PCOS & Hyperandrogenism
A boards-focused PCOS lesson tracing pathophysiology (↑LH:FSH plus insulin resistance) through Rotterdam diagnosis-of-exclusion, tumor red flags, and goal-directed management, anchored by next-best-step vignettes and a hyperandrogenism differential table. Emphasizes high-yield exam pivots: unopposed-estrogen endometrial risk, testosterone/DHEA-S tumor cutoffs, and letrozole as first-line ovulation induction.
Pathophysiology: two engines of PCOS
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive-age women (~6–12%) and the leading cause of anovulatory infertility. Two engines drive it.
First, increased GnRH pulse frequency raises the LH:FSH ratio. High LH stimulates ovarian theca cells to overproduce androgens (testosterone, androstenedione), while relatively low FSH stalls follicle maturation → chronic anovulation.
Second, insulin resistance with compensatory hyperinsulinemia amplifies theca androgen output and suppresses hepatic SHBG, raising free testosterone.
Anovulation means no corpus luteum, so progesterone is absent and estrogen acts unopposed — the key link to endometrial hyperplasia and carcinoma. Peripheral aromatization of excess androstenedione to estrone in adipose tissue sustains this tonic estrogen state. The result is the clinical triad of hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology.
- Menstrual: oligomenorrhea/amenorrhea, anovulatory infertility
- Hyperandrogenism: hirsutism, acne, androgenic (female-pattern) alopecia
- Metabolic: central obesity, acanthosis nigricans, insulin resistance
- Classic labs: ↑ free testosterone; ↑ LH:FSH (often >2–3:1, supportive only); mildly ↑ DHEA-S in a minority
- Long-term risk: type 2 diabetes, metabolic syndrome, dyslipidemia, NAFLD, OSA, and endometrial carcinoma (unopposed estrogen)
- Lean women can have PCOS — obesity is common but not required
- Red flag: frank virilization (clitoromegaly, deep voice, temporal balding, rapid onset) is NOT PCOS → hunt for an androgen-secreting tumor
Vignette: A 24-year-old woman reports periods every 2–3 months, worsening facial hair, and acne since her late teens. BMI 31. Exam: coarse hair on chin/upper lip and velvety hyperpigmentation of the axillae. β-hCG negative.
- Diagnosis: PCOS (Rotterdam — ≥2 of anovulation, hyperandrogenism, polycystic ovaries — after excluding mimics).
- Next best step (workup): exclude mimics — TSH, prolactin, 17-hydroxyprogesterone, β-hCG; measure total/free testosterone to confirm hyperandrogenism.
- Best initial management (not seeking pregnancy): lifestyle/weight loss + combined oral contraceptives (regulates cycles, treats hirsutism, protects the endometrium).
- Persistent hirsutism → add spironolactone (antiandrogen; always pair with reliable contraception — teratogenic, risks feminization of a male fetus).
Differentiating causes of hyperandrogenism
| Cause | Onset / clue | Key lab |
|---|---|---|
| PCOS | Gradual, peripubertal; obesity, acanthosis | ↑ free testosterone, ↑ LH:FSH |
| Nonclassic CAH (21-hydroxylase def.) | Gradual, peripubertal; mimics PCOS | ↑ 17-hydroxyprogesterone |
| Ovarian androgen tumor (e.g. Sertoli–Leydig) | Rapid virilization | Testosterone >150 ng/dL |
| Adrenal tumor | Rapid virilization | DHEA-S >700 µg/dL |
| Cushing syndrome | Striae, moon facies, HTN, proximal weakness | ↑ cortisol; fails dexamethasone suppression |
Vignette: A 32-year-old woman develops rapidly progressive facial hair, deepening voice, temporal balding, and clitoromegaly over 6 months. Total testosterone 210 ng/dL; DHEA-S normal.
- Diagnosis: red flags for an androgen-secreting ovarian tumor (e.g., Sertoli–Leydig cell tumor) — NOT PCOS. PCOS is gradual and does not cause frank virilization.
- Localize by marker: testosterone >150 ng/dL → ovarian source; DHEA-S >700 µg/dL → adrenal source.
- Next best step: pelvic/transvaginal ultrasound for a testosterone-driven picture (adrenal CT if DHEA-S is the elevated marker).
- Rapid onset + virilization + very high androgens = image for a tumor — do not simply start an OCP.
- Rotterdam criteria — diagnose PCOS with ≥2 of 3:
- Oligo-/anovulation
- Clinical or biochemical hyperandrogenism
- Polycystic ovarian morphology on ultrasound
- Diagnosis of exclusion — first rule out thyroid disease, hyperprolactinemia, nonclassic CAH, Cushing, and androgen-secreting tumors.
- US threshold: classically ≥12 follicles (2–9 mm) per ovary or ovarian volume ≥10 mL; updated guidance raises the count to ≥20 per ovary with high-resolution (≥8 MHz) probes.
- Do NOT diagnose on LH:FSH ratio alone — supportive, not required.
- Screen every patient for metabolic disease: 2-hr OGTT / HbA1c, fasting lipids, blood pressure.
- First-line for everyone: lifestyle / weight loss — restores ovulation, lowers androgens and insulin.
- Not seeking pregnancy: combined OCPs — first-line for cycle control, hirsutism, and endometrial protection.
- Hirsutism persisting on an OCP: add spironolactone (antiandrogen; requires contraception).
- Insulin resistance / prediabetes: metformin.
- Seeking pregnancy → ovulation induction: LETROZOLE is first-line (aromatase inhibitor; higher live-birth rate than clomiphene, esp. in obese women). Clomiphene is an alternative; metformin is an adjunct, not primary ovulation induction.
- On no OCP and oligomenorrheic? Give cyclic progestin to shield the endometrium from unopposed estrogen.
HAIR-AN syndrome — a severe insulin-resistant subtype of PCOS whose acronym also names the core clinical cluster:
- HyperAndrogenism (hirsutism, acne)
- Insulin Resistance
- Acanthosis Nigricans
Rotterdam = 2 of 3 — the three criteria are simply P-O-A:
- Polycystic ovaries on ultrasound
- Ovulatory dysfunction (oligo-/anovulation)
- Androgen excess (clinical or biochemical)
Ovulation-induction hook: *"Let her ovulate"* → LETrozole is first-line.
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