Pharma - 4th Asessment - Steroid Hormones - 3 Feb 2007

STEROID HORMONES – PHYSIOLOGY & PHARMACOLOGY  Testes

-

Testosterone

 Ovary

-

Estradiol & Progesterone

 Adrenal - Glucocorticoids & Mineralocorticoids

STEROID HORMONES – BIOSYNTHESIS Cholesterol p450 Pregnenolone Glucocorticoids ● Cortisol ● Corticosterone

Mineralocorticoids Sex Steroids ● Aldosterone ● Estradiol ● Deoxycorticosterone ● Progesterone ● Testosterone

LUTEAL PHASE

FOLLICULAR PHASE Pregnenolone

Pregnenolone

17α-Hydroxypregnenolone

Progesterone

Dehydroepiandrosterone

17α-Hydroxyprogesterone 18

O

H3 C 19

2 3

O

4

H3 C

11

1

9

10 5

12

13 14

H3 C

17

16 15

8 6 7

H3 C O

Testostersone

Androstenedione H3 C C A HO

OH OH

D

H3 C

O

H3 C

OH

B HO

Estriol

16α-Hdroxyestrone

OH

O

H3 C

OH

HO

HO

Estrone 2-Hydroxyestrone and other metabolites

17ß-Estradiol 2-Hydroxyestradiol and other metabolites

NUCLEUS CYTOSOLIC RECEPTOR DNA TRANSCORTIN

mRNA

STEROID NEW PROTEIN

RIBOSOMES

Schematic model of the mechanism of action of glucocorticoids

SEX HORMONES – INTERMEDIATES  17 – hydroxy – pregnenolone - Follicular  17 – hydroxy – progestrone - Luteal  Androstenedione

ESTROGENS/PROGESTERONE – FUNCTIONS  Secondary Sex Characteristics  Ovulatory/ Menstrual Cycle  Pregnancy  Metabolism

Steroidal, Natural H3 C

OH

H3 C

HO

HO

Estrone

Estradiol H3 C

HO

Estriol

OH OH

O

ESTROGENS - SOURCE  Premenopausal - Ovary  Postmenopausal - Dehydroepiandro sterone (DHA)  Pregnancy - Androstenedion ↑ Fetoplacental Unit

17-ß-Estradiol

H3 C

OH

HO

Hydroxylation

Reduction Oxidation H3 C

HO

O

H3 C

Hydroxylation

Estrone

Reduction

OH

HO

Estriol

Natural estrogens and their metabolic interconversions

OH

ESTROGENS – GENITAL EFFECTS  Growth- Uterus, Vagina, Fallopian Tubes  ↑ Size and Number- Endometrium Cells  Amount and Elasticity- Cervical mucus  Breast Enlargement

ESTROGENS – METABOLIC ACTION  Accelerate Growth at Puberty  Stimualte Closure of Epiphysis  Maintain Bone Mass   Prolactin Secretion   Antithrombin III & LDL   SBG, TBG, VII, X, HDL

ESTROGENS – CLINICAL USES  Menopausal Symptoms  Senile Atrophic Vaginitis  Dysmenorhea  Postmenopausal Osteoporosis  Prostate Carcinoma  Hirsutism  Contraception

ESTROGENS – SYNTHETIC ANALOGS  Ethinyl Estradiol (Estinyl)  Quinestrol (Estrovis)  Conjugated Estrogens (Premarin)  Diethylstillbestrol (Stilphostrol)

ESTROGENS – SIDE EFFECTS  Endometerial Hyperplasia + Bleeding  Breast Engorgement  Thromboembolic Events  Carbohydrate Intolerance  Na+ , H2O Retention  Cholestatic Jaundice

DRUG INTERACTION  Warfarin  Phenytoin  Carbamazepine  Rifampin  Phenylbutazone

ANTIESTROGENS  Tamoxifen – Nolvadex  Clomiphene – Clomid  Raloxifene

PROGESTINS – BIOLOGICAL ACTIONS  Enhances estrogen-primed endometrial activity  Suppresses gonadotropin secretion  Promotes breast development and lactation  Elevates body temperature  Decreases fallopian tube contraction

PROGESTERONE – CLINICAL USES  Contraception  Dysfunctional Uterine Bleeding  Dysmenorrhea  Endometriosis  Postpone Mensturation  Postpartum Suppression of Lactation

PROGESTERONE – SIDE EFFECTS  Edema  Epiphysis Closure  Glucose Intolerance  TBG, Clotting Factors (VII, VIII, IX, X)

ESTROGENS, PROGESTERONE – CONTRAINDICATION  Thromboembolic Disease  Impaired Liver Function  Breast Carcinoma  Migraine Headache

ANTIPROGESTINE  Ru 486 - Mifepristone

ORAL CONTRCEPTIVES  Combination Pills  Progestin Pills  Progestin Implants  Postcoital Contraception

ORAL CONTRACEPTIVES – SIDE EFFECTS  Glucose Intolerance  Hypertension and MI  Thromboembolic Disorders  Vaginal and Uterus Carcinoma  LDL ( Progesterone) HDL

ESTROGENS – ORAL CONTRACEPTIVES  Ethinylestradiol  Mestranol PROGESTINS– ORAL CONTRACEPTIVES  Norgestrol  Norethindrone

PROGESTERONE – SYNTHETIC ANALOGS  Medroxyprogesterone (Provera)  Northindrone (Aygestin)  Megestrol (Megace)  Noregestimate  Desogestrel

POSTCOITAL CONTRACEPTIVES  Conjugated Estrogen  Ethinyl Estradiol  Diethylstillbestrol  Norgestrol  Mifepriston (Ru 486)

UTERINE DRUGS A. Induction of Labor ● Oxytocin ● PGE2 (Dinoprostone) B. Induction of Abortion ● Mifepristone ● PGE1 (Gemeprost) C. Uterine Relaxants ● ß2 - Adrenoreceptor

 Salbutamol ● Magnesium Sulfate