Polycystic Ovary Syndrome (PCOS)

1. Introduction

• Goldman-Cecil Medicine, p. 2560; Berek & Novak's Gynecology, p. 1919

2. Etiology

Genetic Factors

• Likely polygenic/multifactorial inheritance; familial clustering is well established
• Genome-wide association studies (GWAS) have identified susceptibility loci including YAP1 (11q22.1), THADA (2p21), FSHB (11p14.1), ERBB4 (2q34), KRR1 (12q21.2), and RAD50 (5q31.1); the first four have been confirmed in both European and Han Chinese cohorts
• Candidate genes cluster into four categories:
  1. Insulin resistance (IR)-related genes (IRS-1, IRS-2, insulin receptor at 19p13.3)
  2. Genes involved in androgen biosynthesis and action (CYP17, CYP19, CYP11A)
  3. Genes encoding inflammatory cytokines
  4. Other candidate genes (SHBG, TCF7L2, FBN3/D19S884)
• Theca cells in PCOS show elevated mRNA for CYP11A, 3BHSD2, and CYP17 with corresponding overproduction of testosterone and androstenedione

Environmental Factors

• Obesity is both a trigger and an amplifier - increasing body fat worsens hyperinsulinemia, which drives androgen excess
• Sedentary lifestyle and caloric excess promote insulin resistance
• PCOS may emerge or worsen in adulthood coincident with the onset of obesity
• Berek & Novak's Gynecology, pp. 1926-1927

3. Pathophysiology

A. Ovarian Compartment (Primary)

• The ovary is the most consistent contributor of excess androgens in PCOS
• CYP17 dysregulation (the androgen-forming enzyme in both ovaries and adrenals) is a key pathogenetic mechanism
• Ovarian stroma, theca, and granulosa cells are all stimulated by elevated LH
• Total and free testosterone levels correlate directly with LH levels
• Ovaries are more sensitive to gonadotropic stimulation, possibly due to CYP17 dysregulation
• GnRH agonist treatment effectively suppresses serum testosterone and androstenedione, confirming ovarian origin

B. Hypothalamic-Pituitary Compartment

• Increased frequency (but not amplitude) of GnRH pulses from the hypothalamus
• This drives increased LH secretion relative to FSH, explaining the characteristically elevated LH:FSH ratio
• FSH is not proportionally elevated because the increased pulse frequency plus synergistic negative feedback from chronically elevated estrogen and follicular inhibin suppress FSH selectively
• ~25% of PCOS patients have mildly elevated prolactin from abnormal estrogen feedback to the pituitary

C. Insulin Resistance and Hyperinsulinemia

• Insulin resistance is a central feature, present across all racial/ethnic groups - implying a common underlying defect
• Compensatory hyperinsulinemia directly stimulates ovarian theca cell androgen production (via LH-receptor pathways)
• Insulin also suppresses hepatic sex hormone-binding globulin (SHBG) production, increasing free (bioactive) androgens
• ~1/3 of obese PCOS patients have impaired glucose tolerance (IGT); 7.5-10% have overt type 2 diabetes
• Even non-obese PCOS women have elevated rates: ~10% IGT, ~1.5% T2DM vs. 7.8% and 1% in general population respectively

D. Adrenal Compartment

• Adrenal androgens (DHEAS, DHEA) are mildly elevated in ~50% of PCOS patients
• Adrenal CYP17 dysregulation may contribute

E. Peripheral (Adipose Tissue)

• Adipose tissue converts androgens to estrogens (aromatization), creating a cycle of chronically elevated estrogen
• This sustained estrogen, without cyclic progesterone, prevents the LH surge needed for ovulation
• Increased adiposity also independently worsens insulin resistance

Ovarian Pathology

• Macroscopically: Ovaries are 2-5x normal size, with a white thickened cortex and multiple small cysts (<1 cm)
• Microscopically: Fibrotic, hypocellular superficial cortex; increased follicles with luteinized theca interna; stromal luteinized cells; atretic follicles
• Berek & Novak's Gynecology, pp. 1986-1988, 1983

4. Clinical Features

Menstrual Irregularities (75-85%)

• Oligomenorrhea (cycles >35 days) is most common
• Amenorrhea (primary or secondary)
• Dysfunctional uterine bleeding (irregular, often heavy)
• Classically begins at or near menarche; may worsen with time

Hyperandrogenism

• Hirsutism (~70% in US patients): excess terminal hair in androgen-sensitive areas (upper lip, chin, chest, abdomen, inner thighs) - scored by the modified Ferriman-Gallwey scale
• Acne: often severe or treatment-resistant
• Androgenic alopecia: male-pattern hair thinning at the crown/frontal scalp

Obesity

• Present in >50% of PCOS patients
• Characteristically central/android distribution (increased waist-to-hip ratio)
• Worsens hyperinsulinemia and hyperandrogenism

Infertility

• Most common cause of anovulatory infertility
• Results from chronic anovulation

Metabolic Features

• Dyslipidemia (up to 70% prevalence): elevated triglycerides, LDL, total cholesterol; decreased HDL
• Impaired fibrinolysis: elevated plasminogen activator inhibitor (PAI-1)
• Hypertension: risk increases with age, reaching ~40% by perimenopause
• Acanthosis nigricans: velvety, hyperpigmented skin folds in the neck, axillae - marker of severe insulin resistance (HAIR-AN syndrome variant)

Psychological

• Depression in 35-40% (vs. ~10.7% in controls, even after adjusting for BMI)
• Anxiety disorders and eating disorders are also more common

Long-term Risks

• Endometrial carcinoma: unopposed estrogen from chronic anovulation
• ~7-fold increased risk for myocardial infarction
• Increased atherosclerosis and cardiovascular disease
• In pregnancy: increased risk of early miscarriage, gestational diabetes, gestational hypertension, preeclampsia, and preterm birth
• Berek & Novak's Gynecology, pp. 1951-1953; Goldman-Cecil Medicine, p. 1851

5. Diagnostic Criteria and Investigations

Diagnostic Criteria (Rotterdam 2003 - most widely used)

1. Oligoovulation or anovulation
2. Clinical and/or biochemical hyperandrogenism
3. Polycystic ovarian morphology on ultrasound

• HA + ovarian dysfunction + PCO morphology (classic, most severe)
• HA + ovarian dysfunction
• HA + PCO morphology
• Ovarian dysfunction + PCO morphology

Investigations

• Fasting glucose and 2-hour 75-g OGTT: screening for IGT and T2DM
  • Normal 2-hr glucose: <140 mg/dL
  • IGT: 140-199 mg/dL
  • T2DM: ≥200 mg/dL
• Fasting lipid profile: total cholesterol, HDL, LDL, triglycerides
• HbA1c: useful for chronic hyperglycemia detection
• Waist circumference and BMI at every visit

• PCO morphology criteria: ≥20 follicles in either ovary measuring 2-9 mm in diameter, and/or ovarian volume >10 mL
• A single ovary meeting criteria is sufficient
• Note: PCO appearance alone (without clinical/endocrine features) is found in ~23% of reproductive-age women and is not diagnostic of PCOS

• Berek & Novak's Gynecology, pp. 1934, 1966; Goldman-Cecil Medicine, p. 1857-1858

6. Management

A. Lifestyle Modification (First-Line for All)

• Weight loss of 5-10% in overweight/obese women:
  • Reduces insulin levels by ~40% per 10 kg lost
  • Reduces testosterone by ~35% per 10 kg lost
  • Restores ovulation in >75% of women
  • Improves dyslipidemia, blood pressure, and quality of life
• Exercise reduces insulin resistance independently of weight loss
• Dietary management: caloric restriction, low glycemic index diet

B. Hormonal Contraceptives (Not Desiring Pregnancy)

1. Progestin component suppresses LH → reduces ovarian androgen production
2. Estrogen component increases hepatic SHBG → reduces free androgens
3. Directly suppresses adrenal androgen production
4. Provides endometrial protection against hyperplasia and carcinoma
5. Reduces hair growth in ~2/3 of hirsute patients

• Use the lowest effective estrogen dose (cyclic or continuous)
• If inadequate response after 6 months, add antiandrogens

C. Antiandrogens (Adjunctive for Hirsutism)

• Mechanisms: competitive inhibition of DHT at the intracellular receptor; suppresses testosterone biosynthesis; inhibits skin 5α-reductase
• Dose: 50-100 mg twice daily (200 mg/day for maximal effect)
• 70-80% show at least modest improvement in hirsutism at ≥100 mg/day for 6 months
• Side effects: menstrual irregularity (>50% at 200 mg/day), mastodynia, hyperkalemia - monitor potassium and creatinine
• Must use contraception (theoretical risk of feminizing a male fetus)
• Combine with OCP for synergistic effect

D. Insulin Sensitizers

• Suppresses hepatic gluconeogenesis
• Improves insulin sensitivity
• Reduces insulin and androgen levels
• Can restore ovulation in 60-70% of affected women
• Indicated for: overweight/obese PCOS for cardiometabolic risk prevention; adjunct to diet/exercise; women with IGT or T2DM
• Not recommended as monotherapy for: endometrial protection, hirsutism treatment, ovulation induction, prevention of gestational diabetes

E. Ovulation Induction (Desiring Pregnancy)

• 5 mg on days 3-7 of the cycle
• Superior to clomiphene in live birth rates for PCOS
• Preferred over metformin alone

• 50 mg on days 3-7
• ~75-80% of women conceive with letrozole or clomiphene

• Multiple punctures of the ovary with diathermy or laser
• Achieves unifollicular ovulation or improves response to medical induction
• Reserved for women resistant to medical therapy
• Risk: ovarian adhesions → infertility

F. Endometrial Protection

• COCPs (preferred)
• Cyclic progestins
• Levonorgestrel-releasing IUD

G. Metabolic Syndrome Management

• Waist circumference >88 cm (F)
• Triglycerides >150 mg/dL
• HDL <50 mg/dL
• Blood pressure >130/85 mmHg
• Fasting glucose 110-126 mg/dL or 2-hr OGTT 140-199 mg/dL
• Blood pressure measurement at every visit (target <120/80)
• Lipid profile at baseline; repeat every 2 years or sooner with weight gain
• Screening for obstructive sleep apnea if appropriate
• Vitamin D assessment and supplementation when deficient

H. Psychological Support

• Screen for depression (PHQ-2 as initial screen), anxiety, and eating disorders at diagnosis and regularly
• Lifestyle modification programs improve depression and quality of life

Summary Table

Recent Evidence Update (2024-2025)

• GLP-1 receptor agonists (e.g., semaglutide, liraglutide) show efficacy for weight loss and hormonal regulation in obese PCOS women - a meta-analysis of RCTs (PMID 39178623, 2024) supports their use as an emerging option
• Lifestyle interventions remain cornerstone therapy - a 2025 systematic review (PMID 39861440) confirms comprehensive lifestyle management significantly improves reproductive and metabolic outcomes
• Pregnancy outcomes in PCOS remain worse than controls even with treatment - a 2024 meta-analysis (PMID 38965226) found increased risks of gestational diabetes, preeclampsia, and preterm birth, reinforcing the need for preconception counseling