Polycystic Ovary Syndrome (PCOS)

Definition & Epidemiology

• Hyperandrogenism (HA) — clinical or biochemical
• Chronic anovulation
• Polycystic ovarian (PCO) morphology
• Frequent association with insulin resistance (IR) and obesity

Diagnostic Criteria

NIH 1990 Criteria (both required):

1. Clinical and/or biochemical hyperandrogenism
2. Chronic anovulation (Exclusion of other disorders)

Rotterdam 2003 Criteria (2 of 3 required):

1. Menstrual cycle anomalies (amenorrhea, oligomenorrhea)
2. Clinical and/or biochemical hyperandrogenism
3. Polycystic ovaries on ultrasound

1. HA + ovarian dysfunction + PCO morphology
2. HA + ovarian dysfunction
3. HA + PCO morphology
4. Ovarian dysfunction + PCO morphology

The Rotterdam criteria are ratified by the Endocrine Society (2013) for adult women. In adolescents, diagnosis requires persistent anovulation + clinical/biochemical HA.

Clinical Features

Hyperandrogenism

• Hirsutism: ~70% of PCOS patients in the US (10–20% in Japan — due to genetic differences in skin 5α-reductase activity)
• Acne
• Male-pattern alopecia

Menstrual Dysfunction

• Ranges from amenorrhea to oligomenorrhea (from anovulation/oligo-ovulation)
• Classically lifelong, with abnormal menses from puberty
• May emerge in adulthood with onset of obesity

Ultrasound (PCO Morphology)

• ≥20 follicles in either ovary, each measuring 2–9 mm in diameter and/or ovarian volume >10 mL
• A single ovary meeting criteria is sufficient
• PCO appearance occurs in ~23% of reproductive-age women, but only 5–10% have clinical PCOS

Obesity

• Present in >50% of PCOS patients
• Usually central (android) obesity; higher waist-to-hip ratio signals increased CV risk
• Geographic variation: 20% (Spain) to 69% (US)

Insulin Resistance & Metabolic Features

• IR and compensatory hyperinsulinemia are hallmarks
• ~1/3 of obese PCOS patients have impaired glucose tolerance (IGT)
• 7.5–10% have type 2 diabetes mellitus
• Rates are mildly increased even in nonobese PCOS women
• PCOS confers a 4–7× increased risk of type 2 DM vs. age-matched controls
• Screening: fasting glucose 100–125 mg/dL = IFG; 2-h 75g OGTT ≥200 mg/dL = DM

Pathophysiology

Ovarian Compartment

1. Excess ovarian androgen production (androgens → estrogens via aromatization in adipose tissue)
2. Increased LH activity stimulates theca cell androgen production
3. FSH levels are relatively low — insufficient for follicle maturation and ovulation

Estrogen Metabolism

1. Elevated E1 (estrone) from peripheral aromatization of androstenedione
2. E2 (estradiol) remains at follicular phase levels
3. In obesity: decreased 2-hydroxylation → more active 16-hydroxyestrogens (estriol)
4. Chronic hyperestrogenic state, with reversed E1:E2 ratio, unopposed by progesterone

Hypothalamic-Pituitary Axis

1. Increased GnRH pulse frequency → increased LH pulse frequency
2. Elevated LH and elevated LH:FSH ratio
3. FSH not elevated — suppressed by elevated estrogens and follicular inhibin
4. ~25% of PCOS patients have mildly elevated prolactin (abnormal estrogen feedback to pituitary)

Genetics

• Complex multigenic disorder (gene-environment interaction)
• GWAS candidate genes relate to: insulin signaling, FSH receptor, insulin receptor, steroid hormone function, type 2 DM, IL-6, GABA-A receptors, and endocytosis
• Confirmed loci include: YAP1 (11q22.1), THADA (2p21), FSHB (11p14.1), ERBB4 (2q34)
• Other candidates: CYP11A, Calpain 10, IRS-1, IRS-2, SHBG, TCF7L2, FBN3 (D19S884)

Long-Term Risks

Treatment

1. Lifestyle Modification (First-Line for Obese/Overweight)

• Weight loss of 5–10% recommended as initial goal
• Reduces free/total testosterone, adrenal androgens; improves SHBG, fasting insulin, glucose tolerance, lipids, and menstrual function
• A 5–7% weight loss over 6 months can restore ovulation in >75% of women
• Structured exercise reduces IR significantly
• Components: dietary management, structured exercise, behavior modification, stress management
• Dietary target: <30% calories from fat, <10% from saturated fat, increased fiber and whole grains; caloric reduction of 500–1,000 kcal/day

2. Oral Contraceptives (OCs)

1. Progestin → suppresses LH → reduces ovarian androgen production
2. Estrogen → increases SHBG → reduces free androgen levels
3. Progestin → reduces adrenal androgen precursors
4. Reduces LH-driven thecal androgen secretion

3. Antiandrogens

All antiandrogens must be combined with contraception due to risk of feminization of a male fetus.

4. Insulin Sensitizers

• Metformin: reduces IR; may restore ovulatory function; also used for hirsutism
• Combination of metformin + flutamide + drospirenone OC effective in hyperinsulinemic adolescent PCOS

5. GnRH Agonists

• Suppress ovarian androgen production
• Used for severe cases; typically add-back estrogen to prevent bone loss

6. Glucocorticoids

• Used for adrenal component of androgen excess

7. Pharmacologic Anti-obesity Agents

• Orlistat, sibutramine, rimonabant — adjuncts when lifestyle fails
• Bariatric surgery: indicated when BMI >40 kg/m² or >35 kg/m² with high-risk comorbidities, after failure of other treatments

8. Endometrial Protection

• Progestational interruption of unopposed estrogen is mandatory in all women with significant ovulatory dysfunction — via OCs, cyclic progestins, or ovulation induction

Diagnostic Algorithm

Psychological Assessment

1. Little interest or pleasure in doing things (0–3)
2. Feeling down, depressed, or hopeless (0–3)

Source: Berek & Novak's Gynecology (ISBN 9781496380357), Chapter 35, pp. 1919–1940