Polycystic Ovary Syndrome (PCOS) : Chronic hyperandrogenic anovulation.

also known as Stein-Leventhal syndrome → The leading cause of anovulatory infertility

Epidemiology Familial, More common in South Asia.
Heterogenicity of symptoms and signs.
PCO in US : Found in 20-30% of asymptomatic females without the clinical syndrome.
Prevalence 5-10% in the developed world.
2 out of 3 ESHRE/ASRM Rotterdam Hyperandrogenism
Diagnostic Criteria: Clinical signs: Acne, hirsutism, alopecia.
Criteria 1. Oligo- and/or Anovulation. Biochemical signs: ↑ free testosterone (2-5~nmol/L).
2. Clinical or biochemical Hyperandrogenism. Polycystic Ovaries on US
3. Polycystic ovaries on US. 12 or more follicles (2-9 mm) and/or ovarian volume
>10~cm³.
IF Testosterone >5 nmol/L OR rapid onset of hyperandrogenism→ must investigation to exclude ovarian or adrenal
tumors
Diagnosis Requires Exclusion of: Adrenal or Pituitary Diseases: hyperprolactinemia, acromegaly, congenital adrenal
hyperplasia (CAH), Cushing syndrome, androgen-secreting tumors.
Other Causes of irregular Menses: hypothalamic, pituitary, or ovarian dysfunction.
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PCOS in Adolescents
is not made until 2 years after menarche, as menses start to be regular 2 years after menarche.
All three Rotterdam criteria must be found for diagnosis.
Hirsutism is a better marker of hyperandrogenism than acne.
65% of cycles are anovulatory, but they usually progress to ovulatory cycles over time.
Treat cases with troublesome symptoms only.

Pathophysiology
Four mechanisms:
1. Hypothalamic/Pituitary Dysfunction: ↑ LH + ↑ LH:FSH ratio.
2. Androgen Secretion: Androgens & insulin → ↓ Sex Hormone-Binding Globulin (SHBG)→ ↑ free testosterone.
3. Ovarian Androgens: Increased LH stimulates theca cells to produce more androgens.
4. Insulin Resistance & Hyperinsulinemia: Post-receptor defect leads to hyperinsulinemia.

Pathology
Gross Bilaterally enlarged ovaries, Thick 'pearly-white' capsule, Increased stromal tissue, Multiple
Pathology follicles.
Histopatholog Thickened theca interna layer, Thin layer of granulosa cells, Increased stromal & capsular
y thickness. Multiple follicles.

Clinical Picture Complications

- Menstrual Disturbances: Oligo or amenorrhea. 1. Type II Diabetes Mellitus.
- Hyperandrogenism 2. Cardiovascular Risk (d.t obesity, hypertension, dyslipidemia
- Infertility: Due to anovulation. → atherosclerosis, myocardial infarction).
- Obesity: visceral (android) 3. Endometrial hyperplasia & cancers (endometrial biopsy) → Tx
- Psychiatric: Mood swings, depression, anxiety. with progestogens to induce a withdrawal bleed at least every 3-4 m.
4. With Pregnancy: ↑ risk of gestatonal diabetes.
Investigations
1)​ Pelvic Ultrasound: Transvaginal US → characteristic "pearl necklace" appearance (12 follicles).
2)​ Hormonal Profile:
Increased Decreed
Androgens/ LH / Estrogen (Estrone > Estradiol)/ Insulin/ FSH/ Progesterone / SHBG/ HDL/ Apolipoprotein A.
Prolactin/ Anti-Müllerian hormone/ LDL & triglycerides
 Syndromes

HAIR-AN Metabolic Syndrome (Syndrome X) (Insulin resistance syndrome)

Insulin resistance
Hyperandrogenism, Insulin Resistance, Obesity : abdominal (waist > 88~cm or > 35 inches)
Acanthosis Nigricans (dry, dark patches of skin in Dyslipidemia : High triglycerides >150~
the armpits, neck, groin → sign of insulin Low HDL cholesterol <50
resistance) Hypertension >130/85 mmHg

Insulin Resistance Assessment

1) 75 gm Oral Glucose Tolerance Test (OGTT)

When→ BMI>30, BMI>25 in South , BMI<25 with additional risk factors (e.g., age>40)
Impaired fasting glucose: 110-126
Impaired glucose tolerance: 140-199 after 2 hour

2) Other : Fasting glucose-to-insulin ratio, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), HbAlc.
-​ Fasting glucose-to-insulin ratio: (normal<4.5)

Specific Hormonal Measurements

1.​ Screening: Total testosterone (normal: 0.3-1). Other androgens only be measured if total testosterone exceeds 2. .
2.​ High estrogen is confirmed by endometrial US.
3.​ LH and FSH: on menstrual days 1-3 = random samples if the patient is oligomenorrheic or amenorrheic.
4.​ TSH and prolactin in oligo- or amenorrhea to rule out other conditions.
Management
1)​ Lifestyle Changes (1st Line)
Diet, exercise and weight loss
- Bariatric surgery if failure to lose weight + (BMI > 40 OR BMI > 35 with high-risk factors (HTN, type II DM))
- Moderate weight loss (5-10%)→ Restore fertility + Improve metabolic parameters (↓IR, ↓ testosterone & ↓ CV risk).
- 10% reduction of body weight = 30% reduction in visceral fat.

2)​ Drugs
1- Insulin-sensitizing agents (metformin, troglitazone): ↓IR + body weight + fasting & serum insulin + androgen +LH.
↑ SHBG → ↓ testosterone → restores regular cycles.

2- Incretin hormone : ↓ weight, ↑ insulin resistance, not recommended.

3- Orlistat : ↓ weight without changing glucose-insulin homeostasis or lipid.

 Management of Hyperandrogenism

Assessment Modified Ferriman and Gallwey Score to evaluate degree of hirsutism before & during Tx.
Drug therapy takes at least 6-9 months before improvement is perceived.
Non-medical - Physical treatments → (electrolysis, waxing, bleaching).
therapy - Laser and photothermolysis → expensive & longer duration of effect.
(Not permanent)
1) Dianette: First line therapy : Ethinyl-estradiol (35ug) + cyproterone acetate (2mg)→ affects
acne and seborrhea.

2) Oral contraceptives (COCP): Drospirenone (derivative of spironolactone in the COCP Yasmin)

Hormonal therapy →control cycle & hyperandrogenism.
(COCP)
N.B. Use adequate contraception: anti-androgens disturb genital development of a male fetus.
Thromboembolism is considered for PCOS who are overweight).

3) Spironolactone: Weak diuretic + anti-androgenic properties in low doses → if CI to COCP.

If used as monotherapy → Menstrual irregularities → need Progestin.

4) Finasteride (blocks conversion of testosterone to dihydro-testosterone) and Flutamide

(peripheral androgen antagonist) → Not widely used due to potential hepatotoxicity.

Topical Drug Eflornithine → Inhibits hair growth →Inhibit ornithine decarboxylase in hair follicles.
May cause thinning of skin → need sun block.

Management of Anovulatory Infertility

1. General Management

Weight reduction & lifestyle In obese women, weight loss may restore ovulation.
Optimize preconception health Folic acid 400 µg/day (if obese → 5 mg/day).
Partner evaluation Perform semen analysis.
Tubal assessment Assess tubal patency (HSG/laparoscopy).
Induction of ovulation Aim: regular unifollicular ovulation.
2. Ovulation Induction Options

A. Oral Agents

Class Example Mechanism Key Points

Anti-estrogens Clomiphene citrate, Tamoxifen Block estrogen receptors at 1st-line
hypothalamus → ↑ GnRH → ↑ Risk of OHSS & multiple
FSH/LH → follicular growth pregnancy → monitor with serial
US
Aromatase Letrozole ↓ aromatization of androgens → Fewer endometrial/cervical
inhibitors ↓ estrogen → releases HPA from effects lower risk of multiple
feedback pregnancy
Clomiphene Citrate (CC)

Parameter Details
First-line for anovulatory infertility
Timing Start on Day 2–5 of cycle for 5 days
Dosage 50 mg/day → if no ovulation → increase to 100 mg/day
Max effective dose 150 mg/day (no additional benefit)
Excessive response Reduce to 25 mg/day
Success rate Ovulation >80% / pregnancy ≈50%
Monitoring Ultrasound for follicular growth (multiple pregnancy ≈10%)
Side effects ↑ LH, anti-estrogenic effect on endometrium/cervical mucus
Pre-induction If oligo/amenorrhea → exclude pregnancy then induce withdrawal bleed with progestogen
Aromatase Inhibitors (Letrozole)

Mechanism Effects Advantages

Inhibit aromatase enzyme → ↓ ↓ negative feedback on Better endometrial receptivity, improved cervical
estrogen → ↑ FSH release hypothalamic-pituitary axis mucus, lower multiple pregnancy risk
B. Gonadotrophin Therapy

Indication
1.​ Failure to ovulate with anti-estrogens (CC resistance)
2.​ Ovulation with CC but poor conception due to ↑ LH or anti-estrogenic effect
Regimen Low-dose step-up protocol guided by ultrasound monitoring
C. Insulin-Sensitizing Agents

↓ hepatic glucose, ↑ insulin sensitivity & secretion, ↑ Restores ovulation & menses; ↑ pregnancy rate
Metformin SHBG, ↑ circulating sex hormone binding globulin→ with CC (especially in CC resistance)
↓ free testosterone

3. Surgical Ovulation Induction

Laparoscopic Ovarian Diathermy (Drilling) : Monopolar diathermy, Bipolar diathermy, Laser surgery

Indication Mechanism Technical Note Comments

1. Failure to respond to CC Destroys androgen- producing 4 points/ovary × 4 sec reserved for
2. Persistent LH hypersecretion stroma → ↓ estrogen → ↑ at 40 W to (minimize selected cases
3. Unable to attend gonadotrophin monitoring ovarian sensitivity to FSH adhesions)
4. laparoscopy indicated for other reasons
IVF : Indication → Tubal or male factor infertility — Failure to conceive despite ovulation.

4. Monitoring During Ovulation Induction

• Serial transvaginal ultrasound: follicular growth & prevent OHSS/multiple pregnancy.

• Hormonal assays (E2, LH): for assessing response.

Management of menstrual problems

In oligomenorrhea, induction of a withdrawal bleed (every 3-4 months) using:

-​ Cyclical progestogens (>12 days): medroxyprogesterone acetate or dydrogesterone
-​ Combined oral contraceptive pills
-​ Mirena IUD
Notes
-​ Other adrenal or pituitary diseases must be excluded.
-​ Adolescents → dx is made only after 2 years post-menarche and requires all three criteria.
-​ Insulin resistance is a central driver, leading to decreased SHBG in the liver → ↑ free testosterone → signs of
hyperandrogenism.
-​ waist circumference >87 cm indicates increased metabolic risk
-​ circumference >88 cm is a component of Metabolic Syndrome (Syndrome X).
-​ To mitigate the risk of endometrial hyperplasia and cancer from chronic unopposed estrogen, it is recommended to
induce a withdrawal bleed with progestogens at least every 3-4 months.
-​ Anti-androgen therapy can take 6-9 months for hirsutism.
-​ Fat distribution is more important with android obesity being more risky than gynecoid obesity.
Summary Table

Treatment Monitoring Key Risks/Notes

Clomiphene citrate US follicle tracking Multiple pregnancy, anti-estrogenic effects
Letrozole US follicle tracking Lower multiple rate
Gonadotrophins Intensive US monitoring OHSS risk
Metformin Clinical response Useful in PCOS/insulin resistance
Laparoscopic drilling Operative findings Not first-line; avoid adhesions