Polycystic Ovary Syndrome (PCOS)

Definition

PCOS is a heterogeneous endocrine disorder defined by the Rotterdam criteria: diagnosis requires any 2 of the following 3 features, after excluding other causes:

Oligo-ovulation or anovulation
Hyperandrogenism (clinical or biochemical)
Polycystic ovaries on ultrasound (≥12 follicles per ovary, or increased ovarian volume >10 mL)

Goldman-Cecil Medicine, p. 2560

Epidemiology

Affects 6-12% of women of reproductive age - the most common endocrine abnormality in this group
No clear geographic or ethnic predilection
More than 50% of affected women develop type 2 diabetes by age 40
Obesity amplifies the syndrome and is increasingly prevalent alongside it

Pathophysiology

The core defect involves inappropriate gonadal steroid feedback on the hypothalamic-pituitary axis:

The hypothalamic-pituitary unit is structurally intact but functionally deranged
Insulin-like growth factors within the ovary contribute to abnormal gonadotropin secretion
LH is typically elevated relative to FSH (LH:FSH ratio >3), driving excess androgen production from theca cells
Insulin resistance and compensatory hyperinsulinemia are present across all racial/ethnic groups
Hyperinsulinemia directly stimulates ovarian androgen production and reduces hepatic SHBG synthesis, raising free testosterone
Genetic factors include alterations in CYP17 (17α-hydroxylase) and CYP19 (aromatase)

A severely affected subset has ovarian hyperthecosis - markedly increased androgen-producing stromal, hilar, and thecal cells - presenting with acanthosis nigricans, hyperuricemia, severe hirsutism, and glucose intolerance.

Clinical Features

Feature	Details
Menstrual irregularity	Oligomenorrhea, amenorrhea, or dysfunctional uterine bleeding
Hirsutism	Androgen-driven terminal hair in male-pattern distribution
Acne	Androgen-driven sebaceous gland stimulation
Obesity	Central/visceral pattern; present in ~50-60%
Infertility	Anovulation is the predominant cause
Acanthosis nigricans	Marker of insulin resistance
Androgenic alopecia	Temporal hair thinning

Symptoms usually begin at puberty and worsen over time, with some improvement near menopause.

Diagnostic Evaluation

PCOS diagnostic and risk assessment flowchart

Key investigations:

Testosterone (total and free) - typically mildly to moderately elevated
LH/FSH ratio - often >3 (not required for diagnosis but supportive)
SHBG - reduced in insulin resistance
DHEAS - elevated if adrenal androgen contribution
Fasting glucose, HbA1c, OGTT - screen for insulin resistance/T2DM
Fasting lipid panel - metabolic syndrome assessment
Pelvic ultrasound - polycystic ovarian morphology
Thyroid function, prolactin, 17-OHP - to exclude mimics

Conditions to exclude before diagnosing PCOS:

Cushing syndrome
Congenital adrenal hyperplasia (non-classical)
Androgen-secreting tumors (ovarian or adrenal)
Hyperprolactinemia
Thyroid dysfunction

Long-term Complications

System	Risk
Metabolic	Type 2 diabetes (>50% by age 40), metabolic syndrome
Cardiovascular	Hypertension, dyslipidemia, atherosclerosis
Endometrial	Endometrial hyperplasia and carcinoma (from chronic unopposed estrogen)
Reproductive	Infertility, pregnancy complications (GDM, preeclampsia)
Psychological	Depression, anxiety, eating disorders
Hepatic	Non-alcoholic fatty liver disease
Sleep	Obstructive sleep apnea (especially in obese patients)

Management

Management is goal-directed and individualized based on the patient's primary concerns.

1. Lifestyle Modification (First Line for All)

Weight loss of just 5-7% over 6 months can significantly reduce free testosterone, restore ovulation in >75% of women, and improve insulin sensitivity
Exercise targeting large muscle groups (e.g., thighs) reduces insulin resistance
Relevant for all phenotypes regardless of BMI
Berek & Novak's Gynecology, p. 1935

2. Menstrual Regulation / Endometrial Protection

Combined oral contraceptives (COCs): First-line for women not desiring pregnancy
- Suppress LH → ↓ ovarian androgen production
- ↑ hepatic SHBG → ↓ free testosterone
- ↓ DHEAS levels
- Protect endometrium from hyperplasia
Cyclic progestins: (e.g., medroxyprogesterone acetate 5-10 mg for 10-14 days/month) for endometrial protection in women who cannot use estrogen; does NOT reliably suppress ovulation

3. Hirsutism / Hyperandrogenism

Category	Agents
Hormonal suppression	COCs, medroxyprogesterone, GnRH analogues, glucocorticoids
5α-reductase inhibitors	Finasteride
Antiandrogens	Spironolactone, cyproterone acetate, flutamide
Insulin sensitizer	Metformin
Steroidogenic enzyme inhibitors	Ketoconazole
Mechanical	Electrolysis, laser (permanent); threading, waxing (temporary)

COCs reduce hair growth in nearly two-thirds of hirsute patients. Note: antiandrogens require effective contraception due to teratogenicity (feminization of male fetus).

4. Ovulation Induction (Women Desiring Pregnancy)

Letrozole (5 mg days 3-7) - preferred first-line; superior to clomiphene for live birth rates in PCOS
Clomiphene citrate (50 mg days 3-7) - alternative; ~75-80% conception rate with either agent
Metformin (500-2000 mg/day) - less effective than letrozole/clomiphene for ovulation induction alone, but useful adjunctively
Exogenous gonadotropins + hCG - specialist-directed, for clomiphene/letrozole-resistant cases
Laparoscopic ovarian drilling (LOD) - ovarian diathermy or laser; achieves unifollicular ovulation; risk of adhesions limits use to non-responders to medical therapy

5. Metabolic Management

Metformin 1500-2000 mg/day in divided doses: suppresses hepatic gluconeogenesis, improves insulin sensitivity, reduces androgens, restores ovulation in 60-70% of women
Screen and manage dyslipidemia, hypertension, and glucose intolerance
GLP-1 receptor agonists (e.g., semaglutide, liraglutide): 2024 meta-analysis (PMID 39178623) shows efficacy for weight loss and hormonal regulation in obese PCOS women

Recent Evidence (2024-2025)

Lifestyle interventions remain cornerstone therapy per a 2025 systematic review (PMID 39861440) - exercise and dietary changes improve metabolic and reproductive outcomes
GLP-1 agonists show significant benefit for weight loss and androgen reduction in obese PCOS (PMID 39178623)
Probiotics/prebiotics/synbiotics may improve insulin resistance and hormonal profiles in PCOS per a 2024 systematic review (PMID 39599701), though evidence is still emerging

Sources: Goldman-Cecil Medicine, p. 2560; Berek & Novak's Gynecology, pp. 1935-1936; Dermatology 5e (diagnostic flowchart)

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