Polycystic Ovary Syndrome (PCOS)

Overview

• Hyperandrogenism (HA) — clinical or biochemical
• Chronic anovulation
• Polycystic ovarian morphology

Diagnostic Criteria

1990 NIH Criteria (both required)

1. Chronic anovulation
2. Clinical and/or biochemical signs of HA + exclusion of other etiologies

2003 Rotterdam Criteria (2 out of 3 required)

1. Oligoovulation or anovulation
2. Clinical and/or biochemical signs of HA
3. Polycystic ovaries on ultrasound (≥12 follicles 2–9 mm in diameter, OR ovarian volume >10 mL)

Exclusion of other causes is mandatory: androgen-secreting neoplasm, Cushing syndrome, congenital adrenal hyperplasia, hyperprolactinemia, thyroid disease, hypo-/hypergonadotropic disorders.

Four Rotterdam Phenotypes

In adolescents, diagnosis should be based on persistent anovulation and clinical/biochemical HA (Endocrine Society 2013).

Pathology

• Superficial cortex is fibrotic and hypocellular
• Prominent blood vessels
• Increased follicles with luteinized theca interna
• Stroma may contain luteinized stromal cells
• Smaller atretic follicles

Pathophysiology & Laboratory Findings

(i) Ovarian Compartment

• Primary contributor of androgens in PCOS
• Dysregulation of CYP17 (androgen-forming enzyme) is a key pathogenetic mechanism
• The ovarian stroma, theca, and granulosa are stimulated by LH
• Serum total testosterone usually ≤2× upper normal (20–80 ng/dL)
• In ovarian hyperthecosis, values may reach ≥200 ng/dL

(ii) Adrenal Compartment

• DHEAS elevated in ~50% of PCOS patients
• Hyperresponsiveness to ACTH stimulation
• PCOS may arise as an exaggeration of adrenarche (17,20-lyase activation)

(iii) Peripheral (Fat) Compartment

• Adipose tissue is a site of androgen to estrogen conversion (aromatization)
• IR increases androgen bioavailability by reducing SHBG levels
• Obesity worsens IR and HA

(iv) Hypothalamic-Pituitary Compartment

• Increased GnRH pulse frequency → elevated LH pulse frequency
• Elevated LH:FSH ratio (LH elevated, FSH normal or low)
• FSH not elevated due to combined effect of increased gonadotropin pulse frequency + negative feedback from estrogen + follicular inhibin
• ~25% of PCOS patients have mildly elevated prolactin (abnormal estrogen feedback)

Insulin Resistance

• IR is present in 50–70% of PCOS patients
• Insulin directly stimulates ovarian androgen production
• Hyperinsulinemia decreases SHBG → increased free testosterone
• Leads to compensatory hyperinsulinemia with resultant metabolic sequelae
• Impaired type A insulin receptor function (phosphorylation defect) is identified in some patients
• Glucose tolerance testing is recommended for all PCOS patients

Genetics

• Complex multigenic disorder; GWAS-identified susceptibility loci include: YAP1 (11q22.1), THADA (2p21), FSHB (11p14.1), ERBB4 (2q34), KRR1 (12q21.2), RAD50 (5q31.1)
• Candidate genes: CYP11A, IRS-1/2, SHBG, TCF7L2, insulin receptor, follistatin, calpain-10

Cardiovascular and Metabolic Risks

• Impaired fibrinolysis (elevated PAI-1)
• Hypertension — reaches 40% by perimenopause
• 7-fold increased risk of myocardial infarction
• Greater prevalence of atherosclerosis
• Screen for: family history of early CVD, smoking, IGT/T2DM, hypertension, dyslipidemia, obstructive sleep apnea, abdominal obesity

Long-Term Risks

• Endometrial cancer risk from chronic unopposed estrogen
• Cancer risk (endometrial carcinoma is the most significant)
• Depression and mood disorders — higher prevalence in PCOS
• Metabolic syndrome — dyslipidemia (↑ triglycerides, ↓ HDL), central obesity, hypertension, impaired glucose

Vitamin D

• Lower 25-OH vitamin D levels are common in PCOS; supplementation may have metabolic benefits

Treatment

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

• 5–10% weight loss is the initial goal
• Weight loss >5% → significant reduction in testosterone, DHEAS; improved SHBG, fasting insulin, cholesterol, triglycerides; restored ovulation in >75%
• Structured exercise (>30 min/day) reduces IR
• Reduced-energy diets (500–1,000 kcal/day reduction) effective for 7–10% weight loss over 6–12 months
• Bariatric surgery: BMI >40, or >35 with high-risk obesity-related condition after failure of other treatments

2. Medical Treatment of Hyperandrogenism / Hirsutism

Oral Contraceptives (first-line)

• Combination OCs reduce hair growth in ~two-thirds of hirsute patients
• Mechanisms:
  1. Progestin → suppresses LH → ↓ ovarian androgen production
  2. Estrogen → ↑ hepatic SHBG → ↓ free testosterone
  3. ↓ DHEAS (independent of LH/SHBG)
  4. Estrogen inhibits 5α-reductase → ↓ testosterone-to-DHT conversion in skin
• Low-androgenic progestins preferred (desogestrel, norgestimate, gestodene; NOT norgestrel/norethindrone which have androgenic activity)

Medroxyprogesterone Acetate (MPA)

• Injectable MPA suppresses gonadotropins → ↓ androgen levels
• Indicated when OCs contraindicated

GnRH Agonists

• Effective suppression of ovarian androgens
• Usually reserved for severe/refractory cases; costly; cause hypoestrogenism

Glucocorticoids

• Low-dose dexamethasone or prednisone suppresses adrenal androgen excess
• Useful when DHEAS is elevated (adrenal contribution)

Spironolactone (Antiandrogen)

• Competitive androgen receptor antagonist + weak inhibitor of testosterone synthesis + inhibits 5α-reductase
• Effective for hirsutism; requires contraception (risk of feminizing male fetus)

Cyproterone Acetate

• Potent antiandrogen; not available in the US; used in Europe

Flutamide

• Pure nonsteroidal antiandrogen (androgen receptor inhibitor)
• NOT recommended as first-line (Endocrine Society 2008)
• Risk of hepatotoxicity (dose-related); monitor LFTs
• Do not use in women desiring pregnancy

Finasteride

• Specific type 2 5α-reductase inhibitor; approved for BPH (5 mg) and male-pattern baldness (1 mg)
• Comparable efficacy to spironolactone
• Improvement in hirsutism occurs after 6 months of therapy
• Does NOT prevent ovulation
• OCs + finasteride more effective than finasteride alone
• Contraindicated in pregnancy (feminization of male fetus)

Ketoconazole

• Steroidogenic enzyme inhibitor
• Used in refractory cases; hepatotoxicity limits use

Metformin (Insulin sensitizer)

• Reduces IR, hyperinsulinemia → lowers androgen levels
• May restore ovulation; used as adjunct in metabolic management

Mechanical Hair Removal

• Temporary: shaving, depilatory creams, waxing
• Permanent: laser, electrolysis

Medical Treatment Table Summary

Note on fertility: Patients desiring pregnancy require ovulation induction (discussed separately in Chapter 36 of Berek & Novak's). Treatment for hirsutism may not be possible simultaneously. Progestational interruption of unopposed estrogen effects on the endometrium is necessary in all cases with significant ovulatory dysfunction.