Polycystic Ovarian Syndrome (PCOS)

PCOS is the commonest endocrinopathy of reproductive-age women and the leading cause of anovulatory infertility. It is a heterogeneous disorder of androgen excess, ovulatory dysfunction and polycystic ovarian morphology, tightly linked to insulin resistance. For NEET PG the Rotterdam criteria, the LH:FSH ratio, the "necklace/string-of-pearls" sign and clomiphene as first-line ovulation induction are perennial favourites.

Definition and nomenclature

PCOS (also called Stein–Leventhal syndrome in its classic form) is a clinical syndrome, not merely an ultrasound finding. The presence of polycystic ovaries on scan alone (seen in up to 20–25% of normal young women) does not establish the diagnosis. Conversely, a patient can have full-blown PCOS with normal-looking ovaries. This dissociation between morphology and syndrome is heavily tested.

High-yield: "Polycystic ovary" on USG ≠ "Polycystic ovarian syndrome." The syndrome requires androgen excess and/or ovulatory dysfunction, after exclusion of mimics.

Diagnostic criteria

Three sets of criteria exist; Rotterdam (2003) is the most widely used and the default answer in exams.

Criteria set	Year	Requirement	Key feature
NIH	1990	Both hyperandrogenism and oligo/anovulation	Strictest; PCOM not needed
Rotterdam (ESHRE/ASRM)	2003	Any 2 of 3	Broadest; default
AE-PCOS Society	2006	Hyperandrogenism mandatory + (ovulatory dysfunction or PCOM)	Androgen excess is core

Rotterdam — any 2 of the 3:

1. Oligo-ovulation or anovulation (oligo/amenorrhoea).
2. Clinical and/or biochemical hyperandrogenism (hirsutism, acne, raised free testosterone).
3. Polycystic ovarian morphology (PCOM) on USG.

All criteria require exclusion of other causes (thyroid disease, hyperprolactinaemia, non-classical CAH, Cushing's, androgen-secreting tumours).

High-yield: Rotterdam = 2 of 3. This single fact is asked almost every year. Remember the trio: anovulation, androgen excess, polycystic morphology.

Adolescent caveat

In girls within ~8 years of menarche, PCOM should NOT be used as a criterion (multifollicular ovaries are physiological in adolescence). Diagnosis needs both hyperandrogenism and ovulatory dysfunction (effectively NIH criteria). Avoid over-diagnosis in this group.

Etiology and pathophysiology

PCOS is multifactorial — genetic predisposition plus environmental factors (obesity, insulin resistance). The central engine is a vicious cycle of hyperandrogenism and hyperinsulinaemia.

The core loop:

Insulin resistance → compensatory hyperinsulinaemia → ↑ ovarian theca-cell androgen production + ↓ hepatic SHBG → ↑ free testosterone → hyperandrogenism + follicular arrest → anovulation.

Key mechanistic threads:

• Altered GnRH pulsatility: Increased GnRH pulse frequency favours LH over FSH secretion → raised LH and a high LH:FSH ratio (classically ≥ 2–3:1). High LH drives theca-cell androgen synthesis.
• Relatively low FSH → granulosa cells cannot aromatise androgens to oestrogen adequately → follicles arrest at 2–9 mm (the "cysts" are actually arrested antral follicles), none reaching dominance → anovulation.
• Insulin acts as a co-gonadotrophin, synergising with LH on theca cells and reducing hepatic SHBG → more bioavailable free androgen.
• ↑ AMH (anti-Müllerian hormone) from the large pool of small antral follicles — a marker of ovarian reserve excess; increasingly used as a surrogate for PCOM.
• Peripheral aromatisation of androgens in adipose tissue → unopposed acyclic oestrogen → endometrial proliferation (cancer risk) and further suppression of FSH.

High-yield: Insulin resistance is central and present even in lean women with PCOS. SHBG falls → free testosterone rises. This is why metformin and weight loss help.

Clinical features

Onset is typically peri-menarchal with worsening over adolescence/early adulthood.

Domain	Features
Menstrual	Oligomenorrhoea (cycles > 35 days), amenorrhoea, irregular/heavy bleeds
Androgenic	Hirsutism (Ferriman–Gallwey score ≥ 8 in Indian/Asian women — lower threshold), acne, androgenic alopecia
Metabolic	Central obesity, acanthosis nigricans (velvety hyperpigmentation, nape/axillae — marker of insulin resistance), dyslipidaemia
Reproductive	Subfertility/anovulatory infertility, recurrent miscarriage
Other	Obstructive sleep apnoea, mood disorders, NAFLD

High-yield: Acanthosis nigricans + hirsutism + oligomenorrhoea + obesity = HAIR-AN syndrome (HyperAndrogenism, Insulin Resistance, Acanthosis Nigricans) — a severe insulin-resistant variant.

Mnemonic for features — "PCOS":

• Period irregularity (oligo/amenorrhoea)
• Cysts (string of pearls on USG)
• Obesity / insulin resistance
• Skin & hair: hirsutism, acne, acanthosis nigricans

Investigations

Hormonal profile

Best timed in the early follicular phase (day 2–5) of a (induced or spontaneous) cycle.

Test	Typical finding in PCOS	Note
LH	Raised	—
FSH	Normal/low	—
LH:FSH ratio	≥ 2:1 (often 3:1)	Classic but only in ~60%; not required for diagnosis
Total/free testosterone	Mildly raised	Free T more sensitive
SHBG	Low	Drives free androgen up
DHEAS	Normal/mildly raised	Marked rise → suspect adrenal tumour
AMH	Raised	Surrogate for follicle count
Fasting insulin / HOMA-IR	Raised	Insulin resistance
Prolactin, TSH	Normal	To exclude mimics
17-OH progesterone	Normal	Raised → non-classical CAH

High-yield: A modestly raised testosterone is expected. Total testosterone > 150–200 ng/dL (or rapid-onset virilisation) mandates a search for an androgen-secreting ovarian/adrenal tumour, NOT PCOS.

Imaging — investigation of choice

Transvaginal ultrasound (TVS) is the imaging modality of choice (transabdominal if virgin/adolescent).

Rotterdam ultrasound criterion (revised thresholds with high-frequency transducers):

• ≥ 20 follicles of 2–9 mm per ovary, and/or
• Ovarian volume > 10 mL (in absence of dominant follicle/corpus luteum).

Classic appearance: peripherally arranged small follicles giving the "string of pearls" / "necklace sign" with increased echogenic central stroma.

High-yield: The "necklace sign / string of pearls" = peripheral 2–9 mm follicles. Older criterion was ≥ 12 follicles; newer high-resolution machines use ≥ 20.

Screening for comorbidities (do at diagnosis)

• 2-hour 75 g OGTT (preferred over fasting glucose) — to detect impaired glucose tolerance/T2DM.
• Fasting lipid profile, BP, BMI/waist circumference.
• Screen for OSA, mood disorder, endometrial assessment if prolonged amenorrhoea.

Differential diagnosis

Condition	Distinguishing clue
Non-classical CAH (21-hydroxylase deficiency)	↑ 17-OH progesterone (basal > 200 ng/dL; confirm with ACTH stimulation)
Cushing's syndrome	Striae, proximal myopathy, hypertension; ↑ cortisol, failed dexamethasone suppression
Hyperprolactinaemia	↑ prolactin, galactorrhoea
Thyroid disease	Abnormal TSH
Androgen-secreting tumour	Rapid virilisation, very high testosterone/DHEAS
Idiopathic hirsutism	Hirsutism with regular ovulatory cycles, normal androgens
Hypothalamic amenorrhoea	Low LH/FSH, low BMI, no hyperandrogenism

Management

Management is symptom-directed and goal-directed, with lifestyle modification as universal first-line.

Stepwise approach

Step 1 → Lifestyle: weight loss (even 5–10% restores ovulation in many), diet, exercise. Foundation of all therapy. Step 2 → Treat the dominant complaint: menstrual regulation / hyperandrogenism / fertility / metabolic risk. Step 3 → Pharmacotherapy tailored to goal (see below). Step 4 → Second-line fertility measures (letrozole/gonadotrophins/LOD) → IVF if refractory.

A. Not desiring pregnancy — menstrual regulation & androgen control

• Combined oral contraceptive pill (COCP) = first-line. Suppresses LH → ↓ ovarian androgens; raises SHBG → ↓ free testosterone; provides cyclical withdrawal bleeds → endometrial protection. Prefer pills with anti-androgenic progestins (drospirenone, cyproterone acetate).
• Anti-androgens for hirsutism (added after ~6 months if inadequate): spironolactone (commonest), finasteride, flutamide. Always with contraception (teratogenic — feminisation of male foetus).
• Cyclical progestins if COCP contraindicated — to prevent endometrial hyperplasia.
• Cosmetic/eflornithine cream for facial hirsutism; laser/electrolysis.

B. Insulin resistance / metabolic

• Metformin — improves insulin sensitivity, modestly lowers androgens, helps menstrual regularity and metabolic profile; useful in IGT/T2DM and in obese PCOS. Not a primary ovulation drug but an adjunct.
• Inositol (myo-inositol) — adjunct improving insulin signalling.

C. Desiring pregnancy — ovulation induction

High-yield (most-tested): Letrozole (aromatase inhibitor) is now the preferred first-line ovulation induction agent in PCOS — higher live-birth and ovulation rates than clomiphene (PPCOS II trial). Clomiphene citrate remains the classic/traditional first-line and is still a very common answer; know both.

Drug	Mechanism	Notes
Letrozole	Aromatase inhibitor → ↓ oestrogen → ↑ FSH	Current first-line; better in obese; lower multiple-pregnancy risk
Clomiphene citrate	SERM, blocks hypothalamic oestrogen receptor → ↑ FSH	Traditional first-line; risk of anti-oestrogenic endometrial/cervical-mucus effect; multiple pregnancy ~8%
Metformin	Insulin sensitiser	Adjunct; combine with clomiphene in resistant cases
Gonadotrophins (FSH ± LH)	Direct ovarian stimulation	Second-line; needs monitoring; risk of OHSS & multiples
Laparoscopic ovarian drilling (LOD)	Cautery of stroma ↓ androgens	Second-line surgical; for clomiphene-resistant; risk of adhesions/ovarian failure
IVF	—	Final step; antagonist protocol preferred (↓ OHSS)

• Clomiphene is given days 2–5, starting 50 mg, up to 150 mg. "Clomiphene resistance" = failure to ovulate at maximal dose; "clomiphene failure" = ovulation without conception.
• Ovarian drilling classically uses 4 punctures at 4 points × 4 seconds × 40 W — the "four-by-four" memory aid (purely a teaching mnemonic, not a fixed rule).

High-yield: PCOS patients are at high risk of OHSS with gonadotrophins/IVF due to the large antral follicle pool. Use antagonist protocols and GnRH-agonist trigger.

Complications

Short/medium term	Long term
Anovulatory infertility	Type 2 diabetes mellitus, metabolic syndrome
Menstrual irregularity, DUB	Cardiovascular disease, dyslipidaemia
OHSS (with treatment)	Endometrial carcinoma (unopposed oestrogen)
Pregnancy: GDM, pre-eclampsia, miscarriage	NAFLD, OSA, depression/anxiety

High-yield: Chronic anovulation → unopposed oestrogen → endometrial hyperplasia → endometrial carcinoma. Always ensure withdrawal bleeds (progestin/COCP) for endometrial protection. PCOS is NOT classically linked to ovarian or breast cancer.

Recently asked / exam angle

• Rotterdam criteria — "2 out of 3" is the single most repeated stem. Be able to name all three components.
• First-line ovulation induction: be ready for either letrozole (current preferred) or clomiphene (traditional) depending on how the question is framed; if the option set has letrozole as "preferred for live birth," choose it.
• Investigation of choice for ovarian morphology = transvaginal ultrasound; recognise string of pearls/necklace sign in image-based questions.
• LH:FSH ratio ≥ 2–3:1 — know that it is supportive but not part of diagnostic criteria.
• Acanthosis nigricans as a clinical marker of insulin resistance / HAIR-AN syndrome.
• Endometrial carcinoma as the key long-term malignancy risk and reason for cyclical progestins.
• Adolescent diagnosis: PCOM excluded as a criterion within 8 years of menarche.
• New USG threshold ≥ 20 follicles (updated from ≥ 12) with modern transducers.
• Metformin as the drug for the metabolic/insulin-resistance component, not a primary fertility drug.
• Drug to AVOID/caution: spironolactone in pregnancy (teratogenic, needs contraception).

Rapid revision

1. Rotterdam = any 2 of 3: oligo/anovulation, hyperandrogenism, polycystic morphology (after excluding mimics).
2. Commonest cause of anovulatory infertility; commonest endocrinopathy in reproductive-age women.
3. Core pathophysiology = insulin resistance + hyperandrogenism in a self-reinforcing loop; SHBG low, free testosterone high.
4. LH:FSH ≥ 2–3:1 is supportive, not diagnostic; AMH raised.
5. TVS is imaging of choice — ≥ 20 follicles (2–9 mm)/ovary or volume > 10 mL; "string of pearls/necklace sign."
6. Acanthosis nigricans = insulin resistance; severe variant = HAIR-AN syndrome.
7. Lifestyle/weight loss (5–10%) is first-line for everything; restores ovulation.
8. Not desiring pregnancy → COCP (anti-androgenic progestin) ± spironolactone for hirsutism.
9. Desiring pregnancy → letrozole (preferred) or clomiphene (classic) first-line; metformin adjunct; gonadotrophins/LOD second-line; IVF last.
10. Letrozole > clomiphene for live birth (PPCOS II); clomiphene risks anti-oestrogenic endometrium.
11. Long-term: T2DM, metabolic syndrome, endometrial carcinoma (unopposed oestrogen) — give cyclical progestin protection.
12. Total testosterone > 150–200 ng/dL or rapid virilisation → rule out androgen-secreting tumour, not PCOS.