Polycystic Ovary Syndrome (PCOS)

Definition & Epidemiology

PCOS is the most common endocrine disorder in women of reproductive age, affecting 5–10% of women worldwide. It is also the most common cause of hyperandrogenism (HA), hirsutism, and anovulatory infertility in developed countries. First described by Stein and Leventhal in 1935 (bilateral polycystic ovaries + obesity + amenorrhea), it is now understood as a heterogeneous syndrome with reproductive, metabolic, and cardiovascular consequences. Its genetic basis is likely polygenic and multifactorial.

Pathophysiology

Three interrelated disturbances drive the syndrome:

1. Hypothalamic-Pituitary Dysregulation

Increased LH pulse frequency and amplitude, leading to a raised LH:FSH ratio (in ~⅔ of patients)
Excess LH stimulates ovarian theca cells → excess androgen production
Insufficient FSH → arrested follicular development → anovulation

2. Hyperandrogenism

Elevated androgens (testosterone, androstenedione, DHEAS) arise from both the ovaries and adrenal glands
Androgens are converted peripherally (especially in adipose tissue) to estrogens, which exerts positive feedback on LH — creating a self-perpetuating cycle
Skin 5α-reductase converts testosterone → DHT, causing hirsutism and acne (activity varies by ethnicity, explaining why hirsutism appears in ~70% of US patients vs. only 10–20% in Japan)

3. Insulin Resistance & Hyperinsulinemia

Present in the majority, independent of obesity
Hyperinsulinemia directly stimulates ovarian androgen production and suppresses sex hormone-binding globulin (SHBG), increasing free androgen levels
PCOS typically arises at puberty; obesity worsens the phenotype by amplifying hyperinsulinemia

Clinical Features

Domain	Features
Menstrual	Oligomenorrhea, amenorrhea (rarely primary); irregular cycles from menarche
Androgen excess	Hirsutism (~70%), acne, male-pattern alopecia
Metabolic	Obesity (>50%, android/central distribution), insulin resistance, dyslipidemia
Ovarian	Polycystic ovary morphology on ultrasound
Reproductive	Anovulatory infertility, increased miscarriage risk
Psychological	Depression, anxiety (screen at diagnosis)

Diagnosis

PCOS is a diagnosis of exclusion. The 2003 Rotterdam Criteria (most widely used) require 2 of 3:

Oligo-ovulation or anovulation
Clinical and/or biochemical hyperandrogenism (hirsutism, acne, alopecia; or elevated free testosterone)
Polycystic ovarian morphology on ultrasound — ≥20 follicles (2–9 mm) in either ovary and/or ovarian volume >10 mL

In adolescents, diagnosis requires both persistent anovulation and clinical/biochemical HA (PCO morphology alone is insufficient).

Differential Diagnoses to Exclude:

Non-classic congenital adrenal hyperplasia → 17-OHP (follicular phase) to screen
Cushing syndrome → 24-hr urinary cortisol / overnight dexamethasone suppression
Hyperprolactinemia → serum prolactin
Androgen-secreting neoplasm → imaging if testosterone very high
Thyroid disease → TSH

Ancillary Workup at Diagnosis:

Fasting glucose / oral GTT (screen for impaired glucose tolerance/T2DM)
Fasting lipid profile (overweight/obese women)
BMI, waist circumference, blood pressure
PHQ-2 (depression screen)
Consider endometrial biopsy if prolonged anovulation (endometrial hyperplasia risk)

Management

Treatment is tailored to the patient's primary concern (menstrual irregularity, hyperandrogenism, infertility, or metabolic risk).

All Patients — Universal

Lifestyle modification (diet + exercise): first-line for all women; even modest weight loss (5–10%) improves menstrual regularity, hyperandrogenism, and insulin sensitivity
Screen and monitor: obesity, hypertension, glycemic control, depression, anxiety — at diagnosis and at regular intervals

Women Not Seeking Pregnancy

Goal	Therapy
Menstrual regulation + androgen control	Combined oral contraceptive pill (COCP) — first-line; increases SHBG, suppresses LH/androgens
Inadequate response to COCP after 6 months	Add antiandrogens: spironolactone, flutamide
Endometrial protection (if OCP not used)	Cyclic progestin (MPA 10 mg or progesterone 200 mg × 10–14 days every ≥3 months) or levonorgestrel IUD
Cardiometabolic risk reduction	Metformin — especially for overweight/obese women

Women Seeking Pregnancy (Ovulation Induction)

Letrozole (aromatase inhibitor) — first-line for ovulation induction in PCOS
Clomiphene citrate ± metformin — second-line
Injectable gonadotropins — used judiciously (risk of ovarian hyperstimulation syndrome is higher in PCOS)
Metformin — adjunct with diet/exercise in obese women; alone is not recommended for infertility treatment

Metformin is not recommended as monotherapy for endometrial protection, treatment of hyperandrogenic symptoms, prevention of pregnancy loss, or prevention of gestational diabetes.

Complications & Long-term Risks

Reproductive

Anovulatory infertility — most common endocrine cause
Increased risk of early miscarriage, gestational diabetes, gestational hypertension, preeclampsia, preterm birth
Prepregnancy counseling and lifestyle management recommended before conception

Metabolic / Cardiovascular

Type 2 diabetes and impaired glucose tolerance — screen with oral GTT
Dyslipidemia (elevated LDL, triglycerides; low HDL) → increased long-term cardiovascular disease risk
Obstructive sleep apnea — increased prevalence, refer if suspected
Non-alcoholic fatty liver disease

Oncological

Endometrial carcinoma — chronic anovulation leads to unopposed estrogen stimulation; endometrial biopsy if at increased risk

Psychiatric

Higher rates of depression and anxiety — screen at diagnosis and regularly

Recent Evidence (2024–2025)

Inositol (myo-inositol + D-chiro-inositol) was evaluated in a 2024 meta-analysis for the 2023 updated PCOS guidelines — modest evidence for improving metabolic and reproductive outcomes (PMID: 38163998)
Lifestyle interventions remain foundational: a 2025 systematic review confirmed significant improvements in insulin resistance, androgen levels, and menstrual regularity with structured exercise and diet (PMID: 39861440)
Pregnancy outcomes: A 2024 meta-analysis in Nature Communications quantified increased risks of gestational diabetes, preeclampsia, and preterm birth, reinforcing preconception counseling (PMID: 38965226)

Sources: Berek & Novak's Gynecology; Harrison's Principles of Internal Medicine, 22e; Goldman-Cecil Medicine

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