Polycystic ovary syndrome
Description
- Hyperandrogenism + ovulatory dysfunction + polycystic ovarian morphology, after exclusion of mimics
- Not a gynaecological problem - a lifelong metabolic and reproductive one
Phenotypes (all four are PCOS)
| Hyperandrogenism | Anovulation | PCOM | |
|---|---|---|---|
| A (classic, most metabolic) | + | + | + |
| B | + | + | - |
| C (ovulatory) | + | - | + |
| D (non-hyperandrogenic, mildest) | - | + | + |
Clinical features
- Menstrual - oligo/amenorrhoea, anovulatory infertility, dysfunctional bleeding
- Androgenic - hirsutism (Ferriman-Gallwey), acne, androgenic alopecia
- Virilisation - clitoromegaly, deep voice, rapid onset - is not PCOS. Think tumour or CAH
- Metabolic - central obesity, IGT/T2DM, MASLD, dyslipidaemia, OSA, acanthosis nigricans
- Psychological - anxiety, depression, disordered eating, body image distress (guideline mandates screening)
Epidemiology
- 8-13% of reproductive-age women by Rotterdam criteria; up to 21% in Aboriginal and Torres Strait Islander women
- Up to 70% undiagnosed
- Presents from adolescence to the 30s; hyperandrogenism attenuates with age
- Strongly familial - first-degree relatives ~20-40%
- Higher prevalence and worse metabolic phenotype in South Asian women, at lower BMI
Aetiopathogenesis
- Two interacting engines: ovarian/adrenal androgen excess and insulin resistance
Neuroendocrine
- inc GnRH pulse frequency -> inc LH:FSH -> theca cell androgen production
- dec FSH relative to LH -> follicular arrest at the antral stage -> anovulation + the ultrasound appearance
- Progesterone deficiency (anovulation) removes the brake on GnRH pulsatility -> self-perpetuating cycle
Insulin
- Hyperinsulinaemia
- inc theca-cell androgen output in synergy with LH
- inc adrenal androgen response to ACTH
- dec hepatic SHBG -> inc free testosterone (a large part of the measured androgen excess)
- *The ovary stays insulin-sensitive even when muscle and liver are resistant* - so hyperinsulinaemia drives steroidogenesis unopposed
- Insulin resistance is intrinsic (post-receptor serine phosphorylation defect) and independent of BMI, then amplified by adiposity
- AMH from arrested small antral follicles is high -> further inhibits FSH-driven follicle selection
Genetics/other
- Polygenic - DENND1A, THADA, FSHR, LHCGR, INSR
- Developmental programming: prenatal androgen exposure, low birthweight, premature adrenarche
Diagnosis
Criteria - Rotterdam, as refined by the 2023 international guideline
- 2 of 3, with exclusion of other causes
- Clinical or biochemical hyperandrogenism
- Oligo- or anovulation
- Polycystic ovarian morphology on ultrasound OR raised AMH
- *Updated PCOM threshold: >=20 follicles (2-9 mm) per ovary, or ovarian volume >10 mL, on transvaginal ultrasound* (with modern high-frequency transducers)
- The old >=12 follicle count is obsolete - it labels a large fraction of normal women
- *AMH above the assay reference interval is now an accepted alternative to ultrasound - adults only*
- Ultrasound and AMH must not be used within 8 years of menarche - multifollicular ovaries are normal in adolescence
- Adolescents: require both hyperandrogenism and irregular cycles
Defining irregular cycles by gynaecological age
| Time since menarche | Irregular |
|---|---|
| <1 y | Normal (puberty) |
| 1 to <3 y | <21 or >45 days |
| >=3 y | <21 or >35 days, or <8 cycles/yr |
| >=1 y | Any cycle >90 days |
Biochemistry
- Total testosterone + SHBG -> calculated free testosterone / free androgen index (the most sensitive measure)
- Stop the COCP for >=3 months before androgen testing - it raises SHBG and masks the diagnosis
- Androstenedione and DHEAS only if testosterone normal but suspicion persists
Exclude before diagnosing
- TSH, prolactin, 17-hydroxyprogesterone (non-classical CAH)
- Cushing syndrome, acromegaly - only if clinical features
- Androgen-secreting tumour if rapid onset, virilisation, or testosterone >5 nmol/L (~2x upper limit)
- Functional hypothalamic amenorrhoea, primary ovarian insufficiency
Once diagnosed - assess the comorbidity
- OGTT (preferred over HbA1c) at diagnosis and every 1-3 years; more often if obese, family history, or planning pregnancy
- Fasting lipids, BP annually, weight/waist
- Screen for OSA, depression/anxiety, disordered eating at diagnosis
- Endometrial risk: cycle >90 days, or persistent amenorrhoea -> transvaginal ultrasound for endometrial thickness +/- biopsy
Management
Underpinning all of it - lifestyle and weight
- The cornerstone. 5-10% weight loss restores ovulation in many and reduces miscarriage
- No specific diet superior - energy deficit and adherence are what matter
- Frame carefully - weight stigma and disordered eating are highly prevalent in this group
- 2023 guideline endorses anti-obesity pharmacotherapy (GLP-1 RA) and bariatric surgery as adjuncts where BMI criteria are met
- Effective contraception is mandatory on a GLP-1 RA and for 1-2 months before conception
By presenting problem
### A. Hirsutism and acne (not seeking pregnancy)
- COCP is first line - suppresses LH-driven ovarian androgens and raises hepatic SHBG
- No specific preparation is preferred; use the lowest effective oestrogen dose. Avoid the 35 microg ethinyloestradiol + cyproterone products first-line - VTE risk
- Add an antiandrogen after >=6 months if the response is inadequate: spironolactone 50-100 mg/day, or cyproterone acetate
- *Antiandrogens are teratogenic (feminisation of a male fetus) - always with reliable contraception*
- Cosmetic: laser/electrolysis, topical eflornithine
- Hair growth cycle means nothing changes for 6 months - tell her at the start
### B. Menstrual irregularity and endometrial protection
- COCP, or cyclic progestogen, or a levonorgestrel IUD
- Aim for a withdrawal bleed at least every 3 months
- Metformin improves cycle regularity and metabolic profile; not as effective as the COCP for androgen symptoms
### C. Anovulatory infertility
- Weight optimisation first
- Letrozole is first line for ovulation induction - higher live birth rate than clomiphene
- Clomiphene +/- metformin as an alternative; metformin alone if letrozole/clomiphene unavailable
- Then gonadotrophins, or laparoscopic ovarian drilling
- IVF for failure of the above - watch OHSS risk; PCOS ovaries are hyper-responsive
- Note: letrozole and clomiphene are used off-label for this indication in Australia
### D. Metabolic risk
- Metformin for IGT/T2DM prevention, especially BMI >=25 or IGT
- Statin per absolute cardiovascular risk; treat hypertension, MASLD, OSA
- Smoking cessation
### E. Psychological
- Routine screening and treatment for depression, anxiety and disordered eating
Associations
- T2DM and IGT - 3-5x risk; gestational diabetes
- MASLD/MASH, metabolic syndrome, dyslipidaemia (high TG, low HDL)
- Obstructive sleep apnoea - independent of BMI
- Endometrial hyperplasia and carcinoma - 2-6x, from unopposed oestrogen
- Depression, anxiety, disordered eating, reduced quality of life
- Pregnancy: miscarriage, gestational diabetes, pre-eclampsia, preterm birth
- Non-classical CAH, acanthosis nigricans, HAIR-AN syndrome
- Male relatives - early androgenic alopecia, metabolic syndrome
Natural history & complications
- Chronic - but cycles often become more regular with age as follicle number falls
- Fertility is reduced, not absent; most conceive, many spontaneously after weight loss
- Androgenic features usually persist; hirsutism needs ongoing therapy
- Metabolic risk accumulates: T2DM in a substantial minority by midlife
- Cardiovascular risk factors are clearly increased; hard cardiovascular event data remain less definitive
- Endometrial cancer risk is the one that is silently accrued - protect the endometrium in anyone with cycles >90 days
- Menopause does not abolish the metabolic phenotype
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