Polycystic Ovarian Syndrome (PCOS)

Definition

• Robbins & Kumar Basic Pathology, p. 613
• Berek & Novak's Gynecology, p. 1878

Pathophysiology

• Core defect: Dysregulation of enzymes involved in androgen biosynthesis leads to excessive androgen production - this is considered the central feature.
• Insulin resistance and hyperinsulinemia are commonly associated, especially in obese patients, and further drive androgen excess, but are NOT part of the formal diagnostic criteria.
• The etiology remains incompletely understood, involving both environmental and genetic factors.
• The result is chronic anovulation with an unopposed-estrogen state, leading to irregular endometrial growth.

Gross and Histological Pathology

• Thickened, fibrotic ovarian capsule
• Cystic follicles lined by granulosa cells
• Hyperplastic luteinized theca interna
• Conspicuous absence of corpora lutea (due to chronic anovulation)
• Robbins & Kumar Basic Pathology

Diagnostic Criteria (Rotterdam 2003, endorsed by NIH 2012)

1. Oligo-ovulation or anovulation - manifested as oligomenorrhea or amenorrhea
2. Hyperandrogenemia (elevated circulating androgens) or hyperandrogenism (clinical signs of androgen excess - acne, hirsutism, alopecia)
3. Polycystic ovaries on ultrasound (typically ≥12 follicles per ovary, or increased ovarian volume)

LH:FSH ratio (classically >3:1) and hyperinsulinemia are not required for diagnosis.

• Pregnancy
• Significant hyperprolactinemia
• Significant thyroid dysfunction
• Adult-onset congenital adrenal hyperplasia
• Androgen-secreting tumors
• Berek & Novak's Gynecology, p. 1878-1879

Clinical Features

Laboratory Evaluation

• Pregnancy test (exclude)
• TSH, prolactin (exclude thyroid disease, hyperprolactinemia)
• LH, FSH (LH:FSH classically >3:1)
• Testosterone, 17-hydroxyprogesterone (exclude congenital adrenal hyperplasia)
• DHEAS (if virilizing adrenal tumor suspected)
• Fasting glucose / HbA1c, lipid panel (screen for metabolic syndrome and type 2 diabetes)
• Transvaginal ultrasound (not routinely required unless pelvic pain or abnormality found)

Long-Term Complications

• Metabolic syndrome and type 2 diabetes (insulin resistance)
• Hypertension and cardiovascular disease
• Endometrial hyperplasia and carcinoma (from chronic unopposed estrogen)
• Cerebrovascular accidents
• Psychological effects (depression, anxiety, reduced quality of life)

Treatment

1. Lifestyle Modification (First-line for all overweight/obese patients)

• Even 5% weight loss can improve ovulation and pregnancy rates.
• Decrease daily caloric intake by ~500 kcal + regular physical exercise.
• Weight loss should be achieved prior to attempting conception.

2. Menstrual Regulation / Contraception

• Combined oral contraceptive pills (OCPs) - regulate cycles, reduce androgen levels, protect endometrium from hyperplasia.
• Medroxyprogesterone acetate 10 mg/day x 10 days, at least 4 times/year - to induce withdrawal bleeds and protect the endometrium.

3. Hyperandrogenism Management

• Spironolactone - androgen receptor blocker; reduces hirsutism and acne.
• OCPs with anti-androgenic progestin also effective.

4. Insulin Sensitization

• Metformin - improves insulin sensitivity, can restore ovulation, reduce androgen levels.

5. Ovulation Induction (for Fertility)

• Letrozole (aromatase inhibitor) - now preferred first-line agent for ovulation induction in PCOS.
• Clomiphene citrate - binds estrogen receptors in the hypothalamus, increases GnRH pulsatility → increased FSH/LH → follicular development.
• 60-85% of PCOS women will ovulate on clomiphene or letrozole; 15-20% achieve pregnancy per cycle; ~50% pregnant by 6 months.
• Gonadotropins (FSH injections) or IVF for treatment-resistant cases.

Recent Evidence Update

• A 2024 meta-analysis (PMID 38922413) reports global PCOS prevalence may be higher than classic estimates when Rotterdam criteria are applied broadly.
• Anti-Mullerian hormone (AMH) is emerging as a diagnostic biomarker for PCOS and polycystic ovarian morphology (PMID 38944177).
• A 2025 systematic review (PMID 39861440) confirms lifestyle interventions (diet + exercise) are effective as first-line PCOS management, improving hormonal and metabolic profiles.