab. 1981 May;52(5):1023-6 ( urinary aldosterone significantly decreased with increasing age") "

Senescence is associated with disturbances of the circadian cycle of serum aldosterone: reduced amplitude but maintenance of a detectable circadian rhythm with age 6. Cugini P, Lucia P, Di Palma L, Re M, Canova R, Gasbarrone L, Cianetti A. Effect of aging on circadian rhythm of atrial natriuretic peptide, plasma rennin activity, and plasma aldosterone. J Gerontol. 1992 Nov;47(6):B214-9 Aldosterone and one of the mechanisms of senescence Poor gene polymorphisms 7. Newton-Cheh C, Guo CY, Gona P, Larson MG, Benjamin EJ, Wang TJ, Kathiresan S, O'Donnell CJ, Musone

8.

SL, Camargo AL, Drake JA, Levy D, Hirschhom JN, Vasan RS. Clinicai and genetic correlates of aldosterone-to­ renin ratio and relations to blood pressure in a community sample. Hypertension. 2007 Apr;49(4):846-56 Connell JM, Fraser R, MacKenzie SM, Friel EC, lngram MC, Holloway CD, Davies E. The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation. Moi Cell Endocrinol. 2004 Mar 31;217(1-2):243-7

Aldosterone and psychic well-being Quality of life and fatigue: the improvement with fludrocortisone 9. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995 Sep 27;274(12):961-7

Aldosterone and age-related diseases: Dehydration caused by hypotremia and pollakiuria: the improvement with fludrocortisone 10. Celik US, Alabaz D, Yildizdas D, Alhan E, Kocabas E, Ulutan S. Cerebral salt wasting in tuberculous meningitis: treatment with fludrocortisone. Ann Trop Paediatr. 2005 Dec;25(4):297-302 11. Wenzl HH, Fine KD, Santa Ana CA, Porter JL, Fordtran JS. Effect of fludrocortisone and spironolactone on sodium and potassium losses in secretory diarrhea. Dig Dis Sei. 1997 Jan;42(1):119-28

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Orthostatic hypotension, tachycardia, hypovolemia: the association with low aldosterone leveis 12. Jacob G, Robertson D, Mosqueda-Garcia R, Ertl AC, Robertson RM, Biaggioni I. Hypovolemia in syncope and orthostatic intolerance role of lhe renin-angiotensin system. Am J Med. 1997 Aug;103(2):128-33 13. Grenon SM, Hurwitz S, Sheynberg N, Xiao X, Ramsdell CD, Mai CL, Kim C, Cohen RJ, Williams GH. Role of individual predisposition in orthostatic intolerance before and after simulated microgravity. J Appl Physiol. 2004 May;96(5):1714-22 14. Uchiyama M, Otsuka T, Shibuya Y, Sakai K. Abnormal sodium and potassium metabolism in orthostatic dysregulation in childhood. Tohoku J Exp Med. 1984 Nov;144(3):327-8.

Arterial hypotension, dehydration and postura! dizziness: the improvement with fludrocortiosone 15. Schoffer KL, Henderson RD, O'Maley K, O'Sullivan JD. Nonpharmacological treatment, fludrocortisone, and domperidone for orthostatic hypotension in Parkinson's disease. Mov Disord. 2007 Aug 15;22(11):1543-9 16. Vernikos J, Convertino VA. Advantages and disadvantages of fludrocortisone or saline load in preventing post­ spaceflight orthostatic hypotension. Acta Astronaut. 1994;33:259-66 17. Freitas J, Santos R, Azevedo E, Costa O, Carvalho M, de Freitas AF. Clinicai improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone. Clin Auton Res. 2000 Oct;10(5):293-9 18. van Lieshout JJ, ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postura! decrease in cardiac output in autonomic failure. Clin Auton Res. 2000 Feb;10(1 ):35-42 19. Hakamaki T, Rajala T, Lehtonen A. Ambulatory 24-hour blood pressure recordings in patients with Parkinson's disease with or without fludrocortisone. lnt J Clin Pharmacol Ther. 1998 Jul;36(7):367-9 20. Ten Harkel AD, Van Lieshout JJ, Wieling W. Treatment of orthostatic hypotension with sleeping in lhe head-up til! position, alone and in combination with fludrocortisone. J lntern Med. 1992 Aug;232(2):139-45 21. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and lhe chronic fatigue syndrome. JAMA 1995 Sep 27;274(12):961-7 22. Hoehn MM. Levodopa-induced postura! hypotension. Treatment with fludrocortisone. Arch Neurol. 1975 Jan;32(1):50-1 23. Campbell IW, Ewing DJ, Clarke BF. 9-Aipha-fluorohydrocortisone in lhe treatment oi postura! hypotension in diabetic autonomic neuropathy. Diabetes. 1975 Apr;24(4):381-4 24. da Costa D, Mclntosh S, Kenny RA. Benefits of fludrocortisone in lhe treatment of symptomatic vasodepressor carotid sinus syndrome. Br Heart J. 1993 Apr;69(4):308-10

Stroke: the improvement of outcome (less ischemic complications) with fludrocortisone treatment 25. Mori T, Katayama Y, Kawamata T, Hirayama T. lmproved efficiency of hypervolemic therapy with inhibition of natriuresis by fludrocortisone in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 1999 Dec;91(6):947-52 26. Hasan D, Lindsay KW, Wijdicks EF, Murray GD, Brouwers PJ, Bakker WH, van Gijn J, Vermeulen M. Effect oi fludrocortisone acetate in patients with subarachnoid hemorrhage. Stroke. 1989 Sep;20(9):1156-61

Longevity: the improvement in survival with fludrocortisone 27. Axelrod FB, Goldberg JD, Rolnitzky L, Mull J, Mann SP, Gold von Simson G, Berlin D, Slaugenhaupt SA. Fludrocortisone in patients with familial dysautonomia--assessing effect on clinicai parameters and gene expression. Clin Auton Res. 2005 Aug;15(4):284-91 28. Beigel J, Eichacker P. Hydrocortisone and fludrocortisone improved 28-day survival in septic shock and adrenal insufficiency. ACP J Club. 2003 Mar-Apr;138(2):44. 29. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71

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Aldosterone diagnosis 30. Schambelan M, Stockigt JR, Biglieri EG. lsolated hypoaldosteronism in adults. A renin-deficiency syndrome. N Engl J Med. 1972 Sep 21;287(12):573-86. Oelkers W. Adrenal insufficiency. N Engi J Med. 1996;335:12061212. 31. Guy RJ, Turberg Y, Davidson RN, Finnerty G, MacGregor GA, Wise PH. Mineralocorticoid deficiency in HIV infection. BMJ. 1989;298:496-497 32. Perez G, Siegel L, Schreiner GE. Selective hypoaldosteronism with hyperkalemia. Ann lntern Med. 1972 May;76(5):757-63 33. Zipser RD, Davenport MW, Martin KL, Tuck ML, Warner NE, Swinney RR, Davis CL, Horton R. Hyperreninemic hypoaldosteronism in lhe critically ill: a new entity. J Clin Endocrinol Metab. 1981 Oct;53(4):867-73

Serum aldosterone tests Serum aldosterone 34. Hambling C, Jung RT, Browning MC, Gunn A, Anderson JM. Primary hyperaldosteronism--evaluation of procedures for diagnosis and localization. Q J Med. 1993 Jun;86(6):383-92

24-hour urine aldosterone tests Urinary aldosterone 35. Mattingly D, Martin H, Tyler CM. Estimation of urinary aldosterone using thin-layer chromatography and fluorimetry. J Clin Pathol. 1993 Dec;46(12):1109-12 36. Kawasaki T, Nakamuta S, Muratani H, Omae T. A simple radioimmunoassay determination of urinary aldosterone using 1251-labeled ligand [ALDOCTK-125KIT] and its clinicai application. Nippon Naibunpi Gakkai Zasshi. 1984 May 20;60(5):696-705 37. Ding JF. Urinary sodium and aldosterone excretion in normal subjects in various time periods and their relationship to 24 hour total excretions. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1983 Jun;5(3):193-5 38. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002 Dec;40(6):892-6 39. Stokes GS, Monaghan JC, Mennie BA. Use of an intravenous sodium load in screening for primary hyperaldosteronism. Aust N Z J Med. 1984 Jun;14(3):201-7 40. Zadik Z, Levin P, Kowarski A. The diagnostic value of the 24 hour integrated concentration of plasma aldosterone. Clin Exp Hypertens A. 1985;7(9):1233-42 41. Cugini P, Murano G, Lucia P, Letizia C, Lisanu M, Scavo D, Gillum RF, Lee JY, Halberg F, Koga Y. Effects of a mild and prolonged restriction in sodium or food intake on lhe circadian rhythm of aldosterone and related variables. Am J Chronobiol lnt. 1987;4(2):245-50 42. Lijnen P, Hespel P, Vanden Eynde E, Amery A. Biochemical variables in plasma and urine before and after prolonged physical exercise. Enzyme. 1985;33(3):134-42 43. Elenkova A, Grigorova R. Urinary excretion of aldosterone in patients with hypertension. Vutr Boles. 1982;21 (5):69-74 44. Uezono K, Kawasaki T, ltoh K, Cugini P. Effects of a 1 day fast on biohumoral variables associated with human circadian rhythmicity. Clin Exp Pharmacol Physiol. 2002 Jul;29(7):582-8 45. Niarchos AP, Weinstein DL, Laragh JH. Comparison of the effects of diuretic therapy and low sodium intake in isolated systolic hypertension. Am J Med. 1984 Dec;77(6):1061-8 46. Ando K, lto Y, Nada H, Fujita T. The effect of sodium and potassium loading on urinary kallikrein-like activity in young patients with borderline hypertension. Jpn Circ J. 1985 Nov;49(11):1151-8 47. Ogawa K, Hatano T, Yamamoto M, Matsui N. Hormonal response to acute diuresis--a comparative study of furosemide and azosemide. lnt J Clin Pharmacol Ther Toxicol. 1984 Jun;22(6):284-90 48. Kloppenborg PW, Drayer Jl, Smals AG, Benraad TJ. Aldosterone, sodium and potassium in essential hypertension. Clin Exp Hypertens A. 1982;4(9-10):1881-93 49. Davies E, Holloway CD, lngram MC, lnglis GC, Friel EC, Morrison C, Anderson NH, Fraser R, Connell JM. Aldosterone excretion rale and blood pressure in essential hypertension are related to polymorphic differences in lhe aldosterone synthase gene CYP11B2. Hypertension. 1999 Feb;33(2):703-7 50. Jacobson SH. Blood pressure regulation, peripheral renin activity and aldosterone in patients with pyelonephritic renal scarring. Acta Physiol Scand 1987 Oct;131 (2):242-8 51. Rauh W, Gottesdiener K, Chow D, Forster E, Saenger P, Levine LS, New Ml. Aldosterone response to prolonged ACTH infusion in juvenile hypertension. Pediatr Res. 1980 Sep;14(9):1035-9 52. Lammintausta R, Erkkola R. Effect of spironolactone treatment on lhe renin-aldosterone system during pregnancy. lnt J Clin Pharmacol Biopharm. 1979 Jul;17(7):294-8 53. Pratt JH, Peacock M, Henry DP. Effect of recombinant human grow1h hormone on adreno-cortical function, and on sodium and potassium homeostasis. Pharmacology. 1993 Jul;47(1):36-42

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54. Mantero F, Opocher G, Armanini D, Paviotti G, Boscaro M, Muggeo M. Plasma renin activity and urinary aldosterone in acromegaly. J Endocrinol lnvest. 1979 Jan-Mar;2(1):13-8 55. Oliver WJ, Neel JV, Grekin RJ, Cohen EL. Hormonal adaptation to lhe stresses imposed upon sodium balance by pregnancy and lactation in lhe Yanomama lndians, a culture without sal!. Circulation. 1981 Jan;63(1):110-6] 56. Young WF Jr. Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev. 1999 Jui­ Aug;7(4):207-14 57. Bravo EL. Primary aldosteronism. Cardiol Clin. 1988 Nov;6(4):509-15 58. Takeda Y, Miyamori I, Yoneda T, lki K, Takeda R. Effect of aging on urinary excretion of 19-noraldosterone and 18, 19-dihydroxycorticosterone. J Steroid Biochem Moi Biol. 1995 Apr;52(4):383-6 59. Naka T, Ogihara T, Hata T, Maruyama A, Mikami H, Nakamaru M, Gotoh S, Masuo K, Ohde H, lwanaga K, Kumahara Y. The effect of aging on urinary kallikrein excretion in normotensive subjects and in patients with essential hypertension. J Clin Endocrinol Metab. 1981 May;52(5):1023-6 ( urinary a/dosterone significantly "

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Corrective fludrocortisone Therapy Aldosterone medications: fludrocortisone 72. Sebastian A, Schambelan M, Lindenfeld S, Morris RC Jr. Amelioration of metabolic acidosis with fludrocortisone therapy in hyporeninemic hypoaldosteronism. N Engl J Med. 1977 Sep 15;297(11):576-83 73. Soffer LJ. Orr RH. Newer hydrocortisone analogs. Metabolism. 1958;7:398-404 74. Liddle GW. Studies of structure-function relationship of steroids. 11. The 6-alpha-methylcorticoids.

Metabolism

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Fludrocortisone treatment: dosage 76. Lopes LA, Dubuis JM, Vallotton MB, Sizonenko PC. Should we monitor more closely lhe dosage of 9 alpha­ fluorohydrocortisone in salt-losing congenital adrenal hyperplasia? J Pediatr Endocrinol Metab. 1998 Nov­ Dec;11(6):733-7 77. da Costa D, Mclntosh S, Kenny RA. Benefits of fludrocortisone in lhe treatment of symptomatic vasodepressor carotid sinus syndrome. Br Heart J. 1993 Apr;69(4):308-1o 78. Hughes IA, Wilton A, Lole CA, Gray OP. Continuing need for mineralocorticoid therapy in salt-losing congenital adrenal hyperplasia. Arch Ois Child. 1979 May;54(5):350-5

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664

Chapterfourteen:

lnsulin

Senescence is associated with a decline of the insulin axis Senescence is associated with a decline in activity of the insulin-secreting beta cells of Langerhans 1.

R0der ME, Schwartz RS, Prigeon RL, Kahn SE. Reduced pancreatic B cell compensation to the insulin

2.

Gama R, Medina-Layachi N, Ranganath L, Hampton S, Morgan L, Marks V. Hyperproinsulinaemia in elderly

resistance of aging: impact on proinsulin and insulin leveis. J Clin Endocrinol Metab. 2000 Jun;85(6):2275-80 subjects: evidence for age-related pancreatic beta-cell dysfunction. Ann Clin Biochem. 2000 May;37 ( Pt 3):367-71 3.

Fritsche A, Madaus A, Stefan N, Tschritter O, Maerker E, Teigeler A, Haring H, Stumvoll M.Relationships among age, proinsulin conversion, and beta-cell function in nondiabetic humans. Diabetes

2002 Feb;51

Suppl 1:S234-9

Senescence is associated with a decline in insulin releasefrom the beta- cells in vitro 4. Castro M, Pedrosa D, Osuna Jl. lmpaired insulin release in aging rats: metabolic and ionic events. Experientia. 1993 Oct 15;49(10):850-3 (limpaired glucose-induced insu/in release) Coordt MC, Ruhe RC, McDonald RB. Aging and insulin secretion. Proc Soe Exp Biol Med. 1995 5. Jul;209(3):213-22 Senescence is associated with a decline in the insulin secretion after stimulus (glucose, stress, heavy exercise, GIP, ..) 6. Dechenes CJ, Verchere CB, Andrikopoulos S, Kahn SE. Human aging is associated with parallel reductions in insulin and amylin release. Am J Physiol 1998 Nov;275(5 Pt 1):E785-91 7. Tsuchiyama S, Tanigawa K, Kato Y. Effect of aging on the sensitivity of pancreatic beta-cells to insulin secretagogues in rats. Endocrinol Jpn 1991 Oct;38(5):551-7 8. Meneilly GS, Ryan AS, Minaker KL, Elahi D. The effect of age and glycemic levei on the response oi the beta­ cell to glucose-dependent insulinotropic polypeptide and peripheral tissue sensitivity to endogenously released insulin. J Clin Endocrinol Metab. 1998 Aug;83(8):2925-32 9. Ranganath L, Sedgwick I, Morgan L, Wright J, Marks V. The ageing entero-insular axis. Diabetologia. 1998 Nov;41(11):1309-13 10. Bourey RE, Kohrt WM, Kirwan JP, Staten MA, King DS, Holloszy JO. Relationship between glucose tolerance and glucose-stimulated insulin response in 65-year-olds. J Gerontol. 1993 Jui;48(4):M122-7 Krishnan RK, Hernandez JM, Williamson DL, O'Gorman DJ, Evans WJ, Kirwan JP. Age-related differences in 11. the pancreatic beta-cell response to hyperglycemia after eccentric exercise. Am J Physiol. 1998 Sep;275(3 Pt 1):E463-70 12. Aizawa T, Komatsu M, Sato Y, lshihara F, Suzuki N, Nishii N, Hashizume K, Yamada T. lnsulin secretion by the pancreatic beta cell oi aged rats. Pancreas. 1994 Jul;9(4):454-9 Borg LA, Dahl N, Swenne I. Age-dependent differences in insulin secretion and intracellular handling oi insulin 13. in isolated pancreatic islets oi the rat. Diabete Metab. 1995 Dec;21(6):408-14 Senescence is associated with a reduction of the metabolic clearance of insulin 14.

Broughton DL, Webster J, Taylor R. lnsulin sensitivity and secretion in healthy elderly human subjects with

15.

Weber P, Kolacny I. Glucose tolerance in the elderly--changes in insulin, C-peptide and glucagons secretion;

'abnormal' glucose tolerance. Eur J Clin lnvest 1992 Sep;22(9):582-90 Wien Med Wochenschr 1992;142(4):73-8

Senescence is associated with an increase in the extraction and inactivation of insulin by the liver 16. Ahrén B, Pacini G. Age-related reduction in glucose elimination is accompanied by reduced glucose effectiveness and increased hepatic insulin extraction in man. J Clin Endocrinol Metab. 1998 Sep;83(9):33506 Senescence is associated with a decline in the conversion of proinsulin to insulin, resulting in increased (not or poorly active) plasma proinsulin 17. R0der ME, Schwartz RS, Prigeon RL, Kahn SE. Reduced pancreatic B cell compensation to the insulin resistance oi aging: impact on proinsulin and insulin leveis. J Clin Endocrinol Metab. 2000 Jun;85(6):2275-80 18. Shimizu M, Kawazu S, Tomono S, Ohno T, Utsugi T, Kato N, lshi C, lto Y, Murata K. Age-related alteration oi pancreatic beta-cell lunction. lncreased proinsulin and proinsulin-to-insulin molar ratio in elderly, but not in obese, subjects without glucose intolerance. Diabetes Care. 1996 Jan;19(1):8-11

665

Senescence is associated with a decline in orderliness and amplitude of ultradian oscillations of insulin secretion 19. Scheen AJ, Sturis J, Polonsky KS, Van Cauter E. Alterations in the ultradian oscillations of insulin secretion 20.

and plasma glucose in aging. Diabetologia. 1996 May;39(5):564-72 Ve/dhuis JD. Novartis Found Symp 2000;227:163-85

Senescence is associated with a decline in the insulin sensitivity of target cells 21.

Roder ME, Schwartz RS, Prigeon RL, Kahn SE. Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin leveis. J Clin Endocrinol Metab. 2000 Jun;85(6):2275-80

22.

Fernández AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL, Fi/more J, Shu/man G/, Le Roith D. Functional inactivation of lhe IGF-1 and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev. 2001 Aug 1;15(15):1926-34

lnsulin may oppose and insulin deficiency may trigger several mechanisms of senescence Excessive free radical formation: lnsulin may stimulate antioxidant activity 23.

24. 25.

26. 27. 28. 29.

Sindhu RK, Koo JR, Roberts CK, Vaziri ND. Dysregulation of hepatic superoxide dismutase, catalase and glutathione peroxidase in diabetes: response to insulin and antioxidant therapies. Clin Exp Hypertens. 2004 Jan;26(1):43-53 Dosoo DK, Rana SV, Offe-Amoyaw K, Tete-Donkor D, Maddy SQ. Total antioxidant status in non-insu/in­ dependent diabetes mellitus patients in Ghana. West Afr J Med. 2001 Jui-Sep;20(3):184-6. Schiel R, Franke S, Appel T, Voigt U, Ross 18, Kientsch-Engel R, Stein G, Müller UA. lmprovement in quality of diabetes control and concentrations of AGE-products in patients with type 1 and insulin-treated type 2 diabetes mellitus studied over a period of 10 years (JEVIN). J Diabetes Complications. 2003 Mar­ Apr;17(2):90-7 Kostolanská J, Jakus V, Barák L. Glycation and /ipid peroxidation in children and adolescents with type 1 diabetes mellitus with and without diabetic complications. J Pediatr Endocrinol Metab. 2009 Jul;22(7):635-43 Hoeldtke RD, Bryner KD, Corum LL, Hobbs GR, Van Dyke K. Lipid peroxidation in early type 1 diabetes mellitus is unassociated with oxidative damage to DNA. Metabolism. 2009 May;58(5):731-4 Shamir R, Kassis H, Kaplan M, Naveh T, Shehadeh N. Glycemic control in adolescents with type 1 diabetes mellitus improves lipid serum leveis and oxidative stress. Pediatr Diabetes. 2008 Apr;9(2):104-9 Peerapatdit T, Likidlilid A, Patchanans N, Somkasetrin A. Antioxidant status and lipid peroxidation end products in patients of type 1 diabetes mellitus. J Med Assoe Thai. 2006 Nov;89 Suppl 5:8141-6

lmbalanced apoptosis: lnsulin inhibits undesirable apotosis 30.

Lv GF, Chen B, Zhang WF, Dong ML, Zhu XX, Hu DH. [The anti-apoptosis effect of intensive insulin treatment on cardiac myocytes in severe scald rats]. Zhonghua Shao Shang Za Zhi. 2008 Jun;24(3):179-82

31.

Zhang L, Zhang L, Li YH, Zhang HY, Chen ML, Gao MM, Hu AH, Yang HS, Yang HS. High-dose glucose­ insulin-potassium treatment reduces myocardial apoptosis in patients with acute myocardial infarction. Eur J Clin lnvest. 2005 Mar;35(3):164-70. PubMed PMID: 15733070. Yamanaka M, Shirai M, Shiina H, Tanaka Y, Tsujimura A, Matsumiya K, Okuyama A, Dahiya R. Diabetes induced erectile dysfunction and apoptosis in penile crura are recovered by insulin treatment in rats. J Urol. 2003 Jul;170(1):291-7

32.

AGE (advanced glycation end) products, crosslinking: lnsu/in reduces both 33. Schiel R, Franke S, Appel T, Voigt U, Ross 18, Kientsch-Engel R, Müller UA, Stein G. lmprovement of lhe quality of diabetes control and decrease in lhe concentrations of AGE-products in patients with type 1 and insu/in-treated type 2 diabetes mellitus: results from a 1O year-prospective, population-based survey on lhe quality of diabetes care in Germany (JEVIN). Eur J Med Res. 2004 Aug 31;9(8):391-9 Malabsorption of important nutrients: insulin improves macronutrient uptake 34. Argilés JM, Zegrí A, Arbós J, García C, López-Soriano FJ. The role of insulin in lhe intestinal absorption of glucose in lhe rat. lnt J Biochem. 1992 Apr;24(4):631-6 35. Caspary WF. Effect of insulin and experimental diabetes mellitus on the digestive-absorptive function of lhe small intestine. Digestion. 1973 Oct;9(3):248-63 Failure of repair systems: lnsulin reduces damage and accelerates repair 36. Kayal RA, Alblowi J, McKenzie E, Krothapalli N, Silkman L, Gerstenfeld L, Einhorn TA, Graves DT. Diabetes causes lhe accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Bone. 2009 Feb;44(2):357-63

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lmmune deficiency: Low insulin leveis are associated with immune deficiency 37.

lshibashi T, Kitahara Y, Harada Y, Harada S, Takamoto M, lshibashi T.lmmunologic features of mice with streptozotocin-induced diabetes: depression of their immune responses to sheep red blood cells. Diabetes. 1980 Jul;29(7):516-23

lnsulin improves the immune system Geerlings SE, Hoepelman AI. lmmune dysfunction in patients with diabetes mellitus (DM). FEMS lmmunol Med Microbiol. 1999 Dec;26(3-4):259-65

38.

Limits to healthy cell proliferation: lnsulin stimulates fibroblast proliferation and differentiation Monaco S, lllario M, Rusciano MR, Gragnaniello G, Di Spigna G, Leggiero E, Pastare L, Fenzi G, Rossi G, Vitale M. lnsulin stimulates fibroblast proliferation through calcium-calmodulin-dependent kinase 11. Cell Cycle. 2009 Jul 1;8(13):2024-30 Komorov IS, Fedotov VP. Effect of insulin on the proliferation and kinetics of mitotic cycle of lhe murine 40. 39.

fibroblast (L) in vitro. Probl Endokrinol (Mosk). 1974 Nov-Dec;20(6):52-5

Poor gene polymorphisms: P insulin gene polymorphisms may increase lhe risk of age-related diseases, and insulin dysfunction may increase lhe risk of phenotypic expression of other unfavourable gene polymorphisms 41.

Rudovich N, Pivovarova O, Fisher E, Fischer-Rosinsky A, Spranger J, Mõhlig M, Schulze MB, Boeing H, Pfeiffer AF. Polymorphisms within insulin-degrading enzyme gene determine insulin metabolism and risk of type 2 diabetes. J Moi Med.2009 Nov;87(11):1145-51

42.

Müssig K, Staiger H, Machicao F, Kirchhoff K, Guthoff M, Schãfer SA, Kantartzis K, Silbernagel G, Stefan N, Holst JJ, Gallwitz B, Hãring HU, Fritsche A. Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion. Diabetes. 2009 Jul;58(7):1715-20

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Goulart AC, Germer S, Rexrode KM, Martin M, Zee RY. Polymorphisms in advanced glycosylation end product-specific receptor (AGER) gene, insulin resistance, and type 2 diabetes mellitus. Clin Chim Acta. 2008 Dec;398(1-2):95-8

44.

Huang XH, Rantalaiho V, Wirta O, Pasternack A, Koivula T, Hiltunen T, Nikkari T, Lehtimãki T. Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM. Hum Gene!. 1998 Mar;102(3):372-8

lnsulin and psychic well-being Lower quality of life, lower energy stores and fatigue: the association with lower insulin leveis 45.

Franciosi M, Maione A, Pomili B, Amoretti R, Busetto E, Capani F, Bruttomesso D, Di Bartolo P, Girelli A, Leonelli F, Morviducci L, Ponzi P, Vitacolonna E, Nicolucci A. Correlatas of quality of life in adults with type 1 diabetes treated with continuous subcutaneous

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Slinger JD, van Breda E, Keizer H, Rump P, Hornstra G, Kuipers H. lnsulin resistance, physical fitness, body composition and leptin concentration in 7-8 year-old children. J Sei Med Sport. 2008 Apr;11(2):132-8

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Draznin B, Solomons CC, Emler CA, Schalch OS, Sussman KE. Decreased insulin binding and degradation associated with depressed intracellular ATP content. Diabetes. 1980 Mar;29(3):221-6.

Lower quality of life and fatigue: the improvement with insulin treatment Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health related quality of life, treatment satisfaction and costs associated with intraperitoneal versus subcutaneous insulin administration in

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type 1 diabetes. A randomized controlled trial. Diabetes Care. 2010 (Feb 25, Epub ahead of print) 49.

Rubin RR, Peyrot M. Treatment Satisfaction and Quality of Life for an lntegrated Continuous Glucose Monitoring/lnsulin Pump System Compared to Self-Monitoring Plus an lnsulin Pump. J Diabetes Sei Technol. 2009 Nov 1;3(6):1402-1410

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Lee IT, Liu HC, Liau YJ, Lee WJ, Huang CN, Sheu WH. lmprovement in health-related quality of life, independent of fasting glucose concentration, via insulin pen device in diabetic patients. J Eval Clin Pract. 2009 Aug;15(4):699-703

Depression: the association with lower insulin leveis Ruhwinkel B, Tõlle R. Modified insulin treatment of therapy refractory depression. Psychiatr Prax. 1995 51. Mar;22(2):64-7

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Menna-Perper M, Rochford J, Mueller PS, Swartzburg M, Jekelis AW, Manowitz P. Differential response of plasma

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fatty

acids

to

insulin

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á&.-

Nathan RS, Sachar EJ, Asnis GM, Halbreich U, Halpern FS. Relative insulin insensitivity and cortisol secretion in depressed patients. Psychiatry Res. 1981 Jun;4(3):291-300

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Williams K, Smith J, Glue P, Nutt D. The effects of electroconvulsive therapy on plasma insulin and glucose in

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Barnard KD, Skinner TC, Peveler R. The prevalence of co-morbid depression in adults with Type 1 diabetes:

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Weber-Hamann B, Gilles M, Schilling C, Onken V, Frankhauser P, Kopf O, Lederbogen F, Deuschle M.

depression. Br J Psychiatry. 1992 Jul;161 :94-8 systematic literature review. Diabet Med. 2006 Apr;23(4):445-8 lmproved insulin sensitivity in 51 nondiabetic depressed inpatients remitting during antidepressive treatment with mirtazapine and venlafaxine. J Clin Psychopharmacol. 2008 Oct;28(5):581-4 Depression: the improvement with insulin treatment 57.

Gendelman N, Sneii-Bergeon JK, McFann K, Kinney G, Paul Wadwa R, Bishop F, Rewers M, Maahs DM. Prevalence and correlates of depression in individuais with and without type 1 diabetes. Diabetes Care. 2009 Apr;32(4):575-9

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Plengvidhya

N,

Leelawatana

R,

Pratipanawatr

T,

Deerochanawong

C,

Krittiyawong

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Bunnag P,

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1 diabetes had significant elevated (SIR +60%), and endometrium (+170%))

800 (Patients with type

risks of overa/1

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Cancer in type 1 diabetes: no significant effect with insulin treatment 183.

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0.83 , 95% C/ 0.64-1.07). lnsu/in users overa/1 and 95%

insulin users with diabetic complications had decreased risks, compared to non-diabetic men (HR 0.49,

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chaptertifteen:

Estrogens and Progesterone in women

Senescence is associated with a decline of the ovarian-estrogen axis Decrease of estrogen and progesterone leveis with senescence, including in women with normal cycles 1. Khosla S, Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL. Relationship of serum sex steroid leveis and bone turnover markers with bone mineral density in rnen and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab.1998 Jul;83(7):2266-74 MacNaughton J, Banah M, McCioud P, Hee J, Burger H. Age related changes in follicle stimulating hormone, 2. luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol (Oxf). 1992 Apr;36(4):339-45. 3. Sherman BM, West JH, Korenman SG. The menopausa! transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab. 1976 Apr;42(4):629-36 Cahill DJ, Prosser CJ, Wardle PG, Ford WC, Hull MG. Relative influence of serum follicle stimulating 4. hormone, age and other factors on ovarian response to gonadotrophin stimulation. Br J Obstei Gynaecol.

5.

1994 Nov;101(11):999-1002 (Women over 40 have a significantly lower serum oestradiol in comparison with women less than 40 years old) Sherman BM, West JH, Korenman SG. The menopausa! transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab. 1976 Apr;42(4):629-36 (Perimenopause: shorter cycles with lower estradiol and progesterone; in women at or above age 36 years; also lower serum oestradiol at stimulation for in vitro fertilization)

Decrease of serum estradiol leveis with senescence at stimulation for in vitro fertilization 6. Lau WN, So WW, Yeung WS, Ho PC. The effect of ageing on female fertility in an assisted reproduction programme in Hong Kong: retrospective study. Hong Kong Med J. 2000 Jun;6(2):147-52 (Compared with women aged s 30 years, women aged � 36 years had a significantly higher cycle cancellation rale, fewer oocytes retrieved per retrieval cycle, fewer oocytes fertilised per retrieval cyc/e, fewer c/eaving embryos per retrieval cycle, and lower serum oestradiol despite a larger amount of human menopausa/ gonadotrophin having been used) Decrease in urinary progesterone metabolites with senescence Santoro N, Lasley B, McConnell D, Allsworth J, Crawford S, Gold EB, Finkelstein JS, et ai. Body size and 7. ethnicity are associated with menstrual cycle alterations in women in lhe early menopausa! transition: The Study of Women's Health across the Nation (SWAN) Daily Hormone Study. J Clin Endocrinol Metab. 2004 Jun;89(6):2622-31 Decrease of metabolic clearance of the estrogens with senescence 8. Longcope C. Metabolic clearance and blood production rales of estrogens in postmenopausal women. Am J Obstet Gynecol.1971 Nov;111(6):778-81

A historv of prior pregnancy or induced abortion is associated with a decline of the ovarian-estroqen axis Windham GC, Elkin E, Fenster L, Waller K, Anderson M, Mitchell PR, Lasley B, Swan SH. Ovarian hormones 9. in premenopausal women: variation by demographic, reproductive and menstrual cycle characteristics. Epidemiology. 2002 Nov;13(6):675-84 (lower urinary estrogen and progesterone metabolites) Tubal ligation is associated with a decline of the ovarian-estrogen axis 10. Rojansky N, Halbreich U. Prevalence and severity of premenstrual changes after tubal sterilization. J Reprod Med. 1991 Aug;36(8):551-5 11. Alvarez-Sanchez F, Segal SJ, Brache V, Adejuwon CA, Leon P, Faundes A. Pituitary-ovarian function after tubal ligation. Fertil Steril.1981 Nov;36(5):606-9

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Estrogen treatment may oppose and estrogen deficiency may trigger several mechanisms of senescence Excessive free radical formation: Estrogens have antioxidant activity Estrogens 12. Bokov AF, Ko O, Richardson A. The effect oi gonadectomy and estradiol on sensitivity to oxidative stress. Endocr Res. 2009;34(1-2):43-58 13. Tasset I, Pena J, Jimena I, Feijóo M, Dei Carmen Mufíoz M, Montilla P, Túnez I. Effect oi 17beta-estradiol on olfactory bulbectomy-induced oxidative stress and behavioral changes in rats. Neuropsychiatr Ois Treat. 2008 Apr;4(2):441-9 14. 15.

16.

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Barp J, Araujo AS, Fernandes TR, Rigatto KV, Llesuy S, Bello-Kiein A, Singal P. Myocardial antioxidant and oxidative stress changes due to sex hormones. Braz J Med Biol Res. 2002 Sep;35(9):1075-81 Azevedo RB, Lacava ZG, Miyasaka CK, Chaves SB, Guri R. Regulation oi antioxidant enzyme activities in

18.

male and female rat macrophages by sex steroids. Braz J Med Biol Res. 2001 May;34{5):683-7 Massafra C, Gioia O, De Felice C, Picciolini E, De Leo V, M Bonifazi, Bernabei A. Effects oi estrogens and androgens on erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase activities during lhe menstrual cycle. J Endocrinol. 2000 Dec;167(3):447-52

Progesterone and estrogens 19. Ozacmak VH, Sayan H. The effects oi 17beta estradiol, 17alpha estradiol and progesterone on oxidative stress biomarkers in ovariectomized female rat brain subjected to global cerebral ischemia. Physiol Res. 2009;58(6):909-12 Testosterone and estrogens 20. Tarn NN, Ghatak S, Ho SM. Sex hormone-induced alterations in lhe activities oi antioxidant enzymes and lipid peroxidation status in lhe prostate oi Noble rats. Prostate. 2003 Apr 1;55(1): 1-8 21. 102. Ahlbom E, Prins GS, Ceccatelli S. Testosterone protects cerebellar granule cells from oxidative stress­ induced cell death through a receptor mediated mechanism. Brain Res. 2001 Feb 23;892(2):255-62 Cross-linking of proteins: Estrogen reduce cross-linking 22. Falconer C, Ekman-Ordeberg G, Ulmsten U, Westergren-Thorsson G, Barchan K, Malmstrom A. Changes in paraurethral connective tissue at menopause are counteracted by estrogen. Maturitas. 1996 Jul;24(3):197204. lmbalanced apoptosis: Estrogen inhibit undesirable apotosis 23. Murdoch WJ. lnhibition by oestradiol oi oxidative stress-induced apoptosis in pig ovarian tissues. J Reprod Fertil. 1998 Sep;114(1):127-30 Failure of repair systems: Estrogen accelerate repair 24. Strehlow K, Werner N, Berweiler J, Link A, Dirnagl U, Priller J, Laufs K, Ghaeni L, Milosevic M, Bohm M, Nickenig G. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes 25.

neointima formation. Circulation. 2003 Jun 24;107(24):3059-65 Krasinski K, Spyridopoulos I, Asahara T, van der Zee R, lsner JM, Losordo DW. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation. 1997 Apr 1;95{7):1768-72

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Poor gene polymorphisms: Poor estrogens and progesterone gene polymorphisms may increase the risk of age­ related diseases 35.

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701

TOPICSOED!SCUSSJON·

CONTROVERSY ON THE USE OR AVO!DANCE OE EEMALE HRT IN WOMEN

I) Arguments against the use of non-bio-identical estrogens and progestogens in women

1) The two major studies that have brought the present controversy on the use of female hormone replacement have shown that non-bio-identical hormones mav increase the risk of disease Women's Health lnitiative (WHI) study: non-bio-identical hormones increase the cardiovascular and breast cancer risks 1.

Wriling group for lhe Women's Heallh lnilialive lnvesligalors. Risks and benefils of eslrogen plus progeslin in heallhy poslmenopausal women. JAMA. 2002; 288: 321-333

Facts: Premature stop of this large doub/e-blind placebo-controlled study because of the increased risk of (RR) invasive breast cancer (1.26) et increased global risk index (1.15); The global risk would have remained negative at the end of the study, even if the results for prevention of cardiovascu/ar disease wou/d have inversed (low probability)) Critics:

Th?. P.9.P.Yi<J!i9n. 9.t !h?. �t11.c!Y. i$. n9.t fi /?.P.!!'i$.�!1t<J!iV?. .P..QP.IIf?J.iP.D 9./Qft[.P.Ji: !!?n!$ (mean age: 63 years); patients have not been under H.R. T. before inc/usion (period of no HRT between menopause and 63 yrs) =>no real" primary prevention»:

n9.Li:J.h?.i:J!tiJY..P.QP.\Ilf!ti_qn: 2/3 of patients were overweight (BM/?.25Kglm2), 1/3 had morbid obesity (BM/?.30Kg!m2); 35,7 % were hypertensive or treated for hypercholestero/emic; 4,4 % were diabetic or treated for diabetes

hypertension;12,5

%

were

T9.!Si9.fqçfp_f: about 50 % of the 8,500 women on HRT were smokers or had been smokers (Mueck AO, Seeger H. Smoking, estradiol metabolism and hormone replacement therapy. Arzneimittelforschung. 2003;53(1): 1-11. Women's University Hospital, Tubingen, Germany. endo.meno@ med.uni-tuebingen. de) •

not a representative population of European patients

Th?..f!Jftçfjç_i:Ji! 9.f.J j�. IJQ! ..i:J. !.�P.[?I�?.fJ!?.ti.V:?..i:J.rJç/_.$.i:J!!'i. (?f!!?./_�. h9.[f!J9.1J�. !.�P.li:Jf?!!l.?n!. !h?!.<JP.Y...association of conjugated estrogens with medroxyprogesterone acetate)

lt is a popular medication in the USA, not in Europe The type of hormones is not bio-identical The !.QU(? of administration for estrogens is the oral one. Results are possibly/probably not true for transdermal estrogens and for estradiol and progestogens of bio-identical structure (Stevenson JC, Whitehead M/. Hormone replacement therapy. BMJ. 2002 Ju/ 20;325(7356): 113-4)

t-f.Q!. ?-n. ?.i:J,S.Y.$.(llçt_y;. (.J.�M!l. ?.r1it9!i?J)

high drop-out rate: 42% of women have stopped the treatment during the study

10.7% of placebo group have began a H.R. T.

Million Women Study: the breast cancer risk 2.

Beral

>

99.97% of the hormones used where non-bio-identical hormones, which increased

V. Million Women Sludy Collaboralors. Breasl cancer and hormone-replacemenl lherapy in lhe Million

Women Sludy. Lancei. 2003 Aug 9;362(9382):419-27

(Critics: Same critics as above; Additional:

!h?.. $(Ucf Y..IY.?-.$.1JQ!.?..r/.QUQ}?.:9JifJ.cf.P./_i:Jç_?f:l9.:Ç9.1J!!9.ij?.çf_ study, but an observational study based on patient's reports

•

f!l.?-r!Y..Qf.t/]gp_qrt!çjp_qf]( $_/J.i: J.c!§.Vfj!ç_f]?.cj from one medication over to another during the study !mf!J. !h?.W9.@?.tjP.n. t/Jf!t. W!'i.h?-X?. /?.9?.iX?.cf •. 9.1J!Y..?-.t/9.11.! -�9.0. _qf_ !h?..Q.rJ?..f!Jiili9.fJ.."Y.Q!!I.?n. P.t. ttt�. �t11.c!Y. ./Jf!çf_ !?.lsstn.((<J.rJ$.c!?.rf!Jf!i. ?.$lr?-.c!!9J. !h?!.Ji: P.Y,.f!if!JP.$!. f!!!_ _qn. t/J.? ..�$_tr.<Jçfq f / P..i:J!ç_fJ,. wh!çh.m<JY. P.!.QY.i.cf?..!�$.$. s:<9.fJ$.(<Jnt ft$_I!.Qg?n.l?Y?!$ (and of those only some 30 had taken the estradiol gel- that carne out in the U.K. as official brand only two years after the start of the study and two years before its end)

r!9.fJ.�.. 9.t. JfJ?... IY.9.f!J!'!IJ...fJ?.r!. ..ti:Jk?n..P/Q9?.$(?.(Q.rJ?. (f!J!Ç!.QIJil.?.cf,.. t/J.?.. ki9:ir!.?nti.9?L 9.1J? ), solely synthetic derivatives of progesterone were taken

702

2) Other studies that show that estrogens with a NON 810-IDENTICAL (foreign-to-the-human-bodyl structure may adversely affect the body 2-a) Absorption of non-bio-identical estrogens provides abnormal estrogens in the blood: Treatments with equine estrogens (the Prempro of the WHI and Million Women studies) supply the blood with abnormal estrogens. Equine estrogens contain estrone sulfate (53-61%), equilin sulfate (23-30%) equilenin, 17 a-dihydroequilin, 17 alpha-estradiol, 17 a-dihydroequilenin and numerous other horse estrogens

3.

Morgan MR, Whittaker PG, Dean PD, Lenton EA, Sexton L, Cooke 10. Plasma equilin concentrations in an oophorectomized woman following ingestion of conjugated equine oestrogens (Premarin). Eur J Clin lnvest. 1979 Dec;9(6):473-4

4.

Bhavnani BR, Sarda IR, Woolever CA. Radioimmunoassay of plasma equilin and estrone in postmenopausal women after the administration of premarin. J Clin Endocrinol Metab. 1981 Apr;52(4):741-7

5.

Utian WH, Katz M, Davey DA, Carr PJ. Effect of premenopausal castration and incrementai dosages of conjugated equine estrogens on plasma follicle-stimulating hormone, luteinizing hormone, and estradiol. Am J Obste! Gynecol. 1978 Oct 1;132(3):297-302

Treatments with ethinylestradiol (the Million women study): 6.

Goldzieher JW. Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinicai implications. Am J Obste! Gynecol. 1990 Jul;163(1 Pt 2):318-22

7.

Shenfield GM, Griffin JM. Clinicai pharmacokinetics of contraceptive steroids. An update. Clin Pharmacokinet. 1991 Jan;20(1):15-37.

2b) Non-bio-identical hormones are almost always provided through the ORAL ROUTE, which is not the best route. nor a totally safe one:

2b-1) Treatments with oral estrogens provide imbalanced serum leveis of estrogens and urinary leveis of estrogen metabolites (an abnormally high serum estrone levei and an abnormal increase of urinary 16alpha-hydroxy-estrone) 8.

Powers

MS,

Schenkel

L,

Darley PE,

Good

WR,

Balestra

JC,

Place VA.

Pharmacokinetics

and

pharmacodynamics of transdermal dosage forms of 17-beta-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obste! Gynecol. 1985 Aug 15;152(8):1099-106 9.

Chetkowski RJ, Meldrum DR, Steingold KA, Randle O, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biologic effects of transdermal estradiol. N Engl J Med. 1986 Jun 19;314(25):1615-20

2b-2) Treatments with oral estrogens excessively increase the serum leveis of the plasma binding proteins How? Oral estrogens, after absorption in lhe intestinal tract, are transported to lhe tiver where they accumulate. The tiver produces under this "estrogen dominance" excessive amounts of hormone plasma bnding proteins, resulting in high serum leveis of lhe plasma binding proteins, which bind greater amount of various hormones in the serum, thus reducing the amount of hormones bioavai/able for lhe target cells. 10.

Stumpf PG. Pharmacokinetics of estrogen. Obste! Gynecol. 1990 Apr;75(4 Supp1):9S-14S; discussion 15S17S

2-b-3) Treatments with oral estrogens reduce the leveis and activities of other hormones

Treatments with oral estrogens reduce serum /GF-1/eve/s and thus GH metabolic activity 11.

Wolthers T, Hoffman DM, Nugent AG, Duncan MW, Umpleby M, Ho KK. Oral estrogen antagonizes the metabolic actions of growth hormone in growth hormone-deficient women. Am J Physiol Endocrinol. Metab. 2001 Dec;281(6):E1191-6

12.

Paassilta M, Karjalainen A, Kervinen K, Savolainen MJ, Heikkinen J, Backstrom AC, Kesaniemi YA. lnsulin­ like growth factor binding protein-1 (IGFBP-1) and IGF-1 during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) leveis. Atherosclerosis. 2000 Mar;149(1):157-62

13.

Janssen YJ, Helmerhorst F, Frolich M, Roelfsema F. A switch from oral (2 mg/day) to transdermal (50 1-lQ/day) 17beta-estradiol therapy increases serum insulin-like growth factor-1 leveis in recombinant human growth hormone (GH)-substituted women with GH deficiency. J Clin Endocrinol Metab. 2000 Jan;85(1):464-7

703

14. 15.

16.

17.

18.

Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults. J Clin Endocrinol Metab. 1999 Nov;84(11):3956-60 Cano A, Castelo-Branco C, Tarin JJ. Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3 leveis. Fertil Steril. 1999 Feb;71(2):261-7 Bellantoni MF, Vittone J, Campfield AT, Bass KM, Harman SM, Blackman MR. Effects of oral versus transdermal estrogen on the growth hormone/insulin-like growth factor I axis in younger and older postmenopausal women: a clinicai research center study. J Clin Endocrinol Metab. 1996 Aug;81(8):2848-53 Ho KK, Weissberger AJ. lmpact of short-term estrogen administration on growth hormone secretion and action: distinct route-dependent effects on connective and bone tissue metabolism.J Bone Miner Res. 1992 Jul;7(7):821-7 Weissberger AJ, Ho KK, Lazarus L. Contrasting effects oi oral and transdermal routes oi estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth lactor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 1991 Feb;72(2):374-81

Treatments with oral estrogens reduce the excretion of melatonin metabolites and thus melatonin activity

19.

Luboshitzky R, Shen-Orr Z, Herer P, Nave R. Urinary 6-sullatoxymelatonin excretion in hyperandrogenic women with polycystic ovary syndrome: the effect of ethinyl estradiol-cyproterone acetate treatment. Gynecol Endocrinol. 2003 Dec;17(6):441-7

Treatments with oral estrogens reduce serum free thyroid hormones, in particular serum free T3, and thus thyroid activity

20.

Rudorff KH, Herrmann J, Dieterich T, Kruskemper HL. Effect of estrogen upon thyroid metabolism. Med Klin. 1978 Aug 4;73(31):1109-13

Treatments with oral estrogens reduce cortisol levels, and thus glucocorticoid activities

21.

Hammerstein J, Daume E, Simon A, Winkler UH, Schindler AE, Back DJ, Ward S, Neiss A. lnlluence oi gestodene and desogestrel as components of low-dose oral contraceptives on the pharmacokinetics of ethinyl estradiol (EE2), on serum CBG and on urinary cortisol and 6 beta-hydroxycortisol. Contraception. 1993 Mar;47(3):263-81

Treatment with oral estrogens reduce free and total testosterone, DHT, DHEA, free cortisol, and thus androgen and glucocorticoid activities

22.

Coenen CM, Thomas CM, Borm GF, Rolland R. Comparative evaluation of the androgenicity oi lour low-dose, fixed-combination oral contraceptives. lnt J Fertil Menopausa! Stud. 1995;40 Suppl 2:92-7

23.

De Lignieres B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, Guyene TI, Mairon N, Corvol P, Guy-Grand B, et ai. Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab. 1986 Mar;62(3):536-41

2-c) Non-bio-identical hormones such as those of oral birth-control pills may not be better through the transdermal route (as transdermal patches): They cause similar and on some points worse adverse effects than through the oral route. They increase similarly or even to a greater extent the leveis oi the plasma binding proteins They may cause similar or even to a greater extent reductions of hormone activities 24.

Heger-Mahn D, Warlimont C, Faustmann T, Gerlinger C, Klipping C. Combined ethinylestradiol/gestodene contraceptive patch: two-center, open-label study of ovulation inhibition, acceptability and safety over two cycles in lemale volunteers. Eur J Contracept Reprod Health Care. 2004 Sep;9(3):173-81))

2c-1) The transdermal contraceptive patch (Ortho Evra/Evra, 1 patch per week of 20 f.J9 ethinyl estradiol with 150 f.l9 norelgestromin, the active metabolite oi the progestogen norgestimate, structurally related to 19-nortestosterone) The transdermal contraceptive patch provides higher leveis of ethinylestradiol and SHBG, than the oral pill, but similar increase of on CBG 25.

Devineni D, Skee D, Vaccaro N, Massarella J, Janssens L, LaGuardia KD, Leung AT. Pharmacokinetics and pharmacodynamics of a transdermal contraceptive patch and an oral contraceptive. J Clin Pharmacol. 2007 Apr;47(4):497-509.

704

The transdermal contraceptive patch provides a higher levei of SHBG and similar lowering effect on key serum androgen leveis (DHEAs, free testosterone and androstanediol glucuronide) as oral contraceptive pills

26.

White T, Jain JK, Stanczyk FZ. Effect of oral versus transdermal steroidal contraceptives on androgenic markers. Am J Obstei Gynecol. 2005 Jun;192(6):2055-9 (patch versus oral contraceptive: 449% vs 274% increase in SHBG; -40 % vs -39% reduction of free testosterone, -26% versus 32 % reduction in DHEA sulphate, and- 52 % versus -51% reduction in androstanediol g/ucuronide) -

The transdermal contraceptive patch provides higher leveis of SHBG and TBG and greater increase of CRP compared to the oral pill 27.

White T, Ozel B, Jain JK, Stanczyk FZ. Effects of transdermal and oral contraceptives on estrogen-sensitive hepatic proteins. Contraception. 2006 Oct;74(4):293-6

The transdermal contraceptive patch causes a higher incidence of breast pain, dysmenorrhoea and application site reactions than the oral pill 28.

Radowicki S, Skorzewska K, Szlendak K. [Safety evaluation of a transdermal contraceptive system with an oral contraceptive] Ginekol Pol. 2005 Nov;76(11):884-9.

The transdermal contraceptive patch causes a similar increase in risk of nonfatal venous thromboembolism for the contraceptive patch as for the oral contraceptive pills 29.

Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 micrograms of ethinyl estradiol. Contraception. 2006 Mar;73(3):223-8

The transdermal contraceptive patch causes similar unfavourable lipid changes: increases in total cholesterol and total triglycerides compared to lhe oral group 2c-2) Other transdermal contraceptive patch: ethinylestradiol/gestodene (.9 mg ethinylestradiol and 1.9 mg gestodene ) 2c-3) The vaginal contraceptive ring (Nuvaring, 1 per 3 weeks; 2,7 mg of ethinylestradiol and 11,7 mg of etonogestrel, which supply 12 �g of etonogestrel and 15 �g of ethinylestradiol per day) supplies much less ethynylestradiol to lhe body 30.

van

den

Heuvel

MW,

van

Bragt

AJ,

Alnabawy

AK,

Kaptein

MC.Comparison

of

ethinylestradiol

pharmacokinetics in three hormonal contraceptive formulations: lhe vaginal ring, lhe transdermal patch and an oral contraceptive. Contraception. 2005 Sep;72(3):168-74. 2d) Studies where oral and/or structurally non-bio identical estrogen treatments were associated with adverse effects on the cardiovascular system Treatments with oral estrogens, including conjugated estrogens, disturb blood coagulation: Treatments with oral estrogens increases factor VIl activity 35. Nozaki M, Ogata R, Koera K, Hashimoto K, Nakano H. Changes in coagulation factors and fibrinolytic components of postmenopausal women receiving continuous hormone replacement therapy. Climacteric. 1999 Jun;2(2):124-30 Treatments with oral estrogens reduce tissue factor pathway inhibitor, a major inhibitor of the extrinsic coagulation pathway, and increase C-reactive protein, a component of the acute phase 36. Luyer MD, Khosla S, Owen WG, Miller VM. Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammation in postmenopausal women. J Clin Endocrinol Metab. 2001 Aug;86(8):3629-34

705

Treatments with high doses of oral estrogens significantly increase serum alpha

1-antitrypsin and

plasminogen leveis 37.

Alkjaersig N, Fletcher AP, de Ziegler D, Steingold KA. Meldrum DR, Judd HL. Blood coagulation in postmenopausal women given estrogen treatment: comparison of transdermal and oral administration. J Lab Clin Med. 1988 Feb;111(2):224-8

Treatments with oral estrogens significantly reduce antithrombin 111 and protein S activities 38.

Lobo RA, Bush T, Carr BR, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril. 2001 Jul;76(1):13-24

39.

Bonduki CE, Lourenco DM, Baracat E, Haidar M, Noguti MA, da Motta EL, Lima GR. Effect of estrogen­ progestin hormonal replacement therapy on plasma antithrombin 111 of postmenopausal women. Acta Obste! Gynecol Scand. 1998 Mar;77(3):330-3

Treatments with oral estrogens increase in matrix meta/loproteinase-9 within the vessel wa/1: could digest and weaken fibrous caps of vulnerable plaques, thus provoking thrombosis 40.

Zanger D, Yang BK, Ardans J, Waclawiw MA, Csako G, Wahl LM, Cannon RO 3rd. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medicai management. J Am Coll Cardiol 2000 Nov 15;36(6):1797-802

Treatments with oral estrogens increase the risk of venous thromboembolism, especially during the first year 41.

Oger E, Scarabin PY. Assessment of lhe risk for venous thromboembolism among users of hormone replacement therapy. Drugs Aging. 1999 Jan;14(1):55-61

Treatments with oral estrogens increase the risk of ischaemic stroke among postmenopausal women 42.

Oger E, Scarabin PY. Hormone replacement therapy in menopause and the risk of cerebrovascular accident. Ann Endocrinol (Paris). 1999 Sep;60(3):232-41

Treatments with oral estrogens and tibolone significantly increase serum CRP, while transdermal estradiol has no significant effect on serum CRP 43.

Prelevic GM, Kwong P, Byrne DJ, Jagroop IA, Ginsburg J, Mikhailidis DP. A cross-sectional study of lhe effects of horrnon replacement therapy on lhe cardiovascular disease risk profile in healthy postmenopausal women. Fertil Steril. 2002 May;77(5):945-51

44.

Decensi A, Omodei U, Robertson C, Bonanni B, Guerrieri-Gonzaga A, Ramazzotto F, Johansson H, Mora S, Sandri MT, Cazzaniga M, Franchi M, Pecorelli S. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Circulation. 2002 Sep 3;106(10):1224-8

2e) Studies where treatments with structurally NON BIO-IDENTICAL estrogens were associated with an increased breast cancer risk In vitro treatments with conjugated estrogens excessively stimulate epithelial proliferation in breast tissue, an effect worsened with the addition of medroxyprogesterone acetate (MPA) 45.

Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab. 1999 Dec;84(12):4559-65.

Treatments with conjugated or other non-bio-identical estrogens increase the breast cancer risk Writing group for lhe Women's Health lnitiative lnvestigators. Risks and benefits of estrogen plus progestin in 46. healthy postrnenopausal women. JAMA. 2002; 288:321-333 47.

Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in lhe Million Women Study. Lance!. 2003 Aug 9;362(9382):419-27

706

Studies with associations between hormone replacement treatments and increased risk of breast cancer Studies where female hormone replacement treatments (generally with oral, non-bio-identical estrogens and synthetic progestogens) were associated with an increase in risk of breast cancer 48.

Persson I, Thurfjell E, Bergstrom R, Holmberg L. Hormone replacement therapy and lhe risk oi breast cancer. Nested case-controlstudy in a cohort oi Swedish women attending mammography screening. lnt J Cancer 1997 Sep 4;72(5):758-61

49.

Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausa! estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000 Jan 26;283(4):485-91

50.

LeBianc ES, Viscoli CM, Henrich JB. Postmenopausal estrogen replacement therapy is associated with adverse breast. J Womens Health Gend Based Med 1999 Jui-Aug;8(6):815-23

51.

Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect oi hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer lnst 2000 Feb 16;92(4):328-32

52.

Vessey MP. Effect oi endogenous and exogenous hormones on breast cancer: epidemiology. Verh Dtsch Ges Pathol 1997;81:493-501

Studies that contest the validity of the above-mentioned studies 53.

Creasman WT. ls there an association between hormone replacement therapy and breast cancer? J Womens

54.

Sitruk-Ware R Hormone therapy oi menopause and risk of breast cancer. Polemics and Controversies. Presse

Health 1998 Dec;7(10):1231-46 Med 1994 Jan 8-15;23(1):38-42

55.

Franceschi S. Replacement therapy in menopause and risk for breast tumors. Ann 1st Super Sanita 1997;33(2):207 -11

Studies where female hormone replacement treatments (generally with oral, non-bio-identical estrogens) were associated with an increase in risk of breast cancer in women with familial breast cancer 56.

Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM, Flanders WD, Berkelman RL. A meta-analysis of lhe effect oi estrogen replacement therapy on lhe risk of breast cancer.JAMA 1991 Apr 17;265(15):1985-90 (higher risk of breast cancer in women with familial historuy of breast cancer if ever use of estrogen therapy; cirtic: other studies have shown that estrogen replacement did not induce a greater rusk oif breast cancer, but did reduce lhe overa/1 mortality of women with familial history of breast cance, see furtherr)

3) Studies that show that progestogens with NON BIO-IDENTICAL structure may adversely affect the body:

3a) Studies where treatments with synthetic derivatives of progesterone (medroxyprogesterone acetate (MPA) and olher progestogens) were associated with adverse effects on the cardiovascular system Treatments with structurally modified progestogens block the beneficiai effects of estrogens on the cardiovascular system (not lhe case with natural progesterone) 57.

Clarkson TB. Progestogens and cardiovascular disease. A criticai review. J Reprod Med. 1999 Feb;44(2 Suppl): 180-4

58.

Lahdenpera S, Puolakka J, Pyorala T, Luotola H, Taskinen MR. Effects oi postmenopausal estrogen/progestin replacement

therapy

on

LDL

particles;

comparison

of

transdermal

and

oral

treatment

regimens.

Atherosclerosis. 1996 May;122(2):153-62 59. 60.

Wakatsuki A, Sagara Y.Effects oi continuous medroxyprogesterone acetate on lipoprotein metabolism in postmenopausal women receiving estrogen. Maturitas. 1996 Aug;25(1 ):35-44 Cerquetani E, Leonardo F, Pagnotta P, Galetta P, Onorati D, Fini M, Rosano GM. Anti-ischemic effect oi chronic oestrogen replacement therapy alone or in combination with medroxyprogesterone acetate in different replacement schemes. Maturitas. 2001 Sep 28;39(3):245-51

61.

Duvernoy CS, Rattenhuber J, Seifert-Kiauss V, Bengel F, Meyer C, Schwaiger M. Myocardial blood flow and flow reserve in response to short-term cyclical hormone replacement therapy in postmenopausal women. J Gend Specif Med. 2001;4(3):21-7,47

62.

Williams JK, Hall J, Anthony MS, Register TC, Reis SE, Clarkson TB. A comparison oi tibolone and hormone replacement therapy on coronary artery and myocardial function in ovariectomized atherosclerotic monkeys. Menopause 2002 Jan-Feb;9(1 ):41-51

707

63.

Mueck AO, Seeger H, Wallwiener D. Medroxyprogesterone acetate versus norethisterone: effect on estradiol­ induced changes of markers for endothelial function and atherosclerotic plaque characteristics in human female coronary endothelial cell cultures. Menopause 2002 Jul;9(4):273-281

64.

Wakatsuki A, Okatani Y, lkenoue N, Fukaya T. Effect of medroxyprogesterone acetate on endothelium­ dependent vasodilation in postmenopausal women receiving estrogen. Circulation 2001 Oct 9;104(15):1773-8

65.

Register TC, Adams MA, Golden DL, Clarkson TB. Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys. Arterioscler Thromb Vasc Biol 1998 Jul;18(7):1164-71

66.

Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid

67.

Adams MA, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes

protection against coronary vasospasm. Nat Med 1997 Mar;3(3):324-7 inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997 Jan;17(1):217-21 68.

Luckas MJ, Gleeve T, Biljan MM, Buckett WM, Aird IA, Drakeley A, Kingsland CR. The effect of progestagens on lhe carotid artery pulsatility index in postmenopausal women on oestrogen replacement therapy. Eur J Obste! Gynecol Reprod Biol. 1998 Feb;76(2):221-4

69.

Gorodeski Gl, Yang T, Levy MN, Goldfarb J, Utian WH. Modulation of coronary vascular resistance in female rabbits by estrogen and progesterone. J Soe Gynecol lnvestig. 1998 Jui-Aug;5(4):197-202

Treatments with MPA have adverse effects on cardiovascular parameters, increasing the serum triglycerides 70.

Johnson JV, Davidson M, Archer D, Bachmann G. Postmenopausal uterine bleeding profiles with two forms of continuous combined hormone replacement therapy. Menopause. 2002 Jan-Feb;9(1 ):16-22

Treatments with MPA have adverse effect on coronary arteries, increasing arteriosclerosis (not the case with bio-identical progesterone) 71.

Miyagawa K, Vidgoff J, Hermsmeyer K. Ca2+ release mechanism of primate drug-induced coronary

72.

Minshall RD, Stanczyk FZ, Miyagawa K, Uchida B, Axthelm M, Novy M, Hermsmeyer K. Ovarian steroid

vasospasm. Am J Physiol. 1997 Jun;272(6 Pt 2):H2645-54 protection against coronary artery hyperreactivity in rhesus monkeys. J Clin Endocrinol Metab. 1998 Feb;83(2):649-59 73.

3) Seeger H, Wallwiener D, Mueck AO. Effect of medroxyprogesterone acetate and norethisterone on serum­ stimulated and estradiol-inhibited proliferation of human coronary artery smooth muscle cells. Menopause. 2001 Jan-Feb;8(1):5-9

Treatments with MPA stimulate atheroma development (no effect of norethisterone) 74.

Seeger H, Wallwiener D, Mueck AO. Effect of medroxyprogesterone acetate and norethisterone on serum­ stimulated and estradiol-inhibited proliferation of human coronary artery smooth muscle cells. Menopause. 2001 Jan-Feb;8(1 ):5-9

75.

Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids. 2000 Oct-Nov;65(1 0-11):651-8

Treatments with structurally modified progestogens may stimulate vasospasm of the coronary arteries (not lhe case with natural progesterone) 76.

Paris JM, Williams KJ, Hermsmeyer KR, Delansorne R. Nomegestrol acetate and vascular reactivity: nonhuman primate experiments. Steroids. 2000 Oct-Nov;65(10-11):621-7

Progestins increase the risk of venous thrombo-embolic events, but increase is small compared to the other benefits 77.

Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13

78.

Levesque H, Courtois H. Estrogen therapy and venous thromboembolic disease. Rev Med Interne. 1997;18 Suppl 6:620s-625s

708

3b) Studies where treatments with progestogens that have a NON-BIO-IDENTICAL STRUCTURE may increase the possibility of breast cancer development Some progestins (pregnanes) derived from progesterone stimulate apoptosis leading to breast cancer cell death; most cannot stimulate breast cancer cell multiplication; others such as estranes or gonanes derived from testosterone, stimulate breast cell multiplication in vitro through an estrogen receptor-mediated pathway 79. 80.

Sitruk-Ware R, Plu-Bureau G. Progestins and cancer. Gynecol Endocrinol. 1999 Jun;13 Suppl 4:3-9 Department of Endocrinology, Hôpital Saint-Antoine, Paris. Fournier A, Berrino F, Riboli E, Avenel V, Clavei-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. lnt J Cancer. 2005 Apr 10;114(3):448-54

11. Arguments in favour of the use of bio-identical estrogens and bio-identical progesterone in women

1) Studies that show that transdermal and bio-identical estradiol may be superior to oral ancl/or non-bio- identical estrogens Transdermal estradiol may avoid the adverse effects generally attributed to oral and/or non-bio-identical estrogens. 1a) Transdermal or implant estradiol treatments provide normal estrone-estradiol levels, while oral estrogen treatments do not 81.

82. 83. 84.

1b)

Slater CC, Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ. Markedly elevated leveis of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women. Menopausa. 2001 May-Jun;8(3):200-3 Lippert TH, Seeger H, Mueck AO. Estradiol metabolism during oral and transdermal estradiol replacement therapy in postmenopausal women.Horm Metab Res. 1998 Sep;30(9):598-600 Notelovitz M, Johnston M, Smith S, Kitchens C. Metabolic and hormonal effects of 25-mg and 50-mg 17 beta­ estradiol implants in surgically menopausa! women. Obstet Gynecol. 1987 Nov;70(5):749-54 Balfour JA, Heel RC. Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausa! complaints. Drugs. 1990 Oct;40(4):561-82 Transdermal estradiol treatments have no adverse effects on hemostatic factors cardiovascular risk factors (no CRP increase e.g.), while oral estrogen treatments do

and

other

85.

Meilahn EN. Hemostatic Factors and lschemic Heart Disease Risk Among Postmenopausal Women. J Thromb Thrombolysis. 1995;1(2):125-131

86.

Vehkavaara S, Silveira A, Hakala-Aia-Pietila T, Virkamaki A, Hovatta O, Hamsten A, Taskinen MR, Yki­ Jarvinen H. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost. 2001 Apr;85(4):619-25 Tikkanen MJ. The menopausa and hormone replacement therapy: lipids, lipoproteins, coagulation and fibrinolytic lactors. Maturitas. 1996 Mar;23(2):209-16 Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and librinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):3071-8 Akkad AA, Halligan AW, Abrams K, ai-Azzawi F.Differing responses in blood pressure over 24 hours in normotensive women receiving oral or transdermal estrogen replacement therapy. Obstei Gynecol. 1997 Jan;89(1):97-103. Nieto JJ, Cogswell D, Jesinger D, Hardiman P. Lipid effects oi hormone replacement therapy with sequential transdermal 17-beta-estradiol and oral dydrogesterone. Obstei Gynecol. 2000 Jan;95(1 ):111-4 Perera M, Saltar N, Petrie JR, Hillier C, Small M, Connell JM, Lowe GD, Lumsden MA. The effects oi transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study. J Clin

87. 88.

89.

90. 91.

92. 93.

Endocrinol Metab. 2001 Mar;86(3):1140-3 Mueck AO, Seeger H, Lippert TH. Effect oi transdermal versus oral estradiol administration on the excretion oi vasoactive markers in postmenopausal women. Gynakol Geburtshilfliche Rundsch. 2000;40(2):61-7 Chen FP, Lee N, Soong YK, Huang KE. Comparison oi transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk lactors. Menopausa. 2001 Sep-Oct;8(5):347-52

709

1c) Transdermal estradiol treatments have a higher beneficiai effect on weight, and lean and fat mass than oral estrogen treatments 94.

O'Sullivan AJ, Crampton LJ, Freund J, Ho KK. The route o! estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women. J Clin lnvest. 1998 Sep 1;102(5):1035-40

Garvan lnstitute o! Medicai Research, St. Vincent's Hospital, Sydney NSW 2010, Australia 95.

Chmouliovsky L, Habicht F, James RW, Lehmann T, Campana A, Golay A. Beneficiai effect o! hormone replacement therapy on weight loss in obese menopausa! women. Maturitas. 1999 Aug 16;32(3):147-53

1d) Transdermal estradiol treatments spare the liver (no liver accumulation o! estrogens), while oral estrogens do not (first passage through the liver after absorption, resulting in an excessive accumulation of estrogens in lhe liver).

1e) Transdermal estradiol treatments do not excessively increase the leveis and liver production of plasma binding proteins such as SHBG, TBG, transcortine, GHBP, etc, while oral estrogens do. 96.

Steingold KA, Matt DW, DeZiegler D, Sealey JE, Fratkin M, Reznikov S. Comparison o! transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab. 1991 Aug;73(2):275-80

97.

Van Erpecum KJ, Van Berge Henegouwen GP, Verschoor L, Stoelwinder B, Willekens FL. Different hepatobiliary effects o! oral and transdermal estradiol in postmenopausal women. Gastroenterology. 1991 Feb;100(2):482-8

98.

De Lignieres B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, Guyene TI, Mairon N, Corvo! P, Guy-Grand B, et ai. Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab. 1986 Mar;62(3):536-41

1f) Other benefical influences of transdermal estradiol compared to oral estrogens

99.

Lufkin EG, Ory SJ. Relative value o! transdermal and oral estrogen therapy in various clinicai situations. Mayo Clin Proc. 1994 Feb;69(2):131-5

1g) Study where treatments with parenteral (especially transdermal) 810-IDENTICAL estradiol proved to be safer than oral estradiol Study where treatments with intravenous estradiol stimulate less tumour development than oral estradiol in animais 100.

Kerdelhue B, Jolette J. The influence o! lhe route o! administration o! 17beta-estradiol, intravenous (pulsed) versus oral, upon DMBA-induced mammary tumour development in ovariectomised rats. Breast Cancer Res Treat. 2002 May;73(1):13-22

1h) Studies where bio-identical and parenteral, in particular transdermal, estrogen treatments were associated with beneficiai cardiovascular effects: more efficient and safer Studies where low bio-identical estradiol leveis are found in premenopausal women with coronary heart disease 101.

Hanke H, Hanke S, lckrath O, Lange K, Bruck B, Muck AO, Seeger H, Zwirner M, Voisard R, Haasis R, Hombach V. Estradiol concentrations in premenopausal women with coronary heart disease. Coron Artery Dis. 1997 Aug-Sep;8(8-9):511-5

102.

Bairey Merz CN, Johnson BD, Sharaf BL, Bittner V, Berga SL, Braunstein GD, Hodgson TK, Matthews KA, Pepine CJ, Reis SE, Reichek N, Rogers WJ, Pohost GM, Kelsey SF, Sopko G; WISE Study Group. Hypoestrogenemia o! hypothalamic origin and coronary artery disease in premenopausal women: a repor! from lhe NHLBI-sponsored WISE study. J Am Coll Cardiol. 2003 Feb 5;41(3):413-9

710

2)

Studies with beneficiai cardiovascular effects of estroqen therapy, qenerally obtained with the use of transdermal and bio-identical estradiol

Treatments with transdermal estradiol cause vasodilatation of the brachial and forearm arteries in postmenopausal women 103.

Blumel JE, Castelo-Branco C, Leal T, Gallardo L, Saini J, Ferron S, Haya J. Effects of transdermal estrogens

104.

Gerhard M, Walsh BW, Tawakol A, Haley EA, Creager SJ, Seely EW, Ganz P, Creager MA. Estradiol therapy

on endothelial function in postmenopausal women with coronary disease. Climacteric. 2003 Mar;6(1):38-44 combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998 Sep 22;98(12):1158-63 105.

Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO 3rd. Acute vascular effects of estrogen in postmenopausal women. Circulation. 1994 Aug;90(2):786-91

Treatments with oral estradiol causes vasodilatation of the brachial artery in postmenopausal women 106.

Lieberman EH, Gerhard MD, Uehata A, Walsh BW, Selwyn AP, Ganz P, Yeung AC, Creager MA. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann lntern Med. 1994 Dec 15;121(12):936-41.

Treatments with intracoronary or intravenous estradiol cause vasodilatation and increased distensibility of coronary arteries 107.

Gilligan DM, Quyyumi AA, Cannon RO 3rd. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation. 1994 Jun;89(6):2545-51

108.

Guetta V, Quyyumi AA, Prasad A, Panza JA, Waclawiw M, Cannon RO 3rd. The role of nitric oxide in coronary vascular effects of estrogen in postmenopausal women. Circulation. 1997 Nov 4;96(9):2795-801

109.

Gorodeski Gl, Yang T, Levy MN, Goldfarb J, Utian WH. Modulation of coronary vascular resistance in female rabbits by estrogen and progesterone. J Soe Gynecollnvestig. 1998 Jui-Aug;5(4):197-202

Treatments with subcutaneous implants of 17-beta estradiol reduce coronary artery disease in female monkeys 110.

Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks JS, Wolfe MS, Clarkson TB. lnhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis. 1990 Nov-Dec;10(6):1051-7

Treatments with subcutaneous injections of 17-beta-estradiol protect dogs against mycocardial ischemia 111.

Kim YD, Chen B, Beauregard J, Kouretas P, Thomas G, Farhat MY, Myers AK, Lees DE. 17 beta-Estradiol prevents dysfunction oi canine coronary endothelium and myocardium and reperfusion arrhythmias after briel ischemia/reperfusion. Circulation. 1996 Dec 1;94(11 ):2901-8

Treatments with intravenous 17-beta-estradiol protect cats against acute myocardiac ischemia 112.

Delyani JA, Murohara T, Nossuli TO, Lefer AM. Protection from myocardial reperfusion injury by acute administration oi 17 beta-estradiol. J Moi Cell Cardiol. 1996 May;28(5):1001-8

Treatments with transdermal estrogen reduce angina in postmenopausal women with angina and normal coronary arteries 113.

Roque M, Heras M, Roig E, Masotti M, Rigol M, Betriu A, Balasch J, Sanz G. Short-term effects oi transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angiograms. J Am Coll Cardiol. 1998 Jan;31(1}:139-43

114.

Albertsson PA, Emanuelsson H, Milsom I. Beneficiai effect oi treatment with transdermal estradiol-17-beta on exercise-induced angina and ST segment depression in syndrome X. lnt J Cardiol. 1996 Apr 19;54(1):13-20

Treatments with implants of estradiol protect arteries of rats against atherosclerosis: preveni LDL-binding to arterial wall, reduce endothelial layer permeability 115. Walsh BA, Mullick AE, Banka CE, Rutledge JC. 17beta-estradiol acts separately on lhe LDL particle and artery wall to reduce LDL accumulation. J Lipid Res. 2000 Jan;41(1):134-41

711

Overview on vascular protective effects of estrogen 116.

Farhat MY, Lavigne MC, Ramwell PW. The vascular protective effects of estrogen. FASES J. 1996 Apr;10(5):615-24

Treatments with oral estradiol cause vasodilatation and increased distensibility of arteries 117.

Angerer P, Kothny W, Stork S, von Schacky C. Hormone replacement therapy and distensibility of carotid arteries in

postmenopausal women:

a

randomized,

controlled trial.

J

Am Coll

Cardiol.

2000 Nov

15;36(6):1789-96

Treatments with transdermal estradiol reduce the carotid artery wall thickness and thus atherosclerosis in postmenopausal women 118.

Sumino H, lchikawa S, Kasama S, Kumakura H, Takayama Y, Sakamaki T, Kurabayashi M. Effect of transdermal hormone replacement therapy on carotid artery wall thickness and leveis of vascular inflammatory markers in postmenopausal women. Hypertens Res. 2005 Jul;28(7):579-84

119.

Takahashi K, Tanaka E, Murakami M, Mori-Abe A, Kawagoe J, Takata K, Ohmichi M, Kurachi H. Long-term hormone replacement therapy delays the age related progression of carotid intima-media thickness in healthy postmenopausal women. Maturitas. 2004 Oct 15;49(2): 170-7

120.

Hashimoto M, Miyao M, Akishita M, Hosoi T, Toba K, Kozaki K, Yoshizumi M, Ouchi Y Effects of long-term and reduced-dose hormone replacement therapy on endothelial function and intima-media thickness in postmenopausal women. Menopause. 2002 Jan-Feb;9(1):58-64

3) Studies where structurally 810-IDENTICAL, especially TRANSDERMAL, estradiol treatment was shown to be safer for the breast from the cancer perspective than treatments with non-bio-identical estrogens EXOGENOUS 810-IDENTICAL ESTRADIOL In vitro study where a treatment with estradiol provided less epithelial proliferation than with conjugated estrogens in breast tissue, addition of bio-identical progesterone was even more reassuring as it greatly reduced the moderate bio-identical estradiol-induced proliferation 121.

Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de Lignieres B. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998 May;69(5):963-9

A study where the treatments associating transdermal estradiol to a progestogen other than MPA do not significantly increase the breast cancer risk (83% of participants took transdermal estradio/ and other progestins than MPA were used) 122.

de Lignieres B, de Vathaire F, Fournier S, Urbinelli R, Allaert F, Le MG, Kuttenn F. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 2002 Dec;5(4):332-40

ENDOGENOUS 810-IDENTICAL ESTRADIOL: Studies where high leveis of endogenous estrogens are associated with less breast cancer or longer survival after breast cancer

Studies where high leveis of endogenous 810-IDENTICAL estrogens are associated with a lower incidence of cancer or longer survival after breast cancer 123.

Holmberg L, Norden T, Lindgren A, Wide L, Degerman M, Adami HO. Pre-operative oestradiollevels- relation to survival in breast cancer. Eur J Surg Oncol. 2001 Mar;27(2):152-6

124.

MacMahon B, Cole P, Brown JB, Aoki K, Lin TM, Morgan RW, Woo NC. Urine oestrogen profiles of Asian and North American women. lnt J Cancer. 1974 Aug 15;14(2):161-7

125.

MacMahon B, Cole P, Brown JB, Aoki K, Lin TM, Morgan RW, Woo N. Oestrogen profiles of Asian and North American women. Lance!. 1971 Oct 23;2(7730):900-2

126.

Ursin G, Wilson M, Henderson BE, Kolonel LN, Monroe K, Lee HP, Seow A, YuMC, Stanczyk FZ, Gentzschein E Do urinary estrogen metabolites reflect the differences in breast cancer risk between Singapore Chinese and United States African-American and white women? Cancer Res. 2001 Apr 15;61(8):3326-9

127.

Ursin G, London S, Stanczyk FZ, Gentzschein E, Paganini-Hill A, Ross RK, Pike MC.

Urinary 2-

hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer lnst. 1999 Jun 16;91(12):1067-72

712

128.

Lemon HM. Pathophysiologic considerations in the treatment of menopausa! patients withoestrogens; the role of oestriol in lhe prevention of mammary carcinoma. Acta Endocrinol Suppl. (Copenh). 1980;233:17-27

129.

Vorherr H, Messer RH. Breast cancer: potentially predisposing and protecting factors. Role of pregnancy, lactation, and endocrine status. Am J Obste! Gynecol. 1978 Feb 1;130(3):335-58

A study where a high levei of bio-identical estradiol at the moment of tumour surgery is associated with a better prognosis 130.

Holmberg L, Norden T, Lindgren A, Wide L, Degerman M, Adami HO. Pre-operative oestradiol levels - relation to survival in breast cancer. Eur J Surg Oncol 2001 Mar;27(2):152-6

Studies where increased leveis of bio-identical estrogens (such as those found in mature young women compared to the leveis of girls before puberty) are associated with a lower cancer mortality 131.

Adami HO, Bergstrom R, Holmberg L, Klareskog L, Persson I, Ponten J.The effect of female sex hormones on cancer survival. A register-based study in patients younger than 20 years at diagnosis. JAMA. 1990 Apr 25;263(16):2189-93

132.

Adami HO, Holmberg L, Persson I. Survival and age at diagnosis in breast cancer. N Engl J Med. 1987 ; 316(12): 750-2

Studies where a high levei of estriol compared to estrone and estradiol may be associated with a reduced incidence of breast cancer 133.

MacMahon B, Cole P, Brown JB, Aoki K, Lin TM, Morgan RW, Woo NC. Urine oestrogen profiles of Asian and North American women. lnt J Cancer. 1974 Aug 15;14(2):161-7.

134.

MacMahon B, Cole P, Brown JB, Aoki K, Lin TM, Morgan RW, Woo N. Oestrogen profiles of Asian and North American women. Lancet. 1971 Oct 23;2(7730):900-2.

135.

Ursin G, Wilson M, Henderson BE, Kolonel LN, Monroe K, Lee HP, Seow A, YuMC, Stanczyk FZ, Gentzschein E Do urinary estrogen metabolites reflect the differences in breast cancer risk between Singapore Chinese and United States African-American and white women? Cancer Res. 2001 Apr 15;61 (8):3326-9.

136.

Ursin G, London S, Stanczyk FZ, Gentzschein E, Paganini-Hill A, Ross RK, Pike MC.

Urinary 2-

hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer lnst 1999 Jun 16;91(12):1067-72 137.

Lemon HM. Pathophysiologic considerations in the treatment of menopausa! patients withoestrogens; the role of oestriol in the prevention of mammary carcinoma. Acta Endocrinol Suppl (Copenh) 1980;233:17-27

138.

Vorherr H, Messer RH. Breast cancer: potentially predisposing and protecting factors. Role of pregnancy, lactation, and endocrine status. Am J Obstet Gynecol 1978 Feb 1;130(3):335-58

Studies where breast cancer tumours rich in estrogen receptors (that thus responds well to estrogens) had a better prognosis (more differentiated, less malignant tumour) 139.

Salazar-Esquivel EL, Morales-Najar R, Calzada-Sanchez L. lnfiltrating duct breast carcinoma: the role of estradiol and progesterone receptors. Ginecol Obste! Mex. 1994 Mar; 62: 85-90

140.

Heise E, Gorlich M. Estradiol receptor and prognosis in human breast cancer and its metastases. Neoplasma. 1993;40(1):55-7

141.

Nagai MA, Marques LA, Yamamoto L, Fujiyama CT, Brentani MM. Estrogen and progesterone receptor mRNA leveis in primary breast cancer: association with patient survival and other clinicai and tumor features. lnt J Cancer. 1994 Nov 1; 59(3): 351-6

142.

Mason BH, Holdaway IM, Mullins PR, Yee LH, Kay RG.Progesterone and estrogen receptors as prognostic

143.

Genazzani AR, Gadducci A, Gambacciani M.Controversial issues in climacteric medicine 11. Hormone

variables in breast cancer. Cancer Res 1983 Jun;43(6):2985-90 replacement therapy and cancer. lnternational Menopause Society Expert Workshop. 9-12 June 2001, Operadel Duomo, Pisa, ltaly. Climacteric 2001 Sep;4(3):181-93

713

TRANSDERMAL

810-IDENTICAL

ESTRADIOL:

Studies

where

treatments

with

estrogens

taken

by

TRANSDERMAL ROUTE were associated with an increased risk of breast cancer or of conditions that may predispose to breast cancer

A high urinary excretion of 16-alpha- OH-estrone is associated with increased risks of mammary hyperplasia and breast cancer 144.

Meilahn EN, De Stavola B, Allen DS, Fentiman I, Bradlow HL, Sepkovic DW, Kuller LH. Do urinary oestrogen metabolites predict breast cancer? Guernsey 111 cohort follow-up. Br J Cancer. 1998 Nov;78(9):1250-5

Treatments with oral estradiol cause a major increase in urinary 16-alpha- OH-estrone, not the case with transdermal estradiol 145.

Seeger H, Mueck AO, Lippert TH. Effect of norethisterone acetate on estrogen metabolism in postmenopausal women. Horm Metab Res. 2000 Oct;32(10):436-9

Treatments with oral estrogens induce supraphysiological increases in estrone sulphate and estrone serum leveis, not the case with transdermal estradiol 146.

Fahraeus

L,

Larsson-Cohn

U.

Oestrogens,

gonadotrophins

and

SHBG during

oral

and cutaneous

administration of oestradiol-17 beta to menopausa! women. Acta Endocrinol (Copenh). 1982 Dec;101(4):5926

4) Studies with beneficiai or neutral effects of 810-IDENTICAL PROGESTERONE on lhe cardiovascular system

Treatment with vaginal progesterone gel delays exercise-induced myocardial ischemia in postmenopausal women with coronary heart disease and/or previous myocardial infarction 147.

Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficiai effect of estrogens on exercise­ induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000 Dec;36(7):2154-9

Treatments with transdermal or intravenous progesterone (4 weeks) protect against severe prolonged coronary vasoconstriction, and reduce lipoprotein (a) in non and preatherosclerotic and atherosclerotic female monkeys 148.

Hermsmeyer RK, Mishra RG, Pavcnik D, Uchida B, Axthelm MK, Stanczyk FZ, Burry KA, lllingworth DR, Juan C, Nordt FJ. Prevention of coronary hyperreactivity in preatherogenic menopausa! rhesus monkeys by transdermal progesterone. Arterioscler Thromb Vasc Biol. 2004 May;24(5):955-61

149.

Minshall RD, Pavcnik D, Browne DL, Hermsmeyer K. Nongenomic vasodilator action of progesterone on primate coronary arteries. J Appl Physiol. 2002 Feb;92(2):701-8

Treatments with intravenous progesterone increase coronary blood flow in pigs 150.

Molinari C, Battaglia A, Grossini E, Mary DA, Stoker JB, Surico N, Vacca G. The effect of progesterone on coronary blood flow in anaesthesized pigs. Exp Physiol. 2001 Jan;86(1):101-8

Treatments with progesterone in vitro relax isolated animal coronary smooth muscles cells and arteries 151.

Jacob MK, White RE. Diazepam, gamma-aminobutyric acid, and progesterone open K(+) channels in

152.

Crews JK, Khalil RA. Antagonistic effects of 17 beta-estradiol, progesterone, and testosterone on Ca2+ entry

153.

Jiang CW, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Progesterone induces endothelium­

myocy1es from coronary arteries. Eur J Pharmacol. 2000 Sep 8;403(3):209-19. mechanisms of coronary vasoconstriction. Arterioscler Thromb Vasc Biol. 1999 Apr; 19(4): 1034-40 independent relaxation of rabbit coronary artery in vitro. Eur J Pharmacol. 1992 Feb 11 ;211(2):163-7

714

Treatments with progesterone have no negative effect on estradiol-induced protection of coronary arteries 154.

Adams MR, Kaplan JR, Manuck 58, Koritnik DR, Parks JS, Wolfe MS, Clarkson T8. lnhibition oi coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack oi an effect oi added progesterone. Arteriosclerosis. 1990 Nov-Dec;10(6):1051-7

155.

Gerhard M, Walsh 8W, Tawakol A, Haley EA, Creager SJ, Seely EW, Ganz P, Creager MA. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998 Sep 22;98(12):1158-63

5) Studies with protective or neutra! effects of bio-identical progesterone against breast cancer

5-1) EXOGENOUS 810-IDENTICAL PROGESTERONE: Studies where progesterone/progestogen treatment reduced the breast cancer risk in women with breast cysts 156.

Plu-8ureau G, Le MG, Sitruk-Ware R, Thalabard JC, Mauvais-Jarvis P. Progestogen use and decreased risk oi breast cancer in a cohort study oi premenopausal women with benign breast disease. 8r J Cancer 1994 Aug;70(2):270-7

157.

Plu-8ureau G, Le MG, Thalabard JC, Sitruk-Ware R, Mauvais-Jarvis P. Percutaneous progesterone use and risk oi breast cancer: results lrom a Frenchcohort study oi premenopausal women with benign breast disease. Cancer Detect Prev 1999;23(4):290-6 (the physiological increase of endogenous progesterone during luteal

phase coincided with a /ower proliferation of breast epithelial cells) 158.

de Lignieres 8. Effects oi progestogens on the postmenopausal breast. Climacteric. 2002 Sep;5(3):229-35

Treatments with transdermal estradiol alone or combined to a synthetically modified progestin increases the BC risk, but combined to bio-identical progesterone causes a -10% decrease of the breast cancer risk 159.

Fournier A, 8errino F, Riboli E, Avenel V, Clavei-Chapelon F. 8reast cancer risk in relation to different types of hormone replacement therapy in lhe E3N-EPIC cohort. lnt J Cancer. 2005 Apr 10;114(3):448-54

5-2) ENDOGENOUS 810-IDENTICAL PROGESTERONE: Studies where lower endogenous 810-IDENTICAL progesterone leveis are associated with a lower overall or breast cancer incidence 160.

Cowan LO, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence in women with a history oi progesterone deliciency. Am J Epidemiol 1981 Aug;114(2):209-17

161.

Adami HO, 8ergstrom R, Holmberg L, Klareskog L, Persson I, Ponten J.The effect oi lemale sex hormones on cancer survival. A register-based study in patients younger than 20 years at diagnosis. JAMA. 1990 Apr 25;263(16):2189-93

162.

Adami HO, Holmberg L, Persson I. Survival and age at diagnosis in breast cancer. N Engl J Med. 1987; 316(12): 750-2

163.

Mohr PE, Wang DY, Gregory WM, Richards MA, Fentiman IS. Serum progesterone and prognosis in operable breast cancer. Br J Cancer. 1996 Jun;73(12):1552-5

164.

Badwe RA, Wang DY, Gregory WM, Fentiman IS, Chaudary MA, Smith P, Richards MA, Rubens RD. Serum progesterone at lhe time oi surgery and survival in women with premenopausal operable breast cancer.Eur J Cancer. 1994;30A(4):445-8

Studies where the prognosis is better when the breast cancer tumour is surgically removed in the luteal phase (particularly rich in progesterone) 165.

Cooper LS, Gillett CE, Patel NK, 8arnes DM, Fentiman IS. Survival oi premenopausal breast carcinoma patients in relation to menstrual cycle timing oi surgery and estrogen receptor/progesterone receptor status oi lhe primary tumor. Cancer 1999 Nov 15;86(10):2053-8

166.

Senie RT, Rosen PP, Rhodes P, Lesser ML.Timing oi breast cancer excision during lhe menstrual cycle

167.

Saad Z, Vincent M, Bramwell V, Stitt L, Duff J, Girotti M, Jory T, Heathcote G, Turnbull l, Garcia 8. Timing oi

inlluences duration of disease-lree survival. Ann lntern Med 1991 Sep 1;115(5):337-42 surgery inlluences survival in receptor-negative as well as receptor-positive breast cancer. Eur J Cancer 1994;30A(9):1348-52.

715

168.

Saad Z, Bramwell V, Duff J, Girotti M, Jory T, Heathcote G, Turnbull I, Garcia B, Stitt L.Timing of surgery in relation to the menstrual cycle in premenopausal women with operable breast cancer.: Br J Surg 1994 Feb;81(2):217-20

169.

Veronesi U, Luini A, Mariani L, Del Vecchio M, Alvez D, Andreoli C, Giacobone A, Merson M, Pacetti G, Raselli R, et ai. Effect of menstrual phase on surgical treatment of breast cancer. Lancet 1994 Jun 18;343(8912):1545-7

170.

Holli K, Isola J, Hakama M. Prognostic effect of timing of operation in relation to menstrual phase of breast cancer patient-fact or fallacy. Br J Cancer 1995 Jan;71(1):124-7

171.

Love RR, Duc NB, Dinh NV, Shen TZ, Havighurst TC, Allred DC, DeMets DL. Mastectomy and oophorectomy by menstrual cycle phase in women with operable breast cancer. J Natl Cancer lnst 2002 May 1 ;94(9):662-9

172.

Goldhirsch A, Gelber RD, Castiglione M, O'Neill A, Thurlimann B, Rudenstam CM, Lindtner J, Collins J, Forbes J, Crivellari D, Coates A, Cavalli F, Simoncini E, Fey MF, Pagani O, Price K, Senn HJ. Menstrual cycle and timing of breast surgery in premenopausal node-positive breast cancer: results of the lnternational Breast Cancer Study Group (IBCSG) Trial VI. Ann Oncol 1997 Aug;8(8):751-6

173.

Vanek VW, Kadivar TF, Bourguet CC. Correlation of menstrual cycle at time of breast cancer surgery to

174.

Lemon HM, Rodriguez-Sierra JF. Timing of breast cancer surgery during the luteal menstrual phase may

175.

Badwe RA, Mittra I, Havaldar R. Timing of surgery during the menstrual cycle and prognosis of breast cancer.

disease-free and overall survival. South Med J 1997 Aug;90(8):780-8 improve prognosis. Nebr Med J 1996 Mar;81(3):73-8 J Biosci 2000 Mar;25(1):113-2 176.

Mangia A, De Lena M, Barletta A, Marzullo F, Attolico M, Stea B, Petroni S, Labriola A, Cellamare G, Digiesi G, Altieri R, Schittulli F, Paradiso A.Timing of breast cancer surgery within the menstrual cycle: tumor proliferative activity, receptor status and short-term clinicai outcome. J Exp Clin Cancer Res 1998 Sep;17(3):317-23

177.

Tsuchiya A, Furukawa H, Kanno M, Kimijima I, Abe R. Lack of the relationship between menstrual status and timing of surgery in survival of premenopausal patients with breast cancer. Fukushima J Med Sei. 1996 Dec;42(1-2):11-6.

178.

Jager W, Sauerbrei W. Effect of timing of surgery during the menstrual cycle of premenopausal breast cancer patients. Breast Cancer Res Treat 1995 Jun;34(3):279-87

179.

Zhang B, Shao Y, Wang C. Prognosis of patients with breast cancer related to the timing of operation during menstrual cycle: a report of 218 patients. Zhonghua Zhong Liu Za Zhi 1996 May;18(3):203-7

180.

Milella M, Nistico C, Ferraresi V, Vaccaro A, Fabi A, D'Ottavio AM, Botti C, Giannarelli D, Lopez M, Cortesi E, Foggi CM, Antimi M, Terzoli E, Cognetti F, Papaldo P.Breast cancer and timing of surgery during menstrual cycle: a 5-year analysis of 248 premenopausal women. Breast Cancer Res Treat 1999 Jun;55(3):259-6

Studies where lhe presence of mastalgia, breast cysts or uterin fibroids, conditions generally related to lower progesterone leveis, is associated with an increased risk of breast cancer 181.

Plu-Bureau G, Thalabard JC, Sitruk-Ware R, Asselain B, Mauvais-Jarvis P. Cyclical mastalgia as a marker of breast cancer susceptibility: results of a case-control study among French women. Br J Cancer 1992 Jun;65(6):945-9

182.

Deschamps M, Band PR, Coldman AJ, Hislop TG, Longley DJ. Clinicai determinants of mammographic dysplasia patterns. Cancer Detect Prev 1996;20(6):610-9

183.

Dixon JM, McDonald C, Elton RA, Miller WR. Risk of breast cancer in women with palpable breast cysts: a

184.

Bruzzi P, Dogliotti L, Naldoni C, Bucchi L, Costantini M, Cicognani A, Torta M, Buzzi GF, Angeli A. Cohort

prospective study. Edinburgh Breast Group. Lancet 1999 May 22;353(9166):1742-5 study of association of risk of breast cancer with cyst type in women with gross cystic disease of the breast. BMJ 1997 Mar 29;314(7085):925-8 185.

Dupont WD, Page DL, Pari FF, Vnencak-Jones CL, Plummer WD Jr, Rados MS, Schuyler PA. Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med 1994 Jul 7;331 (1):10-5

716

111. Arguments in favour of the use of female hormones in women (as well bio-identical as non-bio-identical): The therapy may be neutral or even protect against breast cancer

I) Studies with cancer-preventive effects of estrogen (with or without progestogen} treatment Studies where estrogen treatment was associated with a reduction of overall cancer occurrence 186.

Henderson BE, Paganini-Hiii,A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch lntern Med. 1991; 151:75

187.

Paganini Hill A. The Leisure World Cohort Study in The Treatment of the Postmenopausal Women- Lobo RA, Ed Paven Press- NY, 1994; p. 401: table 1.

Studies where estrogen therapy reduced the incidence of breast cancer 188.

Gambrell RD Jr. Hormones in lhe etiology and prevention of breast and endometrial cancer. South Med J.1984 Dec:

189.

Gambrell RD Jr, Maier RC, Sanders Bl. Decreased incidence of breast cancer in postmenopausal estrogen

77(12): 1509-15. progestogen users.. Obste! Gynecol 1983 Oct;62(4):435-43

190.

Wingo PA, Layde PM, Lee NC, Rubin G, Ory HW.. The risk of breast cancer in postmenopausal women who have used estrogen replacement therapy. JAMA. 1987 Jan 9; 257(2): 209-15.

191.

Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement

11: A prospective study in

the relationship to carcinoma and cardiovascular and metabolic problems. Obste! Gynecol. 1979; 54: 7 4-9

192.

Lauritzen C et ai. Risks of endometrial and mammary cancer morbidity and mortality in long-term estrogen treatment. In The Climacteric.-An Update, ed by van Herendael H

& B, Riphagen FE, Goessens L, van der

Pars H Lancaster, England, MTP Press Ltd 1984; 207

193.

Davelaar EM, Gerretsen G, Relyveld J.. No increase in the incidence of breast carcinoma with subcutaneous

194.

Rosenberg L, Miller DR, Kaufman DW, Helmrich SP, Stolley PD, Schottenfeld. D; Shapiro S. Am J Epidemiol

195.

Kaufman DW, Miller DR, Rosenberg, Miller DR, Rosenberg L, Helmrich SP, Stolley P, Schottenfeld D, Shapiro

196.

Hammond CB, Jelovsek FR, Lee Kl,

administration of estradiol Ned Tijdsch Geneeskd. 1991 Apr 6 ; 135(14): 613-5 1984 Feb;119(2):167-76Breast cancer and oral contraceptive use. S. Noncontraceptive estrogen use and the risk of breast JAMA 1984 Jul 6;252(1):63-7

WT, Parker. Effects of long term estrogen replacement therapy. 11 -

Neoplasia. Am J Obste! Gynecol. 1979; 133: 537.

197.

Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined estrogen and progestin hormone replacement therapy in relation to riskn of breast cancer in middle-aged women. JAMA. 1995 Jul 12;274(2):137-42 (reduced

BC risk for long time estrogen users � 8 years)

Studies where the use of estrogens before having breast cancer was associated with smaller, less aggressive tumours with more positive hormone receptors (more differenciated, less malignant tumour), less metastases, better prognosis, less recurrence 198.

Gajdos C, Tartter Pl, Babinszki A. Breast cancer diagnosed during hormone replacement therapy. Obstet Gynecol 2000 Apr;95(4):513-8

199.

Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol 1998 Sep;16(9):3115-20

200.

Ursin G, Tseng CC, Paganini-Hill A, Enger S, Wan PC, Formenti S, Pike MC, Ross RK. Does menopausa! hormone replacement therapy interact with known factors to increase risk of breast cancer? Arch 1 : J Clin Oncol 2002 Feb 1;20(3):699-706

201.

Magnusson C, Holmberg L, Norden T, Lindgren A, Persson I. Prognostic characteristics in breast cancers after hormone replacement therapy. Breast Cancer Res Treat. 1996;38(3):325-34 (''breast cancers occurring

after treatment with HRT, especially the combined estrogen-progestin regimen, seem to have more tavourable tumour features than tumours in non-treated women")

Studies where the current use of estrogens at the moment of diagnosis of breast cancer was associated with a reduced breast cancer mortality 202.

Schairer C, Gail M, Byrne C, Rosenberg PS, Sturgeon SR, Brinton

LA, Hoover RN. Estrogen replacement

therapy and breast cancer survival in a large screening study. J Natl Cancer lnst. 1999 Feb 3;91(3):264-70 203.

Nanda K, Bastian LA, Schulz K. Hormone replacement therapy and the risk of death from breast cancer: a systematic review. Am J Obste! Gynecol. 2002 Feb; 186 (2):325-34

717

204.

Willis DB, Calle EE, Miracle-McMahill HL, Heath CW Jr. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control. 1996 Jul;7(4):449-57

Studles where the current use of estrogens at the moment of diagnosis of breast cancer was associated with a reduced overall mortality 205.

Ettinger B, Friedman GD, Bush T, Quesenberry CP Jr. Reduced mortality associated with long-term

206.

Henderson BE, Paganini-Hiii,A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch

207.

Jernstrom H, Frenander J, Ferno M, Olsson H. Hormone replacement therapy before breast cancer diagnosis

postmenopausal estrogen therapy. Obste! Gynecol. 1996 Jan;87(1):6-12 lntern Med 1991; 151:75. significantly reduces the overall death rale compared with never-use among 984 breast cancer patients. Br J Cancer 1999 Jul;80(9):1453-8 208.

Hunt K, Vessey M, McPherson K. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obste! Gynaecol. 1987; 94: 620-35 (Lower overa/1 mortality , but

increased BC risk becauseof the use of unopposed ethinylestradiol) Studies where estrogen therapy reduced overall mortality in women 209.

Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffe M, Rosner B, Fuchs C, Hankinson SE, Hunter DJ, Hennekens CH, Speizer FE. Postmenopausal hormone therapy and mortality. N Engl J Med 1997; 336:1769-75

Studies where estrogen therapy did not increase the breast cancer incidence, but increased the lifespan in women with familial risk of breast cancer 210.

Sellers TA, Mink PJ, Cerhan JR, Anderson KE, Kushi LH, Folson AR. The role of hormone replacement therapy in lhe risk for breast cancer and total mortality in women with a family history of breast cancer. Ann lntern Med. 1997; 127:973-80 ("HRT use in women with a family history of breast cancer is not associated

with a significantly increased incidence of breast cancer but is associated with a significantly reduced total mortality rale, including overa/1 cancer mortality'? 2) Studies with cancer protective effects of ESTROGEN TREATMENT (with or without progestogen) In women who have had breast cancer Publication where the use of corrective female hormone therapy is adviced two years after a surgical cure of a hormone negative tumour 211.

Birkhauser M. Hormone replacement therapy afier treatment of breast carcinoma. Schweiz Med Wochenschr. 1998 Oct 24;128(43):1675-89

Studies where the use of HRT reduced the recurrence of breast cancer in women with previous breast cancer 212.

Dew JE, Wren BG, Eden JA. Tamoxifen, hormone receptors and hormone replacement therapy in women previously treated for breast cancer: a cohort study. Climacteric. 2002;5(2):151-5

213.

Dew J, Eden J, Beller E, Magarey C, Schwartz P, Crea P, Wren B. A cohort study of hormone replacement therapy given to women previously treated for breast cancer. Climacteric.1998;1(2):137-42

Studies where the use of HRT (pill, conjugated estogens, estradiol patch, ..) did not increase the risk of breast cancer in women with previous breast cancer 214.

Peters GN, Fodera T, Sabol J, Jones S, Euhus D. Estrogen replacement therapy after breast cancer: a 12year follow-up. Ann Surg Oncol 2001 Dec;8(10):828-32

Studies where estrogen treatment of women with previous breast cancer reduced the breast cancer recurrence and increased longevity/survival time 215.

Peters GN, Fodera T, Sabol J, Jones S, Euhus D. Estrogen replacement therapy after breast cancer: a 12year follow-up." Ann Surg Oncol 2001 Dec;8(10):828-32

216.

Dew J, Eden J, Beller E, Magarey C, Schwartz P, Crea P, Wren B. A cohort study of hormone replacement therapy given to women previously treated for breast cancer. Climacteric 1998 Jun;1(2):137-42

718

217.

Beckmann MW, Jap D, Djahansouzi S, Nestle-Kramling C, Kuschel B, Dali P, Brumm C, Bender HG. Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bane mineral density and recurrence rales. Oncology 2001;60(3):199-206

218.

Natrajan PK, Soumakis K, Gambrell RD Jr. Estrogen replacement therapy in women with previous breast

219.

Wile AG, Opfell RW, Margileth DA. Hormone replacement therapy in previously treated breast cancer patients.

220.

O'Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after

cancer. Am J Obstet Gynecol 1999 Aug;181 (2):288-95 Am J Surg. 1993 Mar;165(3):372-5 a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer lnst. 2001 ;93(10):754-62 221.

Durna EM, Wren BG, Heller GZ, Leader LR, Sjoblom P, Eden JA. Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. Med J Aust. 2002 Oct 7;177(7):347-51

222.

Meurer LN, Lena S. Cancer recurrence and mortality in women using hormone replacement therapy: meta­ analysis. J Fam Pract. 2002 Dec;51(12):1056-62 (meta-analyss)

Reviews that discuss the need of breast cancer patients to have HRT 223.

Seifert M, Galid A, Kubista E. Estrogen replacement therapy in women with a history of breast cancer. Maturitas 1999 Jun 21 ;32(2):63-8

224.

Plu-Bureau G. Hormone replacement therapy after breast cancer. J Gynecol Obstei Biol Reprod (Paris) 2000 May;29(3):292-4 (review)

225.

Marsden J, Whitehead M, A'Hern R, Baum M, Sacks N. Are randomized trials of hormone replacement therapy in symptomatic women with breast cancer feasible? Fertil Steril 2000 Feb;73(2):292-9

3) Administerinq female hormones to women who have had breast cancer may reduce breast cancer recurrence and mortality

Studies with cancer protective effects of ESTROGEN TREATMENT (with or without progestogenl in women who have had breast cancer Publication where the use of corrective female hormone therapy is adviced two years after a surgical cure of a hormone negative tumour 226.

Birkhauser M. Hormone replacement therapy after treatment of breast carcinoma. Schweiz Med Wochenschr. 1998 Oct 24;128(43):1675-89

Studies where the use of HRT reduced the recurrence of breast cancer in women with previous breast cancer 227.

Dew JE, Wren BG, Eden JA. Tamoxifen, hormone receptors and hormone replacement therapy in women previously treated for breast cancer: a cohort study. Climacteric. 2002;5(2):151-5

228.

Dew J, Eden J, Beller E, Magarey C, Schwartz P, Crea P, Wren B. A cohort study of hormone replacement therapy given to women previously treated for breast cancer. Climacteric.1998;1(2):137-42

Studies where the use of HRT (pill, conjugated estogens, estradiol patch, ..) did not increase the risk of breast cancer in women with previous breast cancer 229.

Peters GN, Fodera T, Sabol J, Jones S, Euhus D. Estrogen replacement therapy after breast cancer: a 12year follow-up. Ann Surg Oncol 2001 Dec;8(10):828-32

Studies where estrogen treatment of women with previous breast cancer reduced the breast cancer recurrence and increased longevity/survival time 230.

Peters GN, Fodera T, Sabol J, Jones S, Euhus D. Estrogen replacement therapy after breast cancer: a 12-

231.

Dew J, Eden J, Beller E, Magarey C, Schwartz P, Crea P, Wren B. A cohort study of hormone replacement

year follow-up." Ann Surg Oncol 2001 Dec;8(10):828-32 therapy given to women previously treated for breast cancer. Climacteric 1998 Jun;1(2):137-42 232.

Beckmann MW, Jap D, Djahansouzi S, Nestle-Kramling C, Kuschel B, Dali P, Brumm C, Bender HG. Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bane mineral density and recurrence rales. Oncology 2001;60(3):199-206

233.

Natrajan PK, Soumakis K, Gambrell RD Jr. Estrogen replacement therapy in women with previous breast cancer. Am J Obstei Gynecol 1999 Aug;181(2):288-95

719

234.

Wile AG, Opfell RW, Margileth DA. Hormone replacement therapy in previously treated breast cancer patients. Am J Surg. 1993 Mar;165(3):372-5

235.

O'Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after

236.

Durna EM, Wren BG, Heller GZ, Leader LR, Sjoblom P, Eden JA. Hormone replacement therapy after a

237.

Meurer LN, Lena S. Cancer recurrence and mortality in women using hormone replacement therapy: meta­

a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer lnst. 2001;93(10):754-62 diagnosis of breast cancer: cancer recurrence and mortality. Med J Aust. 2002 Oct 7;177(7):347-51 analysis. J Fam Pract. 2002 Dec;51(12):1056-62 (meta-analyss)

Reviews that discuss the need of breast cancer patients to have HRT 238.

Seifert M, Galid A, Kubista E. Estrogen replacement therapy in women with a history of breast cancer. Maturitas 1999 Jun 21 ;32(2):63-8

239.

Plu-Bureau G. Hormone replacement therapy after breast cancer. J Gynecol Obstei Biol Reprod (Paris) 2000

240.

Marsden J, Whitehead M, A'Hern R, Baum M, Sacks N. Are randomized trials of hormone replacement

May;29(3):292-4 (review) therapy in symptomatic women with breast cancer feasible? Fertil Steril 2000 Feb;73(2):292-9

Studies where treatments with progestogens reduced the breast cancer risk 241.

Lauritzen C et ai. Risks of endometrial and mammary cancer morbidity and mortality in long-term estrogen treatment. In The Climacteric -An Update, ed by van Herendael H & B, Riphagen FE, Goessens L, van der Pars H Lancaster, England, MTP Press Ltd 1984; 207

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Gambrell RD Jr, Maier RC, Sanders Bl. Decreased incidence of breast cancer in postmenopausal estrogen progestogen users. Obstet Gynecol 1983 Oct;62(4):435-43

243.

Gambrell RD Jr. Hormones in lhe etiology and prevention of breast and endometrial cancer. South Med J.1984 Dec: 77(12): 1509-15

4) NO effect of HRT on breast cancer risk Studies with no increased breast cancer risk (or a nonsignificant lower risk) with the use offemale hormone replacement therapy (conjugated estrogens or other estrogens): 244.

Kaufman DW, Miller DR, Rosenberg, Miller DR, Rosenberg L, Helmrich SP, Stolley P, Schottenfeld D, Shapiro S. Noncontraceptive estrogen use and lhe risk of breast JAMA 1984 Jul 6;252(1):63-7

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Rosenberg L, Miller DR, Kaufman DW, Helmrich SP, Stolley PD, Schottenfeld. D; Shapiro S. Breast cancer

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Wingo PA, Layde PM, Lee NC, Rubin G, Ory HW. The risk of breast cancer in postmenopausal women who

and oral contraceptiva use. Am J Epidemiol 1984 Feb;119(2):167-76 have used estrogen replacement therapy. JAMA. 1987 Jan 9; 257(2): 209-15 248.

Peters GN, Fodera T, Sabol J, Jones S, Euhus D. Estrogen replacement therapy after breast cancer: a 12year follow-up. Ann Surg Oncol 2001 Dec;8(10):828-32

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Basavilvazo Rodriguez MA, Diaz Quiroz A, Lemus Rocha R, Angeles Victoria L, Zarate A, Hernandez­ Valencia M. Hormonal replacement therapy and breast cancer. A case-control study. Ginecol Obstet Mex. 2004 Jan;72(1):10-5

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Natrajan PK, Soumakis K, Gambrell RD Jr. Estrogen replacement therapy in women with previous breast cancer. Am J Obstei Gynecol 1999 Aug;181(2):288-95

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IV. Arguments in favour of the use of female hormones in women with female hormone deficiency: The therapy may preserve and improve body, mind and longevity

The importance of estrogen and progesterone for women in pre· and postmenopause is supported by evidence that the lack of these hormones is associated with psychic and physical diseases, and that their use in corrective hormone therapy reduces the severity of the associated psychic and physical diseases

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Freedman MA. Quality of life and menopause: the role of estrogen. J Womens Health (Larchmt). 2002

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Carette S, Dessureault M, Belanger A. Fibromyalgia and sex hormones. J Rheumatol. 1992 May;19(5):831

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Burger HG, Hailes J, Menelaus M, Nelson J, Hudson B, Balazs N. The management of persistent menopausa! symptoms with oestradiol-testosterone implants: clinicai, lipid and hormonal results. Maturitas.

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Ulrich LG, Barlow DH, Sturdee DW, Wells M, Campbell MJ, Nielsen B, Bragg AJ, Vessey MP. Quality of life and patient preference for sequential versus continuous combined HRT: the UK Kliofem multicenter study experience. UK Continuous Combined HRT Study lnvestigators. lnt J Gynaecol Obste!. 1997 Oct;59 Suppl 1:S11-7

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*

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Hip fractures: the association with lower estrogen leveis 736.

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after stopping estrogen use=> /oss of protection against hip fractures)

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(-50 % /ess hip fractures)

postmenopausal women. The Framingham Study. N Engl J Med. 1987 Nov 5;317(19):1169-74 estrogens on lhe risk for hip fracture among women. Ann lntern Med. 1992 May 1;116(9):716-21 741.

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Longevity: the improvement with progesterone treatment 747.

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733

ESTROGEN DEFICIENCIES with SERUM ESTROGEN LEVEL S within the REFERENCE R A NGE:to TREAT or NOTto TREA?

Should women with symptoms and signs of estrogen deficiency, but serum and urinary estrogen leveis within the normal reference range for their age, be treated with estrogen (combined to progesterone)?

Old view: Only at menopause, when lhe avaries totally stop their estrogen and progesterone secretion, should women be treated with female hormones and then by lhe lowest dose possible. Scientific publications support the view that Milder degrees of estrogen deficiency exist in women with estradiol levels within the reference range. lndeed, research shows lha! women with estrogen leveis within lhe reference range (situated in lhe lower three quarters, lower two thirds, lower half, lower third, lower forth, lower fifth or lower 10% of lhe reference range) have a significant increased risk of various types of disease or dysfunction. These associations suggest lha! they suffer from a degree of ovarian failure, as lhe increased risk may be reducible or preventable by increasing lhe estrogen leveis in lhe upper two thirds, upper half, upper third or upper quarter of lhe reference range through supplementation with estrogen. Premenopausal women with leveis of estrogen, progesterone and their metabolites within the reference range are not necessarily healthy and may suffer from estrogen and/or progesterone deficiency and may safely benefit from bio-identical estrogen supplementation, at personalized doses, together with bio-identical progesterone.

Studies that show that subjects who are at or below the 901h percentile of serum estradiol (or estrone) leveis have an increased risk of disease or dysfunction: this concerns rnost studies that show an inverse associalion belween estrogen leveis and lhe risk of palhology

Hot flashes in middle-aged women 1.

Schilling C, Gallicchio L, Miller SR, Langenberg P, Zacur H, Flaws JA. Genetic polymorphisms, hormone leveis, and hot flashes in midlife women. Maturitas. 2007 Jun 20;57(2):120-31 (Hol flashes are associaled with a low free serum estradiol index)

Lower serum estradiol leveis in the follicular phase of premenopausal women are associated with Smaller diameter of dominant follicle and reduced thickness of endometrium in lhe luteal phase oi premenopausal women 2.

Bakos O, Lundkvist O, Wide L, Bergh T. Ultrasonographical and hormonal description oi lhe normal ovulatory menstrual cycle. Acta Obstei Gynecol Scand. 1994 Nov;73(10):790-6 (The serum eslradiol level is correlaled wilh lhe diameler of lhe dominanl follicle (p

=

0.0001) and wilh lhe lhickness of lhe endomelrium)

Lower bone density in the lumbar spine and femoral neck in amng non-oral contraceptive users 3.

Rubin MR, Schussheim DH, Kulak CA, Kurland ES, Rosen CJ, Bilezikian JP, Shane E. ldiopathic osteoporosis in premenopausal women. Osteoporos lnt. 2005 May;16(5):526-33

734

Lower serum estradiol (and/or estronel leveis in postmenopausal women are associated with Lower bone density in the spine and other sites 4.

Studd J, Savvas M, Waston N, Garnett T, Fogelman I, Cooper D. The relationship between plasma estradiol and the increase in bone density in postmenopausal women after treatment with subcutaneous hormone implants. Am J Obste! Gynecol. 1990 Nov;163(5 Pt 1):1474-9 (Lower bane density in the spine and other sites)

5.

Yasui T, Uemura H, Umino Y, Takikawa M, Kuwahara A, Saito S, Matsuzaki T, Maegawa M, Furumoto H, Miura M, lrahara M. Serum estradiol concentration as measured by HPLC-RIA and bone mineral density in

6.

7.

postmenopausal women during hormone replacement therapy. Horm Res. 2004;61(3):117-25 (The serum estradiol is significantly and positively correlated with % change in /umbar BMD) Murphy S, Khaw KT, Sneyd MJ, Compston JE. Endogenous sex hormones and bone mineral density among community-based postmenopausal women. Postgrad Med J. 1992 Nov;68(805):908-13. (A significant and positive correlation between the free E2 indices and bane mineral density at ali sites) Rossini M, Del Marco A, Dal Santo F, Gatti D, Braggion C, James G, Adami S. Prevalence and correlates of vertebral fractures in adults with cystic fibrosis. Bone. 2004 Sep;35(3):771-6 Rheumatology Unit, Osteoporosis Center, University of Verona, 37122, Verona, ltaly. [email protected] (Serum estradio/ levels were found

below the normal range in 23% of the women and were significantly related to femur bane mineral values) 8.

Sowers M, Randolph JF Jr, Crutchfield M, Jannausch ML, Shapiro B, Zhang B, La Pietra M. Urinary ovarian and gonadotropin hormone leveis in premenopausal women with low bone mass. J Bone Miner Res. 1998 Jul;13(7):1191-202. Department of Epidemiology, University of Michigan, Ann Arbor, USA.

(A significant and

positive correlation between the serum EI glucuronide leve/ and bane mass) Osteoporotic fractures 9.

Kuchuk NO, van Schoor NM, Pluijm SM, Smit JH, de Ronde W, Lips P. The association of sex hormone leveis with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women. Clin Endocrinol (Oxf). 2007 Aug;67(2):295-303 Department of Endocrinology, VU University Medicai Centre, 1007 MB Amsterdam, The Netherlands. (Women, leveis of bioavailable estradiol below the median were

associated with a

+

53% higher risk of osteoporotic fractures after ali adjustments)

CUTOFF leveis for serum estradiol in women, below which the risk of disease or dysfunction increases

A number of studies show that individuais with serum IGF-1 leveis within the normal (reference range), but at or below a precise cutoff serum levei may be at a higher risk of developing a disease. The first table below presents the estradiol and estrone reference ranges:

Menstrual cycle Follicular phase, day 2 to 3 Follicular phase, early Follicular phase, periovulatory Luteal phase Untreated postmenopause

Reference ranges for Estradiol

Reference ranges for Estrone

0-84 pg/ml

0-308 pmol/1

0-160 pg/ml

0-587 pmol/1

30-150 pg/ml

110-554 pmol/

34-400 pg/ml

125-1468 pmol/1

60-600 pg/ml

221-1109 pmol/

27-246 pg/ml

99-903 pmol/1

40-200 pg/ml

148-739 pmol/1

0-30 pg/ml

0-11O pmol/1

10-60 pg/ml

37-222 pmol/1

Note: From the Clinicai reference range Guide at http://www.hosp.uky.edu/Ciinlab!report.pdf and Centraal laboratorium guide (Brusse/s, edition 1998) for estrone

735

The seeond table presents the threshold been reported to signifieantly inerease.

or cutoff leveis

of serum estradiol, below whieh the risk of disease has

Thresholds or cutoff leveis of serum estradio for disease within the reference range The cutoff levei is

the ref. range for serum E2 of postmenopausa! women

CUTOFF levei of Serum Estradiol

Within

Within ref. r. of Post menop.

-

-

women Premen. w. fali. phase

the ref. range for serum estradiol of

18

66

pg/ml

pmol/1

27

99

pg/ml

pmol/1

at eyele days 2 to 4 38

140

pg/ml

pmol/1

50

184

pg/ml

pmol/1

Above

52

191

pg/ml

pmol/1

post-

menopausa! women the referenee range of premenopausa! women,

Within

follicular

phase

56

206

pg/ml

pmol/1

60

220

pg/ml

pmol/1

so-ao

220-294

pÇJ/ml

pmol/1

60-90

220-330

pg/ml

pmol//1

81

297

pg/ml

pmol/1

Morbidity BELOW the cutoff levei

Publication

Comment

10. Sipilã S, Heikkinen E, Cheng S, Suominen H, Saari P, Kovanen V, Below 6 pg/ml Alén M, Rantanen T. Endogenous (22 pmol/1): 3Fall-related hormones, musele strength, and fold higher risk limb fracture risk of fall-related fraetures in older of fall-related women. J Gerontol A Biol Sei Med limb fraetures Sei. 2006 Jan;61(1 ):92-6. 11. Child TJ, Sylvestre C, Pirwany I, Tan SL. Basal Lower serum leveis of FSH and estradiol in ovulatory and pregnancy anovulatory women undergoing treatment by in-vitro rate in in vitro maturation of immature ooeytes. Hum Reprod. 2002 fertilizations AuQ;17(8):1997-2002 12. Wang Z, Guo JX, Wang X, Zhao YM, Hou LF. The Coronary relationship between serum ealeitonin gene-related heart disease peptide, sex hormone, homoeysteine and eoronary in postmenoartery disease in postmenopausal women. Zhonghua pausa! women Nei Ke Za Zhi. 2004 Sep;43(9):679-81 13. Bairey Merz CN, Johnson BD, Sharaf BL, Bittner V, Berga SL, Braunstein GD, Hodgson TK, Matthews KA, Pepine CJ, Reis SE, Reiehek N, Rogers WJ, Coronary heart disease Pohost GM, Kelsey SF, Sopko G; WISE Study Group. Hypoestrogenemia of hypothalamie origin and in premenopausa! women eoronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol. 2003 Feb 5;41(3):413-9 14. Ahokas A, Aito M, Rimón R. E2: Serum Positive treatment effeet of Psyehotie: 13 Psychosis* estradiol in postpartum psyehosis: 90 Normal: a pilot study. J Clin Psyehiatry. pg/ml 2000 Mar;61(3):166-9 15. Ahokas A, Kaukoranta J, Wahlbeek Serum E2: K, Aito M. Estrogen defieieney in Post-partal severe postpartum depression: depression: Postpartum treatment sueeessful with 22 pg/ml; depression sublingual physiologie 17beta- Normal estradiol: a preliminary study. J Clin women: 90pÇJ/ml Psyehiatry. 2001 May;62(5):332-6 16. Williams JK, Shively CA, Clarkson TB. Dilatation Lack of Determinants of eoronary artery o aeetylcoronary reaetivity in premenopausal female eholine of artery dilation eynomolgus monkeys with diet-indueed athero1994 selerotie in monkeys atheroselerosis. Cireulation. arteries AuQ;90(2):983-7 Cyclic 17. de Lignieres B. Menstrual migraine. Rev Prat. 1990 Feb 11;40(5):395-8. migraine 18. Reginster JY, Sarlet N, Deroisy R, Albert A, Gaspard U, Franehimont P. Bone density Minimal leveis of serum estradiol loss See note* prevent postmenopausal bane loss. Calei! Tissue lnt. 1992 Nov;51(5):340-3. Lower bone 19. Studd JW, Holland EF, Leather AT, Smith RN. The density in dose-response of pereutaneous oestradiol implants postmenop. on lhe skeletons of postmenopausal women. Br J women Obstet Gynaeeol. 1994 Sep;101(9):787-91.

736

Thresholds or cutoff leveis of serum estradio for disease within the reference range The cutoff levei is

Within lhe reference range of premeno

CUTOFF levei of Serum Estradiol

94 pg/ml

348 pmol/1

Morbidity BELOW the cutoff levei

Coronary heart disease in premenopausal women

-

pausal women, luteal phase

105 pg/ml

385 pmol/1

Comment

Publication 20. Hanke H, Hanke S, lckrath O, Lange K, Bruck B, Mück AO, Seeger H, Zwirner M, Voisard R, Haasis R, Hombach V. Estradiol concentrations in with premenopausal women coronary heart disease. Coron Artery Dis. 1997 AuQ-Sep;B(B-9):511-5

Serum E2: Coronary heart disease: 78; Normal: 110 pg/ml)

21. Choma S, Skorupski P, Postawski K, Women The with no Jakowicki J, Rechberger T. analysis of serum lipid profile in ovulation: anovulatory and ovulatory women in 92; Normal fifth decade of life] Ginekol Pol. 1998 women: Oct;69{10):761-6 123 pq/ml

Absence of ovulation

Note: The Cutoff is estimated as lhe median value between the serum estradiol (E2) of women with disease and that of normal women. *Women with circulating leveis of E2 between 60 and 90 pg/ml have a significant (P

<

0.01) reduction of urinary

calei um to creatinine and hydroxyproline to creatinine versus those with lower leveis of E2. Higher values of E2 do not provide any additional benefit.

Study of diseases associated with lower estrogen leveis within the reference range, suggesting that lhe lower leveis might contribute to the disease Psychotic disorders 22. Huber TJ, Rollnik J, Wilhelms J, von zur Mühlen A., Emrich HM, Schneider U. Estradiol leveis in psychotic disorders. Psychoneuroendocrinology2001; 26 (1): 27-35 (Only 28% of lhe women exhibiled eslradiol and progeslerone leveis indicaling a peri- or poslovulalory phase and ali of lhe eslradiol leveis on admission were eilher wilhin lhe Jower part of lhe cycle-dependenl normal range or be/ow normal)

737

PROGESTERONE DEFICIENCIES with SERUM PROGESTERONE LEVELS within the REFERENCE RANGE: to TREAT or NOT to TREAT?

Should women with symptoms and signs of progesterone deficiency; but serum progresterone and urinary preganandiol levels within the normal reference range for their age, be treated with progesterone?

Scientific publications support the view that Milder degrees of progesterone deficiency exist in women with leveis within the reference range. lndeed, research shows lha! women with lhe leveis of progesterone and its metabolites within lhe reference range (situated in lhe lower three quarters, lower two thirds, lower half, lower third, lower forth, lower fifth or lower 10% of lhe reference range) have a significant increased risk of various types of disease or dysfunction. These associations suggest that they suffer from a degree of ovarian failure, as lhe increased risk may be reducible or preventable by increasing lhe female hormone leveis and lha! of their metabolites leveis in lhe upper two thirds, upper half, upper third or upper quarter of lhe reference range through supplementation with estrogen and progesterone.

Premenopausal women with the leveis of progesterone and of its metabolites within the reference range are necessarily healthy, may suffer from progesterone deficiency and safely benefit from supplementationwith bio-identical progesterone at personalized doses. not

Study that shows that a single lab tests for progesterone may not well reflect the daily production because of major and quick fluctuations of the progesterone levei 1.

Filicori M, Butler JP, Crowley WF Jr. Neuroendocrine regulation of lhe corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin lnvest. 1984 Jun;73(6):1638-47 (lmportant progesterone fluctuations: in

the mid· and late lutea/ phases the plasma progesterone rapidly f/uctuated during 24 hours from 2.3 to 40. 1 nglml within minutes)

Studies that show that subjects who are at or below the 901h percentile of serum progesterone leveis have an increased risk of disease or dysfunction: this concerns most studies that show an inverse association between progesterone leveis and lhe risk of disease or dysfunction Hot flashes in middle-aged women 2.

Schilling C, Gallicchio L, Miller SR, Langenberg P, Zacur H, Flaws JA. Genetic polymorphisms, hormone leveis, and hot flashes in midlife women. Maturitas. 2007 Jun 20;57(2):120-31

(Hot flashes are associated with a low

serum progesterone leve/) Premenopausal women Higher body weight 3.

Westhoff C, Gentile G, Lee J, Zacur H, Helbig D. Predictors of ovarian steroid secretion in reproductive-age women. Am J Epidemiol. 1996 Aug 15;144(4):381-8.

(A higher body weight was associated with a lower serum

progesterone leve/, even in ovulatory women) Lower bone mass 4.

Sowers M, Randolph JF Jr, Crutchfield M, Jannausch ML, Shapiro B, Zhang B, La Pietra M. Urinary ovarian and

gonadotropin hormone leveis in premenopausal women with low bone mass. J Bone Miner Res. 1998

Jul;13(7):1191-202 (Significantly lower amounts of pregnanediol g/ucuronide (p

0.002) in premenopausa/ women with BMD of the lumbar spine, femoral neck, and total body less than the 1Oth percentile of the distributioncompared to premenopausal women with BMD between the 50th and 75th percentile)

738

=

Breast cancer? 5.

Véilker W, Leipert KP, Gehrlings H, Stauch G, von zur Mühlen A, Schneider J. [Mastopathy and breast cancer: is there a typical hormone profile?] Geburtshilfe Frauenheilkd. 1986 May;46(5):284-9 (Lower progesterone during the second half of the cycle is associated with an increased incidence of luteal insufficiency and may promote breast cancer)

Postmenopausal women Higher increases in systolic and diastolic blood pressure after angiotensin 11 6.

Szmuilowicz ED, Adler GK, Ricchiuti V, Hopkins PN, Seely EW. Relationships between endogenous sex hormone concentrations and vascular function in postmenopausal women. J Clin Endocrinol Metab. 2007

Dec;92(12):4738-41. (Higher endogenous progesterone within low postmenopausal range 0.1-1 nglml were associated with lower increases in systolic and diastolic blood pressure and vascular resistance after angiotensin

//)

Studies that show that women who are at or below the 33th percentile (in the lower tertile) of serum progesterone leveis have a near significant higher risk of the following disease: Breast cancer in premenopausal women (near significantly higher risk) 7.

Micheli A, Muti P, Secreto G, Krogh V, Meneghini E, Venturelli E, Sieri S, Pala V, Berrino F. Endogenous sex

hormones and subsequent breast cancer in premenopausal women. lnt J Cancer. 2004 Nov 1 ;112(2):312-8

(Premenopausal women with a serum progesterone in the 20-24th day of their menstrual cycle in the highest tertile had a near significant -60 to -88% lower risk of breast cancer -p

=

0.077); the risk of breast cancer is 8

times less when menstrual cvcles are regular) 8.

Sturgeon SR, Potischman N, Malone KE, Dorgan JF, Daling J, Schairer C, Brinton LA. Serum leveis of sex hormones and breast cancer risk in premenopausal women: a case-control study (USA). Cancer Causes Control. 2004 Feb;15(1):45-53. Department of Biostatistics and Epidemiology, University of Massachusetts, 715 North Pleasant Street, Arnold House 407, Amherst, MA 01003-9304, USA. [email protected] (For luteal progesterone: -45% lesss risk of breast cancer for the highest versus lowest tertile (trend to significance:0.2-1.4))

Studies that show that women who are at or below the 25th percentile (in the lower guartilel of serum progesterone leveis have an increased risk of disease Breast cancer (significant higher risk) in premenopausal women 9.

Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, Secreto G, Amiano P, et ai.. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective lnvestigation into Cancer and Nutrition (EPIC). J Natl Cancer lnst. 2005 May 18;97(10):755-65

(A

higher serum progesterone in the upper

quartile is associated with a significant -39% lower breast cancer risk.

The absolute risk of breast cancer for

women below the 40 years fo/lowed up for 10 years for the highest and lowest quartiles of progesterone

=

1.7%

and 2.6% respectively)

Preterm birth in pregnant women 10. Ruiz RJ, Saade GR, Brown CE, Nelson-Becker C, Tan A, Bishop S, Bukowski R. The effect of acculturation on progesterone/estriol ratios and preterm birth in Hispanics. Obstet Gynecol. 2008 Feb;111(2 Pt 1):309-16 (Pregnant women in the lowest quartile of the progesteronelestriol ratio had a significant 3-fold increase in risk of preterm birth)

739

Studies of diseases that are associated with lower progesterone leveis within the reference range, suggesting that the lower leveis might contribute to lhe disease Breast cancer in premenopausal women

11.

Bernstein L, Yuan JM, Ross RK, Pike MC, Hanisch R, Lobo R, Stanczyk F, Gao YT, Henderson BE. Serum hormone leveis in pre-menopausal Chinese women in Shanghai and white women in Los Angeles: results from

1990 Jul;1(1):51-8 (Overa/1, breast cancer patients had a lower serum progesterone than contrais) Thomas HV, Key TJ, Allen DS, Moere JW, Dowsett M, Fentiman IS, Wang DY. A prospectiva study of endogenous serum hormone concentrations and breast cancer risk in premenopausal women on the island of Guernsey. Br J Cancer. 1997;75(7):1075-9 (Sma/1, not statistically significant -9% lower progesterone in the two breast cancer case-control studies. Cancer Causes Control.

12.

tuteat phase progesterone in cases compared to contrais)

CUTOFF leveis for serum progesterone, below which the risk of disease or dysfunction increases A number of studies show that individuais with serum progesterone leveis within the normal (reference range), but at or below a precise cutoff serum levei may be at higher risk of developing a disease. The first table below presents the progesterone reference range in the serum.

Menstrual cycle

Reference ranges for Progesterone

Follicular phase

0.2-0.9 ng/ml

0.6-2.9 nmol/1

3.0-30 ng/ml

9.5-95.4 nmol/1

t Pregnancy, 1s trimester

15-50 ng/ml

47.7-159.0 nmol/1

3rd trimester

80 -200 ng/ml

254.4-636.0 nmol/1

Luteal phase

Pregnancy,

Untreated postmenopausal

0-0.3

ng/ml

0-0.95

nmol/1

Note: Data from lhe Clinicai reference range Guide at http://www.hosp.uky.edu/Ciinlablreport.pdf

740

The second table presents the threshold or cutoff leveis of serum progesterone, below which lhe risk of disease or dysfunction has been reported to significantly increase. Thresholds or cutoff leveis of serum Progesterone for disease within the reference range The Serum Progesterone cutoff levei is

Serum Progesterone CUTOFF levei of

Within the ref.

range of postmenopausa l women

Within the reference range of premenopausal women, luteal phase

0.3

Coronary heart disease

nmol/1

in postmenopausal women

4.5

14

No ovulation

ng/ml

nmol/1

(anovulation)

ng/ml

25

ng/ml

nmoi/L mid luteal P4

9.4

30

ng/ml

nmol/1

2.5

8.0

10

31.8

7.5

ng/ml

Pregnancy, t 1s trimester

1

Morbidity BELOW the cutoff levei

ng/ml

nmol/1

nmoVI

0.8 MoM at

7 weeks

Ovarian failure at hyperstimulation

Lower limit of optimal fertility Trophoblastic malignancy Not viable pregnancy

Early pregnancy loss

741

Publication

Comment

13. Wang Z, Guo JX, Wang X, Zhao YM, Hou LF. The relationship between serum calcitonin gene-related peptide, sex hormone, homocysteine and coronary artery disease in postmenopausal women. Zhonghua Nei Ke Za Zhi. 2004 Sep;43{9):679-81 14. Choma S, Skorupski P, Postawski K, Jakowicki J, Rechberger T. [The analysis of serum lipid profile in anovulatory and ovulatory women in fifth decade of life] Ginekol Pol. 1998 Oct;69{10):761-6 15. Costello MF, Emerson S, Lukic J, Sjoblom low A P, Garrett D, Hughes G, Steigrad S. midluteal P4 of Predictive value mid luteal levei � 25 progesterone concentration before luteal nmoi/L may controlled ovarian support in help predict with hyperstimulation intrauterine treatment insemination. Aust N z J Obstei failure Gynaecol. 2004 Feb;44(1):51-6 16. Hull MG, Savage PE, Bromham DR, lsmail AA, Morris AF. The value of a single serum progesterone measurement in the midluteal phase as a criterion of a potentially fertile cycle ("ovulation") derived form treated and untreated conception cycles. Fertil Steril. 1982 Mar;37(3):355-60 17. Rodriguez GC, Hughes CL, Soper JT, Berchuck A, ClarkePearson DL, Hammond CB. Serum progesterone for the exclusion of early pregnancy in women at risk for recurrent gestational trophoblastic neoplasia. Obstei Gynecol. 1994 Nov;84(5):794-7 18. Lower AM, Yovich JL. The value of Below 0.8 MoM of serum oestradiol, leveis for P4 at 7 wks beta-human progesterone and => 2.8 x risk of in lhe chorionic gonadotrophin unstimulated prediction of early pregnancy loss. cycles Hum Reprod. 1992 May;l(5):711-7

SERUM FSH LEVELS within the REFERENCE RANGE associated with DISEASE: to TREAT or NOT to TREAT?

Should women with symptoms and signs of female hormone deficiency but serum FSH and female hormone leveis within the normal reference range for their age be treated with female hormones?

Studies that show that above certain cutoff leveis of serum FSH increased risks of disease ordysfunction are found

A number of studies show that individuais with serum FSH leveis within lhe normal (reference range), but at or above a precise cutoff serum levei may be at higher oi developing a disease. The iirst table below presents the FSH reference range.

Reference ranges for serum FSH

Menstrual cycle

2.8- 11.3 mlU/ml

Follicular phase Ovulatory phase

5.8- 21 miU!ml 1.2 - 9 mlU/ml

Luteal phase Postmenopausal

22-153 mlU/ml

Note: Data from the Clinicai reference range Guide at http://www.hosp.uky.edu/Ciinlablreport.pdf

The second table presents the threshold or cutoff leveis of serum FSH, above which the risk oi disease has been reported to signiiicantly increase. Thresholds or cutoff leveis of serum FSH for disease within the reference range The cutoff levei is ...

WITHINthe

premenopausa! range for serum FSH

CUT OFF levei of Serum FSH

Morbidity AT or ABOVE the cutoff levei

J, serum E2 J, numbers oi mature iollicles J, oocyte production

6 miU!mL

in response to gonadotrophin stimulation

7 miU!mL

Higher serum leveis of total and LDL cholesterol (independent of

age)

Publication

Cahill DJ, Prosser CJ, Wardle PG, Ford WC, Hull MG. Relative influence of serum iollicle stimulating hormone, age and other to ovarian response iactors on gonadotrophin stimulation. Br J Obstet Gynaecol.1994 Nov;101(11):999-1002 Chu MC, Rath KM, Huie J, Taylor HS. Elevated basal FSH in normal cycling women is associated with unfavourable lipid leveis and increased cardiovascular risk. Hum Reprod. 2003 Auq;18(8):1570-3

Studies that show that women with breast cancer who are at or below the 251h percentile (in the lower quartile) of serum FSH leveis have an increased risk of dying More aggressive (invasive) breast cancerin pre- and post menopausa! women

Eskelinen M, Nordén T, Lindgren A, Wide L, Adami HO, Holmberg L. Preoperative serum leveis oi iollicle stimulating hormone (FSH) and prognosis in invasive breast cancer. Eur J Surg Oncol. 2004 Jun;30(5):495-500 (Higher FSH leveis in breast cancer patients is associated with a -15% (postmenopasual women) to -37% (premenopausal women) reduction of the breast cancer mortality (highest compared with the lowest quartile))

742

Chapter sixteen:

Testosterone in women

Senescence is associated with a decline of the adrenal- and ovarian-testosterone axes: Senescence is associated with a reduction of the serum testosterone levei in women 1.

Zumoff B, Strain GW, Miller LK, Rosner W. Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab. 1995 Apr;80(4):1429-30

2.

Bernini GP, Sgro' M, Moretti A, Argenio GF, Barlascini CO, Cristofani R, Salvetti A. Endogenous androgens and carotid intimai-mediai thickness in women. J Clin Endocrinol Metab. 1999 Jun;84(6):2008-12

3.

Debing E, Peeters E, Duque! W, Poppe K, Velkeniers B, Van den Brande P. Endogenous sex hormone leveis in postmenopausal women undergoing carotid artery endarterectomy. Eur J Endocrinol. 2007 Jun;156(6):68793

Testosterone derives in women for more than 90% from the much quicker declining serum DHEA Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L, Gomez JL, Candas B., DHEA and lhe 4. intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids, 1998;63(5-6):322-8 Testosterone treatment may oppose and testosterone deficiency may tr igger some mechanisms of senescence in women lmmune deficiency: testosterone may improve the immune resistance in certain conditions 5. Dalal M, Kim S, Voskuhl RR. Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in lhe autoantigen-specific T lymphocyte response. J lmmunol. 1997 Jul 1;159(1):3-6 6. Buggage RR, Matteson DM, Shen de F, Sun B, Tuaillon N, Chan CC.Effect of sex hormones on experimental autoimmune uvearetinitis (EAU). lmmunal lnvest. 2003 Nav;32(4):259-73 7. Nakazawa M, Fantappie MR, Freeman GL Jr, Elai-Santas S, Olsen NJ, Kavacs WJ, Secar WE, Calley DG. Schistasoma mansoni: susceptibility differences between male and female mice can be mediated by testasterane during early infection. Exp Parasitai. 1997 Mar;85(3):233-40

Testosterone and psychic well-being in women Lower quality of life and fatigue in women: the association with lower testosterone leveis Abrahamssan L, Hackl H, Lindstram B, Sagn J. Lang-term treatment af virilized women with cypraterane

8.

acetate. Wien Klin Wachenschr. 1981 Sep 18;93(17):552-6

Quality of life in women: the improvement with testosterone treatment 9.

Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testasterane therapy impraves well-being, maod, and sexual function in premenapausal wamen. Menopause. 2003 Sep-Oct;10(5):390-8

Lower physical performance in women: the association with lower testosterone leveis Cardinale M, Stane MH. ls testosterane influencing explasive performance? J Strength Cand Res. 2006 Feb;20(1):103-7

10.

Vasomotor symptoms in women: the improvement with testosterone treatment 11. Simon J, Klaiber E, Wiita B, Bowen A, Yang HM. Differential effects of estragen-andragen and estragen-anly therapy an vasamotar symptams, ganadatropin secretion, and endagenaus androgen biaavailability in postmenopausal women. Menopause. 1999 Summer;6(2):138-46 Depression in women: the association with lower testosterone leveis Rahr UD. The impact of testosterane imbalance an depressian and wamen's health. Maturitas. 2002 Apr 15;41 Suppl 1:S25-46

12.

Depression in women: the improvement with testosterone treatment Shifren JL, Braunstein GD, Simon JA, Cassan PR, Buster JE, Redmand GP, Burki RE, Ginsburg ES, Rasen RC, Leiblum SR, Caramelli KE, Mazer NA. Transdermal testasterone treatment in wamen with impaired

13.

sexual function after aaphorectamy. N Engl J Med. 2000 Sep 7;343(10):682-8

743

14.

Sherwin BB. Affective changes with estrogen and androgen replacement therapy in surgically menopausa! women. J Affect Disord. 1988 Mar-Apr;14(2):177-87

Negative symptoms in women: the association with lower serum testosterone leveis 15.

Goyal RO, Sagar R, Ammini AC, Khurana ML, Alias AG. Negative correlation between negative symptoms of schizophrenia and testosterone leveis Ann N Y Acad Sei. 2004 Dec;1032:291-4

Anxiety in women: the association with lower testosterone leveis 16. Landen M, Baghaei F, Rosmond R, Holm G, Bjorntorp P, Eriksson E. Dyslipidemia and high waist-hip ratio in women with self-reported social anxiety. Psychoneuroendocrinology. 2004 Sep;29(8):1037-46 (Serum leveis

of total testosterone (1.6+1-0.8 vs. 2.2+1-1.1, P=0.013) and free thyroxin (14+1-2 vs. 16+1-4, P=0.04) were lower in subjects confirming social anxiety) Anxiety in women: the improvement with testosterone treatment 17.

Hermans EJ, Putman P, Baas JM, Koppeschaar HP, van Honk J. A single administration of testosterone reduces fear-potentiated startle in humans. Biol Psychiatry. 2006 May 1;59(9):872-4

18.

van Honk J, Peper JS, Schutter DJ. Testosterone reduces unconscious tear but not consciously experienced anxiety: implications for lhe disorders of tear and anxiety. Biol Psychiatry. 2005 Aug 1;58(3):218-25

19.

Montgomery JC, Appleby L, Brinca! M, Versi E, Tapp A, Fenwick PB, Studd JW. Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lance!. 1987 Feb 7;1(8528):297-9

20.

van Honk J, Peper JS, Schutter DJ. Testosterone reduces unconscious tear but not consciously experienced anxiety: implications for the disorders of tear and anxiety. Biol Psychiatry. 2005 Aug 1;58(3):218-25

Memory loss and Alzheimer's disease in women: the association with lower testosterone leveis 21.

Simpson E, Davis S. Why do the clinicai sequelae of estrogen deficiency affect women more than men? J Clin Endocrinol Metab. 1998 Jun;83(6):2214

Memory in women: the improvement with testosterone treatment 22.

Wisniewski AB, Nguyen TI, Dobs AS. Evaluation of high-dose estrogen and high-dose estrogen plus methyltestosterone treatment on cognitive task performance in postmenopausal women.

Horm Res.

2002;58(3):150-5 Love in women: the association with higher testosterone in women 23.

Marazziti

D,

Canale

D.

Hormonal

changes

when

falling

in

lave.

Psychoneuroendocrinology.

2004

Aug;29(7):931-6 Loss of sexual drive, sexual gratification, intercourse frequency in women: the association with lower testosterone leveis 24.

Persky H, Lief H I, Miller WR, O'Brien CP. Plasma testosterone levei and sexual behavior of couples. Arch Sex Behav. 1978 May; 7(3):157-73

Sexuality decline in women: the improvement with testosterone treatment 25.

Davis SR, McCioud P, Strauss BJ, Burger H. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas. 2008 Sep-Oct;61(1-2):17-26

26.

Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testosterone therapy improves well-being,

27.

Penotti M, Sironi L, Cannata L, Vigano P, Casini A, Gabrielli L, Vignali M. Effects of androgen supplementation

mood, and sexual function in premenopausal women. Menopause. 2003 Sep-Oct;10(5):390-8 of hormone replacement therapy on lhe vascular reactivity oi cerebral arteries.

Fertil Steril.

2001

Aug;76(2):235-40 28.

Shifren JL, Braunstein GD, Simon JA, Casson PR, Suster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000 Sep 7;343(10):682-8

29.

Davis SR, McCioud P, Strauss BJ, Burger H. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas. 1995 Apr;21(3):227-36

30.

Sarrel P, Dobay B, Wiita B.Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual behavior and neuroendocrine responses. J Reprod Med. 1998 Oct;43(10):847-56

31.

Sarrel PM. Psychosexual effects oi menopause: role of androgens. Am J Obstet Gynecol. 1999 Mar; 180(3 Pt

32.

Tutten A, Laan E, Panhuysen G, Everaerd W, de Haan E, Koppeschaar H, Vroon P. Discrepancies between

2):S319-24 genital responses and subjective sexual function during testosterone substitution in women with hypothalamic amenorrhea. Psychosom Med. 1996 May-Jun;58(3):234-41

744

33.

Tuiten A, Van Honk J, Koppeschaar H, Bernaards C, Thijssen J, Verbaten R. Time course of effects of testosterone administration on sexual arousal in women. Arch Gen Psychiatry. 2000 Feb;57(2):149-53

34.

Shifren JL. The role of androgens in female sexual dysfunction. Mayo Clin Proc. 2004 Apr;79(4 Suppi):S19-24 Riley AJ. Life-long absence of sexual drive in a woman associated with 5-dihydrotestosterone deficiency. J Sex Marital Ther. 1999 Jan-Mar;25(1):73-8 Penotti M, Sironi L, Cannata L, Vigano P, Casini A, Gabrielli L, Vignali M. Effects of androgen supplementation 2001 of hormone replacement therapy on lhe vascular reactivity of cerebral arteries. Fertil Steril.

35. 36.

37.

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Castlo-Branco C, Martinez de Osaba MJ, Fortuny A, lglesias X, Gonzalez-Merlo J. Circulating hormone leveis in menopausa! women receiving different hormone replacement therapy regimens. A comparison. J Reprod Med. 1995:40:556-60

161.

Goh HH, Wong PC, Ratnam SS. Effects of sex steroids on lhe positive estrogen feedback mechanism in intact

162.

Vermesh M, Silva PD, Rosen GF, Vijod AG, Lobo RA. Effect of androgen on adrenal steroidogenesis in

women and castrate men. J Clin Endocrinol Metab. 1985 Dec;61(6):1158-64 normal women. J Clin Endocrinol Metab. 1988 Jan;66(1):128-30

Testosterone treatment in women: follow-up 163.

Bird CE, Finnis W, Boroomand K, Murphy J, Clark AF. Kinetics of testosterone metabolism in normal postmenopausal women and women with breast cancer. Steroids. 1978 Oct;32(3):323-35

164.

Bassindale T, Cowan DA, Dale S, Hutt AJ, Leeds AR, Wheeler MJ, Kicman AT. Effects of oral administration of androstenedione on plasma androgens in young women using hormonal contraception. J Clin Endocrinol Metab. 2004 Dec;89(12):6030-8

165.

White T, Jain JK, Stanczyk FZ. Effect of oral versus transdermal steroidal contraceptives on androgenic markers. Am J Obste! Gynecol. 2005 Jun;192(6):2055-9

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TOPICSofDISCUSSION: TESTOSTERONE DEFICIENCIES IN WOMEN with SERUM ANDROGEN LEVELS within lhe REFERENCE RANGE: to TREAT or NOT to TREAT?

Should women with symptoms and signs of testosterone deficiency, but serum androgen leveis within lhe normal reference range for their age, be treated with testosterone?

Old view: Testosterone is for men, not for women. Testosterone supplementation may produce at any dose signs oi virilization (increased body hair, lower voice tone, oily skin and hair, etc.) in women. Testosterone is bad for lhe heart. Testosterone supplementation may not be given to women, or only in extreme cases when laboratory tests are well below lhe lower limil oi lhe reference range. Scientific publications support lhe view that Testosterone is also a woman's hormone with many benefits for her, provided lhe dose that is given is adapted to her. Testosterone at 20 times a lower dose than in men is safe for women at lhe condition that they receive at lhe same time female hormone supplements at sufficient doses (blocks the expression oi virilizing signs with testosterone). Women with testsoterone leveis within lhe reference range (situated in lhe lower three quarters, lower two thirds, lower half, lower third, lower forth, lower filth or lower 10% oi lhe reference range) have a signilicant increased risk oi various types oi disease.

This suggests that they suffer from a degree oi ovarian and/or

adrenal cortex failure, as lhe increased risk may be reduced or prevented by increasing testosterone leveis in lhe upper two thirds, upper half, upper third or upper quarter oi lhe reference range through supplementation with testosterone. Thus, milder degrees oi testosterone deficiency exist with leveis within lhe reference range. Milder degrees of testosterone deficiency exist in women with leveis within lhe reference range that cause disease or dysfunction. Research shows that women with testosterone leveis within lhe reference range (situated in lhe lower three quarters, lower two thirds, lower half, lower third, lower forth, lower filth or lower 10% oi lhe reference range) have a significant increased risk oi various types oi disease. These associations suggest that they suffer from a degree oi testosterone deficiency, as lhe increased risk may be reduced or prevented by increasing testosterone leveis in lhe upper two thirds, upper half, upper third or upper quarter oi the reference range through supplementation with testosterone. Women with testosterone leveis leveis within lhe reference range may safely benefit from testosterone supplementation i! lhe treatment is associated with a female hormone treatment and doses are kept low.

The following studies confirm links oi testosterone leveis within lhe reference range to higher risks oi disease in women

Studies that show that women who are ai or below lhe 901h percentile of serum testosterone leveis have an increased risk of disease or dysfunction: this concerns most studies that show an inverse association between testosterone leveis and the risk of pathology Lower HDL and higher triglycerides in middle-aged women 1.

Khatibi A, Agardh CD, Shakir YA, Nerbrand C, Nyberg P, Lidfeldt J, Samsioe G. Could androgens prateei middle-aged women from cardiovascular events? A population-based study of Swedish women: The Women's Health in lhe Lund Area (WHILA) Study. Climacteric. 2007 Oct;10(5}:386-92. Department of Clinicai Sciences in Lund, Lund University, and Department of Gynecology and Obstetrics, Lund University Hospital, Sweden

(Testosterone was positively associated with HDL cholestero/ (p<0.001) in ali women, but negatively associated

with leveis of triglycerides)

752

2.

Shakir YA, Samsioe G, Nyberg P, Lidfeldt J, Nerbrand C, Agardh CD. Do sex hormones influence features of lhe metabolic syndrome in middle-aged women? A population-based study of Swedish women: lhe Women's Health in lhe Lund Area (WHILA) Study. Fertil Steril. 2007 Jul;88(1):163-71. Department of Clinicai Sciences in Lund, University, Lund, Sweden. [email protected] (Serum total testosterone was positively associated with HDL. cho/esterol)

Lund

Higher serum CRP (risk for cardiovascular disease) in postmenopausal women) 3.

Joffe HV, Ridker PM, Manson JE, Cook NR, Buring JE, Rexrode KM. Sex hormone-binding globulin and serum testosterone are inversely associated with C-reactive protein leveis in postmenopausal women at high risk for cardiovascular disease. Ann Epidemiol. 2006 Feb;16(2):105-12. Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA 02215, USA (lnverse associations of

CRP with serum testosterone in postmenopausal women)

Higher CRP in women with hypopituitarism 4.

Sesmilo G, Miller KK, Hayden D, Klibanski A. lnflammatory cardiovascular risk markers in women with hypopituitarism. J Clin Endocrinol Metab. 2001 Dec;86(12):5774-81. Neuroendocrine Uni!, Massachusetts General Hospital and Harvard Medicai School, Boston, Massachusetts 02114, USA.

with total T

(P

=

0.0020), and free T

(P

=

Premature atherosclerosis (severely increased carotid 5.

(CRP correlated negatively

0.031) intima-media thickness) in postmenopausal women

Bernini GP, Moretti A, Sgró M, Argenio GF, Barlascini CO, Cristofani R, Salvetti

A. lnfluence of endogenous

androgens on carotid wall in postmenopausal women. Menopause. 2001 Jan-Feb;8(1):43-50. Dipartimento di Medicina Interna, University of Pisa, ltaly. (The free testosterone was negatively associated with severe carotid

intimai-media/ thickness in postmenopausat women) 6.

Debing E, Peeters E, Duque! W, Poppe K, Velkeniers B, Van den Brande P. Endogenous sex hormone leveis in postmenopausal women undergoing carotid artery endarterectomy. Eur J Endocrinol. 2007 Jun;156(6):687-93

(Significant inverse relationship between serum free testosterone athero�clerosis of interna/ carotid artery)

(P

=

0.028) with the presence of severe

Studies that show that women who are at or below the 67th percentile (in the lower two tertilew) of serum testosterone leveis have an increased risk of disease Premature atherosclerosis (lncreased carotid intima-media thickness) in pre- and 7.

postmenopausal women

Bernini GP, Moretti A, Sgró M, Argenio GF, Barlascini CO, Cristofani R, Salvetti A. lnfluence of endogenous androgens on carotid wall in postmenopausal women. Menopause. 2001 Jan-Feb;8(1):43-50

8.

Bernini GP, Sgro' M, Moretti A, Argenio GF, Barlascini CO, Cristofani R, Salvetti A. Endogenous androgens and carotid intimai-mediai thickness in women. J Clin Endocrinol Metab. 1999 Jun;84(6):2008-12

Studies that show that women who are at or below the 33th percentile (in the lower tertile) of serum testosterone leveis have an increased risk of disease lncreased risk of ovarian cancer in postmenopausal women 9.

Rinaldi S, Dossus L, Lukanova A, Peeters PH, Allen NE, Key T, Bingham S, Khaw KT, et ai. Endogenous androgens and risk of epithelial ovarian cancer: results from lhe European Prospective lnvestigation into Cancer and Nutrition (EPIC). Cancer Epidemia! Biomarkers Prev. 2007 Jan;16(1):23-9. IARC, Lyon, France {In

postmenopausa/ women, free testosterone concentrations were inversely related to risk of ovarian cancer: highest versus lowest tertile odds ratio 0.45 (0.24-0.86); P 0.01) =

Studies, which show that women with disease or a predisposition to a disease have lower testosterone or testosterone metabolite leveis, suggesting that lhe low leveis may contribute to lhe disease Family history of breast cancer 10. Jernstrõm HC, Olsson H, Borg A. Reduced testosterone, 17 beta-oestradiol and sexual hormone binding globulin, and increased insulin-like growth factor-1 concentrations, in healthy nulligravid women aged 19-25

753

years who were first and/or second degree relatives to breast cancer patients. Eur J Cancer Prev. 1997 Aug;6(4):330-40. Department of Oncology, University Hospital, Lund, Sweden. (Significantly lower testosterone

leveis in women with a family history of breast cancer - with at /east one first and/or second degree relative with breast cancer)

Coronary heart disease 11. Kaczmarek A, Reczuch K, Majda J, Banasiak W, Ponikowski P. The association of lower testosterone levei with coronary artery disease in postmenopausal women. lnt J Cardiol. 2003 Jan;87(1):53-7. Cardiac Department, Military Hospital, UI. Weigla 5, 50891 Wroclaw, Poland (Women with coronary artery disease had decreased

testosterone levei and lower free testosterone index (T: 0.99 P=0.04, CAD+ vs. CAD-, respectively).

vs. 1.41

nmo/11, P=0.005; TFI: 3.2 vs. 4.2,

HIV-infection 12. Sinha-Hikim I, Arver S, Beall G, Shen R, Guerrero M, Sattler F, Shikuma C, Nelson JC, Landgren BM, Mazer NA, Bhasin S. The use of a sensitive equilibrium dialysis method for lhe measurement of free testosterone leveis in healthy, cycling women and in human immunodeficiency virus-infected women. J Clin Endocrinol Metab. 1998 Apr;83(4):1312-8. 13. Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059, USA.

(Serum total [0.50 (14.60) vs. 1.2nmoi/L (34.3 ng/dL); P < 0.0001} and free testosterone leveis (5.56 (1.58) vs. 128 . pmoi/L (3.4 pg/mL); P < 0.0001) were significantly lower in HIV-infected women (n = 37) than in healthy women Serum total and free testosterone leveis were also significantly lower in HIV-infected women who were menstruating normally.)

754

Chapter seventeen:

Testosterone in men

Senescence is associated with a decline of the pituitary-testosterone axis in men Senescence in men is associated with a decline in testosterone leveis 1. Lam KS. Serum total and bioavailable testosterone leveis, central obesity, and muscle strength changes with aging in healthy Chinese men. J Am Geriatr Soe. 2008 Jul;56(7):1286-91 ('The rales of decline in serum total

testosterone and bioavailable testosterone leveis were 0.2% and 1.14% per year") 2.

Martínez Jabaloyas JM, Queipo Zaragoza A, Ferrandis Cortes C, Queipo Zaragoza JA, Gil Salom M, Chuan Nuez P. [Changes in sexual hormones in a male Actas Urol Esp. 2008 Jun;32(6):603-10 ("Age was

associated with a significant decrease (p < 0.05) in total testosterone (0.6% per year), free testosterone (1.3% per year") 3. 4.

5.

6. 7.

8.

9.

10.

11.

Martínez Jabaloyas JM, Queipo Zaragoza A, Ferrandis Cortes C,]Queipo Zaragoza JA, Gil Salom M, Chuan Nuez P. Changes in sexual hormones in a male Actas Urol Esp. 2008 Jun;32(6):603-10 Andersson AM, Jensen TK, Juul A, Petersen JH, Jargensen T, Skakkebrek NE. Secular Decline in Male Testosterone and Sex Hormone Binding Globulin Serum Leveis in Danish Population Surveys. J Clin Endocrinol Metab. 2007 Dec;92(12):4696-4705 Takahashi PY, Votruba P, Abu-Rub M, Mielke K, Veldhuis JD. Age attenuates testosterone secretion driven by amplitude-varying pulses oi recombinant human luteinizing hormone during acute gonadotrope inhibition in healthy men. J Clin Endocrinol Metab. 2007 Sep;92(9):3626-32 Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The relative contributions oi aging, health, and lilestyle lactors to serum testosterone decline in men. J Clin Endocrinol Metab. 2007 Feb;92(2}:549-55 Mohr BA, Bhasin S, Link CL, O'Donnell AB, McKinlay JB. The effect oi changes in adiposity on testosterone leveis in older men: longitudinal results lrom lhe Massachusetts Male Aging Study. Eur J Endocrinol. 2006 Sep;155(3):443-52 Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, Blackman MR, Metter EJ. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab. 2006 Feb;290(2):E234-42 Chen RY, Wittert GA, Andrews GR. Relative androgen deliciency in relation to obesity and metabolic status in older men. Diabetes Obes Metab. 2006 Jui;8(4):429-35.Barud W, Palusiríski R, Piotrowska-Swirszcz A, Ostrowski S, Makaruk B. Sex hormones, HDL cholesterol and other lipoproteins in older males. Pol Merkur Lekarski. 2005 Mar;18(105):295-7 Sato Y, Kato S, Ohnishi S, Nakajima H, Nanbu A, Nitta T, Koroku M, Akagashi K, Hanzawa T, Kato R, Hisasue S, Masumori N, ltoh N, Tsukamoto T, Tanda H. Analysis oi clinicai manilestations and endocrinological aspects oi patients having PADAM-Iike symptoms. Nippon Hinyokika Gakkai Zasshi. 2004 Jan;95(1):8-16 Gennari L, Merlotti D, Martini G, Gonnelli S, Franci B, Campagna S, Lucani B, Dal Canto N, Valenti R, Gennari C, Nuti R. Longitudinal association between sex hormone leveis, bane loss, and bone turnover in elderly men. J Clin Endocrinol Metab. 2003 Nov;88(11):5327-33 (With age, an increase in aromatase, serum

estradiol and lhe serum ratio estradiol to testosterone was found with a decrease of testosterone) 12.

Tan MO, Karabiyik I, Uygur MC, Diker Y, Erol D. Serum concentrations oi sex hormones in men with severe lower urinary tract symptoms and benign prostatic hyperplasia. In! Urol Nephrol. 2003;35(3):357-63

13.

Gapstur SM, Gann PH, Kopp P, Colangelo L, Longcope C, Liu K. Serum androgen concentrations in young men: a longitudinal analysis oi associations with age, obesity, and race. The CAROlA male hormone study. Cancer Epidemiol Biomarkers Prev. 2002 Oct;11(10 Pt 1):1041-7 Szulc P, Munoz F, Claustrat B, Garnero P, Marchand F, Duboeul F, Delmas PD. Bioavailable estradiol may be

14.

an important determinant oi osteoporosis in men: lhe MINOS study. J Clin Endocrinol Metab. 2001 Jan;86(1):192-9 15.

Bernini GP, Sgro' M, Moretti A, Argenio GF, Barlascini CO, Cristolani R, Salvetti A. Endogenous androgens and carotid intimai-mediai thickness in women. J Clin Endocrinol Metab. 1999 Jun;84(6):2008-12

16.

Deslypere JP, Vermeulen A. lnlluence oi age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men. J Clin Endocrinol Metab. 1985 Oct;61(4):648-53 Deslypere JP, Vermeulen A. Leydig cell lunction in normal men: effect oi age, lile-style, residence, diet, and activity. J Clin Endocrinol Metab. 1984 Nov;59(5):955-62 Morer-Fargas F, Nowakowski H. The urinary excretion oi testosterone in males. Acta endocrinol (Copenh). 1965 Jul;49:443-52 Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR; Baltimore Longitudinal Study oi Aging. Longitudinal effects oi aging on serum total and lree testosterone leveis in healthy men. Baltimore Longitudinal Study oi Aging. J Clin Endocrinol Metab. 2001 Feb;86(2):724-31 {lhe incidence of (over1)

17. 18. 19.

hypogonadal testosterone leveis increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed)

755

20.

Drafta D, Schindler AE, Stroe E, Neacsu E. Age-related changes of plasma steroids in normal adult males. J

21.

Morley JE, Kaiser F, Raum WJ, Perry HM 3rd, Flood JF, Jensen J, SilverAJ, Roberts E. Potentially predictive

Steroid Biochem. 1982 Dec;17(6):683-7 and manipulable blood serum correlates of aging in lhe healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and lhe ratio of insulin-like growth factor 1 to growth hormone. Proc NatlAcad Sei U SA. 1997 Jul 8;94(14):7537-42

The speed of age-related decline of serum testosterone in men 22. Vermeulen A. Plasma leveis and secretion rale of steroids with anabolic activity in man. Environ Qual Sal Suppl. 1976;(5):171-80 Senescence in men is associated with a decline in metabolic clearance of testosterone Wang C, Catlin DH, Starcevic B, Leung A, DiStefano E, Lucas G, Hull L, Swerdloff RS. Testosterone metabolic clearance and production rales determined by stable isotope dilution/tandem mass spectrometry in normal men: influence of ethnicity and age. J Clin Endocrinol Metab. 2004 Jun;89(6):2936-41 24. Baker HW, Burger HG, de Kretser DM, Hudson B, O'Connor S, Wang C, Mirovics A, Court J, Dunlop M, Rennie GC. Changes in lhe pituitary-testicular system with age. Clin Endocrinol (Oxf). 1976 Jul;5(4):349-72 23.

Senescence in men is associated with alterations of the circadian cycle of serum testosterone leveis: reduced amplitude and desynchonisation of its circadian rhythm 25.

Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone leveis with aging in normal men. J Clin Endocrinol Metab. 1983 Jun;56(6):1278-81

The age-related decline of serum testosterone starts in middle age in men 26.

Luboshitzky R, Shen-Orr Z, Herer P. Middle-aged men secrete less testosterone at night than young healthy men. J Clin Endocrinol Metab. 2003 Jul;88(7):3160-6

Senescence in men is associated with a loss of the circadian rhythm of serum testosterone 27.

Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone leveis with aging in normal men. J Clin Endocrinol Metab. 1983;56:1278-81

Senescence in men is associated with an increased peripheral conversion of androgens into estrogens: the increased estrogen levei in aging males may inhibit the androgen production 28. Gennari L, Merlotti D, Martini G, Gonnelli S, Franci B, Campagna S, Lucani B, Dal Canto N, Valenti R, Gennari C, Nuti R. Longitudinal association between sex hormone leveis, bane loss, and bone turnover in elderly men. J Clin Endocrinol Metab. 2003 Nov;88(11):5327-33 29. Tan MO, Karabiyik I, Uygur MC, Diker Y, Erol D. Serum concentrations of sex hormones in men with severe lower urinary tract symptoms and benign prostatic hyperplasia. In! Urol Nephrol. 2003;35(3):357-63 Drafta D, Schindler AE, Stroe E, Neacsu E. Age-related changes of plasma steroids in normal adult males. J 30. Steroid Biochem. 1982 Dec;17(6):683-7 ("The age related changes of plasma steroids in elderly men, were suggestive of decreased testicular function with increased peripheral conversion of androgens into estrogens. ... The negative correlation between estrone and 17-0H-P (precursor of testosterone) found in elderly men, suggested that increased estrogen levei in aging males may be considered able to inhibit the testicular androgen production'? Senescence in men is associated with a reduced sensitivity of the testosterone-producing Leydig cells to LH 31. Liu PY, Takahashi PY, Roebuck PD, lranmanesh A, Veldhuis JD. Aging in healthy men impairs recombinant human luteinizing hormone (LH)-stimulated testosterone secretion monitored under a two-day intravenous pulsatile LH clamp. J Clin Endocrinol Metab. 2005 Oct;90(10):5544-50 Testosterone treatment may oppose and testosterone deficiency may trigger several mechanisms of senescence in men Excessive free radical formation: Testosterone has antioxidant activity

Testosterone and estrogens 32.

Tam NN, Ghatak S, Ho SM. Sex hormone-induced alterations in lhe activities of antioxidant enzymes and lipid

33.

Ahlbom E, Prins GS, Ceccatelli S. Testosterone protects cerebellar granule cells from oxidative stress-induced

peroxidation status in lhe prostate of Noble rats. Prostate. 2003Apr 1;55(1):1-8 cell death through a receptor mediated mechanism. Brain Res. 2001 Feb 23;892(2):255-62

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Testosterone 34. Klinger W, Lupp A, Karge E, Baumbach H, Eichhorn F, Feix A, Fuldner F, Gernhardt S, Knels L, Kost B, Mertens G, Werner F, Oettel M, Romer W, Schwarz S, Elger W, Schneider B. Estradiol, testosterone,

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dehydroepiandrosterone and androstenedione: novel derivatives and enantiomers. lnteractions with rat liver microsomal cytochrome P450 and antioxidanl/radical scavenger activities in vitro. Toxicol Lett. 2002 Mar 10;128(1-3):129-44 Juliet PA, Hayashi T, Daigo S, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, lguchi A, lgnarro LJ. Combined effect of testosterone and apocynin on nitric oxide and superoxide production in PMA-differentiated THP-1 cells. Biochim Biophys Acta. 2004 Sep 17;1693(3):185-91 Tam NN, Gao Y, Leung YK, Ho SM. Androgenic regulation of oxidative stress in lhe rat prostate: involvement of NAD(P)H oxidases and antioxidant defense machinery during prostatic involution and regrowth. Am J Pathol. 2003 Dec;163(6):2513-22

Díhydrotestosterone 37.

Lee MN, Lee SH, Lee MY, Kim YH, Park JH, Ryu JM, Yun SP, Lee YJ, Kim MO, Park K, Han HJ. Effect of dihydrotestosterone on mouse embryonic stem cells exposed to H202-induced oxidative stress. J Vet Sei. 2008 Sep;9(3):247-56

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Skakkebaek N, Bancroft J, Davidson D, Wamer P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol (Oxf). 1981;14:49-61

Sublingual testosterone for men Salehian B, Wang C, Alexander G, Davidson T, McDonald V, Berman N, Dudley RE, Ziel F, 8werdloff RS. Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate- a clinicai research center study. J Clin Endocrinol Metab 1995;80:3567-75

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lntramuscular injections of testosterone enanthate or cyprionate for men 450.

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Schurmeyer T, Nieschlag E. Comparative pharmacokinetics of testosterone enanthate and testosterone cyclohexanecarboxylate as assessed by serum and salivary testosterone leveis in normal men lnt J Androl 1984;7:181-7

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lntramuscular ínjectíons of nandrolone decanoate for men 457. Strawford A, Barbieri T, Neese R, Van Loan M, Christiansen M, Hoh R, Sathyan G, Skowronski R, King J, Hellerstein M. Effects oi nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss. J Acquir 1mmune Defic Syndr Hum Retrovirol. 1999 Feb 1;20(2):137-46 ("lt is reasonable to expand the criteria for androgen treatment in AIDS waisting syndrome to include at least patients in the lowest 458.

quartile of serum testosterone'} Flicker L, Hopper JL, Larkins RG, Lichtenstein M, Buirski G, Wark JD. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporos lnt. 1997;7(1):29-35

lntramuscular ínjectíons of testosterone undecanoate for men 459. Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for lhe treatment oi male hypogonadism. Expert Opin Pharmacother. 2005 Aug;6(10):1751-9 460. Schubert M, Minnemann T, Hubler D, Rouskova D, Christoph A, Oettel M, Ernst M, Mellinger U, Krone W, Jockenhovel F. lntramuscular testosterone undecanoate: pharmacokinetic aspects oi a novel testosterone formulation during long-term treatment oi men with hypogonadism. J Clin Endocrinol Metab. 2004 Nov;89(11):5429-34 461. von Eckardstein S, Nieschlag E. Treatment oi male hypogonadism with testosterone undecanoate injected at extended intervals oi 12 weeks: a phase 11 study. J Androl. 2002 May-Jun;23(3):419-25. 462. Behre HM, Abshagen K, Oettel M, Hubler D, Nieschlag E. lntramuscular injection oi testosterone undecanoate for the treatment oi male hypogonadism: phase I studies. Eur J Endocrinol. 1999 May;140(5):414-9 Testosterone pellets for men 463.

Handelsman D, Conway A, Boylan L. Suppression oi human spermatogenesis by testosterone implants. J Clin

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Chemana D, Morville R, Fiel J, Villette JM, Tabuteau F, Brerault JL, Passa P. Percutaneous absorption oi 5alpha-dihydrotestosterone in man. 11. Percutaneous administration oi 5 alpha-dihydrotestosterone in hypogonadal men with idiopathic haemochromatosis; clinicai, metabolic and hormonal effectiveness. lnt J

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Kuhn J, Lauda! M, Roca R, Dugue M, Luton J, Bricaire H. Gynecomastia: effect oi prolonged treatment with dihydrotestosterone by the percutaneous route. Presse Med 1983:12:21-5

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De Lignieres B. Transdermal dihydrotestosterone treatment oi 'andropause'. Annals Med. 1993;25:235-41

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lmportance of reducing excessive leveis of estradiol in men 470.

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Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol. 2002 Feb;167(2 Pt 1):624-9 Chearskul S, Charoenlarp K, Thongtang V, Nitiyanant W. Study of plasma hormones and lipids in healthy elderly Thais compared to patients with chronic diseases: diabetes mellitus, essential hypertension andco ronary heart disease. J Med Assoe Thai. 2000 Mar;83(3):266-77 ("Hypertensive men had the highest plasma estradiol levels'}

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Cengiz K, Alvur M, Dindar U. Serum creatine phosphokinase, lactic dehydrogenase, estradiol, progesterone and testosterone leveis in male patients with acute myocardial infarction and unstable angina pectoris. Mater Med Pol. 1991 Jui-Sep;23(3):195-8 ("Serum estradiol/evels in the patient groups were significantly higher

than the contrai group (p < 0.001). There was a positively good correlation between the serum CPK and LDH leveis in acute myocardial infarction and the serum estradiol leveis. .. These results suggest that hyper estrogenemia may be a risk factor for myocardial infarct in middle-aged men. '? ..... and the lmportance of avoiding too low leveis of estradiol in men: risk of osteoporosis 475.

Carlsen CG, Soerensen TH, Eriksen EF. Prevalence of low serum estradiol leveis in male osteoporosis. Osteoporos lnt. 2000;11(8):697-701

Treatment of borderline androgen deficiencies in men 476.

Strawford A, Barbieri T, Neese R, Van Loan M, Christiansen M, Hoh R, Sathyan G, Skowronski R, King J, Hellerstein M. Effects of nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss. J Acquir lmmune Defic Syndr Hum Retrovirol. 1999 Feb 1;20(2):137-46

Use of youthful (young adult) male reference values 477.

Vermeulen A, Kaufman JM. Diagnosis of hypogonadism in lhe aging male. Aging Male. 2002 Sep;5(3):170-6

("In the absence of convincing arguments for altered requirements with age, we consider that the normal range of (free) testosterone leveis in young adults is also valid for elderly'J Testosterone/androgen treatment in men: dosages 478.

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Gooren L. Long-term safety of lhe oral androgen testosterone undecanoate. lnt J Androl. 1986-9-21-6

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Testosterone/androgen treatment in men: interferences- associations 483.

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Wortsman J, Rosner W, Dufau M. Abnormal testicular function in men with primary hypothyroidism. Am J Med. 1987;82:207-12.

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Santen RJ. Male Hypogonadism. In: Yen SSC, Jaffe RB, eds. Reproductive Endocrinology, 3rd ed. Saunders, Philadelphia, 1991, pp. 739-94

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Griffin JE, Wilson JD. Disorders of lhe Testes and Male Reproductive Tract. In: Wilson JD, Foster DW, eds. William's Textbook of Endocrinology, 8th ed. Saunders, Philadelphia, 1992:799-852

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Nieschlag E, Mauss J, Coert A. Kicovic P. Plasma androgen leveis in men after oral administration of testosterone or testosterone undecanoate. Acta Endocrinol (Copenh}. 1975;79:366-74

488.

Ebert T, Jockenhovel F, Morales A, Shabsigh R. The current status of therapy for symptomatic late-onset hypogonadism with transdermal testosterone gel. Eur Urol. 2005 Feb;47(2):137-46

489.

Babar A, Kaachy A, Cutie AJ, Plakogiannis FM. Gas chromatographic method for simultaneous analysis of urinary testosterone, androsterone and etiocholanolone. Determinations after a single dose of testosterone. Pharm Acta Helv. 1988;63(9-10):278-81

777

TOPICS OE DISCUSSION·

TESTOSTERONE TREATMENT ANO TESTICULAR SUPPRESSION Eull recovery of testosterone (endogenous) secretion testosterone-progestogen treatment for contraception 1.

and serum leveis after stopping high dose

Fogh M, Corker CS, Mclean H, Hunter WM, Petersen IB, Philip J, Schou G, Skakkebaek NE. Clinicai trial with levo-norgestrel and testosterone oenanthate for male fertility contrai. Acta Endocrino. (Copenh). 1980 Oct;95(2):251-7

2.

Foegh M, Damgaard-Pedersen F, Gormsen J, Knudsen JB, Schou G. Oral levo-norgestrel - testosterone effects

on

spermatogenesis,

hormone

leveis,

coagulation

factors and

lipoproteins

in

normal

men.

Contraception. 1980Apr;21(4):381-91

Full recovery of testosterone production to youthful (young adult) leveis in old animais after long-term suppression of endogenous testosterone secretion by high doses of exogenous testosterone (Leydig cell aging was prevented by lhe high doses of testosterone treatment) 3.

Chen H, Zirkin BR. Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging. Proc Natl Acad Sei USA. 1999;96(26):14877-81

Up to 14.5 weeks for recovery of normal sperm production after treatment with high doses of testosterone­ progestogen used for contraception (sperm suppression) Ly LP, Liu PY, Handelsman DJ. Rales of suppression and recovery of human sperm output in testosterone-based hormonal contraceptive regimens. Hum Reprod. 2005 Jun;20(6):1733-40

778

TESTOSTERONE TREATMENT ANO PROSTATE CANCER

Old view: ''Testosterone is a cause or favoring factor of prostate cancer''. Deveiopment of prostate cancer: the generation and progression of prostate cancer depends on androgens. Treatment of prostate cancer: should consist of androgen deprivation

=>

The use of androgens is

contraindicated in prostate cancer patients.

Scientific support: poor originated with one study in 1941 on a single patient by Huggins and coworkers- and some in vitro studies

New view: ''Testosterone does not cause, nor favor the development of prostate cancer; adequate testosterone leveis are necessary in men for a good quality of life, a good health and for longevity"

Deveiopment of prostate cancer: nor the generation nor progression of prostate cancer depends on androgens. Testosterone and other andrognes are not adversely associated with prostate cancer. On the contrary studies suggest protective effects of higher serum androgens leveis on tumor progression (evolution to more malignant forms), next to evident quality of life and global health benefits.

Treatment of prostate cancer: should generally not consist of androgen deprivation. Androgen deprivation has => Physicians

no beneficiai effect on survival, but does systematically lower the quality of life and global health

cannot really justify withholding testosterone replacement from symptomatic hypogonadal patients after they have been successful treated for prostate cancer.

Scientific support: large body of evidence supporting the lack of association of testosterone with prostate cancer or the existence of protective effects of testosterone against prostate cancer progression. Extensive research has confirmed the quality of life and health of testosterone supplementation.

Prostate cancer: Epidemiology

Studies that show there is a high incidence of prostate cancer in the general male population (globally not on testosterone treatment) 1.

Frade! Y, Klotz L, Trachtenberg J, Zlotta A. The burden of prostate cancer in Canada. Can Urol Assoe J. 2009 Jun;3(3 8uppl 2):892-81 00. ( 1 in 7 men wi/1 deveiop (a detected) prostate cancer during their iifetime, and

another 1 in 27 wi/1 die because of it) 2.

8akr WA, Grignon DJ, Haas GP, 8chomer KL, Heilbrun LK, Cassin BJ, Powell J, Montie JA, Pontes JE, Crissman JD. Epidemiology of high grade prostatic intraepithelial neoplasia. Pathol Res Pract. 1995 8ep;191(9):838-41. (85% of Afro-Americans and 63% of Caucasians 70 to 79 years have high grade prostatic

intraepitheiia/ neoplasia) 3.

Data from the 8urveillance, Epidemiology, and End Results (8EER) Program 8taff. 8ection 111: lncidence. In: Cancer statistics review 1973-1986. Bethesda, MO: NIH;1989;111.45 (USA statistics)

On the very high incidence of prostate cancer when biopsies are made in men aged 62 or over, even with low serum PSA Meikle AW, 8tanish WM. Familial prostatic cancer risk and low testosterone. J Clin Endocrinol Metab. 1982 4. Jun;54(6):11 04-8 (Among lhe 2950 men (age range, 62 to 91 vears), prostate cancer was diagnosed in 15.2 %; 14.9 % of lhe prostate cancers had a G/eason score of 7 or higher. The prevalence of prostate cancer was 6.6 % among men with a PSA leve/ of up to 0.5 nglml, 10.1 % among those with vaiues of 0.6 to 1.0 nglmi, 17.O % among those with values of 1.1 to 2.O nglmi, 23.9 % among lhose with va/ues of 2.1 to 3.O ng!ml, and 26.9 % among those with values of 3.1 to 4.0 ng/ml. The prevalence of high-grade cancers increased from 12.5 % of cancers associated with a PSA levei of 0.5 ng/ml, or less to 25.0 % of cancers associated with a PSA levei of 3.1 to 4.0 nglml. Conclusions: biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA leveis of 4.0 ng per milliliter or iess - leveis generally thought to be in lhe normal range.)

779

On the real incidence of prostate cancer: much higher prevalence rate of prostate cancer are found at post­ mortem (autopsy) 5.

Soos G, Tsakiris I, Szanto J, Turzo C, Haas PG, Dezso B. The prevalence of prostate carcinoma and its precursor in Hungary: an autopsy study. Eur Urol. 2005 Nov;48(5):739-44 ("8oth prostate cancer and high

grade intraepithefial neoplasia are first detected in the 3rd decade ... in 81 to 95 year-old men 86.6% and 60% had prostate cancer and high grade interepithelil neoplasia'j 6.

Yin M, Bastacky S, Chandran U, Becich MJ, Dhir R. Prevalence of incidental prostate cancer in lhe general population: a study of healthy organ donors. J Urol. 2008 Mar;179(3):892-5; discussion 895. ("Prostate cancer

escalated from the 5th decade with a 1 in 3 chance of carrying incidental cancer in the 60 to 69-year-o/d age 7.

group and with 46% of 70 to 81-year-o/d men harboring prostate cancer'j Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of carcinoma and intraepithelial neoplasia of lhe prostate in young male patients. J Urol. 1993 Aug;150{2 Pt 1):379-85 ("Prostatic intraepithefial neoplasia and histological cancers are surprisingly common in young ma/e patients of both races. Prostatic intraepithefial neoplasia was identified in 0%, 9%, 20 and 44%, and sma/1 toei of histological cancer in 0%, 0%, 27% and 34% of the ma/e patients in the second, third, fourth and fifth decades of age, respectively'j

8.

Stemmermann GN, Nomura AM, Chyou PH, Yatani R. A prospective comparison of prostate cancer at autopsy and as a clinicai event: lhe Hawaii Japanese experience. Cancer Epidemia! Biomarkers Prev. 1992 Mar-Apr;1(3):189-93 ("3.6% of men in fite were diaqnosed with prostate cancer, whereas 27% of autopsied

9.

1O.

Hawaii Japanese men who died after 50 vears of age had prostate cancer, reaching a frequency of 63% among men over 80 years of age. The volume of 48(60%) of these cancers was less than 150 mm3. These sma/1 tumors would probablynot have been discovered in a screening program. Tumors Iarger than 1000 mm3 wou/d probably be discovered using modem diagnostic procedures but were found in only 13 (4.4%) of the autopsied men) Oishi K, Yoshida O, Schroeder FH. The geography of prostate cancer and its treatment in Japan. Cancer Surv. 1995;23:267-80 ('The vast majority of cases of prostate cancer remain undetected during fite, the prevalence of prostate cancer detected at autopsy being 2800 times that of lethal cancer in Japanese in Japan, 570 times in whites in the USA and 470 times in blacks in the USA. A case-contrai study of prostate cancer carried out in Japan and the Netherlands revealed a number of statistically significant risk factors, including ... no morning erections, , episodes of sexually transmitted disease, lower plasma testosterone and dihydrotestosterone concentrations.'? Sanchez-Chapado M, Olmedilla G, Cabeza M, Dona! E, Ruiz A. Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study. Prostate. 2003

Feb

15;54{3):238-47('The prevalence of prostate cancer (CaP) is 3.58, 8.82, 14.28, 23.80, 31.7, and 33.33% in

11. 12. 13.

the 3rd, 4th, 5th, 6th, 7th, and Efh decades, respectively. The rates of high-grade prostatic intraepithefa i l neoplasia (HGPIN) were 7.14, 11.75, 35.71, 38.06, 45.40, and 48.15% at the 3rd, 4th, 5th, and 8th decades of fite ... .in 21/27 cases (77.7%), an association between CaP and HGPIN was found. The prevalence of both Iesions in Caucasian Mediterranean males is significantly Iower than in Caucasian American and Afro­ American males in ali the age groups evaluated.'? Rich AR. J Urol. 1935: 33: 215-33 Baron E et ai. Arch Path. 1941,32:787-93 Dixon RJ et ai. Atlas of Tumor Pathology. 1952, p.197

Prostate cancer patients have a low risk of dying from cancer 14.

Stemmermann GN, Nomura AM, Chyou PH, Yatani R. A prospective comparison of prostate cancer at autopsy and as a clinicai event: lhe Hawaii Japanese experience. Cancer Epidemiol Biomarkers Prev. 1992 Mar-Apr;1{3):189-93. ("Prostate cancer was diagnosed in fite among 274 of 8006 (3.6%) members of a cohort

15.

of Japanese men in Hawaii between 1965 and 1990. Only 55 (20%) of the 274 diagnosed cases died with prostate cancer, and they accounted for only 2% of the 2893 deaths that occurred among the men during this period.') Quinn M. Cancer Trends in lhe USA - A View From Europe. J Nat Cancer lnst. 2003;95{17):1258-61

Prostate cancer, especially non-metastasized is rarely a cause of death in men Oishi K, Yoshida O, Schroeder FH. The geography of prostate cancer and its treatment in Japan. Cancer

16.

Surv. 1995;23:267-80 17.

Oefelein MG, Ricchiuti VS, Conrad PW, Goldman H, Bodner O, Resnick Ml, Seftel A. Clinicai predictors of androgen-independent prostate cancer and survival in lhe prostate-specific antigen era. Urology. 2002 Jul;60(1):120-4

780

Side effects of testosterone/androgen deprivation therapy of prostate cancer Androgen deprivation therapy may severely impair the qua/ity of /ife 18. Daca! K, Sereika SM, Greenspan SL. Quality of life in prostate cancer patients taking androgen deprivation

19.

therapy. J Am Geriatr Soe. 2006 Jan;54(1):85-90 ("Participants receiving androgen deprivation therapy (AOT) reported significantly poorer quality of fite in the areas of physical tunction (P<.001}, general health (P<.001), and physical health component summary (P<.001) than men not receiving ADT; Atter controlling for comorbidity, total testosterone levei rather than ADT accounted for a sma/1 yet statistically significant percentage of the total variance ot the physical health ..'? Chen AC, Petrylak DP. Complications of androgen-deprivation therapy in men with prostate cancer. Curr Urol Rep. 2005 May;6(3):210-6 ("Androgen-deprivation therapy (ADT) is indicated for the treatment of metastatic prostate cancer and /ocal/y advanced disease. In addition to sexual side effects, long-term ADT results in severa! other changes, including hot flashes; gynecomastia; changes in body composition, metabolism, and the cardiovascu/ar system; osteoporosis; anemia; psychiatric and cognitive problems; and fatigue and diminished quality of fite'?

Androgen deprivation causes anemia 20. Choo R, Chander S, Danjoux C, Morton G, Pearce A, Deboer G, Szumacher E, Loblaw A, Cheung P, Woo T. How are hemoglobin leveis affected by androgen deprivation in non-metastatic prostate cancer patients? Can J Urol. 2005 Feb;12(1):2547-52 (''The decline and recovery of hemoglobine testosterone.'?

was closely related to that of

Androgen deprivation causes impotence 21. Basaria S, Lieb J 2nd, Tang AM, DeWeese T, Carducci M, Eisenberger M, Dobs AS. Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol (Oxf). 2002 Jun;56(6):779-86 22. Potosky AL, Knopf K, Clegg LX, Albertsen PC, Stanford JL, Hamilton AS, Gilliland FD, Eley JW, Stephenson RA, Hoffman RM. Quality-of-life outcomes after primary androgen deprivation therapy: results from the prostate cancer outcomes study. J Clin Oncol. 2001 Sep 1;19(17):3750-7 23. Fowler FJ, McNaughton Collins M, Walker Corkery E, Elliott DB, Barry MJ. The impact of androgen deprivation on quality of life after radical prostatectomy for prostate carcinoma. Cancer. 2002 Jul15;95(2):287-95 Androgen deprivation therapy may cause urinary incontinence 24. Miller NL, Bissonette EA, Bahnson R, Wilson J, Theodorescu D. lmpact of a novel neoadjuvant and adjuvant hormone-deprivation approach on quality of life, voiding function, and sexual function after prostate brachy1herapy. Cancer. 2003 Mar 1 ;97(5):1203-1O Androgen deprivation therapy generates a greater rate of bone loss in men with prostate cancer 25. Preston DM, Torrens Jl, Harding P, Howard RS, Duncan WE, McLeod DG. Androgen deprivation in men with prostate cancer is associated with an increased rale of bone loss. Prostate Cancer Prostatic Ois. 2002;5(4):304-10 Testosterone deprivation therapy increases arterial stiffness in men with prostate cancer 26. Dockery F, Bulpitt CJ, Agarwal S, Rajkumar C. Testosterone suppression in men with prostate cancer is associated with increased arterial stiffness. Aging Male. 2002 Dec;5(4):216-22 Dihydrotestosterone deprivation therapy increases the risk of aggressive prostate cancer 27. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on lhe development of prostate cancer. N Engl J Med. 2003 Jul 17;349(3):215-24

Arguments against population-based PSA screening for prostate cancer and against treatment of prostate cancer 1. 2. 3.

4. 5.

28.

High prevalence rales of prostate cancer at postmortem lncreasing biopsy rales leads to overdiagnosis and overtreatment Despite widespread use of such tests in lhe USA, and apparent incidence rales of detected prostate cancer almost 3 times higher than in the U.K., the mortality in lhe USA has for many years been almost lhe same as in lhe U.K. and other European countries 1/3 of screen-detected cases are incurable No clear benefit of treatment

6.

Side effects of prostatectomy include impotence in a large proportion of cases and incontinence in a smaller proportion

7. 8. 9.

Screening and follow-up of treatment (much of which may be unnecessary) is expensive (high costs) Few years of life to gain in many elderly patients No consequent reduction in mortality has yet been demonstrated in a randomized controlled trial

Quinn M. Cancer Trends in lhe USA-A View From Europe. J Nat Cancer lnst. 2003; 95 (17): 1258-61

781

Reasons why the old concept on testosterone treatment and prostate cancer still predominates in the mind of many physicians: OLD THEORY: The concept that testosterone feeds a prostate cancer tumor "arose Irem the work oi Huggins and coworkers, who in 1941 demonstrated dramatic responses to castration among men with advanced prostate cancer. These authors and others also reported a rapid clinicai progression with testosterone administration." CRITICAL OBSERVATIONS: the theory "originated with observations in a special population (castrated men) that is not particularly relevant to testosterone therapy in hypogonadal men" .... Fowler and Whitmore showed in 1981 "that the adverse effect oi testosterone treatment did not occur unless men had been previously castrated" ... "More recent studies have failed to provide clinicai evidence supporting the belief that higher testosterone represents a risk for prostate cancer''. FACTORS CONTRIBUTING TO THE PERSISTENCE OF THE 'testosterone is a cause or favoring factor oi prostate cancer' THEORY include dramatic effects oi castration continued use oi androgen deprivation for treatment oi prostate cancer an influential spokesperson (Huggins) group think (failure to acknowledge evidence inconsistent with the prevalent ideology) an imprecise formulation oi the model ("more T, more cancer growth"), making refutation difficult. 29.

Morgentaler A. Guilt by association: a historical perspective on Huggins, testosterone therapy, and prostate cancer. J Sex Med. 2008 Aug;5(8):1834-40.

ARGUMENTS PRO TESTOSTERONE THERAPIES

HUMAN STUDIES: Recent review and meta-analysis studies that state that Serum androgen leveis, within a broad range, are not associated with prostate cancer risk. at time oi prostate cancer diagnosis, low rather than high serum testosterone leveis have been found to be associated with advanced or high-grade disease. The available evidence indicates that testosterone therapy neither increases the risk oi prostate cancer diagnosis nor affects the progression oi prostate cancer , nor the prostate cancer recurrence in men who have undergone delinitive treatment without residual disease; 30.

lsbarn H, Pinthus JH, Marks LS, Montorsi F, Morales A, Morgentaler A, Schulman C. Testosterone and prostate cancer: revisiting old paradigms. Eur Urol. 2009 Jul;56(1):48-56 (the current European Association of Urology guidelines state that in hypogonadal men who were successfully treated for prostate cancer, testosterone treatment can be considered after a prudent interval)

31.

Rinnab L, Gust K, Hautmann RE, Küfer R. [Testosterone replacement therapy and prostate cancer. The current position 67 years after the Huggins myth] Urologe A. 2009 May;48(5):516-22 (physicians cannot really justify withholding TRT from symptomatic patients after they have been successful treated for prostate cancer)

32.

Morgentaler A, Schulman C. Testosterone and prostate safety. Front Horm Res. 2009;37:197-203 (the

33.

Morgentaler A. Testosterone therapy in men with prostate cancer: scientific and ethical considerations. J Urol.

available evidence strongly suggests that testosterone therapy is safe for the prostate) 2009 Mar;181 (3):972-9 (the safety of testosterone therapy in men with prostate cancer, the limited avai/able evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression) 34.

Shabsigh R, Crawford ED, Nehra A, Slawin KM. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. lnt J lmpot Res. 2009 Jan-Feb;21 (1):9-23 (Of studies that met inclusion criteria, nane demonstrated that testosterone therapy for hypogonadism increased prostate cancer risk or increased Gleason grade of cancer detected in treated vs untreated men)

35.

Morgentaler A. Guilt by association: a historical perspective on Huggins, testosterone therapy, and prostate cancer. J Sex Med. 2008 Aug;5(8):1834-40

36.

Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin North Am. 2007 Nov;34(4):555-63, vii

782

37.

Raynaud JP. Prostate cancer risk in testosterone-treated men. J Steroid Biochem Moi Biol. 2006 Dec;102(15):261-6 (During the clinicai development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed)

38.

Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol. 2006 Sep;7(5):363-9 ('the cancer rate in TRT trials is only approximately 1%, similar to detection rates

39.

in screening programs .. little reason to withhold testosterone rep/acement therapy from men with favorable outcomes after definitive treatment for prostate cancer') Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modem myth. Eur Urol. 2006 Nov;50(5):935-9 ("there is not now-nor has there ever been-a scientific basis for the belief that testosterone causes prostate cancer to grow')

40.

Dobs AS, Morgentaler A. Does testosterone therapy increase the risk of prostate cancer? Endocr Pract. 2008 Oct;14(7):904-11 ("No evidence of an associated relationship between exogenous testosterone therapy and

prostate cancer has emerged from clinicai trials or adverse event report')

Studies where LOW testosterone leveis appears to increase the risk of prostate cancer lhe urinary free testosterone decreases with aging, while the incidence of prostate cancer increases 41. Morer-Fargas F, Nowakowski H. Die Testosteronausscheidung im Harn bei Mánnlichen lndivuen. Acta Endocrinol. 1965; 49: 443-52 42. Data from the Surveillance, Epidemiology, and End Results (SEER) Program Staff. Section 111: lncidence. In: Cancer statistics review 1973-1986. Bethesda, MD: NIH;1989;111.45 Low serum testosterone is associated with an increased prostate cancer risk Stattin P, Lumme S, Tenkanen L, Alfthan H, Jellum E, Hallmans G, Thoresen S, Hakulinen T, Luostarinen T, Lehtinen M, Dillner J, Stenman UH, Hakama M. High leveis of circulating testosterone are not associated with

43.

increased prostate cancer risk: a pooled prospective study. lnt J Cancer. 2004 Jan 20;108(3):418-24 44.

Chen C, Weiss NS, Stanczyk FZ, Lewis SK, DiTommaso D, Etzioni R, Barnett MJ, Goodman GE. Endogenous sex hormones & prostate cancer risk: a case-contrai study nested within the Carotene and Retino! Efficacy Trial. Cancer Epidemiol Biomarkers Prev. 2003;12(12):1410-6

45.

Morgentaler A, Bruning CO 3rd, DeWolf WC. Occult prostate cancer in men with low serum testosterone leveis. JAMA. 1996 Dec 18;276(23):1904-6. (digital rectal examination and PSA leveis are insensitive

indicators of prostate cancer in men with low total or free testosterone leveis) Low serum testosterone leveis have been found in prostate cancer patients Morote J, Planas J, Ramirez C, Gómez E, Raventós CX, Placer J, Catalán R, de Torres IM. Evaluation of lhe serum testosterone to prostate-specific antigen ratio as a predictor of prostate cancer risk. BJU lnt. 2010 Feb 1;105(4):481-4 47. Mearini L, Costantini E, Zucchi A, Mearini E, Bini V, Cottini E, Porena M. Testosterone leveis in benign prostatic hypertrophy and prostate cancer. Urol lnt. 2008;80(2):134-40 48. Karamanolakis D, Lambou T, Bogdanos J, Milathianakis C, Sourla A, Lembessis P, Halapas A, Pissimissis N, Dessypris N, Petridou ET, Koutsilieris M. Serum testosterone: A potentially adjunct screening test for the assessment of the risk of prostate cancer among men with modestly elevated PSA values (> or =3.0 and <10.0 ng/ml). Anticancer Res. 2006 Jui-Aug;26(4B):3159-66. 49. Rivera P, Tagle R, Mir S, González R. Relationship between serum testosterone leveis and prostatic cancer. Actas Urol Esp. 2003 Nov-Dec;27(10):788-92. 50. Zhonghua Yi Xue Za Zhi 1993; 73: 489-90 (mentioned in The natural prostate cure - Proger Mason 2000 ISBN 1-884820-61-1) 51. Kumar VL, Wadhwa SN, Kumar V, Farooq A. Androgen, estrogen, and progesterone receptor contents and serum hormone profiles in patients with benign hypertrophy and carcinoma of the prostate. J Surg Oncol. 1990 Jun;44(2):122-8 46.

52.

Revista Experimental Fisiology 1991; 47: 161-6 (mentioned in The natural prostate cure (Proger Mason 2000

53.

Revista Experimental Fisiology 1990; 46:63-8 (mentioned in The natural prostate cure (Proger Mason 2000

54.

Rannikko S, Adlercreutz H. Plasma estradiol, free testosterone, sex hormone binding globulin binding

ISBN 1-884820-61-1)) ISBN 1-884820-61-1) capacity, and prolactin in benign prostatic hyperplasia and prostatic cancer. Prostate. 1983;4(3):223-9 55.

Meikle AW, Stanish WM. Familial prostatic cancer risk and low testosterone. J Clin Endocrinol Metab 1982 Jun;54(6):1104-8

56.

Zumoff B, Levin J, Strain GW, Rosenfeld RS, O'Connor J, Freed SZ, Kream J, Whitmore WS, Fukushima DK, Hellman L. Abnormal leveis of plasma hormones in men with prostate cancer: evidence toward a "two­ disease" theory. Prostate. 1982;3(6):579-88 (Low testosterone in prostate cancer patients less than 65 years)

783

57.

Vestsi Akademii Medicina Navuk USSR 1980; 3: 72-7

(mentioned in The natural prostate cure (Proger Mason

2000 ISBN 1-884820-61-1)0 58. 59.

Turkes AO, Turkes A, Read GF, Fahmy DR. A sensitive fluorometric enzyme immunoassay for testosterone in plasma and saliva [proceedings] J Endocrinol. 1979 Oct;83(1 ):31P Progress in Clinicai Biological Research 1975; 6: 143-58 (mentioned in The natural prostate cure - Proger

Mason 2000 ISBN 1-884820-61-1)) Close to statistical significance lower testosterone leveis in prostate cancer patients 60. Hulka BS, Hammond JE, DiFerdinando G, Mickey DD, Fried FA, Checkoway H, Stumpf WE, Beckman WC Jr,

61.

62.

Clark TD. Serum hormone leveis among patients with prostatic carcinoma or benign prostatic hyperplasia and clinic controls. Prostate. 1987;11(2):171-82 Gustafsson O, Norming U, Gustafsson S, Eneroth P, Astrom G, Nyman CR. Dihydrotestosterone and testosterone leveis in men screened for prostate cancer:a study of a randomized population. Br J Urol. 1996 Mar;77(3):433-40 Nomura A, Heilbrun LK, Stemmermann GN, Judd HL. Prediagnostic serum hormones and the risk of prostate cancer. Cancer Res. 1988 Jun 15;48(12):3515-7

Low testosterone leveis are found in prostate cancer patients and in their (not yet affected) relatives with familial predisposition to prostate cancer 63. Meikle AW, Stanish WM. Familial prostatic cancer risk and low testosterone. J Clin Endocrinol Metab. 1982 Jun;54(6):1104-8 A high serum SHBG (and thus less bioavailable testosterone) is found in men with family history of prostate cancer 64.

Wu AH, Whittemore AS, Kolonel LN, John EM, Gallagher RP, West DW, Hankin J, Teh CZ, Dreon DM, Paffenbarger RS Jr. Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. Cancer Epidemiol Biomarkers Prev. 1995 Oct-Nov;4(7):735-41

A high incidence of prostate cancer is found in patients with low testosterone and normal digital rectal examination and normal PSA (:s: 4 ng!ml) 65. Morgentaler A, Bruning CO 3rd, DeWolf WC. Occult prostate cancer in men with low serum testosterone leveis. JAMA. 1996 Dec 18;276(23):1904-6. Low serum leveis of total and bio-available testosterone are found in populations with a higher risk of prostate cancer (such as African-Americans and whites) 66. Wu AH, Whittemore AS, Kolonel LN, John EM, Gallagher RP, West DW, Hankin J, Teh CZ, Dreon DM, Paffenbarger RS Jr. Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. Cancer Epidemiol Biomarkers Prev. 1995 Oct-Nov;4(7):735-41

(Asian-Americans had higher total and bioavailable testosterone compared to African-Americans and whites)

Studies where a low serum dihydrotestosterone (DHT) was found in prostate cancer patients 67. Zumoff B, Levin J, Strain GW, Rosenfeld RS, O'Connor J, Freed SZ, Kream J, Whitmore WS, Fukushima DK, Hellman L. Abnormal leveis of plasma hormones in men with prostate cancer: evidence toward a "two­ disease" theory. Prostate. 1982;3(6):579-88 (Low in prostate cancer patients less than 65 years) 68.

Signorello LB, Tzonou A, Mantzoros CS, Lipworth L, Lagiou P, Hsieh C, Stampfer M, Trichopoulos D. Serum steroids in relation to prostate cancer risk in a case-control study (Greece). Cancer Causes Control. 1997 Jul;8(4):632-6

A study where DHT is inversely, significantly, and strongly associated with the risk of prostate cancer 69. Signorello LB, Tzonou A, Mantzoros CS, Lipworth L, Lagiou P, Hsieh C, Stampfer M, Trichopoulos D. Serum steroids in relation to prostate cancer risk in a case-control study (Greece). Cancer Causes Control. 1997 Jul;8(4):632-6 Studies where close to statistical significance lower DHT leveis were found in prostate cancer patients 70. Gustafsson O, Norming U, Gustafsson S, Eneroth P, Astrom G, Nyman CR. Dihydrotestosterone and testosterone leveis in men screened for prostate cancer:a study of a randomized population. Br J Urol. 1996 Mar;77(3):433-40 71. Nomura A, Heilbrun LK, Stemmermann GN, Judd HL. Prediagnostic serum hormones and the risk of prostate cancer. Cancer Res. 1988 Jun 15;48(12):3515-7

784

A low serum levei of androstanediol glucuronide, the major androgen metabolite, increases the risk of prostate cancer 72.

Mohr BA, Feldman HA, Kalish LA, Longcope C, McKinlay JB. Are serum hormones associated with lhe risk of prostate

cancer?

Prospective

results

from

lhe

Massachusetts

Male

Aging

Study.

Urology.

2001

May;57(5):930-5.

High grade prostate cancers are associated with low testosterone leveis, suggesting that higher testosterone leveis may protect against progression of prostate cancer to more aggressive forms (higher Gleason score &for locallyinvasive &for metastatic 73.

Kwon T, Jeong IG, Vou D, Park MC, Hong JH, Ahn H, Kim CS. Effect of prostate size on pathological outcome and biochemical recurrence after radical prostatectomy for prostate cancer: is it correlated with serum testosterone levei? BJU lnt. 2010 Jan 8. [Epub ahead of print] (Jow serum testosterone ís assocíated wíth

greater prostate malígnancy, but not wíth an íncreased rísk of prostate cancer recurrence) 74.

Lane BR, Stephenson AJ, Magi-Galluzzi C, Lakin MM, Klein EA. Low testosterone and risk of biochemical recurrence and poorly differentiated prostate cancer at radical prostatectomy. Urology. 2008 Dec;72(6):12405.

75.

lmamoto T, Suzuki H, Yano M, Kawamura K, Kamiya N, Araki K, Komiya A, Naya Y, Shiraishi T, lchikawa T. Does presence of prostate cancer affect serum testosterone leveis in clinically localized prostate cancer patients? Prostate Cancer Prostatic Ois. 2009;12(1):78-82

76.

Lackner JE, Maerk I, Koller A, Bieglmayer C, Marberger M, Kratzik C, Schatzl G. Serum inhibin--not a cause ot low testosterone leveis in hypogonadal prostate cancer? Urology. 2008 Nov;72(5):1121-4

77.

Mearini L, Costantini E, Zucchi A, Mearini E, Bini V, Cottini E, Porena M. Testosterone leveis in benign prostatic hypertrophy and prostate cancer. Urol lnt. 2008;80(2):134-40

78.

Sekine Y, lto K, Yamamoto T, Nakazato H, Shibata Y, Hatori M, Suzuki K. Pretreatment total testosterone leveis in patients with prostate cancer in the past two decades in Japan. Cancer Detect Prev. 2007;31(2):14953

79.

Yano M, lmamoto T, Suzuki H, Fukasawa S, Kojima S, Komiya A, Naya Y, lchikawa T. The clinicai potential of pretreatment serum testosterone levei to improve the efficiency of prostate cancer screening. Eur Urol. 2007 Feb;51(2):375-80.

80. 81.

(ambívalent study see comment below in sectíon 'Arguments contra testosterone

therapíesj San Francisco I F, Regan MM, Dewolf WC, Olumi AF. Low age adjusted free testosterone leveis correlate with poorly differentiated prostate cancer. J Urol. 2006 Apr;175(4):1341-5 Teloken C, Da Ros CT, Caraver F, Weber FA, Cavalheiro AP, Grazioltin TM.(editorial note A Boh/e). Low serum testosterone leveis are associated with positive surgical margins in radical retropubic prostatectomy: hypogonadism represents bad prognosis in prostate cancer. lnt Braz J Urol. 2005 Nov-Dec;31 (6):609

82.

Teloken C, Da Ros CT, Caraver F, Weber FA, Cavalheiro AP, Graziottin TM. Low serum testosterone leveis are associated with positive surgical margins in radical retropubic prostatectomy: hypogonadism represents bad prognosis in prostate cancer. J Urol. 2005 Dec;174(6):2178-80

83.

lsom-Batz G, Bianco FJ Jr, Kattan MW, Mulhall JP, Lilja H, Eastham JA. Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol. 2005 Jun;173(6):1935-7

84.

lmamoto T, Suzuki H, Fukasawa S, Shimbo M, lnahara M, Komiya A, Ueda T, Shiraishi T, lchikawa T. Pretreatment serum testosterone levei as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol. 2005 Mar;47(3):308-12

85.

Schatzl G, Madersbacher S, Haitel A, Gsur A, Preyer M, Haidinger G, Gassner C, Ochsner M, Marberger M. Associations of serum testosterone with microvessel density, androgen receptor density and androgen receptor gene polymorphism in prostate cancer. J Urol. 2003 Apr;169(4):1312-5

86.

Schatzl G, Madersbacher S, Thurridl T, Waldmüller J, Kramer G, Haitel A, Marberger M. High-grade prostate

87.

Hoffman MA, DeWolf WC, Morgentaler A. ls low serum tree testosterone a marker for high grade prostate

88.

Haapiainen R, Rannikko S, Alfthan O, Adlercreutz H. Pretreatment plasma leveis of testosterone and sex

cancer is associated with low serum testosterone leveis. Prostate. 2001 Apr;47(1):52-8. cancer? J Urol. 2000 Mar;163(3):824-7 hormone binding globulin binding capacity in relation to clinicai staging and survival in prostatic cancer patients. Prostate. 1988;12(4):325-32 Gene polymorphisms with increased risk of high grade prostate cancer are associated with low testosterone leveis 89.

Schatzl G, Marberger M, Remzi M, Grosser P, Unterlechner J, Haidinger G, Zidek T, Preyer M, Micksche M, Gsur A. Polymorphism in ARE-I region of prostate-specific antigen gene associated with low serum testosterone levei and high-grade prostate cancer. Urology. 2005 Jun;65(6):1141-5

785

Metastatic prostate cancer (PC) is associated with a low serum testosterone compared to localized PC 90.

lmamoto T, Suzuki H, Fukasawa S, Shimbo M, lnahara M, Komiya A, Ueda T, Shiraishi T, lchikawa T. Pretreatment serum testosterone levei as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol. 2005 Mar;47(3):308-12

A study that shows that the response to prostate cancer therapy is better in prostate cancer patients with higher serum testosterone, while a low serum testosterone levei in these patients predicts a worse response to androgen withdrawal therapy (progression to androgen-independent prostate cancer) 91. Furuya Y, Nozaki T, Nagakawa O, Fuse H. Low serum testosterone levei predicts worse response to endocrine therapy in Japanese patients with metastatic prostate cancer. Endocr J. 2002 Feb;49(1):85-90 92.

lmamoto T, Suzuki H, Akakura K, Komiya A, Nakamachi H, lchikawa T, lgarashi T, lto H. Pretreatment serum levei of testosterone as a prognostic factor in Japanese men with hormonally treated stage D2 prostate cancer. Endocr J. 2001 Oct;48(5):573-8

Much lower prostate levei of dihydrotestosterone in the prostate tissue of prostate cancer patients than in noncancerous patients 93. Titus MA, Schell MJ, Lih FB, Temer KB, Mohler JL. Testosterone and dihydrotestosterone tissue leveis in recurrent prostate cancer. Clin Cancer Res. 2005 Jul 1;11(13):4653-7. (11-fo/d /ower DHT leve/ in the prostate tissue of prostate cancer patients than in noncancerous patients)

Lower prostate tissue leveis of DHT (but similar leveis of testosterone) are found in men with recurrent prostate cancer compared to men with benign prostate hypertrophy Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS. The androgen 94. axis in recurrent prostate cancer. Clin Cancer Res. 2004 Jan 15;10(2):440-8 Low testosterone leveis are associated with increased prostate cancer mortality in prostate cancer patients 95.

Ribeiro M, Ruff P, Falkson G. Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer. Am J Clin Oncol 1997 Dec;20(6):605-8

96.

lversen P, Rasmussen F, Christensen IJ. Serum testosterone as a prognostic factor in patients with advanced prostatic carcinoma. Scand J Urol Nephrol Suppl. 1994; 157: 41-7

97.

Haapiainen R, Rannikko S, Alfthan O, Adlercreutz H. Pretreatment plasma leveis of testosterone and sex hormone binding globulin binding capacity in relation to clinicai staging and survival in prostatic cancer patients. Prostate. 1988;12(4):325-32

98.

Ribeiro M, Ruff P, Falkson G. Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer. Am J Clin Oncol. 1997 Dec;20(6):605-8

Low testosterone leveis are associated with increased overall mortality in prostate cancer patients Taira AV, Merrick GS, Galbreath RW, Butler WM, Wallner KE, Allen ZA, Lief JH, Adamovich E. Pretreatment serum testosterone and androgen deprivation: effect on disease recurrence and overall survival in prostate cancer patients treated with brachytherapy. lnt J Radial Oncol Biol Phys. 2009 Jul 15;74(4):1143-9. (Prostate cancer patients with baseline low testosterone who a/so were treated with androgen deprivation therapy had a trend toward decreased overa/1 survival)

99.

Studies that show that prostate cancer patients who recover normal testosterone leveis after androgen deprivation therapy have less morbidity, less biochemical progression amllor a better survival rate than PC men whose testosterone remain low after therapy (by remaining on androgen deprivation or no recovering their testosterone leveis after stop of androgen deprivation) 100.

Leibowitz RL, Dorff TB, Tucker S, Symanowski J, Vogelzang NJ. Testosterone replacement in prostate cancer survivors with hypogonadal symptoms. 6. BJU lnt. 2009 Nov 5. [Epub ahead of print]

101.

Conti PD, Atallah AN, Arruda H, Soares BG, El Dib RP, Wilt TJ. lntermittent versus continuous androgen suppression for prostatic cancer. Cochrane Database Syst Rev. 2007 Oct 17;(4):

A study where low testosterone leveis are found in men with benign prostate hypertrophy 102.

Ortega E,

Ruiz E, Mendoza MC, Martin-Andres A, Osorio C. Plasma steroid and protein hormone

concentrations in patients with benign prostatic hypertrophy and in normal men. Experientia. 1979 Jun 15;35(6):844-5

A study where a low androstanediol glucuronide levei was found in patients with benign prostate hypertrophy 103.

Wright F, Poizat, Bongini M,Bozzolan

F Doukani A,

Mauvais-Jarvis P.

Decreased urinary 5-alpha­

androstanediol glucuronide excretion in patients with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1985; 60 (2) 294-8

786

Men with chronic prostatitis have often low testosterone 104. Yunda IF, lmshinetskaya LP. Testosterone excretion in chronic prostatis. Andrologia. 1977 Jan-Mar;9(1}:89-94 ( In 73. 1% o f patients considerable reduction of testosterone excretion was revealed. Reduction of testicular endocrine function is in direct corre/ative dependence on severity of clinicai symptoms, duration of disease and form of chronic prostatis. '?

A history of prostatitis is positively associated with a history of benign prostatic hyperplasia and cancer 105. Daniels NA, Ewing SK, Zmuda JM, Wilt T J, Bauer DC; Osteoporotic Fractures in Men (MrOS) Research Group. Correlates and prevalence of prostatitis in a large community-based cohort of older men. Urology. 2005 Nov;66(5}:964-70 ("We found positive associations for a history of prostatitis with a history of benign prostatic hyperplasia (odds ratio 8.0, 95% confidence inteNal 6.8 to 9.5) and a history of prostate cancer (odds ratio 5.4, 95% C/: 4.4 to 6.6)'?

A study where testosterone treatment at high doses prevented the prostate stromal proliferation that estradiol may induce in the presence of physiological concentrations of testosterone 106. Feyei-Cabanes T, Secchi J, Robel P, Baulieu EE. Combined effects of testosterone and estradiol on rat ventral prostate in organ culture. Cancer Res. 1978 Nov;38(11 Pt 2):4126-34. 107. Feyei-Cabanes T, Robel P, Baulieu EE. Combined effects of testosterone and estradiol on the ventral lobe of the rat postate in organ culture. C R Acad Sei Hebd Seances Acad Sei D. 1977 Oct 31;285(11):1119-22 Studies where testosterone treatment appears to protect against prostate cancer Studies where testosterone/androgen treatment of patients with advanced prostate cancer increased their survival time and quality of life 108. Morales A, Connolly JG, Bruce AW. Androgen therapy in advanced carcinoma of the prostate. Can Med Assoe J. 1971;105(1):71-2 109. Prout GR Jr, Brewer WR. Response of men with advanced prostatic carcinoma to exogenous administration of testosterone. Cancer. 1967 Nov;20(11):1871-8 Studies where testosterone/androgen treatment inhibits the proliferation of human prostate cancer cells or induces their apoptosis in vitro 11O. Joly-Pharaboz MO, Soave MC, Nicolas B, Mebarki F, Renaud M, Foury O, Morei Y, Andre JG. Androgens inhibit the proliferation of a variant of the human prostate cancer cell line LNCaP. J Steroid Biochem Moi Biol 1995 Oct;55(1):67-76 111. Wolf DA, Schulz P, Fittler F. Synthetic androgens suppress the transformed phenotype in human prostate carcinoma cell line LNCaP. Br J Cancer. 1991 Jul; 64 (1): 47-53 112. Andrews P, Krygier S, Djakiew O. Dihydrotestosterone (DHT) modulates the ability of NSAIDs to induce apoptosis of prostate cancer cells. Cancer Chemother Pharmacol. 2002 Mar;49(3):179-86 Studies where testosterone treatment reduces prostate dysfunction complaints (dysuria, nocturia) 113. Flamm J, Kiesswetter H, Englisch M. An urodynamic study of patients with benign prostatic hypertrophy treated conservatively with phytotherapy or testosterone. Wien Klin Wochenschr 1979 Sep 28;91 (18):622-7 114. Kearns WM. Testosterone in the treatment of testicular deficiency and prostatic enlargement. Wisconsin Med J. 1941; 40:927 (testosterone proprionate therapy did not reduce lhe size of lhe prostate, but reduced lhe 115. 116.

dysuria) Meltzer M. Male hormone therapy of prostatic hypertrophy. Lance!. 1939; 59: 279 Trasoff A. The treatment of benign prostatic hypertrophy with testosterone propionate. J Lab Clin Med. 1940;

119.

25: 377 Markham MJ. The clinicai use of peroral methyltestosterone in benign prostatic hypertrophy. Urol Cutan Rev. 1942; 46: 225 Markham MJ. The clinicai use of testosterone propionate in benign prostatic hypertrophy. Urol Cutan Rev. 1941; 45: 35 Laqueur E. Behandlung der Prostathypertropie mit mãnnlichen Hormone (Hombreol) une experimentei!

120.

Begründung dieser Therapie. Schweiz Med Wochenschr. 1934; 64: 1116 South Med J, 1939, 32: 154

117. 118.

Study where testosterone treatment reduces prostate stromal hyperplasia and prostatic complaints (prostatism) 121. South Med J, 1939, 32: 154 Studies where dihydrotestosterone treatment reduced the prostate volume (-15 to -20% after 1 year treatment) 122. de Lignieres B. Transdermal dihydrotestosterone treatment of 'andropause. Ann Med 1993 Jun;25(3):235-41

787

123.

Swerdloff RS, Wang C. Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen

124.

Sitruk-Ware R. Contraception, 1989, 39: 1-191

replacement therapeutic agent. Baillieres Clin Endocrinol Metab. 1998 Oct;12(3):501-6

ANIMAL STUDIES

A study that shows that androgen deprivation (castration) stimulates the progression of androgen­ independent prostate cancer in mice in vivo 125. Jennbacken K, Gustavsson H, Tesan T, Horn M, Vallbo C, Welén K, Damber JE. The prostatic environment suppresses growth oi androgen-independent prostate cancer xenografts: an effect influenced by testosterone. Prostate. 2009 Aug 1;69(11):1164-75. (Castration of mice increased tumor growth of prostate cancer implanted in the prostate.) A study that shows that androgen deprivation stimulates the progression of hormone-sensitive mouse prostate cancer cells to hormone insensitive in vitro 126. Sato N, Watabe Y, Suzuki H, Shimazaki J. Progression of androgen-sensitive mouse tumor (Shionogi carcinoma 115) to androgen-insensitive tumor after long-term remova! of testosterone. Jpn J Cancer Res. 1993 Dec;84(12):1300-8 Studies where antiandrogens (which cause androgen deficiency) may promote DMAB-induced prostate cancer incidence or increase its malignancy 127. Akaza H, Tsukamoto S, Morita T, Yamauchi A, Onozawa M, Shimazui T, ldeyama Y, Shirai T. Promoting effects of antiandrogenic agents on rat ventral prostate carcinogenesis induced by 3,2'-dimethyl-4aminobiphenyl (DMAB). Prostate Cancer Prostatic Ois. 2000 Aug;3(2):115-9 128. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215-24 A study where significantly lower testosterone (and androstenedione) leveis are found in mice with prostate inflammation. This means that testosterone (and androstenedione) may be necessary to counter prostate inflammation. 129. Bondarenko LA, Breslavskii AS, Vartapetov BA, Gladkova AI. Secretion oi testicular androgens under conditions of chronic experimental inflammation of the prostate gland. Probl Endokrinol (Mosk). 1977 Jui­ Aug;23(4):111-5

A study where testosterone treatment may prevent benign prostate hypertrophy by inhibiting stromal proliferation-induced by estradiol and by keeping prostate glandular cells health, preventing their atrophy in vitro 130.

Feyei-Cabanes T, Secchi J, Robel P, Baulieu EE. Combined effects oi testosterone and estradiol on rat ventral prostate in organ culture. Cancer Res. 1978 Nov;38(11 Pt 2):4126-34.

A study where testosterone treatment reduces the proliferation of mouse prostate cancer cells in vitro 131.

Suzuki H, Nihei N, Sato N, lchikawa T, Mizokami A, Shimazaki J. lnhibition of growth and increase of acid phosphatase by testosterone on androgen-independent murine prostatic cancer cells transfected with androgen receptor cDNA. Prostate. 1994 Dec;25(6):310-9

A study where testosterone treatment reduces the proliferation of guines pig prostate stroma cells in vitro 132.

Ricciardelli C, Horsfall DJ, Sykes PJ, Marshall VR, Tilley WD. Effects of oestradiol-17 beta and 5 alpha­ dihydrotestosterone on guinea- pig prostate smooth muscle cell proliferation and steroid receptor expression in vitro. J Endocrinol. 1994 Mar;140(3):373-83

A study where testosterone treatment at high doses does not increase the incidence of prostate cancer cells in mice 133.

Mainwaring Wl. The effect of testosterone on the age-associated changes in the ventral prostate gland of the mouse. Testosterone and ageing of the prostate. Gerontologia. 1968;14(1):133-41

A study where testosterone, DHT and progesterone protects the prostate glandular epithelium against metaplasia and excessive stroma proliferation induced by estrogens in castrated male mice 134. Burrows H. Natura (London). 1936, 138: 164 A study that shows that testosterone treatment of castrated mice can inhibit the progression of androgen­ independent prostate cancer in vivo

788

135.

Jennbacken K, Gustavsson H, Tesan T, Horn M, Vallbo C, Welén K, Damber JE. The prostatic environment suppresses growth of androgen-independent prostate cancer xenografts: an effect influenced by testosterone. Prostate. 2009 Aug 1;69(11):1164·75. (Castration of the mice increased tumor growth of prostate cancer

implanted in lhe prostate. This effect was reversed by testosterone treatment) A study where testosterone treatment of certain species of mice can inhibit prostate cancer growth 136. Umekita Y, Hiipakka RA, Kokontis JM, Liao S. Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride. Proc Natl Acad Sei U S A 1996 Oct 15;93(21):11802·7

Studies where dihydrotestosterone treatment of certain species of rats can inhibit prostate cancer growth 137. Pollard M. Dihydrotestosterone prevents spontaneous adenocarcinomas in the prostate-seminal vesicle in aging L·W rats. Prostate 1998 Aug 1;36(3):168-71 138.

Pollard M, Luckert PH, Snyder D.Prevention and treatment of experimental prostate cancer in Lobund·Wistar rats. I. Effects of estradiol, dihydrotestosterone, and castration. Prostate 1989;15(2):95·103

Studies that show that testosterone can stimulate the production of reactive oxygen species in prostate cancer cells, reducing their growth rate and making their survival more difficult 139. Sun XY, Donald SP, Phang JM. Testosterone and prostate specific antigen stimulate generation of reactive oxygen species in prostate cancer cells. Carcinogenesis. 2001 Nov;22(11):1775·80 140.

Ripple MO, Hagopian K, Oberley TD, Schatten H, Weindruch R. Androgen-induced oxidative stress in human LNCaP prostate cancer cells is associated with multiple mitochondrial modifications. Antioxid Redox Signal. 1999 Spring;1(1):71·81

141.

Ripple MO, Henry WF, Rago RP, Wilding G. Prooxidant-antioxidant shift induced by androgen treatment of human prostate carcinoma cells. J Natl Cancer lnst. 1997 Jan 1;89(1):40·8 ("Physiologic leveis of androgens

are capable of increasing oxidative stress in androgen-responsive LNCaP prostate carcinoma cel/s'J A study where dihydrotestosterone treatment stimulates apoptosis of prostate cancer cells 142. Bruckheimer EM, Kyprianou N. Dihydrotestosterone enhances transforming growth factor-beta-induced apoptosis in hormone-sensitive prostate cancer cells. Endocrinology. 2001 Jun;142(6):2419·26 Breast Cancer in women: protection with testosterone or dihydrotestosterone treatment? 143.

Dimitrakakis C, Jones RA, Liu A, Bondy CA. Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause. 2004 Sep·Oct;11(5):531·535

NEUTRAL EFFECTS OF TESTOSTERONE THERAPIES

REVIEW STUDIES where the authors did not find an adverse effect of testosterone leveis or treatment on the prostate cancer risk Review studies with conclusions that there is no data to support the view that testosterone treatment could increase the risk of prostate cancer, making e.g. a prostate cancer progress from a preclinical to a clinicai stage 144. Rhoden NEJM 2004 ("No compelling evidence at present to suggest that men with higher testosterone leveis are at greater risk of prostate cancer or that treating men who have hypogonadism with exogenous androgens increases this risk. In fact, it shou/d be recognized that prostate cancer becomes more prevalent exactly at the time of a man's fite when testosterone leveis decline.'? 145. Morales A. Androgen replacement therapy and prostate safety. Eur Urol 2002 Feb;41(2):113·20 ('To date there is no evidence that exogenous androgens promote development of prostate cancer'J 146.

Basaria S, Wahlstrom JT, Dobs AS. Anabolic-Androgenic Steroid Therapy in the Treatment of Chronic Diseases. J Clin Endocrinol Metab. 2001 Nov; 86(11):5108-17 (".. recent reviews suggest that the incidence of

prostate cancer is not increased by testosterone administration'J 147.

Morley JE. Testosterone replacement and the physiologic aspects of aging in men. Mayo Clin Proc. 2000 Jan;75 Suppi:S83·7 ('There is no clinicai evidence that the risk of either prostate cancer or benign prostate

hypertrophy increases with testosterone treatment'J 148. 149.

Wirth MP, Hakenberg OW Testosterone and the prostate. Urologe A 2000 Sep;39(5):418·20 Rolf C, Nieschlag E. Potential adverse effects of long-term testosterone therapy. Baillieres Clin Endocrinol Metab. 1998 Oct;12(3):521·34.

789

150.

Prehn RT. On lhe prevention and therapy of prostate cancer by androgen administration. Cancer Res. 1999 Sep 1;59(17):4161-4 ( ... contrary to prevalent opinion, declining rather than high leveis of androgens "

probably contribute more to human prostate carcinogenesis and ;.. androgen supplementation would probably lower lhe incidence of lhe disease. ... consider lhe possibility lha! lhe growth of androgen-independent prostate cancers might be reduced by lhe administration of androgens")

Studies that show that the incidence of prostate cancer is not higher in men treated with testosterone than in the general population of the same age, despite lhe fac! that men on testosterone treatment undergo more prostate checks and thus have greater chances of having a prostate cancer detected ("the cancer rale in testosterone replacement treatment trials is only approximately 1 %, similar to detection rales in screening programs'} 151.

Coward RM, Simhan J,

Carson CC 3rd. Prostate-specific antigen changes and prostate cancer in

hypogonadal men treated with testosterone replacement therapy. BJU In!. 2009 May;103(9):1179-83 (the

152.

153.

incidence of prostate cancer among men with late-onset hypogonadism on testosterone replacement therapy is no greater than that in the general population) Dobs AS, Morgenthaler A. Does testosterone therapy increase lhe risk of prostate cancer? Endocr Pract. 2008 Oct;14(7):904-11 ("reviewed studies investigating the relationship between testosterone therapy and prostate cancer progression. . .. No evidence of an associated relationship between exogenous testosterone therapy and prostate cancer has emerged from clinicai trials ar adverse event reports'j Morgentaler A, Traish AM. Shifting lhe paradigm of testosterone and prostate cancer: lhe saturation model and lhe limits of androgen-dependent growth. Eur Urol. 2009 Feb;55(2):310-20 ('� literature search was

154.

performed of publications dating from 1941 to 2008 that addressed experimental and clinicai effects of androgens on prostate growth .. maximal androgen-receptor binding is achieved at serum testosterone concentrations we/1 below the physiologic range... The evidence clearly indicates that there is a limit to the ability of androgens to stimulate prostate cancer growth'j Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol. 2006 Sep;7(5}:363-9

STUDIES with no association between serum androgen leveis and prostate disease, including cancer Studies with no significant difference in plasma testosterone and/or DHT and/or androstanediol glucuronide between prostate cancer patients and controls 155.

Endogenous Hormones and Prostate Cancer Collaborative Group, Roddam AW, Allen NE, Appleby P, Key T J. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer lnst. 2008 Feb 6;100(3):170-83

156.

Hong SK, Han BK, Jeong JS, Jeong SJ, Moon KH, Byun SS, Lee SE. Serum measurements of testosterone, insulin-like growth factor 1, and insulin-like growth factor binding protein-3 in lhe diagnosis of prostate cancer among Korean men. Asian J Androl. 2008 Mar;10(2):207-13

157.

Mohr BA, Feldman HA, Kalish LA, Longcope C, McKinlay JB. Are serum hormones associated with lhe risk of prostate

cancer?

Prospective

results

from

the

Massachusetts

Male

Aging

Study.

Urology.

2001

May;57(5):930-5. 158.

Schatzl G, Reiter WJ, Thürridl T, Waldmüller J, Roden M, Sõregi S, Madersbacher S. Endocrine patterns in patients with benign and malignant prostatic diseases. Prostate. 2000 Aug 1;44(3):219-24.

159.

Heikkila R, Aho K, Heliovaara M, Hakama M, Marniemi J, Reunanen A, Knekt P. Serum testosterone and sex hormone-binding globulin concentrations and lhe risk of prostate carcinoma: a longitudinal study. Cancer. 1999 Jul 15;86(2):312-5

160.

Dorgan JF, Albanes D, Virtamo J, Heinonen OP, Chandler DW, Galmarini M, McShane LM, Barrei! MJ, Tangrea J, Taylor PR. Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland. Cancer Epidemiol Biomarkers Prev. 1998 Dec;7(12):1069-74.

161.

Vatten LJ, Ursin G, Ross RK, Stanczyk FZ, Lobo RA, Harvei S, Jellum E. Androgens in serum and lhe risk of prostate cancer: a nested case-control study from lhe Janus serum bank in Norway. Cancer Epidemiol Biomarkers Prev 1997 Nov;6(11):967-9

162.

Nomura AM, Stemmermann GN, Chyou PH, Henderson BE, Stanczyk FZ. Serum androgens and prostate cancer. Cancer Epidemiol Biomarkers Prev 1996 Aug;5(8):621-5

163.

Nomura A, Heilbrun LK, Stemmermann GN, Judd HL. Prediagnostic serum hormones and lhe risk of prostate cancer. Cancer Res. 1988 Jun 15;48(12):3515-7.

164.

Carter HB, Pearson JD, Metter EJ, Chan DW, Andres R, Fozard JL, Rosner W, Walsh PC. Longitudinal evaluation of serum androgen leveis in men with and without prostate cancer. Prostate. 1995 Jul;27(1):25-31

165.

Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, Fozard JL, Walsh PC. Longitudinal evaluation of prostate-specific antigen leveis in men with and without prostate disease. JAMA. 1992 Apr 2229;267(16):2215-20.

790

166.

Wright F, Poizat R, Bongini M, Bozzolan F, Doukani A. Mauvais-Jarvis P. Decreased urinary 5-alpha­ androstanediol glucuronide excretion in patients with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1985; 60 (2) 294-8

167.

Habib FK, Lee IR, Stitch SR, Smith PH. Androgen leveis in the plasma and prostatic tissues of patients with benign hypertrophy and carcinoma of the prostate. J Endocrinol 1976 OCT;71(1):99-107

Studies that show that the serum levei of testosterone is not significantly associated with overall survival or serum PSA changes in castration-resistant regional (metastatic) prostate cancer 168.

Armstrong AJ, Halabi S, de Wit R, Tannock IF, Eisenberger M. The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer. Prostate Cancer Prostatic Ois. 2009;12(1):88-93

Studies with no correlation between serum testosterone and serum PSA 169. Monath JR, McCullough DL, Hart LJ, Jarow JP. Physiologic variations of serum testosterone within the normal range do not affect serum prostate-specific antigen. Urology 1995 Jul;46(1):58-61 170. Monda JM, Myers RP, Bostwick DG, Oesterling JE. The correlation between serum prostate-specific antigen and prostate cancer is not influenced by the serum testosterone concentration. Urology 1995 Jul;46(1 ):62-4 171. Schatzl G, Reiter WJ, Thurridl T, Waldmuller J, Roden M, Soregi S, Madersbacher S. Endocrine patterns in patients with benign and malignant prostatic diseases. Prostate 2000;44(3):219-24 172.

Vijayakumar S, Quadri SF, Dong L, lgnacio L, Kathuria IN, Sutton H, Halpern H. Results of a study to correlate serum prostate specific antigen and reproductive hormone leveis in patients with localized prostate cancer. J Natl Med Assoe 1995 Nov;87(11):813-9

Studies that show that there is no association between testosterone leveis and prostate cancer stage (the progression of prostate cancer does not depend on testosterone) 173.

Morote J, Ramirez C, Gómez E, Planas J, Raventós CX, de Torres IM, Catalán R. The relationship between total and free serum testosterone and the risk of prostate cancer and tumour aggressiveness. BJU lnt. 2009 Aug;104(4):486-9. ("Prostate cancer risk and tumour aggressiveness are not related to serum leveis of total

and free testosterone'J 174.

Mikkola AK, Aro JL, Rannikko SA, Saio JO. Pretreatment plasma testosterone and estradiol levels in patients with locally advanced or metastasized prostatic cancer. FINNPROSTATE Group. Prostate. 1999 May 15;39(3):175-81

A study with no correlation between serum testosterone and prostate tumor volume, weight or Gleason score 175. Monda JM, Myers RP, Bostwick DG, Oesterling JE. The correlation between serum prostate-specific antigen and prostate cancer is not influenced by the serum testosterone concentration. Urology. 1995 Jul;46(1 ):62-4 A study where therapeutic androgen deprivation (blockade) has no beneficiai effect on the evolution of the prostate cancer 176. Young HH 2nd, Kent JR. Plasma testosterone leveis in patients with prostatic carcinoma before and after treatment. J Urol. 1968 Jun;99(6):788-92 A study with no significant association of serum testosterone with benign prostate hyperplasia 177. Lagiou P, Mantzoros CS, Tzonou A, Signorello LB, Lipworth L, Trichopoulos O. Serum steroids in relation to benign prostatic hyperplasia. Oncology. 1997 Nov-Dec;54(6):497-501

STUDIES where testosterone/androgen treatments of men with prostate cancer has no adverse effect on the proqression or recurrence of the cancer, but improves qualitv of life and overall health Studies of testosterone treatment of men with non active or cured prostate cancer Morales A, Black AM, Emerson LE. Testosterone administration to men with testosterone deficiency syndrome

178.

after externai beam radiotherapy for localized prostate cancer: preliminary observations. BJU lnt. 2009

5; "Men with testosterone deficiency syndrome after externa/ beam radiotherapy for localised prostate cancer are candidates for testosterone therapy .. no adverse effects from testosterone supplementation'J Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007 Feb 1;109(3):536-41 ( (n 31; For patients with low se rum testosterone leveis

Jan;103(1):62-4 (n

179.

=

=

and symptoms of hypogonadism, testosterone therapy may be used with caution and close follow-up after prostate brachvtherapy/

791

180.

Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J

(n 10 hypogonadal men treated with radical retropubic prostatectomv for organ confined prostate cancer; testosterone replacement therapy can be administered careful/y and with benefit to hypogonadal patients with prostate cancer)

Urol. 2005 Feb;173(2):533-6

=

Studies of testosterone treatment of men with active prostate cancer 181. Morris MJ, Huang D, Kelly WK, Slovin SF, Stephenson RD, Eicher C, Delacruz A, Curley T, Schwartz LH, Scher Hl. Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic

(n 16; "patients with castration-resistant metastatic prostate cancer can be safely treated in clinicai trials using high-dose exogenous testosterone. Patients did not, on average, achieve sustained supraphysiologic serum testosterone leveis'?

prostate cancer. Eur Urol. 2009 Aug;56(2):237-44

182.

=

Szmulewitz R, Mohile S, Posadas E, Kunnavakkam R, Karrison T, Manchen E, Stadler WM. A randomized phase 1 study of testosterone replacement for patients with low-risk castration-resistant prostate cancer. Eur

(n 15; in men with early progressive castration-resistant prostate cancer transdermal testosterone treatment "is a feasible and reasonably we/1-tolerated therapy for men'J

Urol. 2009 Jul;56(1):97-103 183.

=

Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in

(n 7; Each man was treated with an androgen preparation. Afier variable followup periods no biochemical ar clinicai evidence of recurrence was found in any of the group)

hypogonadal men. J Urol. 2004 Sep;172(3):920-2

=

ANECDOTAL STUDIES that show that testosterone treatment of prostate cancer patients did not accelerate the cancer progression 184.

Morgentaler A. Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer. J Sex Med. 2009 Feb;6(2):574-7

('�decline in PSA was noted in a man with

untreated PCa who received T therapy for 2 years'? 185.

Brawer MK. Testosterone replacement therapy for a man with prostate cancer. Rev Urol. 2004;6 Suppl 6:8357..

186.

Morales A, Black A. Testosterone deficiency syndrome and prostate cancer: illustrative annotations for a debate. Can Urol Assoe J. 2008 Feb;2(1):52-4.

187.

Mathew P. Prolonged control of progressive castration-resistant metastatic prostate cancer with testosterone replacement therapy: the case for a prospective trial. Ann Oncol. 2008 Feb;19(2):395-6.

STUDIES where testosterone/androgen treatments had no adverse effect on the risk of prostate disease, including the risk of prostate cancer Small clinicai studies of androgen treatment of prostate cancer patients, performed before the days of PSA, where the androgen treatment did not stimulate the growth of the prostatic tumor and in some cases even inhibited or slowed down the growth of the tumor; the responses were extremely variable 188.

Prout GRJ, Brewer WR. Response of men with advanced prostatic carcinoma to exogenous administration of

189.

Trunnell JD, Duffy BJ Jr. The influence of certain steroids on the behavior of human prostate cancer. Trans.

testosterone. Cancer (Phila.). 1967;20:1871-8 NY Acad Sei. 1950;11:12:238-41 190.

Brendler H, Lowry O, Brock M. Further investigation of hormonal relationships. Arch Surg. 1950,61:433-40

191.

Pearson OH. Discussion of Dr. Huggins' paper: "Contrai of cancers of man by endocrinological methods." Cancer Res. 1957:17:473-9

192.

Morales A, Connolly J, Burr R, Bruce A. The use of radioactive phosphorus to treat bone pain in metastatic carcinoma of the prostate. Can Med Assoe J. 1970;103: 372-3

Studies where testosterone treatment had no significant effect on PSA aml/or prostate volume 193.

Rhoden EL, Morgentaler A. lnfluence of demographic factors and biochemical characteristics on the prostate­ specific antigen (PSA) response to testosterone replacement therapy. lnt J lmpot Res. 2005 Sep 22

(No

statistical increase: average 0.31 nglml after 1 year of treatment of hypogonadal men) =

194.

Shibasaki T, Sasagawa I, Suzuki Y, Yazawa H, lchiyanagi O, Matsuki S, Miura M, Nakada T. Effect of testosterone replacement therapy on serum PSA in patients with Klinefelter syndrome. Arch Androl. 2001 Nov-Dec;47(3):173-6

195.

Cooper CS, Perry PJ, Sparks AE, Maclndoe JH, Yates WR, Williams RD. Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen leveis in healthy young men. J Urol. 1998 Feb;159(2):441-3

196.

Cooper CS, Maclndoe JH, Perry PJ, Yates WR, Williams RD. The effect of exogenous testosterone on total and free prostate specific antigen leveis in healthy young men. J Urol. 1996 Aug;156(2 Pt 1):438-41

197.

Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf). 1994 Mar;40(3):341-9

792

198.

199. 200. 201.

Douglas TH, Connelly RR, McLeod DG, Erickson SJ, Barren R 3rd, Murphy GP. Effect oi exogenous testosterone replacement on prostate-specilic antigen and prostate-specilic membrane antigen leveis in hypogonadal men. J Surg Oncol. 1995 Aug;59(4):246-50 Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997 Jun;82(6):1661-7 Hajjar RR, Kaiser FE, Morley JE. Outcomes oi long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 1997 Nov;82(11):3793-6 Monath JR, McCullough DL, Hart LJ, Jarow JP. Physiologic variations oi serum testosterone within the normal range do not affect serum prostate-specilic antigen. Urology. 1995 Jul;46(1):58-61

A study where dihydrotestosterone treatment had no significant effect on serum PSA 202.

Kunelius P, Lukkarinen O, Hannuksela ML, ltkonen O, Tapanainen JS. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab. 2002 Apr;87(4):1467-72

Studies where testosterone treatment increases the serum PSA but normalizes it in patients with initial atrophic prostate bringing it up to normal leveis without any excessive increase 203. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf). 1994 Mar;40(3):341-9. 204. Behre HM, Nieschlag E. Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and 205. 206. 207.

208.

pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab. 1992 Nov;75(5):1204-10 Guay AT, Perez JB, Fitaihi WA, Vereb M. Testosterone treatment in hypogonadal men: prostate-specific antigen levei and risk of prostate cancer. Endocr Pract. 2000 Mar-Apr;6(2):132-8 McCiellan KJ, Goa KL. Transdermal testosterone. Drugs 1998 Feb;55(2):253-8; discussion 259 Arver S, Dobs AS, Meikle AW, Caramelli KE, Rajaram L, Sanders SW, Mazer NA. Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men. Clin Endocrinol (Oxf). 1997 Dec;47(6):727-37 Tenover JS. Effects oi testosterone supplementation in the aging male. J Clin Endocrinol Metab. 1992 Oct;75(4):1092-8

Testosterone treatment does not increase the incidence of prostate disease d 209. Hartnell J, 72" Endocrine Soe. Meeting, 1990, A 428 A study where previous testosterone propionate treatment (terminated 1 to 7 years before the study) did not increase the risk of prostate hypertrophy or palpable prostate irregularities in men over 45 years, whatever the treatment length or dose 210. Lesser MA, Vose SN, Dixey GM. Effect of testosterone propionate on the prostate gland oi patients over 45. J Clin Endocrinol Metab. 1955 Mar;15(3):297-300 Studies where DHT treatment had no effect on the prostate volume 211.

212.

Kunelius P, Lukkarinen O, Hannuksela ML, ltkonen O, Tapanainen JS. The effects oi transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab. 2002 Apr;87(4):1467-72. Ly LP, Jimenez M, Zhuang TN, Celermajer OS, Conway AJ, Handelsman DJ. A double-blind, placebo­ controlled, randomized clinicai trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of lile in older men with partia! androgen deficiency. J Clin Endocrinol Metab. 2001 Sep;86(9):4078-88

ARGUMENTS CONTRA TESTOSTERONE THERAPIES

Studies that suqqest that testosterone may increase the prostate cancer risk P.r!?l!�!i.t�. !<ª.rl!<��; .t��. !i.�!!9.Ç!l!H9.1J. w!.t.�. !1!9.�. fr�� .t�l!�9.!?.t�rº!1!!. !�Y-�l!! 213. Pierorazio PM, Ferrucci L, Kettermann A, Longo DL, Metter EJ, Carter HB. Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging. BJU lnt. 2009 Sep 14. [Epub ahead of print] (the researchers found a positive association between the free testosterone index in the serum with aggressive high-risk prostate cancer - death from prostate cancer - for men above age 65, not in younger men) 214. Yano M, lmamoto T, Suzuki H, Fukasawa S, Kojima S, Komiya A, Naya Y, lchikawa T. The clinicai potential of pretreatment serum testosterone levei to improve the efficiency of prostate cancer screening. Eur Urol. 2007 Feb;51 (2):375-80. (ambivalent study that compares prostate cancer patients with a wrong contra/ group,

793

namely patients with benign prostate hypertrophy (who tend to have an increased conversion of testosterone to estradiol, cause of their stromal hyperplasia) and not to healthy contrais with smaller prostates wilhoul prostale disease. See Kwon T, el /. BJU /nt. 2010 Jan 8. sludy lhat shows proslale cancer more easily appears in men wilh smaller prostale volume, lhe opposile of benign proslale hypertrophy. In lhis study, inilially higher serum lestosterone predict a higher risk of prostate cancer at biopsy, but when prostate cancer is found, higher serum lesloslerone are associated with /ess aggressive disease) 215.

Parsons JK, Carter HB, Platz EA, Wright EJ, Landis P, Metter EJ. Serum testosterone and lhe risk of prostate cancer:

potential

implications

for

testosterone

therapy.

Cancer

Epidemiol

Biomarkers

Prev.

2005

Sep;14(9):2257-60 (critics: a potential bias may come from nutritional factors: individuais who eat a /ot of food related to a higher cancer risk such as meat, particularly if cooked we/1-done, and/or milk, have also higher leveis of testosterone as we/1 as of olher hormones associated with a higher cancer risk. Moreoever, there is no information in this study on estradiol leveis. This is important as lhe simultaneous presence of high leveis of testosterone and estradiol may, following certain reports, increase the prostate cancer (PC) risk, not testosterone leveis afane; heavy a/cohol drinking, another risk factor for PC, that is in some countries of the world frequent can considerably increase both the estradiol leveis and the PC risk in consumers. Other possible bias: data were not adjusted for other PC risk factors such as smoking, nutritional deficiencies, etc.) 216.

Mydlo JH, Tieng NL, Volpe MA, Chaiken R, Kral JG. A pilo! study analyzing PSA, serum testosterone, lipid profile, body mass index and race in a small sample of patients with and without carcinoma of lhe prostate. Prostate Cancer Prostatic Dis. 2001;4(2):101-105 (critics: no dietary factors were taken into account, only high BMI as a risk factor, nore was serum SHBG analysed: dehydrated persons have usually high SHBG, and thus higher total testosterone, which is bound to it, but generally low aclive, bioavalable and free testosterone leveis)

217.

Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. Prospective study of sex hormone leveis and risk of prostate cancer. J Natl Cancer lnst. 1996 Aug 21 ;88(16):1118-26 (critics: study did not consider dietary or BMI PC risk factors)

218.

Stahl F, Schnorr D, Pilz C, Dorner G. Dehydroepiandrosterone (DHEA) leveis in patients with prostatic cancer, heart diseases and under surgery stress. Exp Clin Endocrinol. 1992;99(2):68-70 (critic: no estrogen leveis, nor dietary factors checked)

A study where higher leveis of testosterone were found in patients who are in the advanced D-stage of PC, compared to the leveis found in patients in the more moderate B and C-stages of prostate cancer 219. lmamoto T, Suzuki H, Akakura K, Komiya A, Nakamachi H, lchikawa T, lgarashi T, lto H. Pretreatment serum levei of testosterone as a prognostic factor in Japanese men with hormonally treated stage D2 prostate cancer. Endocr J. 2001 Oct;48(5):573-8 (note: but those in 0-stege that had lhe highest testosterone had lhe best prognosis, inc/uding tanger cancer-free survival time)

A study where a higher rate of metastasis (-relapse) is found in prostate cancer patients with testosterone > 500 ng/dl that have been locally irradiated (critic: the irradiato i n may change lhe risk) 220.

Zagars GK, Pollack A, von Eschenbach AC. Serum testosterone - a significant determinant of metastatic relapse for irradiated localized prostate cancer. Urology. 1997 Mar;49(3):327-34

A study where testosterone treatment increases the growth of prostate cancer: in vitro 221. Tymchuk CN, Barnard RJ, Ngo TH, Aronson WJ. Role of testosterone, estradiol, and insulin in diet- and exercise-induced reductions in serum-stimulated prostate cancer cell growth in vitro. Nutr Cancer. 2002;42(1):112-6 ALTERNATIVE EXPLANATIONS: The higher testosterone leveis found in men with prostate cancer in some investigations may be explained by I. ê}!J�!!..!!.IJ��Q!!.IJ�!-!�.P.r9.c;I.I:IJ<�l9.r:t.9.U!!���!'.t.«mm�.!:!Y..tf:l.�.P.r9l!��.t�.! the higher testosterone would then be a consequence and marker of prostate cancer and not a cause or favoring factor

An in vitro study that demonstrates the production of testosterone by the (androgen independent) prostate cancer cells 222.

Dillard PR, Lin MF, Khan SA. Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Moi Cell Endocrinol. 2008 Nov 25;295(1-2):115-20

In vivo studies that show that androgen leveis cannot be suppressed to zero despite high dosing with LH antagonists in many men with metastatic prostate cancer, suggesting that the tumor itself could secrete testosterone

794

223.

Koupparis AJ, Tyrrell C. Non-suppression of testosterone in patients with a rising prostate-specific antigen levei receiving luteinising hormone-releasing hormone analogues for metastatic prostate cancer. Clin Oncol (R Coll Radial). 2006 Sep;18(7):571-2.

224.

Morote J, Esquena S, Abascal JM, Trilla E, Cecchini L, Raventós CX, Catalán R, Reventós J. Failure to maintain a suppressed levei oi serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer. Urol lnt. 2006;77(2):135-8.

11. P.iiJ.(é!rY.. (ªç.t!?r.f'!;. [IJ.tJ..C::QIJ.$.1!ffiP.(�qn. !?f. fQ9.ç/_$.!hi!t. ({IXQr..t!!IJ..ç/_f!Y.tJJ.rmmf!nt. !?f.P.f9.$.W�. t;.é!r!9.f!r. .C::QH(çl_ .é!!�9.lJ.f!!P.

P.f.C!f!Ht;.f!.trJSJlmr.tr�E?. .t��(t;J.$!�r9.tJ.I?. !l?.'t.f!($

Studies where the consumption of high amounts of protein and saturated fat such as milk products and meat increased testosterone leveis 225. Sharpe RM, Martin 8, Morris K, Greig /, McKinne/1 C, McNeilly AS, Walker M. lnfant feeding with soy formula milk: effects on the testis and on blood testosterone leveis in marmoset monkeys during the period of neonatal testicular activity. Hum Reprod. 2002 Ju/;17(7}:1692-703 226.

Dorgan JF, Judd JT, Longcope C, Brown C, Schatzkin A, C/evidence BA, Campbe/1 WS, Nair PP, Franz C, Kah/e L, Taylor PR.Effects of dietary fat and fiber on plasma and urine androgens and estrogens in men: a controlled feeding study. Am J Clin Nutr. 1996 Dec;64(6):850-5

227.

Hamalainen E, Ad/ercreutz H, Puska P, Pietinen P. Diet and serum sex hormones in healthy men. J Steroid Biochem. 1984 Jan;20(1):459-64

228.

Volek JS, Kraemer WJ, Bush JA, lncledon T, Boetes M. Testosterone and cortisol in relationship to dietary

nutrients and resistance exercise. J Appl Physiol. 1997 Jan;82(1):49-54

Mílk or meat intake may increase the risk of prostate cancer (in fact the increased risk may disappear if the vegetable intake which is /ower in meat eaters is taken into account)

Link between meat, milk and/or protein intake, and prostate cancer 229.

Norrish AE, Lynnette R. Ferguson, Mark G. Knize, James S. Fe/ton, Susan J. Sharpe, Jackson RT. Heterocyclic Amine Content of Cooked Meat and Risk of Prostate Cancer. J Nat Cancer lnst. 1999;

91(23):2038-44 230.

Wolk A. Diet, lifestyle and risk of prostate cancer. Acta Onco/. 2005;44(3}:277-81

231.

Grant WB. An eco/ogic study of dietary links to prostate cancer. A/tem Med Review 1999; 4(3):162-9 (study in 14 European countries)

795

TESTOSTERONE DEFICIENCIES in MEN with SERUM ANDROGEN LEVELS within the REFERENCE RANGE: to TREAT or NOT to TREAT?

Should men with symptoms and signs of testosterone deficiency, but serum androgen leveis within the normal reference range for their age, be treated with testosterone?

Critics against the value of laboratory tests and their reference ranges to evaluate androgen deficiency

Wide intraindividual fluctuations in blood test results for serum total, free and bioavailable testosterone (T),

dihydrotestosterone (DHT), SHBG, LH, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), oestrone, oestradiol and cortisol : one sample is generally not sufficient to characterize an individual's hormone leveis 1.

Brambilla DJ, O'Donnell AB, Matsumoto AM, McKinlay JB. lntraindividual variation in leveis of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol (Oxf). 2007 Dec;67(6):85362. New England Research lnstitutes, Watertown, Massachusetts, USA. (Paired blood samples were obtained 1-3 days apart at entry and again 3 months and 6 months /ater (maximum six samples per subject). Each sample consisted of a pool of equal aliquots of two blood draws 20 min apart. Study participants were men aged 30-79 years the intraindividua/ standard deviations imply that a clinician can expect to see a difference exceeding 18-28% about half the time when two measurements are made on a subject. The difference wi/1 exceed 27-54% about a quarter of the time.)

Wide variability in of the reference range for serum testosterone

2.

Lazarou S, Reyes-Vallejo L, Morgentaler A. Wide variability in laboratory reference values for serum testosterone. J Sex Med. 2006 Nov;3(6):1085-9. Harvard Medicai School, Division of Urology, Beth Israel Deaconess Medicai Center, Boston, MA, USA. (Of the 25 labs, there were 17 and 13 different sets of reference values for total and free testosterone, respectively. The low reference value for total testosterone ranged from 130 to 450 ngldL (350% difference), and the upper value ranged from 486 to 1,593 ng/dL (325% difference). Age-adjusted reference values were app/ied in four centers for total testosterone and in seven labs for free testosterone. AI/ reference values were based on a standard statistica/ model without reqard for clinicai aspects of hvpoqonadism. Twenty-three of the 25 lab directors responded that clinical/y relevant testosterone reference ranges would be preferable to current standards. CONCLUSIONS. Laboratory reference values for testosterone vary wide/y, and are established without clinicai considerations.)

The higher young adult reference range for serum testosterone is a better reference range to detect androgen

deficiency in men with androgen deficiency symptoms 3.

Saio Y, Kato S, Ohnishi S, Nakajima H, Nanbu A, Nitta T, Koroku M, Akagashi K, Hanzawa T, Kato R, Hisasue S, Masumori N, ltoh N, Tsukamoto T, Tanda H. Analysis of clinicai manifestations and endocrinological aspects of patients having PADAM-Iike symptoms. Nippon Hinyokika Gakkai Zasshi. 2004 Jan;95(1):8-16. Sanjukai Hospital. (A depressed mood, hot flashes and sweating and erectile dysfunction were dominant in these symptom categories. Psychologica/ symptoms, somatovegatative symptoms, and sexual symptoms, accounting for 51%, 36%, and 13%, 21% of men with PADAM-/ike symptoms ...: Depending on the criteria of androgen deficiency, not ali patients had low total-T and free-T leveis) Table: Divergence between lhe % of men with androgen deficiency complaints going to a clinic

and lhe % of them below lhe testosterone reference range % of Men with androgen deficiency symptoms (Partial androÇJen deficiency in lhe aÇJinÇJ male or PADAM-Iike symptoms) % of Men with free testosterone leveis below lhe normal range of men in their twenties (15.2-43.5 pg/ml) % of Men with free testosterone leveis below lhe normal range of their age (9.3-26.5 pg/ml) % of Men with total testosterone levei below 200 ng/dl ( criterion for testosterone replacement recommended by lhe American Association of Clinicai Endocrinologists guidelines) =

Sato Y, et ai. Nippon Hinvokika Gakkai Zasshi. 2004 Jan;95(1):8-16

796

100% 82% 30% 9%

Poor correlations of the testosterone leveis (bioavailable testosterone and calculated free testosterone) with clinicai symptoms with in men aged over 70 years 4.

Lin YC, Hwang TI, Chiang HS, Yang CR, Wu HC, Wu TL, Huang SP. Correlations of androgen deficiency with clinicai symptoms in Taiwanese males. In! J lmpot Res. 2006 Jui-Aug;18(4):343-7 Division of Urology, Department of Surgery, Shin-Kong WHS Memorial Hospital, Taipei, Taiwan, ROC. (An androgen deficiency

questionnaire

might not be a suitable single and should be used together with biochemical markersfor

evaluation of for androgen deficiency)

Studies that show disease and mortality to be associated with testosterone leveis within the {laboratory) reference range

The findings of these studies support lhe view lha! men who may have testosterone leveis within lhe reference, but complain of having testosterone deficiency symptoms might need and benefit from testosterone treatment

1h Studies that show that subjects who are at or below the 90 percentile of serum testosterone leveis have an increased risk of disease or dying: this concerns most studies that show an inverse association between testosterone leveis and the risk of disease/dying lncreased overall, cardiovascular and cancer mortality in men aged 40 to 79 years 5.

Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N. Endogenous testosterone and mortality due to ali causes, cardiovascular disease, and cancer in men: European prospectiva investigation into cancer in Norfolk (EPIC-Norfolk) Prospectiva Population Study. Circulation. 2007 Dec 4;116(23):2694-701 Clinicai Gerontology Uni! Box 251, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. kk101 @medschl. cam.ac.uk (An increase of 6 nmoi/L (173 ngldl or 1730 pglml) serum testosterone (approximately 1

SD) was associated in men aged 40 to 79 years followed up for 6 to 10 years with a significant -19% reduction in overa/1 mortality; lnverse relationships were a/so observed for deaths due to cardiovascu/ar and cancer)

lmpaired cognitive function in men between 61 and 72 years 6.

Hogervorst E, D e Jager C , Budge M , Smith AD. Serum leveis o f estradiol and testosterone and performance in different cognitive domains in healthy elderly men and women. Psychoneuroendocrinology. 2004 Apr;29(3):40521. Oxtord Project to lnvestigate Memory and Ageing and lhe Department of Pharmacology, University of Oxford and Radcliffe lnfirmary Trust, Oxford, OX2 6HE, UK. [email protected] (Men between 61 and 72

years of age had a positive relationship between high total testosterone leveis and speed of information processing)

Higher plasma amyloid beta peptide 40, a risk factor for Alzheimer's disease, in older men with subjective memory loss or dementia 7.

Gillett MJ, Martins RN, Clarnette RM, Chubb SA, Bruce DG, Yeap BB. Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia. J Alzheimers Dis. 2003 Aug;5(4):267-9. Department of Endocrinology and Diabetes, Fremantle Hospital, Western Australia, Australia (In o/der men with either subjective mem01y loss or dementia, serum total

and calculated free testosterone correlated significantly and inversely with plasma leveis of amyloid beta peptide 40)

Alzheimer's disease in older men 8.

Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM. Free testosterone and risk for Alzheimer disease in older men. : Neurology. 2004 Jan 27;62(2):188-93. Laboratory of Personality and Cognition, National lnstitute on Aging, lntramural Research Program, Baltimore, MD 21224, USA (lncreases

in the free testosterone index were associated with a -26% significant decreased risk of Alzheimer's disease for each 10-nmol/nmo/ FTI increase)

797

Dyslipidemia Higher serum triglycerides and lipoprotein a Tibblin G, Adlerberth A, Lindstedt G, Bjõrntorp P. The pituitary-gonadal axis and health in elderly rnen: a study of

9.

men bom in 1913. Diabetes. 1996 Nov;45(11):1605-9. Department of Family Medicine, University of Uppsala, Sweden. (Total testosterone leveis correlated negatively with triglycerides) 10. Zhao SP, Li XP. The association of low plasma testosterone levei with coronary artery disease in Chinese men. lnt J Cardiol. 1998 Jan 31;63(2):161-4. Department of Cardiology, Second Affiliated Hospital, Hunan Medicai University, Changsha, P.R. China. (Negativa association between plasma total testosterone levei and plasma triglyceride levei (P<0.001) and lipoprotein a)

Lower serum HDL cholesterol and higher serum apo 8100 and lipoprotein a in healthy men and men with coronary heart disease 11. Li X, Zhao S, Li Y, Wang Z, Luo L, Zhou H. [Changes of plasma testosterone levei in male patients with coronary heart disease] Hunan Yi Ke Da Xue Xue Bao. 1998;23(1):53-6. Department of Cardiovascular Medicine, Second Affiliated Hospital, Hunan Medicai

University, Changsha. (Plasma testosterone correlated positively with the

HDL-cholesterol, HDL3-cholestero/ level and HDL-cholesterol!total cholestero/ ratio and negatively with apo8100 and lipoprotein a levei) 12. Barud W, Palusinski R, Piotrowska-Swirszcz A, Ostrowski S, Makaruk B. [Sex hormones, HDL cholesterol and other lipoproteins in older males] Pol Merkur Lekarski. 2005 Mar;18(105):295-7. Katedra i Klinika Chorób Wewnetrznych

Akademii

Medycznej

w

Lublinie.

[email protected]

(A

significant

positiva

correlation was found between testosterone and HDL-cholesterol)

Higher serum triglycerides and total and LDL cholesterol in men primary prostate carcinoma after castration 13. Xu T, Wang X, Hou S. Effect of lower androgen leveis on arteriosclerosis. Zhonghua Wai Ke Za Zhi. 2001 Sep;39(9):698-701. Department of Urologic Surgery, People's Hospital, Peking University, Beijing 100044, China.

(Negativa linear correlations were found between total testosterone and free testosterone serum leveis

and triglyceride, total cholesterol, LDL cho/estero/ in men primary prostate carcinoma after castration)

Higher serum glucose and insulin in men at

67 years of age

14. Tibblin G, Adlerberth A, Lindstedt G, Bjõrntorp P. The pituitary-gonadal axis and health in elderly men: a study of men bom in 1913. Diabetes. 1996 Nov;45(11):1605-9. Department of Family Medicine, University of Uppsala, Sweden. (Total and free testosterone leveis correlated negatively with glucose and insulin values in men at 67 years of age) In men primary prostate carcinoma after castration 15. Xu T, Wang X, Hou S. Effect of lower androgen leveis on arteriosclerosis] Zhonghua Wai Ke Za Zhi. 2001 Sep;39(9):698-701. Department of Urologic Surgery, People's Hospital, Peking University, Beijing 100044, China. (Negativa linear correlation between total testosterone and free testosterone serum leveis and fasting insulin and glucose, 2 h insulin and g/ucose in men primary prostate carcinoma after castration)

Excessive coagulation in men primary prostate carcinoma after castration 16. Xu T, Wang X, Hou S. Effect of lower androgen leveis on arteriosclerosis] Zhonghua Wai Ke Za Zhi. 2001 Sep;39(9):698-701. Department of Urologic Surgery, People's Hospital, Peking University, Beijing 100044, China. (Negativa linear correlation between total testosterone and free testosterone serum leveis and plasma fibrinopeptide

A,

plasminogen activator inhibitor-1 in men primary prostate carcinoma after castration)

lncreased atherosclerosis (carotid artery intima-media thickness) In men aged 25-84 years 17. Svartberg J, von Mühlen O, Mathiesen E, Joakimsen O, B0naa KH, Stensland-Bugge E. Low testosterone leveis are associated with carotid atherosclerosis in men. J lntern Med. 2006 Jun;259(6):576-82. Department of Medicine, University Hospital of North Norway, Troms0, Norway. [email protected]

(. ..

found an inverse

association between total testosterone leveis and intima media thickness of lhe carotid artery in men aged 25-84 years) In midd/e-aged men 18. Mãkinen J, Jãrvisalo MJ, Põllãnen P, Perheentupa A, lrjala K, Koskenvuo M, Mãkinen J, Huhtaniemi I, Raitakari OT. lncreased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol. 2005 May 17;45(10):1603-8. Research Centre of Applied and Preventiva Cardiovascular Medicine, University of Turku,

798

Turku, Finland. (Common carotid artery intima-media thickness correlated inversely with serum testosterone (p

=

0.003) and directly with LH (p = 0.006) in middle-aged men, 40- to 70-year-o/d men (mean age 57 years)) In elderly men 19. Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SW, van der Schouw YT. Endogenous sex hormones and progression oi carotid atherosclerosis in elderly men. Circulation. 2004 May 4;109(17):2074-9. Julius Center for Health Sciences and Primary Care,

University Medicai Center Utrecht,

Utrecht, The

Netherlands. (Serum free testosterone was inverse/y related to the mean progression of carotid intima-media thickness in elderly men) 20. van den Beld AW, Bots ML, Janssen JA, Pois HA, Lamberts SW, Grobbee DE. Endogenous hormones and carotid atherosclerosis in elderly men. : Am J Epidemiol. 2003 Jan 1 ;157(1):25-31. Department oi Internai Medicine,

Erasmus

University

Medicai

Center

Rotterdam,

Rotterdam,

The

Netherlands.

[email protected] (Serum testosterone, estrone, and free /GF-1 were inverse/y related to intima-media thickness. The strength of these relations was as powerful in subjects with as in those without prevalent cardiovascu/ar disease) Arterial stiffness 21. Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, Blackman MR, Metter EJ. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab. 2006 Feb;290(2):E234-42. Clinicai Research Branch, National lnstitute on Aging, National lnstitutes oi Health, Baltimore, MO 21225, USA (The free testosterone index correlated negatively with pulse pressure and stiffness index (each P < 0.01) lncreased pulse wave velocity in men with type 2 diabetes mellitus 22. Fukui M, Ose H, Kitagawa Y, Yamazaki M, Hasegawa G, Yoshikawa T, Nakamura N. Relationship between low serum endogenous androgen concentrations and arterial stillness in men with type 2 diabetes mellitus. Metabolism. 2007 Sep;56(9):1167-73 University

oi

Medicine,

Graduate

Department of

School

oi

Endocrinology and Metabolism,

Medicai

Science,

Kyoto

Kawaramachi-Hirokoji,

Prelectural

Kyoto,

Japan.

[email protected] (Pulse wave velocity (PWV) was significantly +7.5% greater in patients with /ower concentrations of free testosterone (<10 pg!mL) than in patients with higher concentrations of free testosterone. lnverse correlations were found between serum free testosterone concentration and PWV (P

=

.0003) in men

with type 2 diabetes mellitus.) Peripheral arterial disease in elderly men 23. Tivesten A, Mellstróm D, Jutberger H, Fagerberg B, Lernlelt B, Orwoll E, Karlsson MK, Ljunggren O, Ohlsson C. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. : J Am Co li Cardiol. 2007 Sep 11;50(11):1070-6 The Wallenberg Laboratory for Cardiovascular Research, Góteborg University, Góteborg, Sweden. [email protected] (Low serum testosterone and high serum estradio/ leveis associa/e with /ower extremity peripheral arterial disease (defines as ankle-brachial index <0. 90) in e/derly men mean age 75.4 years); Free testosterone independently and positively associates with ank/e-brachial index (p < 0.001)) Higher diastolic blood pressure and low ejection fraction in men with coronary heart disease 24. Dobrzycki S, Serwatka W, Nadlewski S, Korecki J, Jackowski R, Paruk J, Ladny JR, Hirnle T. An assessment of correlations between endogenous sex hormone leveis and the extensiveness oi coronary heart disease and the ejection fraction oi the lelt ventricle in males. J Med lnvest. 2003 Aug;50(3-4):162-9. Department ol l nvasive Cardiology, Bialystok University Medicai Center, 24 A. M.

Sklodowskiej-Curie St., 15-276 Bialystok, Poland.

(Lower leveis of total testosterone in men with proven coronary heart disease were associated to higher diastolic blood pressure and higher DUKE index (/ow ejection fraction)) Higher systolic blood pressure in healthy men and men with coronary heart disease 25. Li X, Zhao S, Li Y, Wang Z, Luo L, Zhou H. [Changes of plasma testosterone levei in male patients with coronary heart disease] Hunan Yi Ke Da Xue Xue Bao. 1998;23(1):53-6. Department oi Cardiovascular Medicine, Second Affiliated Hospital, Hunan Medicai University, Changsha. (Plasma testosterone correlated positively with systolic blood pressure)

799

lncreased severity of heart failure in chronic heart failure patients 26. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006 Oct 24;114(17):1829-37. Cardiology Department, Military Hospital, ui. Weigla 5, 50981 Wroclaw, Poland. [email protected]

Loss of muscle mass (sarcopenia) and strength and fitness Loss of skeletal muscle mass 27. lannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol A Biol Sei Med Sei. 2002 Dec;57(12):M772-7. Center on Aging, University of Connecticut Health Center, Farmington 06030, USA. (Bioavailable testosterone is a predictor of skeletal muscle mass in men)

Loss of muscle strength and work capacity in middle-aged and elderly men 28. lzquierdo M, Hii.kkinen K, Antón A, Garrues M, lbaíiez J, Ruesta M, Gorostiaga EM. Maximal strength and power, endurance performance, and serum hormones in middle-aged and elderly men. Med Sei Sports Exerc. 2001 Sep;33(9):1577-87. Centro de lnvestigación y Medicina dei Deporte, Gobierno de Navarra, Navarra, Spain. [email protected] (Significant correlations existed between individual values of serum free testosterone to cortisol ratio, and testosterone, and those of muscle strength and maximal workload)

Loss of muscle mass and exercise capacity 29. Grinspoon S, Corcoran C, Lee K, Burrows B, Hubbard J, Katznelson L, Walsh M, Guccione A, Cannan J, Heller H, Basgoz N, Klibanski A. Loss of Jean body and muscle mass correlates with androgen leveis in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab. 1996 Nov;81(11 ):4051-8. Neuroendocrine Unit, Massachusetts General Hospital, Boston 02114, USA. (Free-testosterone leveis were correlated with total body potassium

(R

=

0.45, P

<

0.05)

and muscle mass

(R

=

0.45, P

<

0.05).

Total­

testosterone leveis were correlated with exercise functional capacity)

Low bone mineral density in healthy men aged 43-73 years 30. Cetin A, Gõkçe-Kutsal Y, Celiker R. Predictors of bane mineral density in healthy males. Rheumatol lnt. 2001 Nov;21(3):85-8. Department of Physical Medicine and Rehabilitation, Hacettepe University Medicai School, Ankara, Turkey. [email protected] (Testosterone, is a determinant of Jumbar spine and femoral bone mineral density in healthy men aged 43-73 years) In men with Klinefelter syndrome 31. Seo JT, Lee JS, Oh TH, Joo KJ. The clinicai significance of bone mineral density and testosterone leveis in Korean men with non-mosaic Klinefelter's syndrome. BJU lnt. 2007 Jan;99(1):141-6. Department of Urology, Cheil Hospital,

Sungkyunkwan University School of Medicine, Seoul, Korea. [email protected]

(Linear

correlation between ali bane mineral density values and serum testosterone leveis in men with Klinefelter's syndrome who had a low serum testosterone levei)

Metabolic Syndrome ln aging men 32. Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw YT. Endogenous sex hormones and metabolic syndrome in aging men.

J Clin Endocrinol Metab. 2005 Aug;90(8):4979; author reply 4979.

J Clin

Endocrinol Metab. 2005 Nov;90(11):6339; author reply 6339. Clin Endocrinol Metab. 2005 May;90(5):2618-23. Julius Center for Health Sciences and Primary Care, University Medicai Center Utrecht, PO Box 85500, Roam D 01.335, 3508 GA Utrecht, The Netherlands (Metabolic syndrome was inversely related to serum leveis of total testosterone

(1

standard deviation increase of circulating total testosterone, reduced the risk of metabolic

syndrome by - 57%) In nonsmoking men 33. Blouin K, Després JP, Couillard C, Tremblay A, Prud'homme D, Bouchard C, Tchernof A. Contribution of age and declining androgen leveis to features of the metabolic syndrome in men. Metabolism. 2005 Aug;54(8):103440. Molecular Endocrinology and Oncology Research Center, Lavai University Medicai Research Center, Quebec, Canada G1V 4G2. (The % frequency of men characterized by syndrome increased with decreasing testosterone)

800

3

or more features of the metabolic

Jncreased víscera/ obesity and presence of components of the metabolic syndrome in o/der men 34. Chen RY, Wittert GA, Andrews GR. Relative androgen deficiency in relation to obesity and metabolic status in

older men. Diabetes Obes Metab. 2006 Jul;8(4):429-35. Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. [email protected] (Serum total testosterone was inversely related to víscera/ obesity and severa/ components of the metabolic syndrome)

Higher body fat, visceral fat, body mass index 35. Shimizu W, Matsuo K, Kokubo Y, Satomi K, Kurita T, Nada T, Nagaya N, Suyama K, Aihara N, Kamakura S, lnamoto N, Akahoshi M, Tomoike H. Sex hormone and gender difference--role of testosterone on male predominance in Brugada syndrome. J Cardiovasc Electrophysiol. 2007 Apr;18(4):415-21. Division of Cardiology, Department of Internai Medicine, National Cardiovascular Center, Suita, Osaka, Japan. [email protected] (Testosterone levei was inverse/y correlated with BM/ and body fat % in both groups. Higher testosterone leve/ was associated with Jower visceral fat) 36. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004 Nov;89(11):5462-8. Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209, USA. (Significant inverse correlation of BMI with free testosterone (r= -0.382; P 0.01) and total testosterone (P < 0.01))

<

Highe risk of diabetes in men aged 55-89 years 37. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL; Rancho Bernardo Study. Endogenous sex horrnones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. : Diabetes Care. 2002 Jan;25(1 ):55-60. Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, California 92093-0607, USA. (Total testosterone was inversely and significantly related to subsequent leveis of fasting and postchallenge glucose and insulin in men aged 55-89 years)

lncreased risk of prostate cancer 38. Pourmand G, Salem S, Mehrsai A, Lotfi M, Amirzargar MA, Mazdak H, Roshan AI, Kheirollahi A, Kalantar E, Baradaran N, Saboury B, Allameh F, Karami A, Ahmadi H, Jahani Y. The risk factors of prostate cancer: a multicentric case-contrai study in iran. Asian Pac J Cancer Prev. 2007 Jui-Sep;8(3):422-8. Urology Research Center, Medicai Sciences/University of Tehran, Sina Hospital, Hassan-Abad Sq., Tehran 1136746911, lran [email protected]. (lncreasingly lower leveis of testosterone, the testosterone to PSA ratio, dihydrotestosterone with the reference range are associated with prostate cancer: one unit elevation in serum testosterone concentration was related to a -21% significant decrease of prostate cancer risk) 39. Severi G, Morris HA, Maclnnis RJ, English DR, Tilley W, Hopper JL, Boyle P, Giles GG. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemia! Biomarkers Prev. 2006 Jan;15(1):86-91. Cancer Epidemiology Centre, The Cancer Council Victoria, University of Melbourne, Melbourne, Australia. [email protected](The risk of prostate cancer was approximately almost halved for a doubling of the concentration of for a doubling of the concentration of testosterone (HR, 0.55; 95% C!, 0.32-0.95)) 40. Karamanolakis D, Lambou T, Bogdanos J, Milathianakis C, Sourla A, Lembessis P, Halapas A, Pissimissis N, Dessypris N, Petridou ET, Koutsilieris M. Serum testosterone: A potentially adjunct screening test for the assessment of the risk of prostate cancer among men with modestly elevated PSA values (> or =3.0 and <10.0 ng/ml). Anticancer Res. 2006 Jui-Aug;26(4B):3159-66. Department of Experimental Physiology, Medicai School, University of Athens, Goudi-Athens, Greece. (Testosterone and the testosterone to PSA ratio were inverse/y and significantly related to prostate cancer. The risk of prostate cancer increasing sharply (12.5 times) with a decrease of the Testosterone to PSA ratio by one standard deviation)

Dihydrotestosterone is strongly and inversely associated with the risk of prostate cancer 41. Signorello LB, Tzonou A, Mantzoros CS, Lipworth L, Lagiou P, Hsieh C, Stampfer M, Trichopoulos D. Serum steroids in relation to prostate cancer risk in a case-contrai study (Greece). Cancer Causes Contrai. 1997 Jul;8(4):632-6. Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, Massachusetts 02115, USA. (DHT was inversely, significantly and strongly associated with the risk of prostate cancer)

801

Higher HIV RNA in HIV-positive men 42. Ferrando SJ, Rabkin JG, Poretsky L. Dehydroepiandrosterone sullate (DHEAS) and testosterone: relation to HIV illness stage and progression over one year. J Acquir lmmune Delic Syndr. 1999 Oct 1;22(2):146-54. Department oi Psychiatry, Cornell University Medicai College, New York, New York,

USA.(Serum free

testosterone was inverse/y correlated with HIV RNA)

Studies that show that men who are at or below the 33th percentile (in the lower tertile) of serum testosterone leveis have an increased risk of the following diseases: Metabolic syndrome In nonsmoking men 43. Blouin K, Després JP, Couillard C, Tremblay A, Prud'homme D, Bouchard C, Tchernol A. Contribution oi age and declining androgen leveis to leatures oi the metabolic syndrome in men. Metabolism. 2005 Aug;54(8):103440. Molecular Endocrinology and Oncology Research Center, Lavai University Medicai Research Center, Quebec, Canada G1 V 4G2. (Men in lhe upper tertile of testosterone leveis had a significant -76% /ower risk of being characterized by 3 or more features of lhe metabolic syndrome independent of age) In middle-aged men

44. Tong PC, Ho CS, Yeung VT, Ng MC, So WY, Ozaki R, Ko GT, Ma RC, Poon E, Chan NN, Lam CW, Chan JC. Association oi testosterone, insulin-like growth lactor-1, and C-reactive protein with metabolic syndrome in Chinese middle-aged men with a lamily

history oi type 2

diabetes.

J Clin Endocrinol

Metab. 2005

Dec;90(12):6418-23 Department oi Medicine and Therapeutics, School oi Public Health, The Chinese University oi Hong Kong, The Prince oi Wales Hospital, Shatin, Hong Kong. [email protected] (The frequency of metabolic syndrome increased with declining tertiles of total testosterone and /GF-1 in men with or without a

family history of diabetes (mean age: 39.1 and 43.9 years), but increasing tertiles of serum CRP. After adjustment for age and smoking history, subjects with ali three

risk factors had a 13-fo/d increase in risk

association with MES compared with those without hormonal and inflammatory risk factors)

Diabetes in men 45. Selvin E, Feinleib M, Zhang L, Rohrmann S, Rilai N, Nelson WG, Dobs A, Basaria S, Golden SH, Platz EA. Androgens and diabetes in men: results lrom lhe Third National Health and Nutrition Examination Survey (NHANES 111). Diabetes Care. 2007 Feb;30(2):234-8. Department oi Epidemiology, Johns Hopkins Bloomberg School oi Public Health, 615

N. Wolle Street, Baltimore, MO 21205, USA. (Low free and bioavailable

testosterone concentrations in the normal range were associated with diabetes, independent of adiposity; Men in lhe first tertile of bioavailable testosterone were approximately four times as likely to have prevalent diabetes compared with men in lhe third tertile )

Lower bone mineral density in o/der men

46. Kenny AM, Prestwood KM, Marcello KM, Raisz LG. Determinants oi bone density in healthy o/der men with low testosterone leveis. : J Gerontol A Biol Sei Med Sei. 2000 Sep;55(9):M492-7. Center on Aging, University oi Connecticut Health Center, Farmington 06030-5215, USA. [email protected] (Femoral neck bone mineral density mean va/ues were 0.86 glcm2 for the lowest tertile, 0.94 for lhe middle tertile, and 0.99 for lhe highest

tertile. 52% of o/der men with /ow bioavai/able testosterone leveis had BMO leveis below lhe young adult normal range associations persisted even after excluding men with clinically abnormal testosterone concentrations defined as total testosterone <3.25 ng/ml or free testosterone <0.07 nglml)

Studies that show that subjects who are at or below the 75thpercentile (in the lower three guartiles) of serum testosterone leveis have an increased risk of dying lncreased overall, cardiovascular and cancer mortality in men aged 40 to 79 years 47. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N. Endogenous testosterone and mortality due to ali causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007 Dec 4;116(23):2694-701 Clinicai Gerontology Uni! Box 251, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. kk101 @ medschl.

802

cam.ac.uk (For increasing quartiles of endogenous testosterone compared with the /owest quartile: -25 %

mortality reduction for the middle low quartile, -38% for the middle high quartile and -41% for the upper quartile)

Studies that show that subjects who are at or below the 25thpercentile (in the lower guartile) of serum testosterone leveis have an increased risk of disease or dying lncreased overall, cardiovascular and respiratory disease mortality in men aged 50-91 years 48. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008 Jan;93(1):68-75. Department of Family and Preventive Medicine, School of Medicine, University

of

California,

San

Diego,

9500

Gilman

Drive,

MC

0631C,

La

Jolla,

California

92093.

[email protected]. (Men aged 50-91 (median 73.6) years followed up for 17 to 20 years whose total

testosterone leveis were in the /owest quartile (<241 ng/dl) were 40% [hazards ratio (HR) 1.40; 95% confidence interval (C/) 1.14-1.71] more likely to die than those with higher leveis, Low testosterone predicted increased risk of cardiovascular (HR 1.38; 95% C/ 1.02-1.85) and respiratory disease (HR 2.29; 95% C/ 1.25-4.20) mortality, but was not significantly related to cancer death (HR 1.34; 95% CI 0.89-2.00).

lncreased risk of peripheral arterial disease 49. Tivesten A, Mellstróm D, Jutberger H, Fagerberg B, Lernfelt B, Orwoll E, Karlsson MK, Ljunggren O, Ohlsson C. Low serum testosterone and high serurn estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. : J Am Coll Cardiol. 2007 Sep 11;50(11):1070-6 The Wallenberg Laboratory for Cardiovascular Research, Góteborg University, Góteborg, Sweden. [email protected]

(Low serum testosterone and high serum estradiol levels are associated with lower extremity peripheral arterial disease (defined as ankle-brachial index <0. 90) in elderly men mean age 75.4 years); free testosterone independently and positive/y associates with ank/e-brachial index (p < 0.001)) free testosterone in the lowest quartile (vs. quartiles 2 to 4; odds ratio 1.65,: p 0.001} and free estradiol in the highest quartile (vs. quarti/es 1 to 3; OR 1.45, p 0.012) independently associate with lower extremity PAD) =

=

=

lncreased risk of diabetes in men aged 55-89 years 50. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL; Rancho Bernardo Study. Endogenous sex hormones and lhe development of type 2 diabetes in older men and women: lhe Rancho Bernardo study. : Diabetes Care. 2002 Jan;25(1 ):55-60. Division of Epidemiology, Department of Family and Preventiva Medicine, University of California, San Diego, California 92093-0607, USA. (The odds for new diabetes were 2.7 (95% C/ 1.1-6.6) for

men in the /owest quartile of total testosterone in men in men aged 55-89 years)

Hip bone density loss in older men with weight loss 51. Ensrud KE, Lewis CE, Lamber! LC, Taylor BC, Fink HA, Barrett-Connor E, Cauley JA, Stefanick ML, Orwoll E; Osteoporotic Fractures in Men MrOS Study Research Group. Endogenous sex steroids, weight change and rales of hip bone loss in older men: lhe MrOS study. Osteoporos lnt. 2006;17(9):1329-36. Department of Medicine 111-0, VA Medicai Center, One Veterans Drive, Minneapolis, MN 55417, USA. [email protected]

(Among o/der men with weight loss, the rate of decline in total hip bane mineral density showed a stepwise increase in magnitude with greater decreases in bioavailable testosterone from baseline (p value for trend <0.001)

Studies that show that subjects who are at or below the 20th percentile (in the lower quintilel of serum testosterone leveis have an increased risk of the following disease: lncreased atherosclerosis (intima media thickness) in men aged 25-84 years 52. Svartberg J, von Mühlen D, Mathiesen E, Joakimsen O, B0naa KH, Stensland-Bugge E. Low testosterone leveis are associated with carotid atherosclerosis in men. J lntern Med. 2006 Jun;259(6):576-82. Department of Medicine,

University

Hospital

of North Norway,

Troms0,

Norway. [email protected]

testosterone leveis in the lowest quintile (<9.0 nmol L(-1)) had an independent OR the highest intima media thickness quintile)

803

=

1.51 (P

=

(Men with

0.015) of being in

Studies that show that subjects who are at or below the 101h percentile of serum testosterone leveis have an increased risk of dying lncreased mortality in chronic heart failure patients 53. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006 Oct 24;114(17):1829-37. Cardiology Department, Military Hospital, ui. Weigla 5, 50981 Wroclaw, Poland. [email protected]

CUTOFF leveis for serum testosterone, below which the risk of disease or death is increased A number of studies show that men with serum IGF-1 leveis within lhe normal (reference range), but at or below a precise cutoff serum levei may at a higher risk of developing a disease or of dying. The first two tables below presents the reference ranges (95th centile) of plasma total testosterone, SHBG,

calculated free testosterone and bioavailable testosterone leveis.

Age-adjusted reference ranges for testosterone in men in nmol, pmol, etc. Patient age group 2(}-39 years 4o-89 years

Notes:

Total Testosterone

SHBG nmol/1

nmol/1 12.4-26.4

4.9-24.4

The

11.7-53.4

18.Q-67.0

bioavailable

Free testosterone (Sode-

(Vermeu-

�heeler)

rgard)

len)

0.236-

0.19Q-

0.256-

0.680

0.665

0.716

nmol/1

nmol/1

nmol/1

0.117-

0.092-

0.131-

0.558

0.552

0.580

reference

range

testosterone

Free Androgen lndex

Nanje-

29.Q-140.6

14.4-89.7

is

obtained

http://www.mayomedicallaboratories.com/test-catalog/Ciinical+and+lnterpretive/83686;

Bioavailable testosterone nmol/1

20-29 yr

2.88-8.92

30-39 yr 40-49 yr 50-59 yr 60-69 yr 2!70 years

2.50-8.15

from Ali

2.12-7.39 1.74-6.59 1.39-5.83

Not established

Mayo lhe

other

Clinic

at

reference

ranges from Teoh YP, Wallace AM. Population reference ranges for plasma testosterone and calculated free testosterone in older men. Endocrine Abstracts 200; 12: 104

Age-adjusted reference ranges for testosterone in men in ng, pg, etc. Patient age group

Total Testosterone

SHBG mg/1

nd/dl

Free testosterone (Sodergard)

(Vermeulen)

pg/ml

pg/ml

(NanjeWheeler)

pg/ml

Free Androgen lndex

2(}-39 years

357-761

1.11-5.14

68-196

55-192

74-206

29.Q-140.6

4Q-89 years

141-703

1.71-6.37

34-161

27-159

38-167

14.4-89.7

804

Bioavailable testosterone ng/dl

20-29 yr

83-257

30-39 yr 40-49 yr 50-59 yr 60-69 yr 2!70 years

72-235 61-213 50-190 40-168 Not established

The second table presents the threshold or cutoff leveis of serum testosterone, below which the risk of disease or death has been reported to significantly increase.

Thresholds/cutoff leveis of serum Total Testosterone for disease within the reference range in men The cutoff levei is

CUTOFF levei of serum Total Testosterone

Morbidity risk BELOW

Reference study

the cutoff levei

Comment

2x greater ris for the lowes tertile versus lhE highest tertile i men with PSA 4 ng/ml >

250

8.7

ng/dl

nmol/1

270

9.4

ng/dl

nmol/1

With in the

reference range for serum Testosterone of

282

9.8

ng/dl

nmol/1

Greater malignancy of prostate cancer

lncreased carotid atherosclerosis

Depression

40-89

year-old men

Prostate cancer

288

10

ng/dl

nmol/1

Type2 Diabetes

Worse HIVinfection 300

10.4

ng/dl

nmol/1

Within lhe

reference range for serum Testosterone of 20-89

year-old men

Greater malignancy of Prostate cancer Loss of vigor

432

15.0

ng/dl

nmol/1

Loss of libido

449

15.6

ng/dl

nmol/1

Type2 Diabetes

54.Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen leveis of 4.0 ng/ml or less. Urology. 2006 Dec;68(6):1263-7

55.Teloken C, Da Ros CT, Caraver F, Weber FA, Cavalheiro AP, Graziottin TM. Low serum testosterone leveis are associated with witt In men positive surgical margins in radical retropubic prostate cancer prostatectomy: hypogonadism represents bad prognosis in prostate cancer. J Urol. 2005 Dec;174(6):2178·80 56.Mãkinen J, Jãrvisalo MJ, Põllãnen P, in middle-agec Perheentupa A, lrjala K, Koskenvuo M, men, 40· to 70 Mãkinen J, Huhtaniemi I, Raitakari OT. mer year-old lncreased carotid atherosclerosis in (mean age 5 andropausal middle-aged men. J Am Coli years) Cardiol. 2005 May 17;45(10):1603-8. Faber S, Nieschlag E. 57.Zitzmann M, Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006 In older men Nov;91(11):4335-43 lnstitute of Reproductive Medicine of the University, Domagkstr. 11, D48129 Münster, 58.Kiein RS, Lo Y, Santoro N, Dobs AS. Androgen leveis in older men who have or who In HIV-infectec are at risk of acquiring HIV infection. Clin lnfect men Ois. 2005 Dec 15;41(12):1794-803 59.Schatzl G, Madersbacher S, Haitel A, Gsur A, Preyer M, Haidinger G, Gassner C, Ochsner M, Marberger M. Associations o f serum witt In men with microvessel density, testosterone prostate cancer androgen receptor density and androgen receptor gene polymorphism in prostate cancer. J Urol. 2003 Apr;169(4):1312-5 Nieschlag E. 60.Zitzmann M, Faber S, Association of specific symptoms and metabolic risks with serum testosterone in In older men older men. J Clin Endocrinol Metab. 2006 Nov;91 (11):4335-43 61.Ding EL, Song Y, Malik VS, Liu S. highe with Men Sex differences of endogenous sex testosterone leveis (range hormones and risk of type 2 449.6-605.2 ng/dl) had diabetes: a systematic review and 42% lower risk of type meta-analysis. JAMA. 2006 Mar diabetes 15;295(11):1288-99

805

Thresholds or cutoff leveis of serum Free Testosterone in men The cutoff levei is

Below the ref. ranges

CUTOFF; levei of serum Free Testosterone

Morbidity risk BELOW the cutoff levei

7.5 pg/ml

0.03 nmoi/L

lncreased mortality

10 pg/ml

0.035 nmoi/L

lncreased arterial stiffness

of young and old men

17.3 pg/ml

0.06 nmoi/L

Premature coronary disease

Within lhe

ref. range of 20-39 year old men (Vermeulen) 40-89 yearold men

61 pg/ml

0.21 nmol/1

Poor cognitive performance

Reference study

Comment

62.Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch lntern Med. 2006 Aug 1428;166(15):1660-5 63.Fukui M, Ose H, Kitagawa Y, Yamazaki M, Hasegawa G, Yoshikawa T, Nakamura N. Relationship between low serum endogenous androgen concentrations and arterial stiffness in men with type 2 diabetes mellitus. Metabolism. 2007 Sep;56(9):1167-73 64.Turhan S, Tulunay C, Güleç S, Ozdõl C, Kilickap M, Altin T, Gerede M, Erol C. The association between androgen leveis and prematura coronary artery disease in men. Coron Artery Dis. 2007 May;18(3):159-62 65.Yeap 88, Almeida OP, Hyde Z, Chubb SA, Hankey GJ, Jamrozik K, Flicker L. Higher serum free testosterone is associated with better cognitiva function in older men, while total testosterone is not. The Health In Men Study. : C!in Endocrinol 2008 (Oxf). Mar;68(3}:404-12.

In older men

In men with type � diabetes mellitus

8elow lhe cut-o value of 17.3 pg/m had an adjustec 3.3-fold o risk developing prematura coronarJ arterv disease

Serum free testosterone � 210 pmol/1 wa associated with -29o/c reduced likelihood o cognitive poor performance on lhe SMMS

Thresholds or cutoff leveis of serum bioavailable testosterone for disease within the reference range CUTOFF levei The cutoff levei is Within lhe ref. range of 20-39 year old men 40-89 year-old men

of serum Bioavailable Testosterone

100 ng/dl

0.21 nmol/1

Morbidity risk BELOW the cutoff levei

Severe erectile dysfunction

Reference study

66.Kratzik CW, Schatzl G, Lunglmayr G, Rücklinger E, Huber J. The impact of age, body mass index and testosterone on erectile dysfunction. J Urol. 2005 Jul;174(1):240-3

Comment

Low

bioavailabl

testosterone ($ 1 ng/ml) => 3 higher o risk erectile severe dysfunction

Studies of diseases that are associated with lower testosterone leveis within the reference range of older men, suggesting that lhe lower leveis might contribute to lhe disease Lower health

67. Mohr BA, Guay AT, O'Donnell A8, McKinlay JB. Normal, bound and nonbound testosterone leveis in normally ageing men: results from lhe Massachusetts Male Ageing Study. Clin Endocrinol (Oxf). 2005 Jan;62(1):64-73. New England Research lnstitutes, Watertown, Massachusetts 02472, USA. [email protected] (Apparently healthy

men had significantly higher hormone concentrations at most time points than did not apparently healthy men)

806

Schizophrenia 68. Rãsãnen P, Hakko H, Visuri S, Paanila J, Kapanen P, Suomela T, Tiihonen J. Serum testosterone leveis, mental disorders and criminal behaviour. Acta Psychiatr Scand. 1999 May;99(5):348-52. Department of Psychiatry, University of Oulu, Finland.(Among schizophrenic males, total (P=0.01) and free testosterone (P=0.01) dec!ined significantly more with age compared to healthy contrais and patients with personality disorders, and a/so correlated with duration of neuro/eptic drug use (r=-0.60, P=O.OOO for total and r=-0.46, P=0.0001 for free testosterone)

Erectile dysfunction 69. Ahn TY, Park JK, Lee SW, Hong JH, Park NC, Kim JJ, Park K, Park H, Hyun JS. Prevalence and risk factors for erectile dysfunction in Korean men: results of an epidemiological study. : J Sex Med. 2007 Sep;4(5):1269-76. Department of Urology, University of Ulsan College of Medicine, Asan Medicai Center, Seoul, Korea.

lnfertility 70. Andersson AM, Jorgensen N, Frydelund-Larsen L, Rajpert-De Meyts E, Skakkebaek NE. lmpaired Leydig cell function in infertile men: a study of 357 idiopathic infertile men and 318 proven fertile controls. J Clin Endocrinol Metab. 2004 Jul;89(7):3161-7. Department of Growth and Reproduction, Copenhagen University Hospital, Section GR 5064, Blegdamsvej 9, DK-2100 Copenhagen OE, Denmark. [email protected] (lmpaired Leydig ce/1 function in infertile men was associated with lower testosterone and testosterone!LH and higher estradiol, estradiol/testosterone, and LH)

Coronary heart disease 71. Zhao SP, Li XP. The association of low plasma testosterone levei with coronary artery disease in Chinese men. In! J Cardiol. 1998 Jan 31;63(2):161-4. Department of Cardiology, Second Affiliated Hospital, Hunan Medicai University, Changsha, P.R. China. (Low plasma TTT leve/ may be a risk factor for CHO) mean plasma total testosterone leveis inpatients with coronary heart (252+1-125 ng/ml) was significantly -39% lower than in the healthy subjects (412+1-309 nglml)) 72. Chearskul S, Charoenlarp K, Thongtang V, Nitiyanant W. Study of plasma hormones and lipids in healthy elderly Thais compared to patients with chronic diseases: diabetes mellitus, essential hypertension and coronary heart disease. J Med Assoe Thai. 2000 Mar;83(3):266-77. Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (Men with coronary heart disease had the lowest testosterone leveis compared with men with essential hypertension or non-insulin dependent diabetes mellitus)

Higher fat mass 73. Vandenput L, Mellstrõm D, Lorentzon M, Swanson C, Karlsson MK, Brandberg J, Lõnn L, Orwoll E, Smith U, Labrie F, Ljunggren O, Tivesten A, Ohlsson C. Androgens and glucuronidated androgen metabolites are associated with metabolic risk factors in men. J Clin Endocrinol Metab. 2007 Nov;92(11):4130-7 Department of Internai Medicine, Gothenburg University, SE-41345 Gothenburg, Sweden. (BENEFICIAL 8oth dihydrotestosterone and testosterone were negative/y associated with different measures of fat mass in both cohorts; ADVERSE:: androstanediof g/ucuronide was independently positive/y associated with fat mass (P 0.001))

<

Higher body mass index and waist to hip ratio 74. Rhoden EL, Ribeiro EP, Teloken C, Souto CA. Diabetes mellitus is associated with subnormal serum leveis of free testosterone in men. BJU lnt. 2005 Oct;96(6):867-70. Urology, Federal Foundation of Medicai Sciences of Porto Alegre, Porto Alegre, RS, Brazil. [email protected] (Subnormal total testosterone leveis were more strongly associated with elevated BMI and WHR (OR 2.6; 95% C/ 1.7-3.9 and 2.0; 1.4-2.9))

Obesity 75. Allan CA, Strauss BJ, Burger HG, Forbes EA, McLachlan RI. The association between obesity and the diagnosis of androgen deficiency in symptomatic ageing men. Med J Aust. 2006 Oct 16;185(8):424-7. Prince Henry's lnstitute, Melbourne, VJC, Australia. (Men aged 54-86 years with mean BM/ 27.3: Obese men (BMI > or = 30.0 kglm2 or WC > or 102 em) had a significant -15% lower total testosterone (TT) (12.7 nmo/11 (366 ng/dl) v15.0 4 =

nmo//L (432 ng/d/); P < 0.001) and -8% lower calculated free testosterone (275.7 v 299.3 +1- 7.4 pmoi/L); P = 0.03) leveis than non-obese men)

807

Diabetes 76. Chen RY, Wittert GA, Andrews GR. Relative androgen deficiency in relation to obesity and metabolic status in older men. Diabetes Obes Metab. 2006 Jul;8(4):429-35. Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. [email protected] (Total testosterone leveis were significantly -15 % lower in diabetic men (mean age of 76.2 years) compared with non-diabetic men (12.1 +1- 0.7 vs. 14.2 visceral obesity and severa/ components of the metabolic syndrome in men with a mean age of 76.2 +1- 0.3 years who were followed up for 8 years) 77. Rhoden EL, Ribeiro EP, Teloken C, Souto CA. Diabetes mellitus is associated with subnormal serum leveis of free testosterone in men. BJU lnt. 2005 Oct;96(6):867-70. Urology, Federal Foundation of Medicai Sciences of Porto Alegre, Porto Alegre, RS, Brazil. [email protected] (Free and total testosterone serum leveis were subnormal in 46% and 34% of diabetics, respectively, and in 24% and 23% of nondiabetics. Subnormal FT leveis were strongly correlated with DM (odds ratio (OR) 2.7; 95% confidence interval (C/) 1.8-4.1) but not with elevated BMI (OR 1.4; 95% C/ 1.0-2.0) 78. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006 Mar 15;295(11):1288-99. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medicai School, Boston, Mass, USA (The testosterone levei was -76.6 ngldl significantly lower on the average in men with type 2 diabetes)

Rheumatoid disease 79. Jiménez-Balderas FJ, Tápia-Serrano R, Fonseca ME, Arellano J, Beltrán A, Y áiíez P, Camargo-Coronel A, Fraga A. High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction. Arthritis Res. 2001;3(6):362-7 Departmento de Reumatología, Hospital de Especialidades, Centro Médico Nacional SXXI IMSS México, DF, México. [email protected] (Surprising/y high frequencies of rheumatic!autoimmune diseases in this sma/1 group of patients with untreated hypogonadism (P < 0.001) and vef}' low serum testosterone leveis (P 0.0005) =

Lower bone mineral density 80. Van Pottelbergh I, Goemaere S, Zmierczak H, Kaufman JM. Perturbed sex steroid status in men with idiopathic osteoporosis and their sons. J Clin Endocrinol Metab. 2004 Oct;89(10):4949-53. Department of Endocrinology, Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, B-9000 Ghent, Belgium. [email protected]
Vertebral fractures 81. Rossini M, Del Marco A, Dal Santo F, Gatti D, Braggion C, James G, Adami S. Prevalence and correlates of vertebral fractures in adults with cystic fibrosis. Bone. 2004 Sep;35(3):771-6. Rheumatology Unit, Osteoporosis Center, University of Verona, 37122, Verona, ltaly. [email protected] (Significantly lower serum estradiol and free testosterone leveis were observed in men with vertebral fractures)

808

Chapter eighteen:

Progesterone in men

Abundance of proqesterone in men: Men have as much progesterone in their blood as young women in the follicular phase of the menstrual cycle Oettel M, Mukhopadhyay AK. Progesterone: the forgotten hormone in men? Aging Male. 2004 Sep;7(3):2361. 57 Senescence is associated with a decline of the proqesterone-adrenal axis in men Reductions of progesterone leveis with senescence in men Belanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez JL, Labrie F. Changes in serum 2. concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J Clin Endocrinol Metab. 1994 Oct;79(4):1086-90 3.

Tietz NW, Shuey DF, Wekstein DR. Laboratory values in fit aging individuais - sexagenarians through

4.

Maki T. Age-related changes in secretion of adrenocortical steroid hormones in normal healthy men. Nippon

centenarians. Clin Chem. 1992 Jun;38(6):1167-85 Naibunpi Gakkai Zasshi. 1986 May 20;62(5):672-82

The progesterone increase after HCG stimulation disappears in elderly men Murono EP, Nankin HR, Lin T, Osterman J. The aging Leydig cell: VI. Response of testosterone precursors to 5. gonadotrophin in men. Acta Endocrinol (Copenh). 1982 Jul;100(3):455-61 Proqesterone treatment may oppose and proqesterone deficiency may triqqer some mechanisms of senescence in men lmmune deficiency: progesterone may improve immune resistance in certain conditions 6.

Vassiliadou N, Tucker L, Anderson DJ. Progesterone-induced inhibition of chemokine receptor expression on peripheral blood mononuclear cells correlates with reduced HIV-1 infectability in vitro. J lmmunol. 1999 Jun 15;162(12):7510-8

Limits to healthy cell proliferation: progesterone may increase the numbers of viable fibroblasts Yu WD, Panossian V, Hatch JD, Liu SH, Finerman GA. Combined effects of estrogen and progesterone on the

7.

anterior cruciate ligament. Clin Orthop Relat Res. 2001 Feb;(383):268-81

Proqesterone and psychic well-beinq in men Hot flashes in men: the improvement with progestogen treatment 8.

Langenstroer

P,

Kramer

B,

Cutting

B,

Amling

C,

Poultan T,

Lance

R,

Thrasher

JB.

Parenteral

medroxyprogesterone for the management of luteinizing hormone releasing hormone induced hot flashes in men with advanced prostate cancer. J Urol. 2005 Aug;174(2):642-5 9.

Barton D, Loprinzi C, Quella S, Sloan J, Pruthi S, Novotny P. Depo-medroxy-progesterone acetate for hot flashes. J Pain Symptom Manage. 2002 Dec;24(6):603-7

Sleep disorder: the improvement with progesterone treatment Oettel M, Mukhopadhyay AK. Progesterone: the forgotten hormone in men? Aging Male. 2004 Sep;7(3):23657 11. Andersen ML, Bittencourt LR, Antunes 18, Tufik 8.152. Effects of progesterone on sleep: a possible pharmacological treatment for sleep-breathing disorders? Curr Med Chem. 2006;13(29):3575-82

1 O.

(Progesterone improves steep apnea in men) Progesterone and aqe-related diseases in men Atherosclerosis in men: the protective effect of progesterone treatment 12. Ma Q, Sun X, Chen Y, Chen X, Zhi G, Tan G. Progesterone leveis and carotid intima-media thickness: a negativa association in older northern Chinese men. Tex Heart lnst J. 2009;36(4):303-8 Lee WS, Harder JA, Yoshizumi M, Lee ME, Haber E. Progesterone inhibits arterial srnooth muscle cell 13. proliferation. Nat Med. 1997 Sep;3(9):1005-8

Vasodilatation of arteries: increased with progesterone treatment Omar HA, Ramirez R, Gibson M. Properties of a progesterone-induced relaxation in human placenta! arteries and veins. J Clin Endocrinol Metab. 1995 Feb;80(2):370-3

14.

809

Obesity in men: the association with lower progesterone leveis Blanchette S, Marceau P, Biron S, Brochu G, Tchernof A. Circulating progesterone and obesity in men. Horm 15. Metab Res. 2006 May;38(5):330-5 Diabetes in men: improvement of arterial alterations with progesterone 16. Carmody BJ, Arara S, Wakefield MC, Weber M, Fox CJ, Sidawy AN. Progesterone inhibits human infragenicular arterial smooth muscle cell proliferation induced by high glucose and insulin concentrations. J Vasc Surg. 2002 Oct;36(4):833-8 Rheumatism in men: the association with lower progesterone leveis 17. Vogl O, Falk W, Oorner M, Scholmerich J, Straub RH. Serum leveis of pregnenolone and 17hydroxypregnenolone in patients with rheumatoid arthritis and systemic lupus ery1hematosus: relation to other adrenal hormones. J Rheumatol. 2003 Feb;30(2):269-75. Kidney impairement in men: progesterone treatment improves renal excretion of urinary sodium 18. Oparil S, Ehrlich EN, Lindheimer MO. Effect of progesterone on renal sodium handling in man: relation to aldosterone excretion and plasma renin activity. Clin Sei Moi Med. 1975 Aug;49(2):139-471 Hair loss in men: progesterone treatment inhibits the conversion of testosterone to the balding hormone DHT in human hair follicles 19. Niiyama S, Happle R, Hoffmann R. lnfluence of estrogens on lhe androgen metabolism in different subunits of human hair follicles. Eur J Oermatol. 2001 May-Jun;11(3):195-8 Loss of fertility in men: progesterone treatment stimulates hypermotility of spermatozoids and fertility of the human sperm 20. Gonzalez-Martinez MT, Bonilla-Hernandez MA, Guzman-Grenfell AM. Stimulation of voltage-dependent calcium channels during capacitation and by progesterone in human sperm. Arch Biochem Biophys. 2002 Oec 21. 22.

23. 24. 25.

26. 27. 28.

15;408(2):205-1o Kay VJ, Coutts JR, Robertson L. Effects oi pentoxilylline and progesterone on human sperm capacitation and acrosome reaction. Hum Reprod. 1994 Oec;9(12):2318-23 Giojalas LC, lribarren P, Molina R, Rovasio RA, Estolan O. Oetermination of human sperm calcium uptake mediated by progesterone may be useful for evaluating unexplained sterility. Fertil Steril. 2004 Sep;82(3):73840 Yang J, Serres C, Philibert O, Robel P, Baulieu EE, Jouannet P. Progesterone and RU486: opposing effects on human sperm. Proc Natl Acad Sei U S A. 1994 Jan 18;91(2):529-33 Uhler ML, Leung A, Chan SY, Wang C. Oirect effects of progesterone and antiprogesterone on human sperm hyperactivated motility and acrosome reaction. Fertil Steril. 1992 Oec;58(6):1191-8 Francavilla F, Romano R, Santucci R, Macerola B, Ruvolo G, Francavilla S. Effect oi human sperm exposure to progesterone on sperm-oocyte lusion and sperm-zona pellucida binding under various experimental conditions. lnt J Androl. 2002 Apr;25(2):106-12 Plant A, McLaughlin EA, Ford WC. lntracellular calcium measurements in individual human sperm demonstrate that lhe majority can respond to progesterone. Fertil Steril. 1995 Oec;64(6):1213-5 Villanueva-Oiaz C, Arias-Martinez J, Bermejo-Martinez L, Vadillo-Ortega F. Progesterone induces human sperm chemotaxis. Fertil Steril. 1995 Oec;64(6):1183-8 Baldi E, Krausz C, Luconi M, Bonaccorsi L, Maggi M, Forti G. Actions of progesterone on human sperm: a model oi non-genomic effects of steroids. J Steroid Biochem Moi Biol. 1995 Jun;53(1-6):199-203

Synthetically derived progestogens in men may act as a male contraceptive Handelsman OJ, Conway AJ, Howe CJ, Turner L, Mackey MA. Establishing lhe rninimurn effective dose and 29. additive effects of depot progestin in suppression of human sperrnatogenesis by a testosterone depot. J Clin Endocrinol Metab. 1996 Nov;81(11):4113-21 30. Soulir JC, Jouannet P, Marson J, Sournah A. Reversible inhibition oi sperm production and gonadotrophin secretion in men following combined oral medroxyprogesterone acetate and percutaneous testosterone treatment. Acta Endocrinol (Copenh). 1983 Apr;102(4):625-32 Traumatic brain injury: the protective association of higher progesterone leveis 31. Wright OW, Bauer ME, Hoffman SW, Stein OG. Serum progesterone leveis correlate with decreased cerebral edema a!ter traumatic brain injury in male rats. J Neurotrauma. 2001 Sep; 18(9):901-9. Traumatic brain injury: the improvement with progesterone treatment 32. Xiao G, Wei J, Yan W, Wang W, Lu Z. lmproved outcomes lrom the administration oi progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Cri! Care. 2008;12(2):R61

810

33.

Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG. ProTECT: A Randomized Clinicai Trial o! Progesterone for Acute Traumatic Brain lnjury. Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2

34.

Cutler SM, Vanlandingham JW, Murphy AZ, Stein DG. Slow-release and injected progesterone treatments enhance acute recovery after traumatic brain injury. Pharmacol Biochem Behav. 2006 Jul;84(3):420-8

35.

Robertson CL, Puskar A, Hoffman GE, Murphy AZ, Saraswati M, Fiskum G. Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss after traumatic brain injury in female rats. Exp Neural. 2006 Jan;197(1):235-43

36.

O'Connor CA, Cernak I, Vink R. Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res. 2005 Nov 16;1062(1-2):171-4

37.

Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits lhe inflammatory agents that accompany traumatic brain injury. Brain Res. 2005 Jul 5;1049(1):112-9

38.

Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma. 2005 Jan;22(1):106-18

39.

Stein DG, Hoffman SW. Estrogen and progesterone as neuroprotective agents in lhe treatment oi acute brain injuries. Pediatr Rehabil. 2003 Jan-Mar;6(1): 13-22

Facial nerve injury: the improvement with progesterone treatment 40.

Chavez-Delgado ME, Mora-Galindo J, Gomez-Pinedo U, Feria-Velasco A, Castro-Castaneda S, Lopez­ Dellamary Toral FA, Luquin-De Anda S, Garcia-Segura LM, Garcia-Estrada J. Facial nerve regeneration through progesterone-loaded chitosan prosthesis. A preliminary repor!. J Biomed Mater Res B Appl Biomater. 2003 Nov 15;67(2):702-11

Prostate hypertrophy/adenoma: the association of a low progesterone levei and a high estradiol 41.

Baranowska B, Zgliczynski S, Szymanowski J.

Hormonal disturbances in men with a prostatic adenoma. J

Urol (Paris). 1980;86(7):551-8

Prostate hypertrophy/adenoma: progesterone/progestogen treatments reduce the prostate volume Onu PE. Depot medroxyprogesterone in lhe management o! benign prostatic hyperplasia. Eur Urol.

42.

1995;28(3):229-35 43.

Chen W, Zhou XM, Chen DY, Kang JS. Effects o! cimetidine, progesterone, cannitracin and tolazoline on lhe weight and DNA content o! lhe testosterone-induced hyperplastic prostate o! lhe rat. Urol Res. 1988;16(5):3636

44.

Shimizu M, Tsutsui T, Kawakami E, Hori T, Fujita M, Orima H, Ogasa A. Effect o! chlormadinone acetate-pellet implantation on lhe volume o! prostate, peripheral blood leveis oi sex hormones and semen quality in the dog. J Vet Med Sei. 1995 Jun;57(3):395-9

45.

Flickinger CJ. The influence o! progestin and androgen on lhe fine structure o! lhe male reproductive tract o! the rat. 11. Epididymis and sex accessory glands. Anal Rec. 1977 Apr;187(4):431-62

Progesterone treatment increases the apoptosis of androgen-sensitive prostate cancer cells in vitro 46.

Andrews P, Krygier S, Djakiew D. Dihydrotestosterone (DHT) modulates the ability oi NSAIDs to induce apoptosis o! prostate cancer cells. Cancer Chemother Pharmacol. 2002 Mar;49(3):179-86

Progestogen treatment inhibits the growth of androgen insensitive prostate cancer cells in vitro 47. Lin MF, Kawachi MH, Stallcup MR, Grunberg SM, Lin FF. Growth inhibition o! androgen-insensitive human prostate carcinoma cells by a 19-norsteroid derivative agent, mifepristone. Prostate. 1995 Apr;26(4):194-204 Progesterone treatment opposes estrogen-induced metaplasia of prostate epithelium in castrated male mice treated with estrogens 48. Burrows H. Nature (London). 1936; 138: 164 Metastatic lesions from prostate cancer lesions express no progesterone receptors 30. Hobisch A, Hittmair A, Daxenbichler G, Wille S, Radmayr C, Hobisch-Hagen P, Bartsch G, Klocker H, Culig Z. Metastatic lesions from prostate cancer do not express oestrogen and progesterone receptors. J Pathol. 1997 Jul; 182(3):356-61

811

Progestogen treatment may induce more subjective remissions of short duration in men with hormone­ resistant prostate cancer 31. Fossa SD, Jahnsen JU, Karlsen S, Ogreid P, Haveland H, Trovag A. High-dose medroxyprogesterone acetate versus prednisolone in hormone-resistant prostatic cancer. A pilo! study. Eur Urol. 1985;11(1):11-6 Longevity: the improvement with progesterone treatment 32. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG. ProTECT: A Randomized Clinicai Trial of Progesterone for Acute Traumatic Brain lnjury. Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2

Progesterone diagnosis Serum progesterone 49. Boudou P, Taieb J, Mathian B, Badonnel Y, Lacroix I, Mathieu E, Millot F, Queyrel N, Somma-Delpero C, Patricot MC. Comparison of progesterone concentration determination by 12 non-isotopic immunoassays and gas chromatography/mass spectrometry in 99 human serum samples. J Steroid Biochem Moi Biol. 2001 Jul;78(1):97-104 Progesterone treatment in men Oral progesterone Romanoff LP, Morris CW, Welch P, Grace MP, Pincus G. Metabolism of progesterone-4-C14 in young and 50. elderly men. J Clin Endocrinol Metab. 1963 Mar;23:286-92

812

Bibliography Recommended Books for Physicians Textbooks of endocrinology Jean D. Wilson, Daniel W.Foster, Henry M. Kronenberg & P. Reed Larsen. (1998) Williams text book of endocrinology. 91h Edition Philadelphia. W.B. Saunders Company. Leslie J. DeGroot & J. Larry Jameson (ed) (2005) Endocrinology 51h Edition Volume 1 to 3 Philadelphia. W.B. Saunders Company

Senescence and hormones John E. Morley & Stanley G. Korenman (ed)

(1992) Endocrinology and Metabolism in the Elderly

Boston. Blackwell Scientific Publications.

Multiple hormone therapies -

Wayne Meikle. Hormone Replacement Therapy. Totowa-New Jersey, Ed. Humana Press Hertoghe Thierry, Jules-Jaques Nabet (2002) "The Hormone Solution" New York.

Ed. Harmony Books,

NewYork

Melatonin -

Arendt Josephine

(1995) Melatonin and the mammalian pineal gland London. Chapman & Hall. (1998) Melatonin in the promotion of health. Amsterdam. Harwood

Ronald R. Watson.

Academic Publishers. Hertoghe Thierry, Melatonin treatment in the perspective of Evidence Based Medicine,

875

p. small

print, also in DVD

Growth hormone therapy in adults Anders Juul an Jens O. L. Jorgenson. (2000· 2nd edition).

Growth hormone therapy in adults.

Cambridge, Cambridge University Press

Oxytocin -

Hertoghe Thierry, Passion, sex and long life, the oxytocin adventure, Ed. lnternational Medicai Books, Luxemburg, 201 O,

160 p.

Thyroid -

Lewis E. Braverman & Robert D. Utiger . (1996) Werner & lngbar's The Thyroid-the fundamental h and clinicai text-i Edition Philadelphia, Lippincott -Raven Publishers.

Cortisol replacement -

William M.Jefferies.

(2004·

3'd

Edition)

Safe Uses Of Cortisol.

Springfield, lllinois, Charles C

Thomas Publishers, Ltd. () Francis DW Lukens.

(1954).

Medicai Uses of Cortisone, including hydrocortisone and corticotrophin;

New York, Ed. Blakiston Company

DHEA Ronald R. Watson. (1999) Health promotion and aging: The role of Dehydroepiandrosterone (DHEA). Amsterdam. Harwood Academic Publishers -

Hertoghe Th., Nabet J.J, "La DHEA, l'hormone du mieux vivre", Ed. Presses du Châtelet, Paris, 2002 , 207 p. (2002)

813

Pregnenolone Ray Sahelian. (1997) Pregnenolone, Nature's Feel Good Hormone Garden City Park, New York. Avery Publishing Group. Female hormone replacement therapy Rogerio A. Lobo. (1994)

Treatment of the Postmenopausal Woman-basic and clinicai aspects

New York. Raven Press. N. Dusitsin and M. Notelovitz. Physiological Hormone Replacment Therapy. Casterton, Lancs, UK, Parthernon Publishing Group Sheldon J. Segal, Luigi Mastroianni Jr. Hormone use in menopause and male andropause. Oxford, Oxford University Press -

Jacques Lorrain, L. Pouffe Jr, V. Ravnikar. L, Speroff & N. Watts. (1995) La Ménopause: prise en charge globale et traitement Canada. Edisem, Maloine. Pierre Mauvais-Jarvis, Gilbert Schaison et Philippe Touraine. (1997- 3'd Edition) Médecine de la Reproduction Paris. Médecines-Sciences, Flammarion. Régine Sitruk-Ware. (1986) La Ménopause France. Flammerion Médecine- Sciences.

Testosterone and/or DHEA in women Male Hormone Therapy (1948) ed. Summit, New Jersy, Ed. Ciba Sheldon J. Segal, Luigi Mastroianni Jr.

Hormone use in menopause and male andropause.

Oxford, Oxford University Press Male hormone replacement therapy E. Nieschlag, H. M. Behre.

(1998- 2nd edition). Testosterone: Action, Deficiency, Substitution.

Berlin, Heidelberg, New York, d. Springer Verlag Carruthers M. (2004), Androgen deficiency in the adult mate: causes, diagnosis ans treatment. Ed. Taylor & Francis Group, Abingdon, Oxfordshire, U.K E. Nieschlag, H. M. Behre.

(1997)

Andrology: Male reproductive health and dysfunction.

Berlin. Spinger. Sheldon J. Segal & Luigi Mastroianni, Jr.

(2003)

Hormone Use in Menopause and Male

Andropause New York. Oxford University Press. -

J. Moller & H. Einfeldt.

(1984)

Testosterone Treatment of Cardiovascular Diseases

Berlin.

Springer-Verlag. P. Mauvais-Jarvis et édité par G. Schaison, P. Bouchard, J. Mahoudeau, F. Labrie.

(1984)

Médecine de la Reproduction Masculine Paris, Médecines-Sciences, Flammarion. Textbooks of anti-aging medicine and nutritional medicine -

Textbook of Lifespan and anti-aging medicine, Ed. lnternational Medicai Books, Luxemburg, 2008

-

Textbook of Nutrient therapy, Ed. lnternational Medicai Books, Luxemburg, 2008 (new edition, hard

(new edition, hard cover, second semester 2010), www.imbooks.info cover, second semester 2010), www.imbooks.info

Smaller version of 'Hormone handbook': Patient hormone handbook (additional chapters on how to work with vitamins, trace lements, minerais, fatty acids and amino acids) Patient hormone handbook, Ed. lnternational Medicai Books, Luxemburg, 2008, 31 O p. How to optimize hormone leveis with the food Hertoghe Th., Enrico M., la dieta ormonale; Ed. Sperling-Küpfer, Milan, 2008 (translated into French: Le régime hormone, Ed Thierry Souccar, Vergêze, France, 2010)

814

Recommended Books for the General Public Recommended Books for the General Public Multiple hormone therapies

Thierry Hertoghe, Jules-Jaques Nabet (2002) The Hormone Solution New York. Ed. Harmony Books, New York. Ronald Klatz. Ten weeks to a younger you. Sports tech Lab, Chicago. Melatonin

Pierpaoli, W. & Regelson, W. with Colman, C. (1995) The Melatonin Miracle New York. Simon Schuster. Sahelian, R. (1995) Melatonin-Nature's Sleeping Pill Marina del Rey. Be Happier Press. Reiter R. Your Body's Natural Wonder Drug. Bantam books. New York.

&

Growth hormone therapy in adults

Ronald Klatz. Grow young with HGH. USA, HarperCollins Publisher Thyroid

Brada Barnes, lawrence Galton. (1976) Hypothyroidism the unsuspected illness New-York, Harper and Row Publishers Mary J. Shomon. Living Well with Hypothyroidism. New-York, ed. Avon Books DHEA

Thierry Hertoghe, Jules -Jaques Nabet. {2002) DHEA L'hormone Du Mieux Vivre Paris. Presses du Châtelet. Ray Sahelian. (1996) DHEA, a practical guide. New York. Avery Publishing Group. Anne Dufour, Pierre Nijs. DHEA, mode d'emploi. Paris, ed. Marabout. Pregnenolone

Ray Sahelian. Group.

{1997)

Pregnenolone, Nature's Feel Good Hormone

New York. Avery Publishing

Cortisol

Williarn M.Jefferies. (2004- 3'd Edition) Safe Uses Of Cortisol. Charles C Thomas Publishers, Ltd. (lllinois) Eugenia Zuckerman and Julie R. lngelfinger. Coping with Prednisolone and other cortisone-related medicines. New York, St. Martin's Griffin Female hormones

Suzanne Somers. (2004). The sexy years. New Yrok Crown Publishers. Testosterone in women:

Susan Rako. (1996) The hormone of desire. Harmony Books, New York Testosterone in men

Malcolm Carruthers. Maximising Manhood. London, HarperCollons Publishers Shippen Eugene, Fryer William. Testosterone Syndrome. (1998) New-York, Ed. Evans Georges Debled. Au-delà de cette limite votre ticket est toujours valuable. Paris, Albin Michel

815

Articles and books by the author Professional medicai publications Articles in medicai journals: Hertoghe T. DHEA: info ou intox? Monde Médical. 1995 (Sept.); 291: 12-5 Hertoghe T. Growth hormone therapy in aging adults. Anti-Aging Medicai Therapeutics (Eds Klatz RM & Goldman R)1997;1:10-28 Hertoghe T. Thyroid Diagnosis & Treatment: Poor reliability of the single plasma TSH-test for diagnosis of thyroid dysfunction and follow-up. Anti-Aging Medicai Therapeutics 2000; IV: 127-37 Hertoghe T. Thyroid Diagnosis & Treatment: Many conditions related to age reduce lhe conversion of thyroxine to triiodothyronine - a rationale for prescribing preferentially a combined T3

+

T4

preparation in hypothyroid adults. Anti-Aging Medicai Therapeutics 2000; IV: 138-53 Hertoghe

T.

Minimizing

obesity

with

hormone

replacement

therapies.

Anti-Aging

Medicai

Therapeutics 2001-2003; V-VIl Hertoghe T. Minimizing obesity with hormone replacement therapies. Anti-aging Clinicai Protocols 2004-2005 Hertoghe T. Diabete: Vitamines, oligo-éléments, acides gras et hormones: que penser de ces thérapies complémentaires ? Gériatrie en médecine générale 2003 ; 47 (Sept): 10-12 and 48 (Oct): 8-11 Hertoghe T. DHEA, mélatonine, vitamines et oligo-éléments : adjuvants efficaces dans la lutte contre le cholestérol et l'athérosclérose? Gériatrie en médecine générale 2003; 49 (Nov):

8-12 and 50

(Dec):8-11 Hertoghe T, Lo Cascio A., Hertoghe J. Considerable improvement of hypothyroid symptoms with two combined T3-T4 medication in patients still symptomatic with thyroxine treatment alone. Anti-Aging Medicine (Ed. German Society of Anti-Aging Medicine-Verlag 2003)2004; 32-43 Hertoghe T. Bio-identical Hormone Replacement. Journal of Complementary Medicine Sept./Oct. 2004; 3 (5): 44-45 TM Hertoghe, B. Everard, B. Duboé, TA Hertoghe, M. François, J. Gouita, A. Gadomski, B. Poutet, D. Van Bruyssel, W. Baisier.

La DHEA : le bilan. Journal de médecine esthétique et chirurgie

dermatologique March 2003 ;. XXX : 117 :7-21 (337 references) Hertoghe T. The "multiple hormone deficiency" theory of aging: is human senescence mainly caused by multiple hormone deficiencies? 2005 Ann N Y Acad Sei. 2005 Dec;1057:448-65 Hertoghe TM, Hertoghe Th, Gadomski A, François M, Everard B, Duboé B*. Melatonin and Sleep : a Review. J Eur Anti-Aging Med. 2005; 1: 32-7 Extensive reviews of the literature on hormone testing in 24-hour urine: Thyroid hormones in 24-hour urine DHEA, Androstenedione and their metabolites in 24-hour urine Cortisol and cortisol metabolites in 24-hour urine Pregnandiol and pregnantriol in 24-hour urine Aldosterone in 24-hour urine Testosterone in 24-hour urine Growth hormone in 24-hour urine Sodium, potassium, magnesium, calcium, phosphorus in 24-hour urine Reports of the Belgian Society of Anti-Aging Medicine by Drs Hertoghe Thierry, Everard B, Duboé B, François M, Hertoghe Thérése, Gadomski A., Poutet B, Baisier W, Rasmussen H. These reports are reviews of the scientific literature on lhe major hormone replacement therapies ordered by lhe Belgian Society of Anti-aging Medicine.

Most of lhe reports are extensive collections of data,

many of them containing lhe largest literature review up to today in anti-aging medicine for some of lhe hormone replacements shown below. Dr T. Hertoghe is the supervisor of the reports and main collector

816

of data. Mos! of lhe reports are still in preparation and no! completely finalized as lhe intent is to edit !hem officially ali together. La DHEA en question : La réponse au rapport de I'Académie de médecine et La réponse au rapport des endocrinologues d'Erasme Melatonin treatment in lhe perspective of Evidence Based Medicine, 875 p. small print, also in DVD Cortisol replacement therapy: Benefits and risks Safe Cortisol replacement therapy: Answers to criticai questions Thyroid replacement: Benefits and risks (in early preparation) Hormones, quality of life and fatigue Corrective GH replacement therapy in adults: Benefits and Risks (midway in preparation) Hormone tests in 24 hour urine Thyroid hormone tests in 24 hour urine Why T4-T3 treatments may work better to treat hypothyroidism in many patients (July 2004) Textbooks (handout formal) for the board certifications of the World society of anti-aging medicine

-

Textbook of Lifespan and anti-aging medicine,

Ed. internationai Medicai Books, Luxemburg, 2008 (new

edition, hard cover, second semester 2010), www.imbooks.info

Textbook of Nutrient therapy,

Ed. internationai Medicai Books, Luxemburg, 2008 (new edition, hard cover,

second semester 2010), www.imbooks.info

General public books by the author

Hertoghe Th., Nabet J.J., "Comment rester jeune plus longtemps", Ed. Albin,-Michel, Paris - France, 2000, 380 p. (translations in Dutch: "Jong en gezond oud worden" en "Taboehormoneri', Antwerp, Standaard Uitgeverij; German: Bleiben sie langer jung, München, Mosaik Verlag; Spanish: "La solución hormonar: Mexico, Aguilar; Danish: Det handler om hormoner. Copenhagen, Lindhardt og Ringhofand; also translations into Russian and Chinese).

Hertoghe Th., Nabet J.J, "La DHEA, l'hormone du mieux vivre", Ed. Presses du Châtelet, Paris, 2002 , 207 p. (2002) Patient hormone hand book, Ed. lnternational Medicai Books, Luxemburg, 2008, 310 p. Hertoghe Th., Jules-Jaques Nabet (2002) ''The Hormone Solution" New York. Ed. Harmony Books, New York Hertoghe Th., Enrico M., la dieta ormonale; Ed. Sperling-Küpfer, Milan, 2008 (translated into French: Le régime hormone, Ed Thierry Souccar, Vergeze, France, 2010) Hertoghe Th., Passion, sex and long life, the oxytocin adventure, Ed. lnternational Medicai Books, Luxemburg, 201O, 160 p. Buy books wriHen by Dr. Thierry Hertoghe

www.imbooks.info

817

HORMONE THERAPY SEMINARS, VIII. LABORATORIES, COMPOUNDING PHARMACIES

Recommended Laboratories for 24-hour urine tests

The list of recommended societies, laboratories and

Vitamin diagnostics-USA

pharmacies will be enriched in

Rt. 35 & Industrial Drive

future editions

07735 USA (732)583-7773 Fax: +1 (732)583-7774 (24h urine tests with T3,T4 and reverse T3) Cliffwood Beach, NJ Phone:+1

Hormone therapy seminars

Contact:

Elypsis - Roman Pais -Europe Rue Seutin 11 , 1400 Nivelles, Belgium

E-mail: medschool@ hertoghe.eu

Fax :

+32-67-89-54-32 +32-67-89-54-54

Phone : Website: www.hertoghe.eu www.intlhormonesociety.org www.wosaam.ws

+32-2-379.34.49 Fax: +32-2-732.57.43 Phone:

Pathlab-Australia

Address: Hertoghe Medicai School,

9 Avenue van Bever 1180 - Brussels Belgium

68 Burwood Hwy. 3125 Burwood, VIC Australia

+61-3-98082122 +61-3-98082247

Phone: lnternational Hormone Society

Fax:

(the society for advanced hormone

website : www.pathlab.com.au

therapies)

e-mail: enquiries@ pathlab.com.au

Web site www.intlhormonesociety.org Fax (international):

+32-2-732.57.43

World society of anti-aging medicine Web site: www.wosaam.ws Fax:

+32-2-732.57.43

820

Recommended compoundinq pharmacies for pharmaceutical grade hormones

Recaptura- pharmaproduktion FIZ Frankfurter lnnovationszentrum

University Compounding Pharmacy

Biotechnologie Mail: UCP, 1875 Third Ave.

Uni-Campus Riedberg

San Diego, CA 92101

Altenhõferallee 3

San Diego County, USA

D-60438 Frankurt am Main

Phone: 800-985-8065

Phone: +49

Phone: 619-683-2005

Fax: +49

Fax: +1- 619-683-2008

E-mail : [email protected]

(O) 69 92 880-300 (O) 69 92 880-333

E-mail: [email protected] www.ucprx.com (very active pharmacy in hormone therapies, organizes successful adult hormone therapy seminars. Us citizens can purchase the Hormone handbook through its web site)

College Pharmacy Australian Custom Pharmaceuticals 3505 Austin Bluffs Parkway, Suíte 101

PO Box 2954

Colorado Springs, CO 80918

TAREN POINT NSW 2229, Australia

Phone: 800-888-9358

Phone: 1300 853 620 (international) +61 2

Fax: 800-556-5893

8536 4100

Phone: +1-800- 888-9358

www.oxytocinprotocol.com.au

or+1-719)-262-0022 Fax: 800-556-5893 or+1-719-262-0035 E-mail : [email protected] Web site: webmaster@ collegepharmacy.com

Women's lnternational Pharmacy 12012 N. 111th Avenue Youngtown, AZ 85363 Phone: +1-623-214-7700, 800-279-5708 Fax: + 1-623-214-7708; toll free : 800-2798011 Email: [email protected]

821

lnternational

20............. .

Date:

Hormone Society·s www .intlhormonesociety.org

Become a member of lhe lnternational Hormone Society and help us defend patient's rights with lhe fines! and safes! hormone therapies. The lnternational Hormone Society is dedicated to defend patients' access to lhe best hormone treatments possible. lt offers training programs for physicians in hormone therapy from lhe basic ones to lhe mos! advanced ones. Vou can subscribe and signs petitions on: www.intlhormonesociety.org

€

Iam a physician and become a member of lhe INTERNATIONAL HORMONE SOCIETY (IHS), the evidence-based

society

on

advanced

"x »in

membership) (P/ease put an

and

traditional

hormone

replacement

fax:+32-27325743);

each box that fits;

therapies

(free

a membership form for

the society can be printed out on your own prínter by registering a second time on the IHS website www.intlhormonesociety.org) Vou would help increase the influence of lhe lnternational Hormone Society and protect your medicai license by reading and signing lhe hormone therapy consensuses (see website for the texts and references)

€

I agree on the IHS's Therapy Statement "on bio-identical hormones" and its ten Therapy Consensuses # 1 to 10 on 'Thyroid Hormone Therapy of Hypothyroidism, Estrogen & Progesterone Treatment of Pre- & Postmenopausal Women; Cortisol Replacement Therapy in Milder Forms of Adrenal Deficiency in Adults, DHEA Therapy of Adrenal Androgen Deficiency in Adults, Growth Hormone Therapy of Milder Forms of Growth Hormone Deficiency in Adults; Melatonin Treatment of Melatonin Deficiency; Testosterone Therapy of Partial Androgen Deficiency in Men; Testosterone

(fax:+32-27325743))

Therapy of Testosterone Deficiency in Women

Please write ali information in PRINT LETTERS very CLEARLV: please add "MO or DO" or "NP" to your name, PRINT CLEARLV Dr.

(MD or DO ar NP): l

FamilyName: FirstName:

Address:

l

Zip code:

1

Country: Phone:

l

l

1

1

_ _

l

l

l

l

l

l

l

l

l

l

l

l

l

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823

I

IX.

INDEX

Acne: 311,312, 336, 340

Blood pressure, low, hypotension: 52, 72,

Aged, prematurely: 47, 56, 171, 386 Aging, prematurely: 333,416

141, 190, 193, 203, 208, 224, 231, 233235, 237, 241-242, 356, 358, 388

Aldosterone: 231-246

Body, thin: 14, 58, 64, 101, 132, 133, 173,

Deficiency, complaints, symptoms: 234

183, 186, 188-189, 208, 223, 231, 243,

Deficiency, physical signs: 235

244, 246-249, 258, 263, 387-388, 392

Diagnosis: 233-236

Bradycardia, slow pulse rate: 47, 127, 387

Diet, food influences: 239

Breasts, droopy, ptosis: 142, 225, 270,

Excess, overdose signs and complaints:

272-273, 283-385, 288-290, 295-296, 389

240

Breasts, smaller, micromastia: 217, 225,

Lifestyle influences: 240

270, 273, 283, 290, 389

Onset of deficiency: 233

Breasts, men: 317, 318, 322, 347, 350,

Production: 232

362, 390

References: 660-664

Breasts: 96, 229, 267-268, 271, 273-274,

Roles, function, actions: 232

278, 286, 288, 291-292, 294, 303, 318,

Senescence, aging: 232

350, 385

Serum tests: 236

Breast enlarged, macromastia: 271, 273,

Therapy, treatment: 237-240 Timing

and

location

of

signs

294, 350, 389 and

symptoms: 234

Bruises, easily, ecchymosis: 200, 303, 322, 389

Treatment problems, problem solver:

Calcitonin: 143-152 Deficiency, complaints, symptoms: 146

241-242

Deficiency, physical signs: 146

Urinary, 24-hour urine: 236

Diagnosis: 145-147

Allergies: 25, 29, 67, 79, 141, 179, 186, 188, 190, 193, 195, 198, 203-204, 208,

Diet, food influences: 150

384, 416

Excess, overdose signs and complaints:

Anxiety, anxious: 46, 53-54, 57, 94, 96-97,

151

101, 139, 141, 172, 180, 182-183, 187,

Lifestyle influences: 150

205, 209, 242, 272, 286, 291, 299, 302-

No inhibition of endogenous calcitonin

303, 308, 321, 379, 381

secretion by intranasal and

Anger: 88, 141, 181, 183, 186-187, 242,

intramuscular calcitonin: 568

272, 286, 291, 299, 380, 381, 388

Onset of deficiency: 145

Anxiety, lack of inner peace (especially at

Production: 144

night): 46, 350, 381

References: 562-568

Anxiety, outbursts of anxiety, panic attacks

Roles, function, actions: 144

:57, 172, 183, 186-187, 224, 272, 286,

Senescence, aging: 144

291, 299, 380-381, 379-388

Serum tests: 147

Anxiety, mild- moderate: 205, 209

Timing

Back pain, low: 126, 146, 157, 302, 383

symptoms: 145

Back pain, middle: 146, 157 Bloating, bloated abdomen: 67, 100, 126,

Therapy, treatment: 148-151

and

location

of

signs

and

Treatment problems, problem solver: 152

127, 179, 188, 189, 247, 286, 291, 297,

Carpa! tunnel syndrome, tingling fingers:

368, 383 Bloating, premenstrual: 272, 283, 385,

68, 126, 180, 383

388, 416

Cellulite: 303, 309, 322, 389-390

Blood pressure diastolic: 21, 81, 124, 127,

Cheeks, sagging: 53, 56, 171, 386

387

Cheeks, flush: 92

Blood pressure, high: 43, 47, 81, 127, 139,

Cheeks, pale: 98, 386, 388

200, 201, 229, 237-238, 240-241, 318,

Cheeks, hollow: 189

323, 349, 386-387

Cheloid: 188,190, 388

Blood pressure increase: 21, 78, 11O, 120,

Cold sweating: 263, 264

184, 193,232, 238, 297, 358, 415

Cold, intolerance: 57,123, 126-127, 133,

Blood pressure, low, drop: 87, 92, 163,

172, 264, 383, 387

203, 352, 356 827

Treatment problems, problem solver:

Cortisol and glucocorticoids: 183-204 Cortisol deficiencies with serum cortisol

217-219 Urinary, 24-hour urine: 211

leveis within the reference range: 621

Heat, intolerance: 126, 383

Cortisol or glucocorticoid treatment and adrenal suppression , 613

Heat production, overheating: 70, 124,

Deficiency, complaints, symptoms: 187-

139-141

188

Constipation: 116, 127,163-164, 321, 350,

Deficiency, physical signs: 189-190

383

Diagnosis: 185-191

Coldness (character): 91, 95-96

Diet, food influences: 196

Colds (rhinitis): 183, 189

Excess, overdose signs and complaints:

Cramps, feet, legs, hands: 126, 157,158,

200

297, 383

Glucocorticoids and bone density: 616

Cravings, salty food: 188,224,234, 384

Lifestyle influences: 196, 198

Cravings, sugar, sweet: 186,188-189,

Memory loss and Alzheimer's disease:

224,242, 245, 247, 248, 383, 384, 388

619

Cystitis: 272,285

Onset of deficiency: 186

Depression, depressive: 46,54,64, 94,

Production: 184

97, 101,126-128, 135,187,205, 209, 225,

References: 599-624

272, 278,288-289, 293, 296, 300,302-

Roles, function, actions: 184

303,307, 309, 321-323, 356, 379, 381,

Senescence, aging: 187

391

Serum tests: 191

Drowsiness, drowsy, zombie-like feeling:

Therapy, treatment: 192-200

48, 65,101, 152, 188, 224, 231, 234-235,

Timing

and

location

of

signs

and

278, 356,358, 380, 384

symptoms: 187

Dyspareunia, painful intercourse: 272

Treatment problems, problem solver:

Emotions, excessive, outbursts of anger or

201-204

anxiety: 57,172,183, 186-187, 224,272,

Urinary, 24-hour urine: 191

286, 291, 299, 381,379-380,388 Erectile dysfunction, sexual impotence:

DHEA and androstenedione: 205-220 Androstenedione deficiency with serum

95-97, 101, 172,224, 248-249, 342,356-

androstenedione leveis within lhe

357, 380, 382, 384, 382

reference range: to treat or not to treat:

Estrogen and progesterone (women):

656

267-298

Deficiency, complaints, symptoms: 209

Controversy on the use or avoidance of

Deficiency, physical signs: 209

female HRT in women: 702

DHEA and adrenal suppression, 643

Deficiency, complaints, symptoms: 272

DHEA and breast cancer: 646

Deficiency, physical signs: 273

DHEA and prostate cancer: 643

Diagnosis: 270-276

DHEA deficiencies with serum DHEA

Diet, food influences: 284, 286

leveis within lhe reference range: 650

Estrogen deficiencies with serum

Diagnosis: 208-211

estrogen leveis within lhe reference

Diet, food influences: 214

range: 734

Excess, overdose signs and complaints:

Excess, overdose signs and complaints:

215

286

Lifestyle influences: 215

Lifestyle influences: 284, 286

Onset of deficiency: 208

Onset of deficiency: 270-271

Production: 207

Production: 268

References: 625-656

Progesterone deficiencies with serum

Roles, function, actions: 206

progesterone leveis or its urinary

Senescence, aging: 207

metabolite within lhe reference range: 738

Serum tests: 21O Timing

and

location

of

signs

and

References: 677-742 Roles, function, actions: 268-269

symptoms: 209

Salivary tests: 276

Therapy, treatment: 212-216

Senescence, aging: 269 828

Serum FSH leveis within the reference

Deficiency, physical signs: 55 Diagnosis: 54-58 Diet,food influences: 63 Excess,overdose signs and complaints:

range associated to disease: 740 Serum tests: 275,287

Therapy, treatment: 277-287 Timing and location of signs and symptoms: 271 Treatment problems,problem solver:

treatment: 465

288-297

GH treatment and adverse effects,the

68-72

Exercise

Urinary,24-hour urine: 276,287

as

an

alternative

to

GH

diabetes controversy: 467

Exhaustion: 53,57,172,382

GH and cancer: 471

Eyeballs,sunken: 107,109,110,112,

GH and cardiovascular system: 469

235,247,387,388

GH treatment and functional capacities,

Eyelids,dark circles: 189,388

metabolic rate: 466

Eyelids,droopy: 53,56,171,386

GH and life span: 476 GH treatment and muscle strength: 466

Eyelids,swollen: 127,180,387 Eyelids,edema: 68,180

GH treatment's influence on GH

Eyelids,tired: 189,47

endogenous secretion: 465

Eyes,bags,tired: 47

Growth hormone secretagogues: 64-66

Eyes,dry: 97,209,273,295,303,322,

Hormone fears,cancer risk: 73

389,390

Lifestyle influences: 67

Eyes,excessive bright: 139

Onset of deficiency: 54

Eyes,soft: 112,235,388

127,180,198,200,201,229,240,241,

Production: 54 References: 444-478 Roles,function,actions: Senescence,aging: 54 Serum tests: 58 Subcutaneous injections,best way to inject: 60 Therapy, treatment: 59-68 Timing and location of signs and symptoms: 55 Treatment problems,problem solver: 69-

273,286,297,387,389

72

Face,dry skin: 387 Face,pain: 157 Face,paie,white: 81,95,96,97,142,235, 267,273,288,303,322,386,388,389, 390

Face,prematurely aged: 321,320, Face,red,flushing: 89,104,105,240,241, 273,291,293,294,338,340,389

Face,swollen,puffy : 87,118,120,123,

Face,swollen,puffy: 87,118,120,123,

Urinary,24-hour urine: 58

127,180,387

Hair dry: 126,157,383

Face,thin,hollow: 55,101,139,186,189,

Hair loss,alopecia,diffuse: 126-127,383

208,231,233,235,243,248,249,273,

Hair loss, alopecia, in plaques, areata:

301,387,388,389

188-189

Face,very small: 168,170,249

Hair loss,alopecia,male pattern: 215-217,

Face,yellow,brown: 388

307,309,311,313,330,336,339,348,

Fatigue when standing up : 52,126,383

369-371

Fatigue when stressed: 72

Hair loss: 126-127,188,215-217,307,

Fatigue,chronic: 224,243,289,295,302,

309,311,313,320,330,336,339,348,

321,381,384,385

383

Fatigue, flu-like : 92,106

Headaches,diffuse: 126-127

Fatigue,tired(ness): 46,139, 140,151,

Hot flushes: 142,271-272,288-290,293,

152,157,163,164,188,190,192,193,

295,302,321,384-385

205,209,224,246 ,24,248,263,264,267,

IGF-1: 167-182 Deficiency,complaints,symptoms: 172 Deficiency, physical signs: 171 Diagnosis: 170-173 Diet,food influences: 177 Excess, overdose signs and complaints:

272,288

Fibroids: 271,273-274,278,280-281,283, 292,374,389

Fibromyalgia: 92,96-97,99-100,102,157158

Growth hormone i(adults): 53-74 Deficiency,complaints,symptoms: 56

180 829

with thyroid tests within reference

6-sulfatoxy-melatonin,urinary,24-hour urine: 47

ranges: 586

Absence of serious scientific studies in

Lifestyle influences: 177 Onset of deficiency: 170

humans: 439

IGF-1 and growth hormone deficiencies

Deficiency,complaints,symptoms: 46

Production: 169

Deficiency,physical signs: 47

References: 574-598

Diagnosis: 45-47

Roles,function,actions: 169

Diet,food influences: 50

Subcutaneous injections: 174-175

Excess,overdose signs and complaints:

Senescence, aging: 169

51-52

Serum tests: 173

Lifestyle influences: 50

Therapy, treatment: 174-180

Onset of deficiency: 45

Timing

and

location

of

signs

Production: 44

and

symptoms: 171

References: 423-443

Treatment problems,problem solver:

Roles,function,actions: 44

181-182

Salivary tests: 47

lmpotence, sexual,erectile dysfunction,:

Saliva tests:,47

95-97,101, 172,224,248-249,342,356-

Senescence,aging: 44

357,380,382,384,382

Therapy, treatment: 48-51

lncontinence,urinary: 272,302,309,358,

Timing of signs and symptoms: 45

385

Treatment and pineal gland inhibition,

lnfections,ear,nose and throat: 188,198,

439

383

Treatment problems,problem solver: 52 Urinary,24-hour urine: 47

lnsulin, 244-266 Deficiency,complaints,symptoms: 248

Memory loss,poor: 81,110-111,127-128,

Deficiency, physical signs: 249

187,221-223,227-228,230,321,324,

Diagnosis: 246-250

391

Diet,food influences: 261-262

Migraine: 126,145-146,148-149,286,

Excess,overdose signs and complaints:

291,296,383

263

MSH: 53-73

Lifestyle influences: 261

Bremelanotide: 78,83

Onset of deficiency: 246-247

Deficiency,complaints,symptoms: 80

Production: 244

Deficiency,physical signs: 81

References: 665-676

Diagnosis: 79-82

Roles,function,actions: 244

Diet,food influences: 85

Senescence,aging: 245

Excess,overdose signs and complaints:

Serum tests: 250

87 lntranasal spray: 84

Therapy, treatment: 251-263 Timing

and

location

of

signs

Lifestyle influences:

and

symptoms: 247

Melanotan I,77-78,85

Treatment problems,problem solver:

Melanotan 11, 77-78,85

264-265

Onset of deficiency: 79

Types of insulin deficiency: 246

Production: 77

lntercourse painful,dyspareunia: 272

References: 479-485

lntolerance to medications: 188,384

Roles,function,actions: 76

lrritability: 46,88,96-97,106, 139,141,

Subcutaneous injections: 83

186-187,242,242,272,286,291,380-

Serum tests: 82

381

Therapy, treatment: 83-87

Kyphosis: 55-56,146,158,171,303,322,

Timing

386-387, Libido, low: 88,224,248,272,299,301-

symptoms: 80

and

location

of

signs

and

Treatment problems,problem solver: 88-

302,306-308,311,342,353-354,386,

89

411

Nails,brittle: 80,157

Melatonin: 43-52 830

Therapy, treatment: 160-163 and location of signs and symptoms: 156 Treatment problems,problem solver: 164-165 Pigmented spots: 191,388 Polydipsia:224; 248-249,264,383 Polyuria:111,118,224,234,248,264, 383,384 Pregnenolone: 221-230 Deficiency,complaints, symptoms:224 Deficiency, physical signs: 225 Diagnosis: 223-226 Diet,food influences: 228 Excess,overdose signs and complaints: 229 Lifestyle influences: 228 Onset of deficiency: 223 Production:222 References: 657-659 Roles,function, actions: 222 Senescence, aging:222 Serum tests:226 Timing and location of signs and symptoms: 223 Therapy, treatment: 227-229 Treatment problems,problem solver: 230 Urinary,24-hour urine:226 Progesterone (men): 347-358 Deficiency,complaints, symptoms:350 Deficiency,physical signs:350

Obese:54,60,79,80,113,125,175,186,

Timing

189,245,254,263,265,284,303,315, 322,329,340,386,388,419 Obesity: 47,57-58,76-77,81, 126,128, 171-173,188,192-194,200201,218, 245-246,284,302,318,321,323,331, 333-335,337-338,340,362-363,383, 390,393,409,418 Orgasm,orgasmic (women): 76,80,91, 92,93,95,96,100,101,102,299,300, 301,302,306,307,382,385,411 Orgasm,orgasmic (women): 76,80,91, 92,93,95,96,100,101,102,299,300, 301,302,306,307,382,385,411 Osteoarthritis: 179,303 Outbursts of panic or rage,emotion:57, 172,184,187,272,379,380,381,388 Overweight: 63,79-81,126-127,164,177, 218,244,254,263,265,284,303,322, 331,342,383,418 Oxytocin: 91-106 Deficiency,complaints, symptoms:96 Deficiency, physical signs:97 Diagnosis: 95-98 Diet,food influences:1 02 Excess,overdose signs and complaints: 104 Lifestyle influences:102 Onset of deficiency:95 Production: 94 References: 485-495 Roles,function, actions:92-93 Senescence, aging: 94 Serum tests:98 Timing and location of signs and symptoms:96 Therapy, treatment: 99-104 Treatment problems, problem solver: 105-106 Panic attacks:187, 380 Paranoid:96, 101 Parathormone: 153-166 Deficiency,complaints, symptoms:157 Deficiency,physical signs:158 Diagnosis: 156-159 Diet, food influences: 162 Excess,overdose signs and complaints: 163 Lifestyle influences:162 Onset of deficiency:156 Production: 155 References: 569-573 Roles,function, actions:154 Senescence,aging: 155 Serum tests:159

Diagnosis: 350-351 Diet,food influences:354 Production: 349 Senescence,aging:349 Excess,overdose signs and complaints: 356

References: 809-812 Roles, function,actions:348-349 Salivary tests:351 Serum tests:351 Therapy, treatment: 352-356 Timing and location of signs and symptoms: 350 Treatment problems,problem solver: 357-358 Urinary,24-hour urine:351 Prostate,hypertrophy,enlarged:93,103, 320-323,332-333,337,344,350-353, 361-364,390 Prostate, infection(s),prostatitis:101,317, 321-322,330,337,368,384,390 Psoriasis:188,190,388 Pulse rate irregular:165 831

Pulse rate slow, bradycardia: 47,127,387

Swollen feet, feet edema: 104-105,118,

Pulse rate, fast, tachycardia: 139,141,

311,336

163-164,190,242,321,343,388

Tachycardia, fast pulse rate: 139,141,

Quality of life, poor, low: 13, 55,57,172,

163-164,190,242,321,343,388 Testosterone (men): 317-346 Deficiency, complaints, symptoms: 321 Deficiency, physical signs: 320 Diagnosis: 320-325 Diet, food influences: 331,336 Excess, overdose signs and complaints: 336 Excessive estradiol levels (treatment): 334 Lifestyle influences: 331,336 Onset of deficiency: 320 Production: 318-319 References, 755-808 Roles, function, actions: 318 Salivary tests: 325 Senescence, aging: 319 Serum tests: 323-324 Therapy, treatment: 326-337 Timing and location of signs and symptoms: 321 Treatment problems, problem solver: 338-345 Urinary, 24-hour urine: 325 Testosterone and prostate cancer: 332333, 779 Testosterone and testicular suppression: 778 Testosterone deficiencies in men with serum testosterone leveis within the reference range: 796 Testosterone (women): 299-316 Deficiency, complaints, symptoms: 302 Deficiency, physical signs: 303 Diagnosis: 301-305 Diet, food influences: 310-311 Excess, overdose signs and complaints: 311-312 Lifestyle influences: 311 Onset of deficiency: 301 Production: 300 References, 743-754 Roles, function, actions: 300 Senescence, aging: 300 Serum tests: 304 Therapy, treatment: 306-311 Timing and location of signs and symptoms: 300 Treatment problems, problem solver: 312-315

332-333,379 Restless legs syndrome: 46,382 Rheumatoid arthritis: 49,67,188,190, 193,195-196,213,225,227,272,303, 384 Sexual arousal, excessive: 104-105,209, 224,336,339 Sexual, low desire, low arousal: 80,96, 248,362,379-380 Skin fold, prolonged after pinching: 112, 171,235,247,386-387 Skin folds, brown: 190,388 Skin folds, loose under the chin: 57,172, 386 Skin folds, tiny, dehydration: 97,112,387 Skin hemorhages, petechiae: 200 Skin rash(es): 67,89,179,183,186-190, 198,204,388 Skin, dry: 123,126-127,157,209,224225,248-249,273,301-302,322,383, 387,389-390 Skin, excessive pigmentation, darkening: 87-88 Skin, lax, loose: 167,172, Skin, oily: 71,215-217,229-230,311,315, 336,343,349 Skin, pale: 97,225,273,303,322,331, 389-390 Skin, swollen: 118,120,273,389 Skin, thin, thinning, atrophy: 58,172, 195, 200,202,205,303,322,390 Skin, wet: 139-140 Skin, white, type 1 and 2: 80-82,87,386 Sleep apnea, snoring: 126 Sleep, poor, light, superficial, disorder, troubles: insomnia: 43,45-46,51-52,57, 70,96,107,109-110,139,172,202,272, 286,291,321,343,352,379,381-382 Social isolation, tendency, few social contacts, withdrawn: 172,321,379, Spasmophilia: 157-158,382 Stiffness, joint: 126,383 Stress, poor or low resistance: 57,72,8081,85,92,96,106,141,172,187,192193,209,218,221,224,242,302,308, 321' 380-381' 391 Sunburn(ed), easily: 75- 76,79-80,84,86, 302,321,382 Swelling, excessive: 1 04 832

Testosterone deficiencies in women with

Lifestyle influences: 117

serum testosterone leveis within the

Onset of deficiency: 109

reference range: 752

Production: 108

Urinary, 24-hour urine: 305

References: 479-485

Thin banes: 55,156,169,170

Roles,function,actions: 108

Thin extreme,abnormally: 188,243-244,

Senescence,aging: 108

246,2482-49,258-259

Serum tests: 113

Thin muscles: 54-57,169-171,258,299

Therapy, treatment: 114-119

Thirst,excessive: 87,107,109-111,118,

Timing

124,126,139-140,224,231,233,234,

symptoms: 109

248-249,264,343,382-384

Treatment problems,problem solver:

Thyroid: 123-142 Controversy

and

location

of

signs

and

120

on

the

best

thyroid

Urinary,24-hour urine: 113,119

treatment: T4 or T4-T3: 534

Vertebral crushes: 143,145-146,148-149,

Deficiency, complaints,symptoms: 126

151,158,160,382

Deficiency, physical signs: 127

Vitiligo: 188,190,388

Diagnosis: 125-129

Weight gain: 27,80,126,193-194,200-

Diet,food influences: 135

202,246,260,263,286,291,293-294,

Does thyroid treatment definitely suppress the thyroid gland: 528

340,383,417 Weight loss: 87,126,139,142,178,247-

Excess,overdose signs and complaints:

249,330,343,383,387,414

139

Wrinkle(s): 54,112,169,225,235,267,

Lifestyle influences: 135

273,282,303,321,387-391

Mild thyroid failure: to treat or not to treat: 529 Onset of deficiency: 125 Production: 124 References: 504-561 Roles,function,actions: 124 Senescence,aging: 124 Serum tests: 126 Serum

TSH:

is

measurement diagnosis

lhe

alone

and

TSH

serum

sufficient

follow-up

of

for

thyroid

deficiency: 518 Therapy, treatment: 130-139 Thyroid hormone deficiencies with thyroid tests within the reference range: 541 Thyroid therapy and bane density: 540 Thyroid treatment and lhe heart: 537 Timing

and

location

of

signs

and

symptoms: 125 Treatment problems,problem solver: 140-142 Urinary,24-hour urine: 126 Tinnitus: 126,321,383 Varicose veins: 303,309,322,329,389 Vasopressin: 107-122 Deficiency, complaints,symptoms: 111 Deficiency,physical signs: 112 Diagnosis: 109-113 Diet, food influences: 117 Excess,overdose signs and complaints: 118 833

NOTES