(10) Anovoulation & Pco

DISORDERS OF OVULATION It includes: 2. Anovulation

2. LPD

3.LUFS

PHYSIOLOGIC CONSIDERATIONS

Chronology of follicle growth during the human menstrual cycle

• In the Follicular phase • Ovulation occurs by the end of the follicular phase • During the luteal phase • If fertilization of the Graafian follicle does not occur • If pregnancy occurs

.Diagram showing LH/FSH surge

:AETIOLOGY OF ANOVULATION

I. Physiological causes: •Before puberty •During pregnancy •After the menopause •Some women during lactation •Short periods after puberty and before the menopause. II. Iatrogenic causes: •Contraceptive pills. •Large doses of oestrogen, gestagens or combined oestrogen/progesterone therapy.

III. Pathological causes: 1. Hypothalamic factors: a. Organic lesions: (brain tumour, scarring). b. Functional disorders: - Polycystic ovarian disease (PCOD).

- Hyperprolactinemia. - Iatrogenic as phenothiazine, reserpine. - Congenital; Kallman’s syndrome.

C. Psychological factors: - Stress or psychiatric disease.

- Anorexia nervosa

- Pseudocyesis.

2. Pituitary factors: • Pituitary insufficiency (Sheehan’s syndrome or Simmond’s disease). • Pituitary tumours: - Acidophil adenoma (gigantism-acromegaly).

- Basophil adenoma (Cushing’s syndrome).

- Chromophobe adenoma (non-functioning or prolactinoma).

3. Ovarian factors (Peripheral defect) 1.Gonadal Dysgenisis (Turner syndrome)

2. Insensitive ovary syndrome. 3. Premature ovarian failure. 4. Ovarian tumours (especially functioning tumours). 5. Bilateral surgical removal of the ovary 6. Destruction of the ovary (Inflammation - radiation chemotherapy).

DIAGNOSIS OF OVULATION 2. Symptoms Suggestive of Ovulatory Cycles • Ovulation pain • Ovulation bleeding • Investigations for Detection of Ovulation • Basal Body Temperature (BBT) chart changes

• • • • • •

Hormonal assays Folliculometry Cervical mucous changes Vaginal cytology Premenstrual endometrial biopsy (PEB) Demonstration of a corpus luteum within the ovary during laparoscopy

TREATMENT OF ANOVULATION •

Clomiphene Citrate (CC) •

CC is a non-steroid compound closely related to diethylstilbestrol (DES)

•

Acts by competing with endogenous E2 at the hypothalamic receptors levels

Indications for treatment with CC:  Intact hypothalamic pituitary axis and normal FSH: •

PCOD,

•

Post-pill amenorrhea,

•

Luteal phase defect, and

• Adrenal hyperfunction Side effects of CC: • Vasomotor flushes, headache and visual symptoms, breast and abdominal discomfort. • Ovarian hyperstimulation (grade I-II), with resultant pelvic pain and discomfort. • Increased risk of multiple pregnancies (10%). • Abortion and preterm labour are more common in stimulated rather than natural cycles.

2. Human Menopausal Gonadotrpins (HMG) •

It is prepared from urine of postmenopausal women.

•

The commercial preparation contains 75 IU FSH, 75 IU LH.

Indications of HMG: 5. Poor or no response to CC (clomid failure), 6. Cases with hypogonadotropic anovulation 7. Cases with hypothalamic disorders with abnormal or blunted Gn-RH release. Side effects of HMG: •

Ovarian Hyperstimulation Syndrome (OHSS):

•

Multiple pregnancies

3. Human chorionic Gonadotropins (hCG) 4. Combined CC and HMG 5. Gonadotropin Releasing Hormone Gn-RH 6. LH-RH Analogues 7. Tamoxifen 8. Cyclofenil 9. Bromocryptine 10. Thyroid extract 11. Cortisone 12. Surgical measures for induction of ovulation (Ovarian Drilling)

Definition: cycles with a short interval between ovulation and menstruation (less than 11 days) in which peak value of progesterone are either normal or more commonly decreased. Causes: 3. Inadequate release of FSH during follicular phase of cycle. 4. Inadequate FSH/LH ratio at time of ovulation. 5. Hyperprolactinemia. 6. Induction of ovulation by clomiphene citrate (not related to the drug rather than endogenous gonadotropins release). 7. Synthetic progestogen has luteolytic action. Diagnosis • Biphasic BBT: with a short interval between ovulation and menstruation (<11 days). • Dated PEB: It should be taken high from the fundus, 1-2 days prior to menses. Secretory changes with an endometrial lag 2 days or more behind the cycle is diagnostic. • Serum progesterone level in midluteal phase (5-10 ng/ml) are only suggestive.

Treatment of LPD 1. Progesterone: •Progesterone in oil 1.25 mg IM/day, 3 days after ovulation till the time of menses. •17 alpha hydroxy progesterone caproate 250 mg IM, 3 days after ovulation. 2. Human chorionic gonadotropin (hCG): HCG stimulates CL production of Progesterone (2500 IU days 4-6-810 postovulatory). 3. Bromocriptine: It is the drug of choice in cases of luteal phase defect with hyperprolactinemia. 4. Clomiphene citrate (CC): 50 mg/day for 5 days starting from 5th day of cycle in cases of inadequate FSH release during luteal phase. Treatment of ULFS: •(clomid + HCG) •(HMG + HCG)

•First described by Stein and Leventhal in 1935. •The classic Stein Leventhal syndrome presents with amenorrhea, hirsutism,obesity and infertility. Enlarged ovaries with pearly white smooth surface as seen during laparoscopy

PATHOGENESIS: •

•

Hyperandrogenism plays a central role in the syndrome: •

Hypothalamic and/or pituitary defect: Increased LH secretion

•

Ovarian enzyme defect: Aromataze enzyme deficiency

•

Suprarenal defect: Congenital adrenal hyperplasia

Insulin resistance and hyperinsulinemia.

Sequelae of hormone disturbances and clinical picture in PCO: a) Hyperandrogenism: • Arrest of follicular growth → anovulation. • Stimulation of hair growth → hirsutism. • Increased estrone levels from peripheral conversion in fatty tissues. b) Hyperestrogenism: • Irregular uterine bleeding • Endometrial hyperplasia • Endometrial carcinoma

INVESTIGATIONS: • •

• •

LH/FSH ratio: If > 2, it is suggestive of PCOS. Endocrine profile: • Elevated free testosterone level • Decreased SHGB • High plasma oestrone and androstenedione • Increased fasting insulin Ultrasound: (Adam's criteria). Laparoscopy: The ovaries are enlarged with pearly white smooth surface.

The peripherally arranged multiple small follicles (Necklace appearance)

TREATMENT OF PCOS (depends on the presenting symptom): • • •

Weight reduction For menstrual irregularities: Cyclic progestagen therapy from day 17 to 26 of the cycle). For infertility (induction of ovulation) • Clomiphene citrate, HMG/HCG, or recombinant FSH and LH can be used. • Anti-diabetic drugs in cases of insulin resistance (e.g. metformin 500 mg t.d.s.). • Corticosteroid therapy is used to suppress ACTH production. • Surgical treatment aims at decreasing ovarian androgen production (Laparoscopic ovarian drilling).

4. For hirsutism: • Anti-androgens as cyproterone acetate • Cosmetic therapy (Depilation or electrolysis)