Hyperandrogenism
Hyperandrogenism is a condition characterized by excessive production or activity of androgens, manifesting clinically with hirsutism, acne, alopecia, and menstrual irregularities, most commonly associated with polycystic ovary syndrome.
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References
[1] Lecture slides: Adrian Lui Gynecology Notes.pdf (Section 2.2.3 – Polycystic Ovarian Syndrome, p40-41) [2] Lecture slides: CFB (OG04) Menstrual Disorders.pdf (p72 – Revised PCOS diagnostic criteria, Rotterdam 2003) [3] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf (p14 – Rotterdam criteria for PCOS) [4] Lecture slides: Adrian Lui Gynecology Notes.pdf (Section 2.2.3 – Polycystic Ovarian Syndrome) [5] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (p14 – Cushing syndrome differential and clinical features) [6] Senior notes: Ryan Ho Endocrine.pdf (p77 – Type 2 DM, metabolic syndrome, insulin resistance progression) [7] Senior notes: Ryan Ho Endocrine.pdf (p77 – Type 2 DM, Metabolic Syndrome, PCOS) [8] AOS material: AOS - Pathology.pdf (p20 – Sertoli-Leydig cell tumour, DICER1 mutations) [9] Senior notes: Maksim Medicine Notes.pdf (p103 – Hyperandrogenism investigations) [10] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf [11] Senior notes: Ryan Ho Endocrine.pdf (p74 – CAH diagnosis and management) [12] Senior notes: Ryan Ho Rheumatology.pdf (p126-127 – Acne vulgaris, hyperandrogenic associations) [13] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (p8-14 – Cushing syndrome, adrenal workup) [14] Senior notes: Ryan Ho Rheumatology.pdf (p126 – Acne Vulgaris) [15] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Principle 1 – Sequence of investigations) [16] Senior notes: Block A - Introduction to Endocrine investigations.pdf (p1-4 – Principles, diurnal rhythm, imaging modalities) [17] Senior notes: Adrian Lui Pediatrics Notes.pdf (p283 – CAH diagnosis and management) [18] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf (p14 – Rotterdam criteria, updated USS threshold) [19] Senior notes: Ryan Ho Chemical Path.pdf (p29 – Diagnosis of Cushing Syndrome, DST) [20] Senior notes: Maksim Medicine Notes.pdf (p103 – Hyperandrogenism management) [21] Senior notes: Ryan Ho Rheumatology.pdf (p127 – Acne management ladder, COCP and spironolactone) [22] Senior notes: Ryan Ho Endocrine.pdf (p74 – CAH management) [23] Senior notes: Adrian Lui Pediatrics Notes.pdf (p283 – CAH outcomes and complications) [24] Senior notes: Ryan Ho Endocrine.pdf (p74 – CAH outcomes and complications)
Hyperandrogenism
Hyperandrogenism literally means "hyper" (excessive) + "andro" (male) + "gen" (producing) — an excess of androgen action in the body. It is a clinical and/or biochemical state characterised by excessive androgen production, increased androgen bioavailability, or enhanced androgen receptor sensitivity, leading to clinical manifestations such as hirsutism, acne, androgenic alopecia, and virilisation.
It is critical to distinguish two related but distinct concepts:
- Clinical hyperandrogenism: the presence of signs/symptoms attributable to androgen excess (hirsutism, acne, androgenic alopecia, virilisation)
- Biochemical hyperandrogenism: elevated circulating androgen levels (total testosterone, free testosterone, DHEA-S, androstenedione) detected on blood testing
A patient can have one without the other — a woman with clinical hirsutism may have normal androgen levels (idiopathic hirsutism due to enhanced peripheral 5α-reductase activity), while another may have elevated androgens without obvious clinical signs (due to differences in androgen receptor sensitivity, ethnicity, or SHBG levels).
Key Distinction
Clinical hyperandrogenism = signs/symptoms (hirsutism, acne, alopecia, virilisation). Biochemical hyperandrogenism = elevated serum androgens. Both are independently significant for diagnosis (e.g., in PCOS, either one satisfies the androgen excess criterion in the Rotterdam criteria). [1]
- Hyperandrogenism is predominantly a disorder of women (though it can occur in men, the clinical significance and differential diagnosis differ markedly)
- Polycystic ovarian syndrome (PCOS) is the most common cause of hyperandrogenism in women of reproductive age, accounting for ~70-80% of all cases of hyperandrogenism [1][2]
- PCOS occurs in ~5-10% of reproductive aged women and is the most common endocrinopathy in reproductive age women [1]
- PCOS accounts for ~75% of all anovulatory disorders causing infertility and ~90% of women with oligomenorrhea [1]
- Hirsutism (the most common clinical manifestation of hyperandrogenism) affects approximately 5-10% of women worldwide
- In Hong Kong and East Asian populations, the prevalence of hirsutism is generally lower than in Mediterranean, Middle Eastern, or South Asian populations due to differences in:
- Androgen receptor sensitivity
- 5α-reductase activity in skin
- Hair follicle density and distribution
- However, PCOS prevalence in Hong Kong Chinese women is still estimated at ~5-8%
- Non-classical congenital adrenal hyperplasia (NCCAH) is the second most common cause (~1-5% depending on ethnicity; less common in East Asian populations)
- Androgen-secreting tumours are rare (<0.5% of cases) but critically important to exclude
Hong Kong Context
In Hong Kong, PCOS remains the dominant cause of hyperandrogenism. However, clinicians should be aware that clinical hirsutism may be underreported in Chinese women due to lower baseline hair density, and the modified Ferriman-Gallwey score thresholds may need adjustment for East Asian populations (some guidelines suggest a lower threshold of ≥4-6 rather than ≥8 used in Caucasian populations).
| Risk Factor | Mechanism |
|---|---|
| Obesity / Insulin resistance | Compensatory hyperinsulinemia → ↑androgen secretion by stimulating theca cell secretion of androgens + inhibiting hepatic sex hormone binding globulin (SHBG) production → more free (bioavailable) testosterone [1] |
| Metabolic risk groups: obesity, insulin resistance, T1/T2/GDM | ~10% of PCOS patients have T2DM, 30% have impaired glucose tolerance [1] |
| Family history | 1st degree family history of PCOS is a significant risk factor [1]; genetic predisposition to altered androgen metabolism |
| History of premature adrenarche | Due to early conversion of estrone from adrenal androgens [1] — early activation of the adrenal androgen pathway |
| Use of anti-epileptic drugs (AEDs): especially valproic acid | Valproate increases androgen production and can induce a PCOS-like phenotype [1] |
| Ethnicity | South Asian, Middle Eastern, Hispanic women have higher rates of clinical hirsutism |
| Exogenous androgen exposure | Anabolic steroids, testosterone replacement, DHEA supplements, some progestins with androgenic activity |
| Cushing syndrome | Excess cortisol → adrenal androgen co-secretion, insulin resistance |
Anatomy and Physiology of Androgen Production
Understanding hyperandrogenism requires understanding where androgens come from and how they are regulated. This is fundamental.
Women produce androgens from three sources:
| Androgen | Source | Relative Potency | Clinical Significance |
|---|---|---|---|
| DHEA (dehydroepiandrosterone) | Primarily adrenal (zona reticularis) | Weak | Precursor; elevated in adrenal causes |
| DHEA-S (sulfated form) | Almost exclusively adrenal | Weak | Long half-life → stable marker of adrenal androgen production |
| Androstenedione | Ovary + adrenal (50:50) | Moderate | Key precursor to testosterone |
| Testosterone | Ovary (25%), adrenal (25%), peripheral conversion (50%) | Strong | The main clinically relevant androgen |
| DHT (dihydrotestosterone) | Peripheral conversion from testosterone by 5α-reductase in skin/hair follicles | Strongest (2-3× testosterone) | The androgen that actually acts on hair follicles and sebaceous glands |
This is a crucial concept for understanding hyperandrogenism:
- SHBG is a glycoprotein produced by the liver that binds testosterone (and other sex steroids) in the bloodstream
- Only free (unbound) testosterone is biologically active — it can enter cells and bind androgen receptors
- Normally, ~60-70% of circulating testosterone is bound to SHBG, ~30-38% to albumin (loosely), and only 1-2% is truly free
- Insulin inhibits hepatic SHBG production [1] → hyperinsulinemia (from obesity/insulin resistance) → ↓SHBG → ↑free testosterone → hyperandrogenism even if total testosterone is normal
This is why measuring total testosterone alone can be misleading — a woman with low SHBG (due to obesity/insulin resistance) may have a normal total testosterone but elevated free testosterone. Always consider checking free testosterone or calculating it from total testosterone, SHBG, and albumin.
| ↑ SHBG | ↓ SHBG |
|---|---|
| Oestrogen (including OCP) | Insulin / Hyperinsulinemia |
| Thyroid hormone (hyperthyroidism) | Androgens |
| Hepatitis / Liver disease (acute) | Obesity |
| Aging | Hypothyroidism |
| Pregnancy | Glucocorticoids |
| Progestins (androgenic types) | |
| Growth hormone / IGF-1 |
- GnRH (hypothalamus) → pulsatile release → stimulates anterior pituitary
- LH (anterior pituitary) → acts on theca cells of the ovary → produces androgens (androstenedione, testosterone)
- FSH (anterior pituitary) → acts on granulosa cells of the ovary → converts androgens to oestrogens via aromatase (CYP19A1)
- The two-cell, two-gonadotropin model: LH drives androgen production in theca cells; FSH drives aromatisation of androgens to oestrogens in granulosa cells. If LH:FSH ratio is abnormally high, androgen production outpaces aromatisation → hyperandrogenism
- CRH (hypothalamus) → ACTH (anterior pituitary) → acts on adrenal cortex
- Zona reticularis produces DHEA, DHEA-S, and androstenedione
- Important in congenital adrenal hyperplasia (CAH) where enzyme deficiencies block cortisol synthesis → loss of negative feedback → ↑ACTH → adrenal hyperplasia → ↑androgen precursors shunted through intact pathways
- 5α-reductase (Types 1 and 2) in skin converts testosterone → DHT (the most potent androgen)
- Type 1: predominant in sebaceous glands and skin
- Type 2: predominant in hair follicles and prostate
- Aromatase in adipose tissue converts androgens → oestrogens
- This is why obese women can have both hyperandrogenism AND hyperestrogenism (chronic unopposed oestrogen → endometrial hyperplasia)
Etiology and Pathophysiology
1. Polycystic Ovarian Syndrome (PCOS) — The Most Common Cause
The pathophysiology of PCOS is a self-reinforcing vicious cycle:
Altered FSH and LH action: ↑serum LH, ↑ovarian expression of LH receptors [1]
- ↑LH to FSH ratio → hypersecretion of androgens in theca cells in ovarian follicles, leading to: [1]
- → impaired follicular development with failed selection of dominant follicles
- → ↓progesterone inhibition on GnRH pulse frequency → ↑LH pulses → ↑PCOS phenotype
- ↓FSH action: due to insufficient FSH stimulation, local inhibition of FSH action → impaired follicular development due to insufficient FSH action [1]
- Insulin resistance: compensatory hyperinsulinemia → ↑androgen secretion by: [1]
- stimulating theca cell secretion of androgens
- inhibiting hepatic sex hormone binding globulin production
- Impaired folliculogenesis results in: [1]
- appearance of multiple small follicles that fail to develop into dominant follicles → anovulation
- prolonged oligo/anovulation → oligo-/amenorrhea with prolonged unopposed estrogen
Why the LH:FSH Ratio Matters in PCOS
In PCOS, the GnRH pulse generator fires too fast. High-frequency GnRH pulses preferentially stimulate LH secretion over FSH secretion from the anterior pituitary. This creates the characteristic ↑LH:FSH ratio (often >2:1 or >3:1). More LH means more androgen production from theca cells. Less FSH means less aromatisation to oestrogen in granulosa cells and failed follicular maturation. The androgens themselves further impair folliculogenesis. It's a vicious cycle. [1]
PCOS is part of the metabolic syndrome cluster [2]:
- Type 2 DM risk: ~10% of PCOS patients have T2DM, 30% have impaired glucose tolerance [1]
- Dyslipidaemia: ↑TG, ↑LDL-C, ↓HDL-C
- Non-alcoholic fatty liver disease (NAFLD)
- Cardiovascular risk: increased long-term CVD risk
- Excess risk of endometrial hyperplasia/carcinoma: due to chronic unopposed estrogen exposure [1]
CAH is a group of autosomal recessive enzyme deficiency disorders affecting adrenal steroidogenesis.
- Classical CAH (severe): presents at birth with ambiguous genitalia (females) ± salt-wasting crisis
- Non-classical CAH (NCCAH): milder enzyme deficiency, presents in adolescence/adulthood with hyperandrogenism mimicking PCOS
The most common form (>90%) is 21-hydroxylase deficiency (CYP21A2 gene):
Why does 21-hydroxylase deficiency cause hyperandrogenism?
- 21-hydroxylase converts 17-hydroxyprogesterone (17-OHP) → 11-deoxycortisol (cortisol pathway) and progesterone → 11-deoxycorticosterone (aldosterone pathway)
- When this enzyme is deficient: cortisol and aldosterone production ↓
- ↓Cortisol → loss of negative feedback on ACTH → ↑ACTH → adrenal hyperplasia
- The accumulated precursors (17-OHP, progesterone) are shunted into the intact androgen pathway → ↑DHEA, androstenedione, testosterone → hyperandrogenism
- In salt-wasting forms: ↓aldosterone → Na⁺ wasting, K⁺ retention, hypovolaemia
The screening test is morning 17-hydroxyprogesterone (17-OHP):
- If basal 17-OHP >6 nmol/L (200 ng/dL) → suspicious for NCCAH
- Confirmed by ACTH stimulation test (Synacthen test): 17-OHP >30 nmol/L (1000 ng/dL) at 60 minutes is diagnostic
Other rarer CAH forms:
- 11β-hydroxylase deficiency: hyperandrogenism + hypertension (↑11-deoxycorticosterone has mineralocorticoid activity)
- 3β-hydroxysteroid dehydrogenase deficiency: very rare
These are rare but dangerous — the key clinical clue is rapid onset and virilisation.
| Feature | Ovarian Tumour | Adrenal Tumour |
|---|---|---|
| Tumour types | Sertoli-Leydig cell tumour, hilus cell tumour, granulosa-theca cell tumour (rarely androgenic), steroid cell tumour | Adrenocortical carcinoma, adrenal adenoma |
| Typical androgens elevated | Testosterone (very high, often >5 nmol/L or >150 ng/dL) | DHEA-S (very high, often >18.9 μmol/L or >700 μg/dL) ± testosterone |
| Clinical features | Rapid virilisation, pelvic mass | Rapid virilisation ± Cushing features, abdominal mass |
| Imaging | Pelvic USS / CT / MRI | CT adrenals |
Red Flags for Androgen-Secreting Tumour
- Rapid onset of hyperandrogenic symptoms (weeks to months, not years)
- Virilisation (deep voice, clitoromegaly, male-pattern balding, ↑muscle mass) — this almost never occurs in PCOS
- Total testosterone >5 nmol/L (>150 ng/dL) or DHEA-S >18.9 μmol/L (>700 μg/dL)
- Any hyperandrogenism in a postmenopausal woman should raise suspicion for a tumour
- Excess cortisol from any cause (ACTH-dependent or independent)
- Cortisol has weak androgenic effects, but ACTH excess drives adrenal androgen co-secretion
- Clinical features: moon face, truncal obesity, striae, proximal myopathy, thin skin, easy bruising, buffalo hump, hypertension, glucose intolerance [3]
- Hyperandrogenism in Cushing's is usually mild (hirsutism, acne) unless there is an adrenocortical carcinoma (which can produce large amounts of androgens)
- Diffuse luteinisation of theca cells in the ovarian stroma (not just in follicles)
- Produces very high testosterone levels (can mimic tumour)
- Typically seen in postmenopausal women
- Associated with severe insulin resistance, acanthosis nigricans
- Bilateral ovarian enlargement on imaging but no discrete tumour
- Distinguished from tumour by: bilateral involvement, gradual onset, no discrete mass on imaging
- Clinical hirsutism with normal androgen levels and regular ovulatory cycles
- Due to increased peripheral 5α-reductase activity in the pilosebaceous unit → more conversion of testosterone to DHT locally
- Or increased androgen receptor sensitivity
- Diagnosis of exclusion after ruling out PCOS, NCCAH, tumours, Cushing's, etc.
| Drug | Mechanism |
|---|---|
| Valproic acid | ↑Androgen production, weight gain, insulin resistance, PCOS-like phenotype [1] |
| Anabolic steroids | Exogenous androgen |
| Testosterone / DHEA supplements | Exogenous androgen |
| Danazol | Synthetic androgen used for endometriosis |
| Some progestins (levonorgestrel, norgestrel) | Androgenic progestin activity |
| Minoxidil | Hypertrichosis (not true hirsutism — generalised, not androgen-dependent) |
| Cyclosporine | Hypertrichosis |
| Glucocorticoids (chronic) | ↑Insulin resistance; ACTH suppression but exogenous steroid effect |
- Hypothyroidism: ↓SHBG → ↑free testosterone; also can cause menstrual irregularity
- Hyperprolactinaemia: ↑prolactin → ↓GnRH pulsatility → ↓FSH/LH → anovulation; also stimulates adrenal DHEA-S production
- Acromegaly: GH/IGF-1 excess → insulin resistance → ↓SHBG → ↑free androgens; also directly ↑ovarian androgen production
Classification
| Category | Features | Common Causes |
|---|---|---|
| Mild hyperandrogenism | Hirsutism, acne, oily skin | PCOS, idiopathic hirsutism, NCCAH |
| Moderate hyperandrogenism | Above + androgenic alopecia, menstrual irregularity | PCOS, NCCAH, Cushing's |
| Virilisation | Deep voice, clitoromegaly, ↑muscle mass, male-pattern balding, breast atrophy | Androgen-secreting tumour, severe CAH, ovarian hyperthecosis, exogenous androgens |
| Source | Causes |
|---|---|
| Ovarian | PCOS, ovarian hyperthecosis, ovarian tumours, luteoma of pregnancy |
| Adrenal | CAH (classical/non-classical), adrenal tumours, Cushing syndrome, premature adrenarche |
| Peripheral | Idiopathic hirsutism (↑5α-reductase), obesity (↓SHBG + ↑peripheral conversion) |
| Exogenous | Anabolic steroids, testosterone, DHEA, valproate, danazol |
| Mechanism | Examples |
|---|---|
| ↑Androgen production | PCOS, CAH, adrenal/ovarian tumours, Cushing's |
| ↓SHBG (↑free testosterone) | Obesity, insulin resistance, hypothyroidism, exogenous androgens |
| ↑Peripheral conversion | Idiopathic hirsutism (↑5α-reductase), obesity (↑aromatase and ↑5α-reductase) |
| ↑Androgen receptor sensitivity | Idiopathic hirsutism (genetic variation in androgen receptor) |
Clinical Features
A. Symptoms (with pathophysiological basis)
- Definition: Excess terminal (coarse, pigmented) hair growth in a male pattern distribution in women — face (upper lip, chin, sideburns), chest, abdomen (linea alba), back, inner thighs
- Mechanism: Androgens (specifically DHT via 5α-reductase) convert vellus hairs (fine, unpigmented) into terminal hairs in androgen-sensitive areas. The hair follicle androgen receptor is activated by DHT, inducing follicular growth phase prolongation and increased hair shaft diameter
- Quantification: Modified Ferriman-Gallwey score — 9 body areas scored 0-4 each (maximum 36). Score ≥8 is the traditional threshold for hirsutism in Caucasian women; some guidelines suggest ≥4-6 for East Asian women
- Important distinction: Hirsutism (androgen-dependent, male-pattern) vs Hypertrichosis (generalised excessive hair growth, not androgen-dependent — caused by drugs like minoxidil, cyclosporine, or hypothyroidism)
Hirsutism is the most common clinical manifestation of hyperandrogenism and is present in ~70% of women with PCOS.
- Often occurs in association with hyperandrogenic states, e.g., PCOS, virilization tumours [4]
- ↑Sebum production (seborrhea): Hormonal influence: ↑ with androgens, progestogens, ↓ with oestrogens [4]
- Onset of acne correlates with ↑DHEA-S at adrenarche → peaks in late puberty [4]
- Mechanism: Androgens stimulate sebaceous gland hypertrophy and sebum production → sebum + keratin obstruct follicular duct → microcomedo → closed/open comedo → follicular rupture → inflammatory papule/nodule. P. acnes proliferates in the anaerobic, lipid-rich environment
- Distribution: typically affects areas with largest, hormone-responsive sebaceous glands, e.g., face, neck, chest, upper back, upper arms [4]
- Acne in hyperandrogenism tends to be: persistent beyond typical adolescent age, inflammatory, treatment-resistant, and distributed on the jawline/lower face ("hormonal acne")
- Mechanism: Paradoxically, while androgens stimulate hair growth in body areas, they cause miniaturisation of hair follicles on the scalp (especially the vertex and frontal areas). DHT shortens the anagen (growth) phase and reduces follicle size → progressively thinner, shorter hairs → eventual follicle involution
- Pattern: In women, typically presents as diffuse thinning over the crown with preservation of the frontal hairline (Ludwig pattern), unlike male androgenic alopecia which shows bitemporal recession and vertex balding (Hamilton-Norwood pattern)
- In severe hyperandrogenism or virilisation, women may develop a male-pattern baldness
- Oligo/amenorrhea [1] — oligomenorrhea (cycles >35 days) or amenorrhea (absence of periods for ≥3 months if previously regular, or ≥6 months if previously irregular)
- Mechanism: Impaired folliculogenesis → failed selection of dominant follicle → anovulation [1]. Without ovulation, there is no corpus luteum, no progesterone secretion, and the endometrium is exposed to continuous unopposed oestrogen → irregular shedding or no shedding
- Some may have intermittent breakthrough bleeding and heavy menstrual bleeding (HMB) instead [1]
- Usually present with normal or slightly delayed menarche with normal cycles → followed by irregular cycles [1]
- Oligomenorrhea developed after 30 years are unlikely to be PCOS-related [1]
- Mechanism: Anovulation → no oocyte released → cannot conceive
- PCOS accounts for ~75% of all anovulatory disorders causing infertility [1]
- Both a cause and consequence of hyperandrogenism
- Mechanism: Insulin resistance → hyperinsulinemia → ↑appetite (central), ↑lipogenesis; androgens promote visceral (central/truncal) fat deposition
- Truncal/central obesity pattern (android distribution) is characteristic
- Depression, anxiety, poor self-esteem, body image disturbance
- Related to cosmetic effects of hirsutism, acne, alopecia, obesity
- Also possibly neuroendocrine effects of androgen excess
- Deepening of voice — androgens cause laryngeal cartilage thickening and vocal cord lengthening/thickening (irreversible)
- Clitoromegaly — androgen-driven clitoral enlargement (clitoral length >10 mm or glans area >35 mm²)
- Increased muscle mass — anabolic effect of androgens on skeletal muscle
- Male-pattern balding — severe androgenic alopecia with bitemporal recession
- Breast atrophy — androgen:oestrogen ratio shift reduces breast glandular tissue
- Libido changes — increased libido (androgen effect on CNS)
Virilisation = Alarm Bell
Virilisation (deepening voice, clitoromegaly, male-pattern balding, ↑muscle mass) is NOT a feature of PCOS. If a woman presents with virilisation, you MUST exclude an androgen-secreting tumour (ovarian or adrenal), classical CAH, ovarian hyperthecosis, or exogenous androgen use. The onset is usually rapid (weeks to months). Total testosterone is typically >5 nmol/L (>150 ng/dL).
B. Signs (with pathophysiological basis)
| Sign | Pathophysiology |
|---|---|
| Hirsutism (male-pattern terminal hair) | DHT-mediated conversion of vellus → terminal hair in androgen-sensitive follicles |
| Acne (inflammatory papules, pustules, comedones on face/back/chest) | Androgen → ↑sebum → follicular plugging → P. acnes → inflammation |
| Androgenic alopecia (diffuse crown thinning or bitemporal recession) | DHT-mediated follicular miniaturisation on scalp |
| Seborrhoea (oily skin) | Androgen stimulation of sebaceous glands |
| Acanthosis nigricans (velvety, dark patches in axillae, neck, groin) | Hyperinsulinemia → insulin/IGF-1 binding to keratinocyte receptors → epidermal hyperplasia and melanocyte stimulation; a cutaneous marker of insulin resistance |
| Central (android) obesity | Insulin resistance + androgen-promoted visceral fat deposition |
| Skin tags (acrochordons) | Associated with insulin resistance (same mechanism as acanthosis nigricans) |
| Sign | Suggests | Pathophysiology |
|---|---|---|
| Diffusely enlarged thyroid | Graves' disease / thyroid dysfunction | If hypothyroid → ↓SHBG → hyperandrogenism |
| Cushing stigmata (moon face, buffalo hump, striae, proximal myopathy, thin skin) | Cushing syndrome | ACTH-driven adrenal androgen co-secretion + cortisol effects |
| Galactorrhoea | Hyperprolactinaemia | Prolactin → ↓GnRH → anovulation; also ↑adrenal DHEA-S |
| Visual field defects (bitemporal hemianopia) | Pituitary macroadenoma | Tumour compressing optic chiasm |
| Abdominal/pelvic mass | Ovarian or adrenal tumour | Direct androgen secretion by tumour |
| Clitoromegaly | Virilisation (tumour, severe CAH, hyperthecosis) | High androgen levels → clitoral growth |
| Male-pattern balding | Severe hyperandrogenism | Severe DHT-mediated follicular loss |
| Deepened voice | Virilisation | Laryngeal effects of androgens (irreversible) |
| Breast atrophy | Virilisation | Androgen:oestrogen ratio shift |
Nine body areas assessed for terminal hair growth (each scored 0–4):
- Upper lip
- Chin
- Chest
- Upper abdomen
- Lower abdomen
- Upper arms
- Thighs
- Upper back
- Lower back
- Score ≥8 (Caucasian) or ≥4-6 (East Asian) = hirsutism
- Clitoral size (normal <5 mm glans width)
- Vaginal mucosa (assess oestrogenisation)
- Bimanual palpation (ovarian mass?)
Approach to a Patient with Suspected Hyperandrogenism
- Onset and progression: Gradual (years) → PCOS / idiopathic; Rapid (weeks-months) → tumour
- Menstrual history: Menarche age, cycle regularity, duration of irregularity, last menstrual period, fertility history
- Associated symptoms: Weight gain, acne, alopecia, voice changes, libido changes, galactorrhoea
- Drug history: Valproic acid [1], anabolic steroids, DHEA supplements, OCP, hormonal treatments
- Family history: 1st degree FHx of PCOS [1], early baldness in male relatives, CAH, DM
- Obstetric history: Difficulty conceiving, gestational diabetes
- Psychological impact: Depression, anxiety, body image
- Screen for metabolic complications: Symptoms of DM (polyuria, polydipsia), OSA (snoring, daytime somnolence)
- BMI and waist circumference (central obesity)
- Ferriman-Gallwey score (hirsutism severity)
- Skin: Acne distribution and severity, androgenic alopecia pattern, acanthosis nigricans (axillae, neck), skin tags, striae
- Signs of virilisation: Voice, muscle bulk, clitoromegaly, breast size
- Signs of Cushing syndrome: Moon face, buffalo hump, striae, proximal myopathy, thin skin
- Thyroid examination: Goitre
- Breast examination: Galactorrhoea
- Abdominal/pelvic examination: Masses
- Blood pressure (hypertension in Cushing's, CAH with 11β-hydroxylase deficiency)
| Pathophysiology | Clinical Feature |
|---|---|
| ↑DHT in pilosebaceous unit | Hirsutism, acne, seborrhoea |
| ↑DHT in scalp follicles | Androgenic alopecia |
| Anovulation (impaired folliculogenesis) | Oligo/amenorrhea, infertility |
| Unopposed oestrogen (anovulation) | Dysfunctional uterine bleeding, endometrial hyperplasia risk |
| Insulin resistance / hyperinsulinemia | Acanthosis nigricans, obesity, T2DM, ↓SHBG |
| ↓SHBG | ↑Free testosterone (amplifies all androgen effects) |
| Very high androgens (tumour/severe CAH) | Virilisation (voice, clitoromegaly, muscle, baldness) |
High Yield Summary
Hyperandrogenism — Key Points for Exams:
- PCOS is the most common cause (~70-80%), affecting ~5-10% of reproductive-aged women [1]
- Three sources of androgens in women: ovaries (LH-driven), adrenals (ACTH-driven), peripheral conversion (5α-reductase)
- SHBG is the gatekeeper — ↓SHBG (from insulin, obesity, androgens) → ↑free testosterone → clinical hyperandrogenism even with normal total testosterone
- Insulin resistance is central to PCOS pathophysiology: hyperinsulinemia → ↑theca cell androgen production + ↓hepatic SHBG [1]
- The LH:FSH ratio is elevated in PCOS because ↑GnRH pulse frequency → preferential LH secretion → ↑ovarian androgen production [1]
- Clinical features: hirsutism (most common), acne, androgenic alopecia, oligo/amenorrhea, infertility, obesity, acanthosis nigricans
- Virilisation (voice deepening, clitoromegaly, male-pattern balding) is a RED FLAG for androgen-secreting tumour — NOT a feature of PCOS
- NCCAH (21-hydroxylase deficiency) is the second most common cause — screen with morning 17-OHP
- Drug causes: especially valproic acid [1]
- Metabolic consequences of PCOS: T2DM (10%), IGT (30%), dyslipidaemia, NAFLD, endometrial hyperplasia/carcinoma [1]
Active Recall - Hyperandrogenism
[1] Lecture slides: Adrian Lui Gynecology Notes.pdf (Section 2.2.3 – Polycystic Ovarian Syndrome) [2] Senior notes: Ryan Ho Endocrine.pdf (p77 – Type 2 DM, Metabolic Syndrome, PCOS) [3] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf [4] Senior notes: Ryan Ho Rheumatology.pdf (p126 – Acne Vulgaris) [5] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Principle 1 – Sequence of investigations) [6] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (p22 – Hypogonadism) [7] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf [8] Lecture slides: GC 149. Premature puberty puberty and related disorders.pdf
Differential Diagnosis of Hyperandrogenism
The differential diagnosis of hyperandrogenism is essentially asking: "Where is the excess androgen coming from, and why?" You systematically work through ovarian, adrenal, peripheral, and exogenous sources, guided by the clinical tempo (gradual vs rapid), severity (mild hirsutism vs frank virilisation), and biochemical pattern.
| Cause | Typical Onset | Key Clinical Clues | Key Biochemistry | Pathophysiological Basis |
|---|---|---|---|---|
| PCOS | Gradual, peri-pubertal | Oligo/amenorrhea, hirsutism, acne, obesity, acanthosis nigricans; NO virilisation | ↑Total testosterone (seldom >150 ng/dL), ↑free T, ↑LH:FSH ratio, ± ↑insulin | ↑LH → theca cell androgen hypersecretion; ↓FSH → impaired aromatisation; hyperinsulinemia → ↓SHBG + ↑theca androgen production [1][9] |
| Idiopathic hirsutism | Gradual, often familial | Hirsutism with regular ovulatory cycles, no other signs | Normal androgen levels, normal ovulatory function | ↑Peripheral 5α-reductase activity → ↑local DHT; or ↑androgen receptor sensitivity; diagnosis of exclusion |
| Non-classical CAH | Gradual, peri-pubertal to young adult | May closely mimic PCOS [1]; hirsutism, acne, menstrual irregularity; more common in Mediterranean, Hispanic and Ashkenazi Jewish women [1] | High morning 17-hydroxyprogesterone (17-OHP) in early follicular phase; exaggerated response to high-dose ACTH stimulation test [1][10][11] | 21-hydroxylase deficiency (partial) → ↓cortisol → ↑ACTH → adrenal hyperplasia → precursors shunted into androgen pathway |
| Classical CAH | Neonatal / childhood | Ambiguous genitalia at birth (46,XX), salt-wasting crisis, precocious puberty | Elevated 17-OHP (>3500-5000 ng/dL) [10][11]; ↓Na, ↑K, metabolic acidosis in salt-wasting form | Severe 21-hydroxylase deficiency → near-complete block of cortisol + aldosterone synthesis → massive androgen shunting |
| Androgen-secreting ovarian tumour | Rapid onset, usually with severe virilisation [1] | Usually associated with severe virilisation (more severe than usual PCOS) [1]; pelvic mass; often post-menopausal | Total testosterone markedly elevated (>150 ng/dL / >5 nmol/L); DHEA-S usually normal | Autonomous testosterone secretion by tumour cells (Sertoli-Leydig cell tumour, hilus cell tumour, steroid cell tumour) |
| Androgen-secreting adrenal tumour | Rapid onset | Virilisation ± Cushing features (if co-secreting cortisol); abdominal mass | DHEA-S markedly elevated (>700 μg/dL / >18.9 μmol/L) ± ↑testosterone; 24-hour urine steroid profiling for adrenal CA [3] | Autonomous adrenal androgen secretion (adrenocortical carcinoma >> adenoma) |
| Ovarian hyperthecosis | Gradual but can be severe | Severe hyperandrogenism mimicking tumour; bilateral ovarian enlargement (no discrete mass); acanthosis nigricans; typically postmenopausal | Very high testosterone (can be >150 ng/dL) but bilateral ovarian enlargement on imaging, no discrete mass | Diffuse luteinisation of ovarian stromal theca cells → autonomous androgen production; strongly associated with insulin resistance |
| Cushing syndrome | Gradual (months-years) | Moon face, buffalo hump, truncal obesity, striae, thin skin, bruising, proximal myopathy, acne [3][12]; hypertension, glucose intolerance | Morning cortisol elevated; confirmed by 1 mg overnight DST, 24h UFC, late-night salivary cortisol [12] | ACTH excess → drives both cortisol AND adrenal androgen co-secretion; cortisol has weak androgenic activity; insulin resistance → ↓SHBG |
| Hyperprolactinaemia | Variable | Galactorrhoea, oligo/amenorrhea, visual field defects (if macroadenoma); headache | Elevated basal non-stressed prolactin [6]; ↓FSH/LH | ↑Prolactin → ↓GnRH pulsatility → hypogonadotrophic hypogonadism → anovulation; also stimulates adrenal DHEA-S production |
| Hypothyroidism | Gradual | Weight gain, cold intolerance, constipation, fatigue, dry skin, menorrhagia or oligomenorrhoea | ↑TSH, ↓fT4 | ↓Thyroid hormone → ↓hepatic SHBG production → ↑free testosterone; also cross-reactivity: TSH is molecularly similar to FSH → high TSH can stimulate FSH receptors [13] |
| Acromegaly | Very gradual (years) | Coarsening of facial features, large hands/feet, hirsutism (56%), hyperhidrosis (>80%), headache, macroglossia, prognathism [14] | ↑IGF-1; OGTT → inadequate GH suppression | GH/IGF-1 excess → insulin resistance → ↓SHBG → ↑free androgens; also direct ↑ovarian androgen production; skin thickening with hyperhidrosis and hirsutism [14] |
| Drug-induced | After drug initiation | Temporal relationship with drug; especially valproic acid [1] | May show ↑testosterone or normal androgens depending on mechanism | Valproate: ↑ovarian androgen production + weight gain + insulin resistance + PCOS-like phenotype; anabolic steroids: direct exogenous androgen; danazol: synthetic androgen; some progestins (levonorgestrel): androgenic activity |
| Obesity / Insulin resistance (without PCOS) | Gradual | Central obesity, acanthosis nigricans, may have mild hirsutism but regular cycles | Mildly ↑free testosterone; ↓SHBG; ↑insulin | Hyperinsulinemia → ↓hepatic SHBG → ↑free testosterone; ↑adipose 5α-reductase; ↑peripheral conversion |
How to Differentiate: Key Distinguishing Features
This is a critical exam distinction because NCCAH may closely mimic PCOS [1].
| Feature | PCOS | NCCAH |
|---|---|---|
| Prevalence | ~5-10% of reproductive-age women | ~1-5% (ethnicity-dependent; less common in East Asian) |
| Onset | Peripubertal | Peripubertal to young adult |
| Clinical features | Oligo/amenorrhea, hirsutism, acne, obesity | Similar — hirsutism, acne, menstrual irregularity; may be more "androgenic" |
| Key differentiating test | Normal 17-OHP | High morning 17-hydroxyprogesterone in early follicular phase; exaggerated response to high-dose ACTH stimulation test [1] |
| LH:FSH ratio | Often ↑ | Usually normal |
| TVUS | Polycystic morphology | Usually normal ovaries |
| Treatment difference | OCP, metformin, spironolactone | Glucocorticoid replacement (hydrocortisone/dexamethasone) to suppress ACTH → ↓androgen precursors |
Must-Know: Always Rule Out NCCAH Before Diagnosing PCOS
NCCAH can closely mimic PCOS. A morning 17-OHP should be checked in ALL women being evaluated for hyperandrogenism, particularly if they are of Mediterranean, Hispanic, or Ashkenazi Jewish descent. Missing NCCAH means missing an autosomal recessive condition with implications for genetic counselling and a fundamentally different treatment (glucocorticoid replacement vs metabolic/anti-androgen therapy). [1][10][11]
| Feature | PCOS | Androgen-Secreting Tumour |
|---|---|---|
| Onset | Gradual (years) | Rapid (weeks to months) |
| Severity | Mild-moderate hirsutism, acne; NO virilisation | Usually associated with severe virilisation [1] — deep voice, clitoromegaly, male-pattern balding, ↑muscle mass |
| Testosterone | Seldom exceeds 150 ng/dL [1] | Markedly elevated, usually >150 ng/dL |
| DHEA-S | Normal or mildly elevated | Very high if adrenal source (>700 μg/dL) |
| Imaging | Polycystic ovaries (bilateral, small follicles) | Discrete ovarian or adrenal mass |
| Age | Reproductive age | Any age; ovarian tumours can be post-menopausal |
"Testosterone seldom exceeds 150 ng/dL in PCOS" [1] — this is a practical threshold. If total testosterone is above this level, you must actively exclude a tumour or ovarian hyperthecosis.
Both can present with truncal obesity, acne, menstrual irregularity, and hirsutism. The key is looking for discriminatory Cushing features:
- Proximal myopathy (cannot rise from chair without hands)
- Purple striae (not the pale/white striae of simple obesity)
- Easy bruising, thin skin (not seen in PCOS)
- Facial plethora
- Osteoporosis in a young woman
- Hypertension and glucose intolerance disproportionate to degree of obesity
Exclude Cushing's with a normal dexamethasone suppression test [1][12]:
- 1 mg overnight DST: morning cortisol should suppress to < 50 nmol/L (1.8 μg/dL)
- If it does not suppress → further workup for Cushing syndrome
Drug classes that can cause hyperprolactinaemia [6]:
- Antipsychotic drugs (risperidone, haloperidol)
- Antiemetics (domperidone, metoclopramide)
- Methyldopa
- H2 antagonists
All reduce dopamine action (dopamine normally inhibits prolactin release from lactotrophs). When prolactin is elevated, GnRH pulsatility is suppressed → ↓FSH/LH → anovulation → menstrual irregularity. While the primary presentation is anovulation/amenorrhea, mild hyperandrogenism can co-exist because:
- Anovulation itself leads to relative androgen excess (no corpus luteum progesterone)
- Prolactin directly stimulates adrenal DHEA-S production
High-Yield GC Slide Point
Rotterdam consensus for PCOS diagnosis requires two out of three criteria: [9]
- Oligo-anovulation
- Clinical and/or biochemical hyperandrogenism
- Sonographic features of polycystic ovaries: follicle number per ovary >20 and/or ovarian volume ≥10 mL
AND exclusion of other aetiologies with similar features, e.g., thyroid disorders, hyperprolactinaemia, CAH, Cushing syndrome, adrenal tumours [1][9]
Differential Diagnosis in Special Populations
In a child presenting with hyperandrogenic features, consider: [13]
| Cause | Key Features |
|---|---|
| Premature adrenarche | Appearance of pubic or axillary hair prior to age 8 (females) or 9 (males) with mild elevation in serum DHEA-S for age [13]; benign, no treatment needed but follow up (risk factor for PCOS) |
| Congenital adrenal hyperplasia (CAH) | Enzymatic defect in adrenal steroid biosynthesis; sex hormone levels vary depending on the adrenal enzyme block; e.g., 21-hydroxylase deficiency, 11β-hydroxylase deficiency [13] |
| Adrenocortical tumours (androgen-secreting) | Rapid virilisation, often palpable abdominal mass, markedly elevated DHEA-S [13] |
| Peripheral precocious puberty — contrasexual | In girls: virilisation (contrasexual); in boys: feminisation (contrasexual) [13] |
| McCune-Albright syndrome | Clinical triad: polyostotic fibrous dysplasia + café-au-lait spots + peripheral precocity; somatic mutation of α-subunit of Gs protein → autonomous hyperfunction [13] |
Hyperandrogenism presenting de novo in a postmenopausal woman should raise high suspicion for a tumour:
| Cause | Notes |
|---|---|
| Ovarian hyperthecosis | Most common cause of severe hyperandrogenism in postmenopausal women; bilateral, no discrete mass |
| Androgen-secreting ovarian tumour | Sertoli-Leydig cell tumour, steroid cell tumour; discrete unilateral mass |
| Adrenal tumour | Adrenocortical carcinoma; elevated DHEA-S |
| Cushing syndrome | Especially ectopic ACTH or adrenal adenoma |
Rule of thumb: New-onset hyperandrogenism in a postmenopausal woman = tumour until proven otherwise.
While hyperandrogenism is predominantly discussed in women, male patients can present with signs of androgen excess in specific contexts:
| Context | Example |
|---|---|
| CAH | Virilisation, short stature (due to early epiphyseal closure), testicular adrenal rest tumours (TARTs) [10][11] |
| Androgen-secreting tumours | Leydig cell tumour → precocious puberty in boys; testosterone-secreting tumours considered in any male with asymmetrical testicular enlargement [13] |
| Exogenous androgens | Anabolic steroid abuse → acne, aggression, testicular atrophy (HPG axis suppression), gynaecomastia (peripheral aromatisation) |
When diagnosing PCOS, the following must be excluded [1][9]:
This is because PCOS is a diagnosis of exclusion — you cannot diagnose PCOS without first ruling out other conditions that share overlapping features.
Biochemical workup as stated by Adrian Lui Gynecology Notes [1]:
- Male hormone profile:
- ↑Total testosterone: normal range 45-60 ng/dL, but PCOS seldom exceeds 150 ng/dL
- ± Normal DHEA-S (to rule out adrenal tumours)
- Normal 17-OH-progesterone (to rule out late-onset CAH)
- Normal dexamethasone suppression test (to rule out Cushing syndrome)
- Female hormone profile (if measured as part of workup for secondary amenorrhoea):
- ↑LH with absence of LH surge
- Normal FSH, E2 with ↑LH:FSH ratio (i.e., normogonadotrophic anovulation)
- Note: many clinicians use LH:FSH ratio ≥2-3:1 as diagnostic criteria but this is NOT DIAGNOSTIC [1]
Exam Trap: LH:FSH Ratio
Many clinicians use LH:FSH ratio ≥2-3:1 as a diagnostic criterion for PCOS, but this is NOT DIAGNOSTIC on its own [1]. The LH:FSH ratio is helpful supportive evidence but is NOT part of the Rotterdam criteria. Up to 40% of PCOS patients may have a normal LH:FSH ratio. Do not use it to rule in or rule out PCOS.
Causes of hyperandrogenism — "PCOS CHAIN":
- P — PCOS (most common)
- C — Congenital adrenal hyperplasia (non-classical)
- O — Ovarian tumour (androgen-secreting)
- S — Syndrome, Cushing
- C — (Drug) Causes (valproate, danazol, anabolic steroids)
- H — Hyperthecosis (ovarian)
- A — Acromegaly / Adrenal tumour
- I — Idiopathic hirsutism
- N — Non-endocrine (hypothyroidism, hyperprolactinaemia)
| Step | Action | Rationale |
|---|---|---|
| 1 | Assess tempo: gradual vs rapid | Rapid onset + virilisation = tumour until proven otherwise |
| 2 | Assess severity: hirsutism only vs virilisation | Virilisation (voice, clitoromegaly, muscle, baldness) = severe cause |
| 3 | Drug history | Valproate, anabolic steroids, danazol, progestins |
| 4 | Check testosterone | >150 ng/dL → tumour or hyperthecosis; <150 ng/dL → PCOS, idiopathic, NCCAH |
| 5 | Check DHEA-S | >700 μg/dL → adrenal tumour |
| 6 | Check 17-OHP | Elevated → NCCAH (confirm with Synacthen test) |
| 7 | Exclude Cushing | 1 mg overnight DST |
| 8 | Check TSH | Hypothyroidism → ↓SHBG |
| 9 | Check prolactin | Hyperprolactinaemia → anovulation |
| 10 | Pelvic USS | Polycystic morphology (PCOS) vs discrete mass (tumour) |
| 11 | If all negative + normal androgens + regular cycles | Idiopathic hirsutism |
High Yield Summary — Differential Diagnosis of Hyperandrogenism
- PCOS is the most common cause (~70-80%) and is a diagnosis of exclusion — must rule out thyroid disease, hyperprolactinaemia, NCCAH, Cushing syndrome, and androgen-secreting tumours [1][9]
- Rotterdam criteria require ≥2 of 3: oligo-anovulation, hyperandrogenism (clinical/biochemical), polycystic ovaries on USS [9]
- NCCAH mimics PCOS — differentiate with morning 17-OHP and ACTH stimulation test [1]
- Androgen-secreting tumours present with rapid onset and virilisation — testosterone usually >150 ng/dL (ovarian source) or DHEA-S >700 μg/dL (adrenal source) [1]
- PCOS testosterone seldom exceeds 150 ng/dL [1] — above this threshold, actively exclude tumour
- LH:FSH ratio ≥2-3:1 is supportive but NOT diagnostic of PCOS [1]
- Cushing syndrome is excluded by a normal dexamethasone suppression test [1][12]
- Idiopathic hirsutism = hirsutism with normal androgens and regular ovulatory cycles; diagnosis of exclusion
- In children: consider premature adrenarche, CAH, adrenocortical tumours [13]
- In postmenopausal women: new-onset hyperandrogenism = tumour until proven otherwise
Active Recall - Differential Diagnosis of Hyperandrogenism
References
[1] Lecture slides: Adrian Lui Gynecology Notes.pdf (Section 2.2.3 – Polycystic Ovarian Syndrome, p40-41) [3] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (p14 – Cushing syndrome differential and clinical features) [6] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (p9 – Other causes of hyperprolactinaemia; p23 – Diagnostic tests) [9] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf (p14 – Rotterdam criteria for PCOS) [10] Senior notes: Adrian Lui Pediatrics Notes.pdf (p283 – CAH diagnosis and management) [11] Senior notes: Ryan Ho Endocrine.pdf (p74 – CAH diagnosis and management) [12] Senior notes: Ryan Ho Chemical Path.pdf (p29 – Diagnosis of Cushing Syndrome) [13] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p674-675 – Peripheral precocious puberty differentials, premature adrenarche) [14] Senior notes: Ryan Ho Endocrine.pdf (p111 – Acromegaly clinical features)
Diagnostic Criteria, Algorithm, and Investigations for Hyperandrogenism
Diagnostic Criteria
Since PCOS is the most common cause of hyperandrogenism (~70-80%), the diagnostic criteria for PCOS are the single most important diagnostic framework to know.
Revised PCOS diagnostic criteria (Rotterdam consensus, 2003): Two out of three: [9][15]
- Oligo- and/or anovulation
- Clinical and/or biochemical signs of hyperandrogenism — and exclusion of other aetiologies (congenital adrenal hyperplasias, androgen-secreting tumours, Cushing's syndrome)
- Polycystic ovaries on scanning
There are two versions of the ultrasound criterion circulating in HKUMed materials. You need to be aware of both:
| Source | USS Criterion |
|---|---|
| CFB (OG04) Menstrual Disorders [15] | ≥12 follicles of 2-9 mm in diameter in at least one ovary OR increased ovarian volume >10 cm³ |
| GC 114 Climacteric symptoms [9] | Follicle number per ovary >20 and/or ovarian volume ≥10 mL |
Which USS Criterion to Use?
The original Rotterdam 2003 criterion used ≥12 follicles [15]. The updated 2018 international PCOS guideline revised this upward to ≥20 follicles per ovary (reflecting improved ultrasound resolution detecting more small follicles) [9]. Both thresholds appear in HKUMed materials. For exams, if the GC slide states >20 follicles, use that as the primary answer since it reflects the updated guideline and was taught in the GC lecture. Mention the historical ≥12 threshold if asked for context. The ovarian volume threshold (≥10 mL) remains unchanged in both versions.
Because the Rotterdam criteria require only 2 of 3 features, four phenotypes exist:
| Phenotype | Anovulation | Hyperandrogenism | Polycystic Ovaries on USS | Metabolic Risk |
|---|---|---|---|---|
| A (classic/full-blown) | ✓ | ✓ | ✓ | Highest |
| B (classic without PCO) | ✓ | ✓ | ✗ | High |
| C (ovulatory PCOS) | ✗ | ✓ | ✓ | Moderate |
| D (non-hyperandrogenic) | ✓ | ✗ | ✓ | Lowest |
Phenotypes A and B carry the greatest metabolic and cardiovascular risk. Phenotype D is the mildest and most controversial — some experts argue it should not be labelled PCOS at all.
- Morning 17-hydroxyprogesterone in early follicular phase [1]:
- Basal 17-OHP < 6 nmol/L (< 200 ng/dL) → NCCAH essentially excluded
- Basal 17-OHP > 6 nmol/L (> 200 ng/dL) → proceed to ACTH stimulation test
- ACTH stimulation test (Synacthen test) [1][10]:
- Stimulated 17-OHP > 30 nmol/L (> 1000 ng/dL) at 60 minutes → diagnostic of 21-hydroxylase deficiency
- Genetic testing (CYP21A2 mutations) for confirmation and family counselling [10]
Three initial screening modalities [12]:
- 24-hour urinary free cortisol (UFC) × 2
- Late-night salivary cortisol × 2
- 1 mg overnight dexamethasone suppression test (DST)
Any one positive screening test requires further confirmatory workup. Exogenous steroid administration is the most common cause of Cushing syndrome in clinical practice [3] — always exclude this first by history.
The workup follows the general endocrine investigation principle: History and PE → Baseline bloods → Screening biochemistry → Confirmatory/dynamic tests → Imaging → Invasive tests [5].
Endocrine is unique in that you need biochemistry before imaging — resolution is too high with our imaging nowadays → so we might find benign lesions, which are not related to the condition [5]. Always confirm biochemical abnormality before ordering imaging.
Investigation Modalities — Detailed Breakdown
A. Hormonal / Biochemical Investigations
| Parameter | Detail |
|---|---|
| What it measures | Total circulating testosterone (bound to SHBG + bound to albumin + free) |
| When to measure | Morning sample (8-10 am) — testosterone follows a diurnal rhythm, peaking in the early morning [5] |
| Timing in menstrual cycle | Early follicular phase (day 2-5) if cycles present; anytime if amenorrhoeic |
| Normal range in women | ~15-70 ng/dL (0.5-2.4 nmol/L) — varies by lab |
| PCOS | Normal range 45-60 ng/dL, but PCOS seldom exceeds 150 ng/dL [1] |
| Tumour threshold | Total testosterone > 150 ng/dL (> 5 nmol/L) → suspect androgen-secreting tumour [1] |
| Caveat | Total testosterone can be falsely normal if SHBG is low (obesity, insulin resistance) — the free fraction may still be elevated |
"Just because in the afternoon you take a spot testosterone test and it's low, doesn't mean it's hypogonadism → need to take first thing in the morning to ensure reproducibility" [5]. The same principle applies in reverse for hyperandrogenism — always measure in the morning.
| Parameter | Detail |
|---|---|
| Why | Free testosterone is the biologically active fraction (~1-2% of total); more sensitive than total testosterone for detecting hyperandrogenism, especially in obesity |
| How measured | Either directly by equilibrium dialysis (gold standard but expensive) or calculated: FAI = (Total testosterone / SHBG) × 100 |
| When useful | When total testosterone is borderline-normal but clinical suspicion remains high (obese patient with low SHBG) |
| Interpretation | Elevated FAI with normal total testosterone = functional hyperandrogenism due to ↓SHBG |
| Parameter | Detail |
|---|---|
| What it measures | The carrier protein for sex steroids; mainly produced by the liver |
| Normal range | ~20-130 nmol/L (varies by lab and sex) |
| In PCOS | Typically low (due to hyperinsulinemia, obesity, androgen excess) |
| Clinical significance | Low SHBG → ↑free testosterone → clinical hyperandrogenism even with normal total T |
| Also low in | Hypothyroidism, exogenous androgens/glucocorticoids, obesity |
| Also high in | Pregnancy, OCP use, hyperthyroidism, liver disease (acute hepatitis) |
| Parameter | Detail |
|---|---|
| What it measures | Almost exclusively an adrenal androgen product (zona reticularis); long half-life → stable marker |
| Why important | Differentiates adrenal from ovarian androgen source |
| Normal range | Age-dependent; typically 35-430 μg/dL in reproductive-age women |
| PCOS | Normal DHEA-S (rules out adrenal tumour) [1] |
| Adrenal tumour | DHEA-S markedly elevated > 700 μg/dL (> 18.9 μmol/L) — strongly suggests adrenocortical carcinoma |
| Adrenarche | Mild elevation of DHEA-S for age in premature adrenarche [13] |
| Parameter | Detail |
|---|---|
| What it measures | Precursor in the cortisol synthesis pathway; accumulates proximal to the 21-hydroxylase enzyme block |
| Why important | Screening test for non-classical CAH (NCCAH) — the most important differential to exclude before diagnosing PCOS [1] |
| When to measure | Morning sample, early follicular phase (day 2-5) [1] — progesterone-related steroids fluctuate with cycle |
| Normal | < 6 nmol/L (< 200 ng/dL) → NCCAH essentially excluded |
| Borderline/elevated | > 6 nmol/L (> 200 ng/dL) → proceed to ACTH stimulation test |
| Classical CAH | Elevated > 3500-5000 ng/dL [10][11] |
| Parameter | Detail |
|---|---|
| When to measure | Early follicular phase (day 2-5) |
| PCOS pattern | ↑LH with absence of LH surge; normal FSH, E2 with ↑LH:FSH ratio (i.e., normogonadotrophic anovulation) [1] |
| Important caveat | Many clinicians use LH:FSH ratio ≥2-3:1 as diagnostic criteria but this is NOT DIAGNOSTIC [1] — not part of Rotterdam criteria |
| Hypogonadotrophic hypogonadism | Both LH and FSH low → pituitary/hypothalamic cause (prolactinoma, Kallmann, functional hypothalamic amenorrhoea) |
| Hypergonadotrophic hypogonadism | Both LH and FSH very high → ovarian failure (premature ovarian insufficiency, menopause) |
Disorders along the HPG axis don't use "primary" and "secondary" — they use hyper vs hypo: [5]
- Hypogonadotrophic hypogonadism → issue in pituitary, "secondary" issue; low oestrogen/testosterone as a consequence of low FSH/LH
- Hypergonadotrophic hypogonadism → issue within ovaries/testes, "primary" issue; low oestrogen/testosterone but high FSH/LH [5]
| Parameter | Detail |
|---|---|
| Why | Exclude thyroid dysfunction as a contributor to menstrual irregularity and hyperandrogenism |
| Hypothyroidism | ↑TSH, ↓fT4 → ↓SHBG → ↑free testosterone; also menstrual irregularity |
| Hyperthyroidism | ↑SHBG (oestrogen-like effect of thyroid hormones) → may mask hyperandrogenism |
| Parameter | Detail |
|---|---|
| Why | Exclude hyperprolactinaemia as cause of anovulation; occurs in 15% of PCOS patients [1] |
| How to measure | Basal, non-stressed prolactin [6] — measure after needle insertion for at least 5 minutes (pain/stress elevates prolactin) |
| Mildly elevated (< 100 ng/mL) | Drug-induced (antipsychotics, antiemetics), PCOS-associated, stalk effect |
| Markedly elevated (> 200 ng/mL) | Prolactinoma (macroprolactinoma if > 250 ng/mL) → pituitary MRI indicated |
High-Yield: Prolactin Measurement Pitfall
Measure prolactin after the needle has been in situ for at least 5 minutes [6] — venepuncture itself is a stress stimulus that can cause a transient rise in prolactin, leading to a false positive result. Also remember that many drugs suppress dopamine and therefore elevate prolactin: antipsychotics (risperidone, haloperidol), antiemetics (domperidone, metoclopramide), methyldopa, H2 antagonists [6].
| Parameter | Detail |
|---|---|
| What it measures | Progesterone level approximately day 21 of a 28-day cycle (7 days before expected period) |
| Why | Confirms ovulation; a progesterone > 16 nmol/L (> 5 ng/mL) indicates ovulation occurred |
| In PCOS | Absence of ovulation → low mid-luteal phase progesterone (if done, probably not if cycles grossly irregular) [1] |
| Caveat | Not useful if cycles are grossly irregular (can't time properly); anovulation is inferred clinically from oligo/amenorrhea |
| Test | Protocol | Interpretation |
|---|---|---|
| 9 am morning cortisol | Fasting morning blood sample | Elevated → suspect Cushing; Low → suspect iatrogenic Cushing (exogenous steroids suppress endogenous cortisol) [3] |
| 1 mg overnight DST | Give 1 mg dexamethasone at 11 pm; measure 9 am cortisol next morning | Normal: cortisol suppresses to < 50 nmol/L (< 1.8 μg/dL) → Cushing excluded. Failure to suppress → further workup [12] |
| Normal dexamethasone suppression test → rules out Cushing syndrome [1] |
- Can be measured but less commonly used in initial workup
- Elevated in both PCOS and NCCAH
- Not as discriminatory as testosterone or DHEA-S
| Test | Purpose | Interpretation |
|---|---|---|
| Fasting glucose | Screen for diabetes | ≥7.0 mmol/L = diabetes; 5.6-6.9 = impaired fasting glucose |
| HbA1c | Long-term glycaemic control | ≥6.5% = diabetes; 5.7-6.4% = pre-diabetes |
| 75g OGTT | More sensitive than fasting glucose for IGT | 2h glucose ≥11.1 = diabetes; 7.8-11.0 = IGT |
| Fasting insulin / HOMA-IR | Quantify insulin resistance | Elevated in PCOS with metabolic syndrome (not routinely done in all centres) |
~10% of PCOS patients have T2DM, 30% have impaired glucose tolerance [1] — metabolic screening is essential.
B. Imaging Investigations
The primary imaging modality for PCOS diagnosis and exclusion of ovarian tumours.
| Finding | Significance |
|---|---|
| Polycystic ovarian morphology ("string-of-pearl sign") [1] | ≥20 follicles in either ovary, each measuring 2-9 mm in diameter; and/or increased ovarian volume >10 mL [1][9] |
| Formula for ovarian volume | 0.5 × length × width × thickness [1] |
| Discrete ovarian mass (solid, mixed) | Suspect ovarian tumour (Sertoli-Leydig cell, steroid cell tumour) → further workup with CT/MRI and tumour markers |
| Bilateral diffuse ovarian enlargement without discrete mass | Ovarian hyperthecosis |
PCOS USS features are found in ~25% of all women, so USS features alone cannot form the diagnosis [1] — must be combined with at least one other criterion.
USS Alone ≠ PCOS
Polycystic ovarian morphology on USS is found in ~25% of all women [1]. An ultrasound showing polycystic ovaries in isolation (without oligo-anovulation or hyperandrogenism) does NOT diagnose PCOS. The Rotterdam criteria require at least 2 of 3 features, and the clinical/biochemical criteria must also be met.
| Indication | When testosterone markedly elevated (tumour suspicion), DHEA-S > 700 μg/dL, or clinical features of Cushing |
|---|---|
| Key findings | Adrenal mass → assess size, Hounsfield units (HU): the higher, the more worrying; the lower = the more fat, less worrying [3], border regularity, washout characteristics |
| Adrenal adenoma | Usually < 4 cm, low HU (< 10 = lipid-rich = benign), smooth borders |
| Adrenocortical carcinoma | Usually > 4 cm, high HU, irregular borders, delayed washout |
| Incidentaloma | Functional or not? Assess with morning cortisol, ARR, 24-hour urine steroid profiling [3] |
Contrast CT for adrenal — pre and post-contrast important for endocrine studies, need to show washout characteristics [5]
| Indication | Equivocal USS findings; suspected ovarian tumour requiring better tissue characterisation |
|---|---|
| Advantage | Superior soft-tissue contrast; better for characterising solid ovarian masses |
| Indication | Markedly elevated prolactin (> 100-200 ng/mL), clinical features of pituitary tumour (visual field defects, headache), suspected Cushing disease |
|---|---|
| Findings | Microadenoma (< 10 mm) or macroadenoma (≥ 10 mm) |
| Contrast MRI for pituitary → soft tissue [5] |
C. Dynamic / Confirmatory Tests
| Step | Detail |
|---|---|
| Indication | Elevated basal 17-OHP → confirm 21-hydroxylase deficiency |
| Protocol | IV/IM 250 μg synthetic ACTH (Synacthen/cosyntropin); measure 17-OHP at baseline and 60 minutes |
| Diagnostic | Stimulated 17-OHP > 30 nmol/L (> 1000 ng/dL) → confirms 21-hydroxylase deficiency [1][10] |
| Heterozygous carrier | Intermediate 17-OHP response (between normal and affected) |
Why does this test work? ACTH stimulates the adrenal cortex to produce all steroid precursors. If there is a partial 21-hydroxylase block, the accumulated 17-OHP upstream of the block rises disproportionately high after ACTH stimulation, because the pathway is stressed and the bottleneck becomes more apparent.
Already covered above (1 mg overnight DST).
If positive, further workup includes:
- Low-dose (2 mg/d × 48h) and high-dose (8 mg/d × 48h) DST to differentiate pituitary (Cushing disease) from ectopic ACTH vs adrenal causes [3][12]
- Plasma ACTH level: high = ACTH-dependent (pituitary adenoma or ectopic); suppressed = ACTH-independent (adrenal adenoma/carcinoma) [3]
- If ACTH-dependent: inferior petrosal sinus sampling (IPSS) to differentiate pituitary from ectopic source [3]
| Indication | All PCOS patients (recommended by international guidelines) for metabolic screening |
|---|---|
| Protocol | Fasting → 75g oral glucose → measure glucose at 0 and 120 minutes |
| Interpretation | 2h glucose < 7.8 = normal; 7.8-11.0 = IGT; ≥ 11.1 = DM |
| Why OGTT over fasting glucose? | OGTT is more sensitive for detecting IGT, which is common in PCOS (30%) but may be missed by fasting glucose alone |
| Investigation | Indication | Findings in PCOS |
|---|---|---|
| Fasting lipid profile | Dyslipidaemia screening | ↑TG, ↑LDL-C, ↓HDL-C |
| Blood pressure | Hypertension screening | May be elevated (metabolic syndrome) |
| Liver function tests | NAFLD screening | May show ↑ALT (fatty liver) |
| Endometrial assessment | If prolonged amenorrhoea (> 3-6 months) or abnormal bleeding | Endometrial thickness > 7 mm in amenorrhoeic patient → consider endometrial biopsy to rule out hyperplasia/carcinoma (excess risk of endometrial hyperplasia/carcinoma due to chronic unopposed oestrogen exposure [1]) |
| Pelvic USS | Endometrial thickness | Thickened endometrium in anovulatory women |
| Sleep study / screening | Obstructive sleep apnoea | Common in PCOS with obesity; screen with questionnaire (e.g. STOP-BANG) |
| Category | Tests |
|---|---|
| Core androgen panel | Total testosterone, free testosterone/FAI, SHBG, DHEA-S |
| Exclusion bloods | 17-OHP (NCCAH), TSH (thyroid), prolactin (hyperprolactinaemia) |
| Gonadotropins | LH, FSH (day 2-5) |
| Cushing screen (if clinical suspicion) | 1 mg overnight DST or 24h UFC or late-night salivary cortisol |
| Metabolic | Fasting glucose/HbA1c, 75g OGTT, fasting lipids, LFTs |
| Imaging | TVUS (ovaries + endometrium), CT adrenals (if DHEA-S elevated or tumour suspected) |
| Dynamic tests | ACTH stimulation test (if 17-OHP elevated), DST (if Cushing suspected) |
Investigation summary from Maksim Medicine Notes [16]:
- Androgen profile: DHEA-S, testosterone
- LH/FSH (> 2.5 in PCOS)
- 17-OH progesterone (CAH)
- CT adrenals and ovaries (tumour)
| Scenario | Most Likely Diagnosis | Next Step |
|---|---|---|
| ↑Total T (< 150 ng/dL), ↑LH:FSH, polycystic ovaries on USS, oligomenorrhoea, normal 17-OHP, normal DHEA-S | PCOS | Metabolic workup; lifestyle modification |
| ↑Total T (> 150 ng/dL), rapid virilisation | Androgen-secreting tumour | Urgent pelvic USS + CT adrenals |
| ↑DHEA-S (> 700 μg/dL) | Adrenal tumour | CT adrenals; 24h urine steroid profiling [3] |
| ↑17-OHP (> 6 nmol/L) | NCCAH | ACTH stimulation test |
| Cushing features + failure to suppress on DST | Cushing syndrome | ACTH level → further localisation |
| ↑Prolactin, galactorrhoea, amenorrhoea | Hyperprolactinaemia | Drug history → pituitary MRI |
| ↑TSH, ↓fT4 | Hypothyroidism | Thyroid hormone replacement |
| Normal androgens, regular cycles, hirsutism | Idiopathic hirsutism | Cosmetic / anti-androgen treatment |
High Yield Summary — Diagnostics of Hyperandrogenism
- Rotterdam criteria for PCOS: ≥2 of 3 (oligo-anovulation, hyperandrogenism, polycystic ovaries) AFTER excluding other causes [9][15]
- PCOS is a diagnosis of exclusion — must check 17-OHP (NCCAH), TSH (thyroid), prolactin (hyperprolactinaemia), DST (Cushing), and testosterone/DHEA-S levels (tumours) [1]
- Endocrine workup: biochemistry BEFORE imaging — high-resolution imaging may find incidentalomas unrelated to the clinical problem [5]
- Testosterone follows a diurnal rhythm — always measure in the morning (8-10 am) [5]
- PCOS testosterone seldom exceeds 150 ng/dL [1] — above this, suspect tumour
- DHEA-S > 700 μg/dL → adrenal tumour; normal DHEA-S → ovarian source
- Morning 17-OHP > 6 nmol/L → ACTH stimulation test → stimulated 17-OHP > 30 nmol/L = NCCAH [1][10]
- Polycystic ovarian morphology on USS found in ~25% of all women — USS alone cannot diagnose PCOS [1]
- LH:FSH ratio ≥2-3:1 is supportive but NOT diagnostic [1]
- Metabolic screening is essential in PCOS: OGTT (30% have IGT, 10% have T2DM), fasting lipids, BP [1]
Active Recall - Diagnostics of Hyperandrogenism
References
[1] Lecture slides: Adrian Lui Gynecology Notes.pdf (Section 2.2.3 – Polycystic Ovarian Syndrome, p40-41) [3] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (p8-14 – Cushing syndrome, adrenal workup) [5] Senior notes: Block A - Introduction to Endocrine investigations.pdf (p1-4 – Principles, diurnal rhythm, imaging modalities) [6] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (p9, p23 – Hyperprolactinaemia, diagnostic tests) [9] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf (p14 – Rotterdam criteria, updated USS threshold) [10] Senior notes: Adrian Lui Pediatrics Notes.pdf (p283 – CAH diagnosis) [11] Senior notes: Ryan Ho Endocrine.pdf (p74 – CAH diagnosis and management) [12] Senior notes: Ryan Ho Chemical Path.pdf (p29 – Diagnosis of Cushing Syndrome, DST) [13] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p674-675 – Precocious puberty differentials) [15] Lecture slides: CFB (OG04) Menstrual Disorders.pdf (p72 – Revised PCOS diagnostic criteria, Rotterdam 2003) [16] Senior notes: Maksim Medicine Notes.pdf (p103 – Hyperandrogenism investigations)
Management of Hyperandrogenism
The management of hyperandrogenism follows a logical hierarchy:
- Treat the underlying cause — if a specific aetiology is identified (tumour, CAH, Cushing's, drug-induced, thyroid/prolactin disorder), treat that directly
- Symptom-directed therapy — for PCOS and idiopathic hirsutism, management targets the specific complaints: hirsutism, acne, menstrual irregularity, infertility, metabolic risk
- Long-term metabolic risk reduction — PCOS is not just a cosmetic or reproductive disease; it carries lifelong cardiometabolic risk
Management from Maksim Medicine Notes [16]:
- Correct underlying cause (e.g., discontinue causative drugs)
- Anti-androgen, e.g., spironolactone
- Surgical resection of tumour
Treatment Modalities — Detailed Breakdown
This is the foundation of PCOS management, regardless of phenotype or primary complaint.
| Intervention | Target | Mechanism | Evidence |
|---|---|---|---|
| Weight loss of 5-10% body weight | Obese/overweight PCOS patients | ↓Adipose tissue → ↓insulin resistance → ↓hyperinsulinemia → ↑SHBG → ↓free testosterone; ↓adipose aromatase activity; may restore ovulatory cycles | Even modest weight loss (5%) can restore ovulation in ~30-50% of anovulatory PCOS women |
| Dietary modification | All PCOS patients | Caloric restriction; low glycaemic index diet preferred (reduces postprandial insulin spikes) | Improves insulin sensitivity independently of weight loss |
| Exercise: 150 min/week moderate intensity | All PCOS patients | ↑AMPK activation → ↑glucose uptake + ↑fatty acid metabolism → ↓insulin resistance [2]; improves cardiovascular fitness | International PCOS guideline 2023 recommendation |
Weight Loss Restores Ovulation
In overweight/obese PCOS women, a 5-10% reduction in body weight is often sufficient to restore spontaneous ovulation, reduce androgen levels, and improve metabolic parameters. This should be attempted for 3-6 months before proceeding to pharmacological ovulation induction. Weight loss is the most cost-effective and least invasive intervention.
B. Combined Oral Contraceptive Pill (COCP) — Menstrual Regulation, Endometrial Protection, and Anti-Androgen Effect
The COCP is the first-line pharmacological treatment for PCOS in women who do not desire pregnancy. It addresses multiple PCOS features simultaneously.
The COCP works through several synergistic mechanisms relevant to hyperandrogenism:
-
Oestrogen component (ethinylestradiol / estradiol):
- ↑Hepatic SHBG production → ↓free testosterone → ↓clinical hyperandrogenism
- Provides oestrogen for endometrial stabilisation
-
Progestogen component:
- Opposes unopposed oestrogen on the endometrium → prevents endometrial hyperplasia/carcinoma
- Suppresses LH secretion (negative feedback on pituitary) → ↓ovarian androgen production from theca cells
- Some progestogens have direct anti-androgenic activity (see below)
-
Combined HPG axis suppression:
- Suppresses GnRH pulsatility → ↓LH and FSH → ↓ovarian follicular activity and androgen production
Not all progestogens are equal — some have androgenic activity, which is counterproductive in hyperandrogenism:
| Progestogen | Androgenic Activity | Notes |
|---|---|---|
| Cyproterone acetate (CPA) | Anti-androgenic | Most potent anti-androgen among progestogens; used in Diane-35 (EE 35 μg + CPA 2 mg); blocks androgen receptor + inhibits 5α-reductase + suppresses gonadotrophins |
| Drospirenone | Anti-androgenic (mild) | Spironolactone analogue; also anti-mineralocorticoid (may cause hyperkalaemia); used in Yasmin/Yaz |
| Desogestrel | Minimal androgenic | Third-generation progestogen |
| Gestodene | Minimal androgenic | Third-generation progestogen |
| Levonorgestrel | Androgenic | Avoid in hyperandrogenism — will worsen acne/hirsutism |
| Norgestrel | Androgenic | Avoid in hyperandrogenism |
For PCOS/hyperandrogenism, choose a COCP containing an anti-androgenic or neutral progestogen — Diane-35 (CPA) or drospirenone-containing pills are preferred.
| Absolute Contraindications (WHO Category 4) | Relative Contraindications (WHO Category 3) |
|---|---|
| Personal history of VTE | Hypertension (140-159/90-99 mmHg) |
| Known thrombophilia | Migraine without aura in women ≥35 years |
| Active/recent breast cancer | Breastfeeding 6 weeks-6 months postpartum |
| Migraine with aura (any age) | Current gallbladder disease |
| Smoker aged ≥35 years (≥15 cigarettes/day) | BMI ≥35 |
| Major surgery with prolonged immobilisation | |
| Uncontrolled hypertension (≥160/100) | |
| Complicated valvular heart disease | |
| Active liver disease / hepatic adenoma |
VTE Risk with COCP
Oestrogen in COCP increases VTE risk (↑hepatic clotting factor synthesis: fibrinogen, factors VII, VIII, X, ↓antithrombin III, ↓protein S). Third-generation progestogens (desogestrel, gestodene) and CPA carry a slightly higher VTE risk than levonorgestrel-containing pills. Always assess VTE risk before prescribing. Cyproterone acetate-containing COCP (Diane-35) carries a higher VTE risk than other COCPs — use the lowest effective dose for the shortest duration needed.
- Hirsutism improvement takes 6-12 months (hair growth cycle is slow; existing terminal hairs must cycle out)
- Acne improvement within 3-6 months
- Menstrual regularity within 1-3 cycles
- Monitor: blood pressure, lipids, glucose, side effects, VTE symptoms
C. Anti-Androgen Therapy
Anti-androgens are used when the COCP alone is insufficient for hirsutism/acne, or as alternatives when COCP is contraindicated.
Critical principle: All anti-androgens are teratogenic — they can cause ambiguous genitalia in a male foetus. Effective contraception is mandatory during anti-androgen therapy. This is why anti-androgens are often combined with the COCP.
| Parameter | Detail |
|---|---|
| Class | Potassium-sparing diuretic / aldosterone receptor antagonist |
| Anti-androgen mechanism | (1) Blocks androgen receptor (competitive antagonist); (2) Inhibits 5α-reductase (↓conversion of T → DHT); (3) Inhibits ovarian and adrenal androgen synthesis (weak); (4) ↑SHBG (mild) |
| Dose | 50-200 mg/day (start low, titrate up) |
| Onset of effect | 6-12 months for hirsutism |
| Side effects | Hyperkalaemia (especially with ACEI/ARB/drospirenone), menstrual irregularity (at high doses), breast tenderness, dizziness, GI upset |
| Monitoring | Renal function + potassium (baseline and 4-6 weeks after starting) |
| Contraindications | Pregnancy (teratogenic — feminisation of male foetus), renal impairment, hyperkalaemia |
Why Spironolactone for Hirsutism?
Spironolactone ("spiro" = coil, "lactone" = chemical ring) was originally developed as a diuretic/anti-aldosterone agent. Its anti-androgenic effects were discovered as a "side effect" — gynaecomastia in men taking it for heart failure. In women with hyperandrogenism, this side effect becomes the therapeutic effect. It works at multiple levels: blocking the androgen receptor in the hair follicle, reducing DHT production, and mildly suppressing androgen synthesis.
| Parameter | Detail |
|---|---|
| Class | Synthetic progestogen with potent anti-androgenic and anti-gonadotrophic activity |
| Anti-androgen mechanism | (1) Competitive androgen receptor blockade; (2) Inhibits 5α-reductase; (3) Suppresses LH/FSH secretion (→ ↓ovarian androgen production); (4) Induces hepatic clearance of testosterone |
| Dose | Low-dose: 2 mg/day (as in Diane-35 COCP); High-dose: 25-100 mg/day on days 1-10 of cycle (reverse sequential regimen with EE) |
| Onset of effect | 6-9 months for hirsutism |
| Side effects | Hepatotoxicity (especially at high doses — monitor LFTs), VTE risk, weight gain, depression, fatigue, loss of libido |
| Contraindications | Pregnancy (teratogenic), active liver disease, history of meningioma (CPA is associated with meningioma risk at high cumulative doses), VTE history |
| Parameter | Detail |
|---|---|
| Class | 5α-reductase inhibitor (Type 2 predominantly) |
| Mechanism | Blocks conversion of testosterone → DHT in target tissues (hair follicles, sebaceous glands) |
| Why useful | DHT is the most potent androgen acting on hair follicles; blocking its production reduces hirsutism |
| Dose | 2.5-5 mg/day |
| Onset | 6-12 months |
| Side effects | Generally well tolerated; rare: headache, GI upset |
| Contraindication | Pregnancy (Category X — causes ambiguous genitalia in male foetus); not to be handled by pregnant women |
| Limitation | Less effective than spironolactone or CPA for hirsutism; more useful for androgenic alopecia |
The name "finasteride" → "fin" relates to its role in "finishing" the conversion of testosterone to DHT.
| Parameter | Detail |
|---|---|
| Class | Non-steroidal androgen receptor antagonist |
| Mechanism | Pure competitive blockade of androgen receptor |
| Dose | 125-250 mg/day |
| Side effects | Hepatotoxicity (potentially fatal — limits clinical use); dry skin, GI upset |
| Status | Rarely used due to hepatotoxicity risk; spironolactone and CPA are preferred |
| Drug | AR Blockade | 5α-Reductase Inhibition | Gonadotrophin Suppression | Key Side Effect |
|---|---|---|---|---|
| Spironolactone | ✓ | ✓ (mild) | ✗ | Hyperkalaemia |
| Cyproterone acetate | ✓✓ | ✓ | ✓✓ | Hepatotoxicity, VTE, meningioma |
| Finasteride | ✗ | ✓✓ (Type 2) | ✗ | Teratogenic |
| Flutamide | ✓✓ | ✗ | ✗ | Hepatotoxicity (severe) |
D. Topical Treatments for Hirsutism
| Parameter | Detail |
|---|---|
| Mechanism | Irreversible inhibitor of ornithine decarboxylase (ODC) — an enzyme essential for polyamine synthesis required for hair follicle cell division and growth |
| Application | Topical, applied to affected facial areas twice daily |
| Onset | Improvement in 4-8 weeks; full effect by 6 months |
| Key point | Slows hair growth but does NOT remove existing hair — must be combined with physical methods (shaving, laser) |
| Side effects | Local irritation, acne, folliculitis at application site |
| Limitation | Effect is reversible — hair growth resumes within 8 weeks of stopping |
| Method | Mechanism | Duration | Notes |
|---|---|---|---|
| Shaving | Cuts hair at skin surface | Days | Does NOT increase hair growth rate or thickness (common myth) |
| Waxing / Epilation | Removes hair from root | 2-6 weeks | Temporary; can cause folliculitis, ingrown hairs |
| Laser hair removal | Selective photothermolysis — melanin in hair shaft absorbs laser energy → destroys follicle | Semi-permanent (requires multiple sessions) | Most effective for dark hair on light skin; less effective for fair or grey hair; can cause skin burns, PIH |
| Electrolysis | Electric current destroys individual hair follicles | Permanent | Time-consuming; suitable for small areas; can cause scarring |
| Intense pulsed light (IPL) | Similar to laser but broader wavelength spectrum | Semi-permanent | Less precise than laser; suitable for larger areas |
Clinical pearl: Systemic anti-androgen therapy takes 6-12 months to show effect on hirsutism because existing terminal hairs must complete their growth cycle and be replaced. Cosmetic methods should be used concurrently for immediate symptomatic relief.
Acne in hyperandrogenic states [4] is managed with the same therapeutic ladder as general acne, but with important additions:
| Severity | First-Line | Alternative/Add-On |
|---|---|---|
| Mild | Topical retinoid (comedonal) or benzoyl peroxide (inflammatory) | Topical combination therapy |
| Moderate | Oral antibiotics + topical retinoid + benzoyl peroxide | Add COCP or oral spironolactone (females) [4] |
| Severe | Oral antibiotics + topical combination; or oral isotretinoin | Add COCP or oral spironolactone (females) [4] |
For women with hyperandrogenism, hormonal therapy (COCP ± anti-androgen) is a key component of acne management — it addresses the root cause (androgen excess driving sebum production) rather than just treating the downstream inflammation.
Isotretinoin (13-cis-retinoic acid):
- Potent retinoid that dramatically reduces sebaceous gland activity
- Reserved for severe nodulo-cystic acne or treatment-resistant acne
- Absolutely teratogenic (Category X) — requires strict pregnancy prevention programme (two forms of contraception, monthly pregnancy tests)
- Side effects: dry skin/lips/eyes, elevated LFTs, hypertriglyceridaemia, mood changes
F. Management of Infertility in PCOS
For PCOS patients desiring pregnancy, the approach is stepwise:
- Weight loss of 5-10% in overweight/obese women
- Optimise metabolic health (glucose, lipids, blood pressure)
- Folic acid supplementation (400 μg/day minimum)
- Duration: 3-6 months trial before pharmacological intervention
| Agent | Mechanism | Protocol | Success |
|---|---|---|---|
| Letrozole (aromatase inhibitor) | Blocks peripheral conversion of androgens → oestrogens → removes oestrogen negative feedback on pituitary → ↑FSH release → follicular development | 2.5-7.5 mg/day for 5 days (days 3-7 of cycle) | ~30% live birth rate per cycle; now considered first-line over clomifene (2023 international guideline) |
| Clomifene citrate | Selective oestrogen receptor modulator (SERM); blocks oestrogen receptors in hypothalamus → ↓negative feedback → ↑GnRH → ↑FSH/LH | 50-150 mg/day for 5 days (days 3-7) | ~20-25% live birth rate per cycle |
Why letrozole over clomifene? Letrozole produces a more physiological mono-follicular response (lower risk of multiple pregnancy and OHSS), has a shorter half-life (less anti-oestrogenic effect on endometrium), and has been shown in large RCTs to produce higher ovulation and live birth rates in PCOS.
Clomifene limitations: anti-oestrogenic effect on endometrium (thins lining, may impair implantation); anti-oestrogenic effect on cervical mucus; risk of multiple pregnancy (~8-10%); maximum 6 ovulatory cycles recommended.
| Agent | Mechanism | Notes |
|---|---|---|
| Gonadotrophins (FSH injections) | Exogenous FSH directly stimulates follicular development | Low-dose step-up protocol preferred in PCOS (start 37.5-50 IU/day, increase slowly); risk of OHSS and multiple pregnancy → requires ultrasound monitoring |
| Metformin (adjunctive) | Insulin sensitiser → ↓insulin → ↓ovarian androgen production → may restore ovulation | Can be combined with clomifene/letrozole; modest benefit alone for ovulation induction |
| Option | Notes |
|---|---|
| Laparoscopic ovarian drilling (LOD) | Electrocautery or laser to ovarian surface → destroys androgen-producing stromal tissue → ↓local androgen environment → may restore ovulation; risk of adhesions and ovarian damage |
| In-vitro fertilisation (IVF) | When above methods fail; GnRH antagonist protocol preferred to reduce OHSS risk in PCOS |
Anti-Androgens Must Be Stopped Before Conception
All anti-androgens (spironolactone, CPA, finasteride, flutamide) are teratogenic and must be discontinued before attempting conception. Spironolactone and CPA can feminise a male foetus; finasteride blocks DHT formation needed for male genital development. Ensure reliable contraception while on these drugs, and stop them at least 1-3 months before planned conception.
For PCOS women with prolonged anovulation who are not seeking pregnancy and not on COCP:
| Method | Protocol | Rationale |
|---|---|---|
| Cyclical progestogen withdrawal | Medroxyprogesterone acetate 10 mg/day for 10-14 days every 1-3 months | Opposes chronic unopposed oestrogen; induces withdrawal bleed; reduces endometrial hyperplasia risk |
| Levonorgestrel IUS (Mirena) | Intrauterine device releasing progestogen locally | Provides endometrial protection + contraception; reduces menstrual bleeding; does not suppress ovarian function (may still have some androgen production) |
| COCP | As above | Combined endometrial protection + anti-androgen effects |
Excess risk of endometrial hyperplasia/carcinoma due to chronic unopposed oestrogen exposure [1] — this is why endometrial protection is mandatory in anovulatory PCOS women, even if they are not bothered by irregular periods.
| Intervention | Indication | Mechanism | Notes |
|---|---|---|---|
| Metformin | IGT/T2DM, adjunct for metabolic improvement, clomifene-resistant anovulation | ↓Hepatic glucose production; ↑peripheral insulin sensitivity (↑AMPK); ↓intestinal glucose absorption | Dose: 500-2000 mg/day (titrate up to reduce GI side effects); does NOT directly lower androgens but indirectly improves them via ↓insulin |
| GLP-1 receptor agonists (liraglutide, semaglutide) | Obesity with PCOS, T2DM | ↑Insulin secretion (glucose-dependent), ↓glucagon, delayed gastric emptying, ↑satiety | Increasingly used for weight management in PCOS; significant weight loss → improves metabolic and reproductive outcomes; contraindicated in pregnancy |
| Statins | Dyslipidaemia | HMG-CoA reductase inhibition → ↓LDL-C | Contraindicated in pregnancy — stop before conception |
| Anti-hypertensives | Hypertension | Standard approach; avoid ACEI/ARB in women of childbearing age unless on reliable contraception (teratogenic) | |
| Bariatric surgery | Severe obesity (BMI ≥40 or ≥35 with comorbidities) refractory to lifestyle modification | Dramatic weight loss → resolution of insulin resistance → may restore ovulation and normalise androgens | Consider in morbidly obese PCOS patients; pre-conception counselling essential |
I. Management of Specific Causes (Non-PCOS)
Management is directed towards glucocorticoid replacement to suppress ACTH stimulation [10][11]:
| Treatment | Detail |
|---|---|
| Glucocorticoid replacement | 10-15 mg/m²/day hydrocortisone in children, then 15-30 mg/day in adults [10][11] |
| Longer-acting form | Consider switching to prednisolone/dexamethasone but associated with ↑risk of Cushingoid features [10][11] |
| Stress dose | Double/triple usual dosages for febrile illness, vomiting/diarrhoea, significant trauma [10][11] |
| Mineralocorticoid replacement | In all classical CAH: fludrocortisone 100 μg/day children, 100-200 μg/day adults [10][11] |
| Fertility | Often associated with oligospermia in males and infertility in females (but much improved with adequate treatment) [10][11] |
| Monitoring | 17-OHP levels, androstenedione, testosterone, growth velocity (children), bone age |
Why glucocorticoids? By replacing cortisol exogenously, you restore negative feedback on ACTH → ↓ACTH → ↓adrenal stimulation → ↓shunting of precursors into the androgen pathway. The goal is to use the lowest dose that adequately suppresses androgens without causing Cushingoid side effects.
- Surgical resection of tumour [16]
- Ovarian tumour → unilateral salpingo-oophorectomy (or tumour excision if fertility desired)
- Adrenal tumour → adrenalectomy (laparoscopic if feasible; open if large/malignant)
- Adrenocortical carcinoma may require adjuvant mitotane ± chemotherapy
- Treated according to the specific aetiology (pituitary adenoma → transsphenoidal surgery; ectopic ACTH → treat primary tumour; adrenal adenoma → adrenalectomy)
- Iatrogenic Cushing's (most common cause in practice) [3] → taper exogenous steroids gradually
- Correct underlying cause (e.g., discontinue causative drugs) [16]
- Valproate → switch to alternative AED (e.g., lamotrigine, levetiracetam) in consultation with neurologist
- Anabolic steroids → cessation; counsel on irreversibility of certain virilising effects (voice deepening)
- Drug-induced → discontinue or substitute offending drug (in consultation with psychiatrist if antipsychotic)
- Prolactinoma → dopamine agonist (cabergoline first-line, bromocriptine alternative) [6]
| Symptom | Time to Improvement | Why |
|---|---|---|
| Acne | 3-6 months | Sebaceous gland activity responds relatively quickly to hormonal changes |
| Hirsutism | 6-12 months minimum | Hair growth cycle is long (anagen phase 4-6 months); existing terminal hairs must complete cycle and regrow as finer hairs |
| Androgenic alopecia | 6-12 months | Follicular miniaturisation takes time to reverse; some damage may be irreversible |
| Menstrual regularity | 1-3 cycles | COCP provides immediate cycle regulation |
| Ovulation (with letrozole/clomifene) | 1-3 cycles | Ovulation may occur within the first treated cycle |
| Metabolic improvement | 3-6 months | Depends on weight loss and insulin sensitisation |
Set Patient Expectations
One of the most important things to tell patients is that hirsutism treatment takes time — at least 6-12 months for visible improvement. Many patients become discouraged and stop treatment prematurely. Cosmetic methods (laser, shaving) should be used concurrently for immediate symptomatic relief while waiting for systemic therapy to take effect. Combination therapy (COCP + anti-androgen + cosmetic methods) is more effective than any single modality alone.
| Drug | Key Contraindications |
|---|---|
| COCP | VTE history, thrombophilia, breast cancer, migraine with aura, smoker ≥35, uncontrolled HTN, active liver disease |
| Spironolactone | Pregnancy, renal impairment, hyperkalaemia |
| Cyproterone acetate | Pregnancy, active liver disease, VTE history, meningioma history |
| Finasteride | Pregnancy (Category X); women should not handle crushed tablets |
| Flutamide | Pregnancy, liver disease |
| Isotretinoin | Pregnancy (Category X) |
| Metformin | eGFR < 30 (contraindicated); eGFR 30-45 (use with caution); lactic acidosis risk with IV contrast |
| Letrozole/Clomifene | Pregnancy, liver disease, unexplained uterine bleeding |
| ACEI/ARB | Pregnancy (teratogenic — renal agenesis) |
| Statins | Pregnancy, active liver disease |
High Yield Summary — Management of Hyperandrogenism
- Lifestyle modification is first-line for ALL PCOS patients — 5-10% weight loss can restore ovulation and improve metabolic parameters
- COCP is first-line pharmacological treatment for menstrual regulation, endometrial protection, and anti-androgen effect; choose a pill with anti-androgenic or neutral progestogen (CPA or drospirenone preferred)
- Anti-androgens (spironolactone, CPA, finasteride) are ALL teratogenic — must be used with effective contraception
- Spironolactone is the most commonly used anti-androgen in practice; blocks androgen receptor + inhibits 5α-reductase; monitor K⁺ and renal function
- Hirsutism takes 6-12 months to improve with systemic therapy; use cosmetic methods concurrently
- Ovulation induction: letrozole is now first-line (superior to clomifene in PCOS); gonadotrophins or LOD as second-line; IVF as third-line
- NCCAH is treated with glucocorticoid replacement (hydrocortisone) to suppress ACTH and reduce androgen precursor shunting [10][11]
- Androgen-secreting tumours → surgical resection [16]
- Drug-induced → discontinue or substitute offending drug [16]
- Endometrial protection is mandatory in anovulatory PCOS women (COCP, cyclical progestogen, or LNG-IUS) to prevent endometrial hyperplasia/carcinoma [1]
- Metabolic screening and management (OGTT, lipids, BP) is essential — PCOS is a lifelong cardiometabolic condition, not just a reproductive one
Active Recall - Management of Hyperandrogenism
References
[1] Lecture slides: Adrian Lui Gynecology Notes.pdf (Section 2.2.3 – Polycystic Ovarian Syndrome, p40-41) [2] Senior notes: Ryan Ho Endocrine.pdf (p77 – Type 2 DM, metabolic syndrome, AMPK) [3] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (p14 – Cushing syndrome, iatrogenic cause) [4] Senior notes: Ryan Ho Rheumatology.pdf (p127 – Acne management ladder, COCP and spironolactone) [6] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (p9 – Hyperprolactinaemia causes and treatment) [10] Senior notes: Adrian Lui Pediatrics Notes.pdf (p283 – CAH management) [11] Senior notes: Ryan Ho Endocrine.pdf (p74 – CAH management) [16] Senior notes: Maksim Medicine Notes.pdf (p103 – Hyperandrogenism management)
Complications of Hyperandrogenism
Complications of hyperandrogenism are best understood as downstream consequences of the underlying pathophysiology — chronic androgen excess, anovulation, insulin resistance, and their interplay. They span reproductive, metabolic, dermatological, oncological, and psychological domains. The severity and spectrum depend heavily on the cause (e.g., PCOS vs. androgen-secreting tumour) and the duration of exposure.
The complications can be organised by system:
| Domain | Key Complications |
|---|---|
| Reproductive | Anovulatory infertility, recurrent pregnancy loss, gestational complications |
| Endometrial / Oncological | Endometrial hyperplasia, endometrial carcinoma |
| Metabolic | Insulin resistance, T2DM, dyslipidaemia, metabolic syndrome, NAFLD/NASH |
| Cardiovascular | Hypertension, accelerated atherosclerosis, increased long-term CVD risk |
| Dermatological | Chronic hirsutism, severe acne with scarring, androgenic alopecia, acanthosis nigricans |
| Psychological | Depression, anxiety, eating disorders, reduced quality of life |
| Obstructive sleep apnoea | Central obesity-mediated upper airway obstruction |
| Skeletal | In CAH: short stature from premature epiphyseal closure |
| Complications of specific causes | CAH-specific, tumour-specific, treatment-related |
A. Reproductive Complications
- The most direct reproductive consequence of hyperandrogenism, especially in PCOS
- PCOS accounts for ~75% of all anovulatory disorders causing infertility [1]
- Mechanism: Impaired folliculogenesis → failed selection of dominant follicle → anovulation [1]. Without ovulation, there is no oocyte release, no corpus luteum formation, no progesterone production, and conception is impossible
- Not all PCOS women are infertile — some have intermittent ovulation, leading to subfertility rather than absolute infertility
- Response to ovulation induction is generally good (letrozole/clomifene → ~30% live birth rate per cycle), but ovarian hyperstimulation syndrome (OHSS) is a specific risk in PCOS women undergoing gonadotrophin stimulation or IVF due to the large number of recruitable follicles
Even when conception is achieved, PCOS women face increased obstetric risks:
| Complication | Mechanism | Relative Risk |
|---|---|---|
| Gestational diabetes mellitus (GDM) | Pre-existing insulin resistance is exacerbated by pregnancy counter-regulatory hormones (hPL, cortisol, progesterone) → β-cells cannot compensate → hyperglycaemia | ~2-3× |
| Pre-eclampsia / gestational hypertension | Endothelial dysfunction from chronic insulin resistance, obesity, and inflammation | ~2-3× |
| Preterm birth | Multi-factorial — related to pre-eclampsia, GDM, and underlying metabolic derangement | ~1.5-2× |
| Macrosomia | Fetal hyperinsulinism secondary to maternal hyperglycaemia (GDM) → excessive fetal growth | Increased |
| Miscarriage | Potentially related to hyperandrogenism, hyperinsulinemia, and endometrial dysfunction; evidence debated | Possibly increased |
| Caesarean section | Higher rates of obstetric complications necessitating operative delivery | Increased |
- Controversial but increasingly recognised association
- Hypothesised mechanisms: elevated LH (may impair oocyte maturation), hyperinsulinemia (may disrupt endometrial receptivity and early trophoblast invasion), androgen excess (may directly impair endometrial decidualisation)
This is one of the most clinically important long-term complications and is frequently examined.
Excess risk of endometrial hyperplasia / carcinoma: due to chronic unopposed oestrogen exposure [1]
Why does anovulation lead to unopposed oestrogen?
In a normal ovulatory cycle:
- Follicular phase → oestrogen stimulates endometrial proliferation
- Ovulation → corpus luteum forms → secretes progesterone
- Luteal phase → progesterone transforms proliferative endometrium into secretory endometrium (opposes oestrogen's proliferative effect)
- If no implantation → corpus luteum regresses → hormone withdrawal → menstruation
In anovulatory PCOS:
- No ovulation → no corpus luteum → no progesterone
- Ongoing oestrogen production (peripheral aromatisation in adipose tissue + some ovarian production)
- Endometrium under continuous proliferative stimulation without progesterone opposition
- Prolonged oligo/anovulation → oligo-/amenorrhoea with prolonged unopposed oestrogen [1]
- Over months to years → endometrial hyperplasia → simple hyperplasia → complex hyperplasia → atypical hyperplasia → endometrial carcinoma (Type 1, oestrogen-dependent, endometrioid type)
| Stage | Histology | Cancer Risk |
|---|---|---|
| Simple hyperplasia without atypia | Cystic glandular dilation, no cytological atypia | ~1% |
| Complex hyperplasia without atypia | Crowded, irregular glands, no atypia | ~3% |
| Simple hyperplasia with atypia | Cytological atypia present | ~8% |
| Complex hyperplasia with atypia (atypical endometrial hyperplasia) | Crowded glands with cytological atypia | ~25-30% → essentially pre-malignant |
Endometrial Protection is Mandatory
Any anovulatory PCOS woman must receive endometrial protection — via COCP, cyclical progestogens, or levonorgestrel IUS [1]. Prolonged amenorrhoea (> 3-6 months) without progestogen opposition is a risk factor for endometrial hyperplasia. If the endometrium is > 7 mm on USS in an amenorrhoeic PCOS patient, endometrial biopsy should be considered to rule out hyperplasia or carcinoma.
Risk factors for endometrial carcinoma that cluster in PCOS include: anovulation (chronic unopposed oestrogen), obesity (↑peripheral aromatisation → ↑oestrogen), insulin resistance/hyperinsulinemia (insulin directly stimulates endometrial stromal proliferation via IGF-1 receptors), and T2DM.
C. Metabolic Complications
These are arguably the most important long-term consequences of PCOS — PCOS is not just a reproductive disorder but a lifelong metabolic condition.
- ~10% of PCOS patients have T2DM, 30% have impaired glucose tolerance [1]
- Metabolic syndrome: obesity, insulin resistance, NAFLD, IGT/T2DM, dyslipidaemia, hypertension, sleep apnoea [1]
- Mechanism: Insulin resistance → compensatory hyperinsulinemia [1]. Over time, β-cells cannot sustain the compensatory output → β-cell failure → progression from IGT to T2DM
- PCOS is itself listed as a manifestation of metabolic syndrome [2] and one of its associated conditions
- Annual screening with OGTT is recommended for high-risk PCOS women (obese, family history of DM, prior GDM)
Progression timeline [2]:
- Hyperinsulinemic euglycaemia: ↑insulin resistance → ↑insulin secretion (glucose still normal)
- Impaired glucose tolerance: β-cells cannot handle ↑metabolic load → gradual β-cell failure
- Early T2DM: relative insulin deficiency → hyperglycaemia; ↑glucose + ↑FFA → glucotoxicity + lipotoxicity → β-cell loss
- Late T2DM: progressive β-cell loss → absolute insulin deficiency
| Lipid Abnormality | Mechanism |
|---|---|
| ↑Triglycerides | Insulin resistance → ↑hepatic VLDL production; ↓lipoprotein lipase activity |
| ↓HDL-C | ↑CETP-mediated exchange of TG from VLDL to HDL → TG-enriched HDL cleared faster |
| ↑LDL-C (small dense) | Insulin resistance drives formation of small dense LDL particles (more atherogenic) |
| ↑Total cholesterol | Combination of above |
This atherogenic lipid profile contributes to accelerated atherosclerosis and increased cardiovascular risk.
- Prevalence in PCOS women: 30-60% (significantly higher than general population)
- Mechanism: Insulin resistance → ↑hepatic de novo lipogenesis + ↑free fatty acid flux to liver from adipose tissue → hepatic steatosis
- May progress to NASH (non-alcoholic steatohepatitis) → fibrosis → cirrhosis
- Androgens themselves may also contribute to hepatic steatosis
Metabolic syndrome is a cluster of metabolic disorders due to insulin resistance [2]:
The International Diabetes Federation (IDF) definition requires central obesity (waist circumference ≥ 80 cm in Asian women) PLUS ≥2 of:
- Fasting TG ≥ 1.7 mmol/L
- HDL-C < 1.29 mmol/L (in women)
- BP ≥ 130/85 mmHg
- Fasting glucose ≥ 5.6 mmol/L
PCOS women have a 2-4× increased prevalence of metabolic syndrome compared to age- and BMI-matched controls.
- PCOS women have an increased long-term cardiovascular risk — though the magnitude is debated and may be most significant for cardiovascular risk factor burden rather than hard cardiovascular events in younger women
- Risk factors clustering: hypertension, dyslipidaemia, insulin resistance/DM, obesity, chronic inflammation, endothelial dysfunction
- Surrogate markers of increased CVD risk seen in PCOS:
- ↑Carotid intima-media thickness (CIMT)
- ↑Coronary artery calcification
- Endothelial dysfunction (impaired flow-mediated dilation)
- ↑C-reactive protein (chronic low-grade inflammation)
- Hypertension: prevalence ~30-40% in PCOS (related to insulin resistance, hyperinsulinemia, sympathetic activation, and obesity)
The cardiovascular risk in PCOS is analogous to the risk in metabolic syndrome — it is the clustering of risk factors that drives atherogenesis, not androgen excess per se.
- Prevalence in PCOS: 5-30× higher than in weight-matched controls
- Mechanism: Central obesity → ↑pharyngeal fat deposition → upper airway narrowing; androgens may also directly promote pharyngeal muscle dysfunction; insulin resistance contributes via central adiposity
- Symptoms: snoring, witnessed apnoeas, excessive daytime somnolence, morning headaches
- OSA further worsens insulin resistance and metabolic parameters (creating another vicious cycle)
- Screen with questionnaire (e.g., STOP-BANG) → confirm with polysomnography
- Treatment: CPAP, weight loss
F. Dermatological Complications
These are the most visible complications and often cause the greatest patient distress.
- Without treatment, hirsutism tends to be progressive — more vellus hairs convert to terminal hairs over time under continuing androgen exposure
- Terminal hair conversion is largely irreversible — once a follicle has been transformed, it tends to remain terminal even if androgens normalise (though the growth rate and thickness may decrease)
- This is why early treatment and combination therapy (systemic anti-androgen + cosmetic removal) is important
- Acne often occurs in association with hyperandrogenic states, e.g., PCOS, virilisation tumours [4]
- Chronic inflammatory acne leads to post-inflammatory hyperpigmentation (PIH) and scarring (atrophic, hypertrophic, or keloidal)
- Scarring is permanent and requires separate management (laser resurfacing, chemical peels, dermal fillers)
- Acne in PCOS tends to be treatment-resistant to conventional topical therapies alone — hormonal therapy is often necessary
- Progressive follicular miniaturisation → thinning crown hair → may progress to visible scalp
- Creates significant psychological distress, particularly in young women
- Partially reversible with treatment (minoxidil, anti-androgens) but response is slow and incomplete
- Marker of severe insulin resistance — velvety, darkened skin in flexural areas (neck, axillae, groin, under breasts)
- Mechanism: hyperinsulinemia → insulin binds to IGF-1 receptors on keratinocytes and fibroblasts → epidermal hyperplasia and melanocyte stimulation
- Important clinical sign — its presence should trigger metabolic screening
- Improves with weight loss and insulin sensitisation (metformin, GLP-1 RA)
These are often underappreciated but profoundly impact quality of life.
| Complication | Prevalence in PCOS | Mechanism |
|---|---|---|
| Depression | 2-3× general population | Multi-factorial: body image disturbance (hirsutism, acne, obesity, alopecia), infertility-related grief, hormonal effects on mood (androgens may affect serotonin/GABA pathways), chronic disease burden |
| Anxiety | 2-3× general population | Body image concerns, health anxiety related to metabolic risks, fertility worries |
| Eating disorders | Increased prevalence | Weight-related stigma, dietary restriction attempts, binge-purge cycles |
| Reduced quality of life | Significant | Cumulative impact of cosmetic symptoms, infertility, chronic disease management |
| Sexual dysfunction | Increased | Hirsutism-related self-consciousness, body image issues, anti-androgen side effects (↓libido) |
| Social isolation | Increased | Embarrassment from visible hyperandrogenic features |
Don't Forget the Psychology
PCOS is often dismissed as a "cosmetic" or "minor" condition, but the psychological burden is substantial. Up to 40% of PCOS women report clinically significant depressive symptoms. Always screen for psychological impact and offer referral for psychological support when needed. The visible nature of hirsutism, acne, alopecia, and obesity makes this condition uniquely distressing.
H. Complications Specific to Underlying Causes
Outcomes of classical CAH [10][11]:
- ↓BMD, short stature, ↑CVD risk with overall 2-4× overall mortality [10][11]
- Fertility: often associated with oligospermia in males and infertility in females (but much improved with adequate treatment) [10][11]
| Complication | Mechanism |
|---|---|
| Short stature | Androgen excess → accelerated bone maturation → premature epiphyseal closure → reduced final adult height (despite being tall for age in childhood) |
| Testicular adrenal rest tumours (TARTs) | Ectopic adrenal tissue in testes responds to ACTH stimulation → forms bilateral testicular masses → can cause obstructive azoospermia → infertility; USS screening recommended [10][11] |
| Reduced bone mineral density | Glucocorticoid replacement therapy (iatrogenic) → ↓bone formation; chronic androgen excess → altered bone metabolism |
| Cardiovascular risk | Chronic glucocorticoid exposure + metabolic syndrome features → accelerated atherosclerosis |
| Adrenal crisis | In salt-wasting CAH: intercurrent illness/stress without adequate stress-dose steroids → mineralocorticoid deficiency → hypovolaemic shock, hyperkalaemia, hyponatraemia → life-threatening |
| Ambiguous genitalia | In 46,XX classical CAH: prenatal androgen exposure → virilised external genitalia (clitoromegaly, labial fusion); reconstructive surgery may be required for virilised females (usually delayed until late puberty) [10] |
| Psychosocial | Gender identity concerns (rare), chronic disease burden, body image issues |
| Complication | Detail |
|---|---|
| Irreversible virilisation | Voice deepening, clitoromegaly — these effects may not fully reverse even after tumour resection |
| Malignancy | Adrenocortical carcinoma: aggressive, often diagnosed late; poor 5-year survival (~20-35%); may metastasise to lungs, liver, lymph nodes |
| Local mass effects | Abdominal pain, compression of adjacent structures |
| Recurrence | Sertoli-Leydig cell tumours have a recurrence risk depending on grade and stage |
| Molecular markers | Somatic DICER1 mutations found in Sertoli-Leydig cell tumours [17] — relevant for molecular diagnosis and prognosis |
If Cushing's is the cause of hyperandrogenism, the complications of chronic hypercortisolism dominate:
- Osteoporosis and fractures
- Immunosuppression and opportunistic infections
- Proximal myopathy
- Psychiatric disturbance (depression, psychosis)
- Poor wound healing
- Hypertension, T2DM, hyperlipidaemia
- Increased cardiovascular mortality
| Treatment | Potential Complication | Prevention/Monitoring |
|---|---|---|
| COCP | VTE, hepatic adenoma, hypertension, migraine, mood changes | Assess VTE risk before prescribing; monitor BP; counsel on warning signs |
| Spironolactone | Hyperkalaemia, menstrual irregularity | Monitor K⁺ and renal function at baseline and 4-6 weeks; always use with contraception |
| Cyproterone acetate | Hepatotoxicity, VTE, meningioma (with prolonged high-dose use) | Monitor LFTs; limit duration; avoid in patients with history of VTE or meningioma |
| Metformin | GI side effects (nausea, diarrhoea), B12 deficiency (long-term), lactic acidosis (rare) | Titrate dose slowly; monitor B12 periodically; avoid if eGFR < 30 |
| Isotretinoin | Teratogenicity, dry mucous membranes, hepatotoxicity, hypertriglyceridaemia | Strict pregnancy prevention; monthly LFTs and lipids |
| Glucocorticoids (in CAH) | Cushingoid features, weight gain, ↓BMD, adrenal crisis if abruptly stopped | Use lowest effective dose; stress dosing for illness [10][11]; DEXA monitoring |
| Ovulation induction agents | OHSS (especially gonadotrophins in PCOS), multiple pregnancy | Low-dose step-up protocol; USS monitoring; consider GnRH antagonist trigger in IVF |
| Timeframe | Complications |
|---|---|
| Acute / Short-term | Acne flares, psychological distress, menstrual irregularity, anovulatory bleeding |
| Medium-term (years) | Progressive hirsutism, androgenic alopecia, infertility, recurrent pregnancy loss, acne scarring |
| Long-term (decades) | T2DM, cardiovascular disease, endometrial hyperplasia/carcinoma, NAFLD/NASH, OSA, osteoporosis (CAH), reduced life expectancy (CAH, untreated tumours) |
High Yield Summary — Complications of Hyperandrogenism
- Endometrial hyperplasia/carcinoma is the most important oncological complication — caused by chronic unopposed oestrogen from anovulation [1]; endometrial protection is mandatory
- Metabolic syndrome is central to PCOS: ~10% have T2DM, 30% have IGT [1]; also dyslipidaemia, NAFLD, hypertension
- Cardiovascular risk is increased through clustering of metabolic risk factors (not androgen excess directly)
- Anovulatory infertility — PCOS accounts for ~75% of anovulatory infertility [1]; but responds well to ovulation induction
- Pregnancy complications in PCOS: ↑GDM, ↑pre-eclampsia, ↑preterm birth
- OSA is 5-30× more common in PCOS — driven by central obesity and possibly androgen effects
- Psychological morbidity is profound: 2-3× rates of depression and anxiety; always screen and refer
- CAH-specific: short stature (premature epiphyseal closure), TARTs, ↓BMD, 2-4× overall mortality [10][11]
- Dermatological complications (hirsutism, acne scarring, alopecia) are often the most distressing to patients and drive presentation
- Treatment complications must be monitored: VTE with COCP, hyperkalaemia with spironolactone, hepatotoxicity with CPA, Cushingoid features with glucocorticoids in CAH
Active Recall - Complications of Hyperandrogenism
References
[1] Lecture slides: Adrian Lui Gynecology Notes.pdf (Section 2.2.3 – Polycystic Ovarian Syndrome, p40-41) [2] Senior notes: Ryan Ho Endocrine.pdf (p77 – Type 2 DM, metabolic syndrome, insulin resistance progression) [4] Senior notes: Ryan Ho Rheumatology.pdf (p126-127 – Acne vulgaris, hyperandrogenic associations) [10] Senior notes: Adrian Lui Pediatrics Notes.pdf (p283 – CAH outcomes and complications) [11] Senior notes: Ryan Ho Endocrine.pdf (p74 – CAH outcomes and complications) [17] AOS material: AOS - Pathology.pdf (p20 – Sertoli-Leydig cell tumour, DICER1 mutations)
High Yield Summary
Hyperandrogenism — Key Points for Exams:
- PCOS is the most common cause (~70-80%), affecting ~5-10% of reproductive-aged women [1]
- Three sources of androgens in women: ovaries (LH-driven), adrenals (ACTH-driven), peripheral conversion (5α-reductase)
- SHBG is the gatekeeper — ↓SHBG (from insulin, obesity, androgens) → ↑free testosterone → clinical hyperandrogenism even with normal total testosterone
- Insulin resistance is central to PCOS pathophysiology: hyperinsulinemia → ↑theca cell androgen production + ↓hepatic SHBG [1]
- The LH:FSH ratio is elevated in PCOS because ↑GnRH pulse frequency → preferential LH secretion → ↑ovarian androgen production [1]
- Clinical features: hirsutism (most common), acne, androgenic alopecia, oligo/amenorrhea, infertility, obesity, acanthosis nigricans
- Virilisation (voice deepening, clitoromegaly, male-pattern balding) is a RED FLAG for androgen-secreting tumour — NOT a feature of PCOS
- NCCAH (21-hydroxylase deficiency) is the second most common cause — screen with morning 17-OHP
- Drug causes: especially valproic acid [1]
- Metabolic consequences of PCOS: T2DM (10%), IGT (30%), dyslipidaemia, NAFLD, endometrial hyperplasia/carcinoma [1]
High Yield Summary — Differential Diagnosis of Hyperandrogenism
- PCOS is the most common cause (~70-80%) and is a diagnosis of exclusion — must rule out thyroid disease, hyperprolactinaemia, NCCAH, Cushing syndrome, and androgen-secreting tumours [1][9]
- Rotterdam criteria require ≥2 of 3: oligo-anovulation, hyperandrogenism (clinical/biochemical), polycystic ovaries on USS [9]
- NCCAH mimics PCOS — differentiate with morning 17-OHP and ACTH stimulation test [1]
- Androgen-secreting tumours present with rapid onset and virilisation — testosterone usually >150 ng/dL (ovarian source) or DHEA-S >700 μg/dL (adrenal source) [1]
- PCOS testosterone seldom exceeds 150 ng/dL [1] — above this threshold, actively exclude tumour
- LH:FSH ratio ≥2-3:1 is supportive but NOT diagnostic of PCOS [1]
- Cushing syndrome is excluded by a normal dexamethasone suppression test [1][12]
- Idiopathic hirsutism = hirsutism with normal androgens and regular ovulatory cycles; diagnosis of exclusion
- In children: consider premature adrenarche, CAH, adrenocortical tumours [13]
- In postmenopausal women: new-onset hyperandrogenism = tumour until proven otherwise
High Yield Summary — Diagnostics of Hyperandrogenism
- Rotterdam criteria for PCOS: ≥2 of 3 (oligo-anovulation, hyperandrogenism, polycystic ovaries) AFTER excluding other causes [9][15]
- PCOS is a diagnosis of exclusion — must check 17-OHP (NCCAH), TSH (thyroid), prolactin (hyperprolactinaemia), DST (Cushing), and testosterone/DHEA-S levels (tumours) [1]
- Endocrine workup: biochemistry BEFORE imaging — high-resolution imaging may find incidentalomas unrelated to the clinical problem [5]
- Testosterone follows a diurnal rhythm — always measure in the morning (8-10 am) [5]
- PCOS testosterone seldom exceeds 150 ng/dL [1] — above this, suspect tumour
- DHEA-S > 700 μg/dL → adrenal tumour; normal DHEA-S → ovarian source
- Morning 17-OHP > 6 nmol/L → ACTH stimulation test → stimulated 17-OHP > 30 nmol/L = NCCAH [1][10]
- Polycystic ovarian morphology on USS found in ~25% of all women — USS alone cannot diagnose PCOS [1]
- LH:FSH ratio ≥2-3:1 is supportive but NOT diagnostic [1]
- Metabolic screening is essential in PCOS: OGTT (30% have IGT, 10% have T2DM), fasting lipids, BP [1]
High Yield Summary — Management of Hyperandrogenism
- Lifestyle modification is first-line for ALL PCOS patients — 5-10% weight loss can restore ovulation and improve metabolic parameters
- COCP is first-line pharmacological treatment for menstrual regulation, endometrial protection, and anti-androgen effect; choose a pill with anti-androgenic or neutral progestogen (CPA or drospirenone preferred)
- Anti-androgens (spironolactone, CPA, finasteride) are ALL teratogenic — must be used with effective contraception
- Spironolactone is the most commonly used anti-androgen in practice; blocks androgen receptor + inhibits 5α-reductase; monitor K⁺ and renal function
- Hirsutism takes 6-12 months to improve with systemic therapy; use cosmetic methods concurrently
- Ovulation induction: letrozole is now first-line (superior to clomifene in PCOS); gonadotrophins or LOD as second-line; IVF as third-line
- NCCAH is treated with glucocorticoid replacement (hydrocortisone) to suppress ACTH and reduce androgen precursor shunting [10][11]
- Androgen-secreting tumours → surgical resection [16]
- Drug-induced → discontinue or substitute offending drug [16]
- Endometrial protection is mandatory in anovulatory PCOS women (COCP, cyclical progestogen, or LNG-IUS) to prevent endometrial hyperplasia/carcinoma [1]
- Metabolic screening and management (OGTT, lipids, BP) is essential — PCOS is a lifelong cardiometabolic condition, not just a reproductive one
High Yield Summary — Complications of Hyperandrogenism
- Endometrial hyperplasia/carcinoma is the most important oncological complication — caused by chronic unopposed oestrogen from anovulation [1]; endometrial protection is mandatory
- Metabolic syndrome is central to PCOS: ~10% have T2DM, 30% have IGT [1]; also dyslipidaemia, NAFLD, hypertension
- Cardiovascular risk is increased through clustering of metabolic risk factors (not androgen excess directly)
- Anovulatory infertility — PCOS accounts for ~75% of anovulatory infertility [1]; but responds well to ovulation induction
- Pregnancy complications in PCOS: ↑GDM, ↑pre-eclampsia, ↑preterm birth
- OSA is 5-30× more common in PCOS — driven by central obesity and possibly androgen effects
- Psychological morbidity is profound: 2-3× rates of depression and anxiety; always screen and refer
- CAH-specific: short stature (premature epiphyseal closure), TARTs, ↓BMD, 2-4× overall mortality [10][11]
- Dermatological complications (hirsutism, acne scarring, alopecia) are often the most distressing to patients and drive presentation
- Treatment complications must be monitored: VTE with COCP, hyperkalaemia with spironolactone, hepatotoxicity with CPA, Cushingoid features with glucocorticoids in CAH
Adrenal Incidentaloma
An adrenal incidentaloma is an adrenal mass > 1 cm found incidentally on imaging performed for a non-adrenal indication; evaluation focuses on hormonal function and malignant potential.
Hypogonadism
Hypogonadism is a condition characterized by deficient gonadal function resulting in inadequate production of sex hormones and/or impaired gametogenesis, classified as primary (gonadal failure) or secondary (hypothalamic-pituitary dysfunction).