Management Of Anovulatory Infertility And Polycystic Ovary Discs

MANAGEMENT OF ANOVULATORY INFERTILITY AND POLYCYSTIC OVARY DISCS INTRODUCTION 2. Anovulatory Cycle: A Menstrual Cycle in which ovulation fails to occur (The women bleeds but do not release an egg) Anovulation Or Ovulatory dysfunction) - Most Common in adolescence and in the years before menopause but tend to occur occassionally in the child bearing years and then translate to difficult in conceptions or infertility.

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(Anovulatory Infertility) • Ovulatory dysfunction is a major cause of infertility in women of reproductive age and accounts for between 20% - 40% of all the causes of infertility depending on the population. • Mechanism of Ovulation • Ovulation is the result of a well synchronized balance between hormones produced by the brain, hypothalamus, pituitary gland and the ovary.

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• Hypothalemus → Gn Rh • Anterior Pitutory → FSH , LH • Ovary → E2 + Progestion • Endometrinum → bleeds 3

• Any dysruption of the complete interactions of the hormones from the Hypothalamus – Pitintary – ovary axis can lead to ovulation dysfunction and impair the reproduction process • Ovulatory dysfunction can present in a variety of ways • 1. Absent ovulation (Anovulation) • 2. Infrequent (irregular) ovulation → Oligo ovulation • 3. Abnormal follicular phase • 4. Abnormal luteal phase (Luteal Phase deficiency) • All these are related to female hormonal imbalance and may present as infertility thus requiring ovulation induction.

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• Classification of Anovulatory Infertility • 1. Hypogonadotrophic anovulation (Hypothalamic in origin) (infertility Group 1 (WHO group 1) • Seen in • (a) Weight loss/anorxia • (b) Stenous Exercise • (c) Chronic Illness • (d) Psychological Stress • Hypolhalamic/Pituitary damage from tumours, cranical irradication, head injuries, sarcoidosis, TB5

• 2. Normogonadotrophic anovulation (Infertility Group 2, WHO group 2) • - Typical example is polycystics ovary syndrome (PCO). • - congenital adrenal hyperplasia • - Androgen secreting tumors • - cushings syndrome, thyroid disease • 3. Hypergonado trophic anovulation • - Premature Ovarian failure (Genetic or infective) - Resistant ovary syndrome • - autoimmine disease of the ovary • - ovarian irradiation. • -G

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4. Hyper Prolactinemic anovulation - Pituitory adenomas < micro/macro - Hypopituitarism - Sheehans Syndrome - Hypothyroidism - Prolactinomas - Idiopathic hyperprolactinemia

• NOTE • FSH Level and prolactin levels represent the basis of this classification

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• WHO Group 1 + WHO Group 2 → Represent almost 30% of all causes of infertility. • In Clinical Practice, WHO Group 2 subjects present much more frequently than WHO group 1 subjects and appear much harder to treat successfully. • Among women classified as WHO Group 2 those diagnosed with PCOS constitute the largest group (60 – 85% and they account for most cases with Oligomenorrhoea (90%) and 30% of those with amenorrhea. • Hypergonatoropic anovulatory Infertility has very poor prognosis. 8

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POLY CYSTIC OVARY SYNDROME - Is a complex, heterogeneous disorder - It includes a spectrum of conditions rather than a single discrete disease. Is the most common cause of anovulatory infertility. Affects 5 – 10% of women in the reproductive age group. It is characterised by a myriad of symptoms and signs that include (a) Menstrual disturbances < Amenorohua hgomemo hypomemo (b) hyper androgenism (c) hirsuits in (Excessive growth of hair on the face, chest, abdomen, thumb or tons). (d) Obesity or weight gain (e) Infertility (f) Insulin resistance → hyper insunlmaena → diabetes 9

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(g) Presence of multiple cystic ovaries(Micro & Macro) on USS (h) Pelvic pain that lasts longer than 6 months (i) Male – Pattern baldiness or thinning hair (j) ACNE out skin or dandruf (k) Patches of imchend and dork brown or black skin on the neck and groin. The aetiology of PCOS is uncertain and error of endocrine metabolism involving steirodogenesis has been implicated. • (l) Skin tags or tiny excess flaps of skin in ampits and neck areas. • (m) high blood pressure (over 140/90) • (n) abnormal hip terals (high or low chotyyoal and frigly cerwes).

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• *The aetiology of PCOS is uncertain and error of endocrine metabolism involving abnormal sterodogenesis has been implicated. • Current evidence however suggest that insulin resistance, androgen excess, abnormal gonadotrophin secretion and genetic predispotion have been suggested as important factors precluding menstrual cyclicity. 11

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Among those genetically susceptible; extreme weights seem to be the initiator of PCO

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Lean OR ↑ Weight gain (BMI < 19 > 30 Kg/m2) ↓ Increasing Insulin resistance ↓ Hyper insunlinaemia ↓ Hyper androgenism ↓ Hypersecretion of LH (a common endocrine abnormality) ↓ Inferefere with folliculogenesis & Folicular Maturation ↓ Ovulatory dysfunction ↓

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• Total and Oligo Ovula folicula vetu lufeal phge defus ∀ ↓ • Amenorhoea Oligomenorhona Hypomenonhoea. • Because the primary cause of PCOS is still unknown, MX is based on the overall clinical picture which includes variables such as age, duration of infertility, degree of ovarian and adrenal androgen excess and presence of weight and insulin resistance problems. • Meticulous evaluation and examination to establish diagnosis before initiating treatment is very important. 13

• Diagnosis is based on combination of clinical features ultrasound findings, laparascopic and biochemical assays. • 1. USS – will show a combinations of micro and megacysts. • 2. Biochemical assays • (a) High LH • (b) Normal Level or slightly Low FSH • (c) ↑ LH/FSH Ratio, > 2 • (d) ↑ 4 Andrestenedione • (e) ↑ DHEA – SO4 • (f) ↑ free testosterone • (g) ↓ S H B G • (h) Normal Estradiol; ↑ Estrone • (i) ↑ prolactin levels – occassionally

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3. Endometrial biopsy – may reveal Prolonged proliferative Short prolifenative Short secretary Long secretary endometrium 4. Ovarian biopsy – will reveal enlarged ovaries with several fluid – filled sacs or cysts with thinning of the Medula and enlarged cortex. • *ALL THESE NEED NOT BE PRESENT TO MAKE A DIAGNOSIS

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MANAGEMENT OF ANOVULATORY INFERTILITY • HX TAKING • (1) To evaluate circumstances that may present hypogonadotropic anovulation in weight loss, Anorexia nervosa etc. • (2) Elucidate features of PCO above – menstrual disturbances etc. • (3) Elucidate feature of hyper prolactinaemia which may manifest as galactorrhoea, frontal headache, visual disturbance and symptoms of increased intracranial pressure, hemianopia • (4) elucidate features of hypergonadotrophic enovulation which may result from H7 of previous irradiation, Hashimoto thyroditis and development of immune completes to the stomach and pancrease which may have existed as a chronic illness.

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• P/E will reveal • 1. Body Mass Index through wt/(ht in m2) Low BMI or High BMI. • 2. Stigmata of Anovulation such as Baldness Virilization, + Hirsutism, Excess hair growth, voice changes • 3. Signs of hypo & hyper thyroidism; ptosis • Wide pulse pressure. • Investigation • The gold standard to sort out the nature of anovulation is to do a comprehensive hormonal assay at the supposed mid cycle: • LH1 FSH, E2, Progesten and Prolactin 17

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Where PCOS is suspected Androgen fractions are further assayed. Serum insulin Free testosterone

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• Generally: The following will go a long way to confirm anovulation. • (1) Low Serum progesterone at the mid luteal phase (< 5 n mol/L) • (2) Monophasic pattern of the temperature on the basal body temperature chart. • (3) Loss of ferning appearance and spinbarkeit phenomenon in cervical mucus at mid cycle. • (4) Failure of dominant folicle at follicular tracking using a vaginal uss at mid cycle • (5) failure of endometrium to show secretary changes in mid luteal phase.

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• Treatment • Two principles must be met before anovulatory infertility is treated. • 1. Anovulation must exist (Hx, P/E and Basic investigation will confirm diagnosis or exclude this) • 2. Other factors of infertility such as male, Tuboperitoneal, uterine, cervical factors must be thoroughly evaluated and excluded. 21

• Ovulation Induction is the treatment of choice and this can be surgical or medical. ∀ → Surgical induction of ovulation is less widely embraced because of • (a) their invasiveness • (b) high cost • (c) poor induction rates • (d) complications of surgery including anaesthesia ∀ → Surgical techniques are limited to polycystic ovarian disease and macro adenoma of the pituitary not responding to medical therapy. 22

• In the MX of PCO, • (a) Bilateral Ovarian wedge resection → limited experience. • (b) Laparoscopic diathermisation ∀ ⇒ accompanied with a lot of complications to bowels c fistular formation – limited experience • (c) carbon dioxide laser fulguration of follicles ⇒ most current method: Limited experience in this locality CO2 laser tends to have better ovulation rate when compared with a and b. • Pitutary Adenoma – may require neuro surgical resection or ablation or radiotherapy. 23

• MEDICAL INDUCTION OF OVULATION • First line of treatment in Ovulation Induction. • To be successful, must be combined with life style modification (which may also be the first line of therapy to induce ovulation) to improve the chance of a successful outcome ∀ ⇒ In those who are overweight or obese, evidence suggests that together with exercise, weight loss may reduce androgen levels and hyper insulinaemia and improved ovulatory function and pregnancy rates. ∀ ⇒ Use of insulin sensitizers (metformin and Rosiglitazone) ∀ ⇒ when this fails as the first line of treatment ⇒ ovulation induction drugs become necessary.

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• *The principle of OI Drug is to stimulate the ovaries to produce a single mature (dominant follicle, to induce ovulation, allow fertilization and pregnancy to occur by natural intercourse. • 01 drug is the predominant intervention used for anovulatory infertility in women categorised into WHO groups I & II. The cause of anovulation will guide the selection of an appropriate treatment plan. • **Ovulation induction requires that the procedure be explained to patients in sufficient detail to ensure realistic expectations • Information regarding the expense, time and psychological impact involved in completing a course of therapy should be provided with potential complications.

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• Chances of success should be outlined • Induction of ovulation should be carried out in specialized centers where there are adequate personnel and facilities for monitoring such as radio-immuno assay, ultrasound and laparascopy if need be.

• O.I. Drugs with their Indications • Chomiphene Citrate (Clomid). • Indicated in WHO groups I & II infertility but more so in WHO group II (PCOS). • It is a first time drug in PCO. • A non steroidal estrogen receptor antagonist agent competing with endogenenous estrogen and preventing the release of cytoplasm estrogen receptor in the hypothalamus. Thereby decreasing further the negative feed back system → release of Gn RH → FSH & LH folliculo – genesis and maturation of follicle → ovulation 26

• It is an anti E2 with no progestational, androgenic or anti androgenic effects. • A programme of CC usually begins early in the proliferation phase on 2nd or 5th day of spontaneous menses or after bleeding induced by progesterone withdrawal. • It is given as a five-day course starting with 50 mg causing an appreciable ↑ in FSH & LH on days 31 41 5 of treatment and E2 levels begins to rise slowly two days after. • Dose ↑ ed in subsequent cycle if no evidence of ovulation . • Dosage up to 250 mg per cycle may be reached. However, > 70% of conceptions related to CC will occur at dosages no higher than 100 mg daily. • While on CC, monitoring with BBT, follicular tracting with uss, pelvic examination and PCT, 6-8 days after stopping cc are desirable to R/O ovarian cyst formation and to evaluate oestrogenic effect on the cervix and sperm penetrability of the mucus.

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• Ovulation Induction rate is about 60-80% but pregnancy rate is just about 30-40% (Luteinazation of unruptured follicles, copus luteum defect, ovum entrapment, anti E2 effect on CX mucus, Hyper insulinaemia and ↑ insulin resistance and abnormal LH levels). ∀ → Response of CC may be influenced by factors such as Px age, drug metabolism, dosage regimen administration period relative to cycle, cause of anovulation, E2 state as well as carry over effects from previous CC cycles and effects of unknown metabolites. • Efficacy of CC is ↓ in the presence of obesity, hyper androgenemia, ↑ testosterone concentration, and severe insulin resistance.

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• CC has been combined with other drugs in the past e.g. (1) Glucocorticoids (Detamethazone, predinisolone) to suppress adrenal source of excessive androgen (Androgens thought to interfere with follicular maturation). • (2) hcg when there is failure of ovulation at dose of 150 – 2000 mg or Luteal phase defect is demonstrated 5 – 10,000 iu given 7 – 10th day of the clomiphen to enhance the LH surge (ovulatory dose). • (3) with Bromocomptime when PCO is associated with hyperprolactinamia • (4) More recently insulin sensitizers such as metformin and Rosihglitazone (Avandia) are added to ↑ sensitivity of insulin and then ↓ Hyper insulinema and ↓ Androgenemia.

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• In many centers this is being considered as first line treatment before commencing clomphene. • Complication of cc include – Ovarian enlargement – 7% – Multiple pregnancy – Hot flushes – Transient blurring of vision *Tamoxifen, an anti Estrogen given an 20mg daily in the same way as clomiphen is an alternative to women who can not tolerate clomiphene. Cyclofenil – a structurally related compound to DES is under trial. 30

Gonado trophin Therapy • Best for WHO group 1 infertility or those who fail to ovulate while on CC • Two main types < HMG (personal) (from urine of post-menopausal women), hpG (from human pituitary at autopsy) • Both contains FSH & LH in equal proportion. • Both are – Effective – Expensive – Associated with hyperstimulation syndrome and multiple pregnancy. 31

• The latest of the gonadotrophin is pure FSH called metrodin or pure gon produced by recombinant DNA • Pure FSH has greater purity and homogeneity than urinary derived gonodotropins and allow better tailoring of treatment to meet the needs of individual patients – not available in Africa • All the gonadotrophins have direct action on the ovary by bringing about follicular maturation and their administration is followed by that of hcG which has biological activity similar to LH to induce ovulation. • Pregnancy rates approach 90% within the first 6 cycles. 32

• Usually administered i.m for 7 – 12 days until a preovulating follicle is developed. When this follicle is about 16 – 20 mm size an ovulatory dose of hcG 5 – 10,000 unit is administered and ovulation occurs within 36 hrs of administration. • Requires adequate monitoring with vaginal uss and serun E2. (Serum E2 of 100 pg/ml is re-assuring: values about 200 pg/ml ⇒ suggestive of OHS. • MX of ovarian hyperstimulation is conservative except in severe cases where ovary enlarges more than 10cm with ascites, hydrothorax, haemoconcentration and oliguria ⇒ This may require ophorectomy. 33

GNRH • Gonadotroplin-Releasing Hormone and Gonadotrophin – Releasing Hormone Agonist. • One of the latest techniques of ovulation induction currently available but these drugs are – Very expensive – Not easily available 34

• GnRh – is an endogenous hypothalamic peptide capable of stimulating pituitary LH & FSH release. • GnRh synthetic peptides are referred to as Gnrh analogues or agonists. • E.g Goserelin – Buserelin – Nafarelin – Leuprolide 35

• All are good for Type I WHO infertility and are currently utilized in super ovulation for IVF. • Besides Anovulatory Infertility, they are used in MX of Leiomyoma, Endometriosis, Premenstrual syndrome, hirsutism, Endometrial ablation Mastalgia, Cancers of the ovary, breast and endometrial. • The drugs cause down regulation of the pituitary which further enhances release of FSH. • Given by pulsed intravenous or subcutaneous administration and results in high rates of ovulation.

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• Disappointing results are experienced with Pxs & with normogonadotrophic anovulatory infertility (WHO Group II). • Low Incidence of OHS and multiple births when compared with gonadotrophin therapy • No need for ovulatory dose of hcG • The usual dose is 5 – 10 mg per pulse IV and 10 – 20 mg per pulse subcutaneously. • Most patients will ovulate 10 – 20 days of pulsatile GnRH therapy. 37

Hypergonadotrophic Anovulatory Infertility • Not common in African women • Very difficult to treat • Problem of Establishing diagnosis and distinguishing between the various Etiological factors. • Ovarian biopsy is the arbiter for diagnosis • Success of outcome is poor • Menstruation may be restored after a prolonged E2 treatment with progynora • Oocyte donation seems to be the only sensible method of treatment.

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Hyper prolactinaemic Anovulating Infertility • Susceptible to treatment, using Bromocriptine mesylate • A semi-synthetic ergot alkaloid with dopamine receptor agonist activity. • Widely used for RX of hyperprolactinaema. • Specific in suppressing prolactin secretion and thus allows normal spontaneous cyclic release of FSH & LH for ovulation to occur. • Initial dose is 1.25 mg daily at night x 7 days and thereafter dose is 1.25 mg b.d and thereafter to 2.5 mg b.d daily. 39

• Measurement of prolactin secretion is vital to assess response • Side effects include Nausea, vomitting, postural hypertension, headaches and nasal congestion. • Ovulation induction rates = 80 – 90% • Women who cannot tolerate bromocriptine may be changed, over to other dopamine agonists such as LISURIDE, Pergolide or mengoline. • Pituitary tumour can be removed surgically 40

Conclusion • Ovulation induction in cases of Anovulatory Infertility could be very rewarding in carefully selected cases. • A proper diagnosis, patient counselling with thorough explanation of complications, and costs inherent in each method of ovulation induction are pre-requisites for successful induction. • THANK YOU. 41