How should I evaluate and manage a patient presenting with virilisation (e.g., deepening of voice, hirsutism, clitoral enlargement, increased muscle mass, or acne)?

Evaluation and Management of Virilisation

Any patient presenting with virilisation—defined by clitoromegaly, deepening voice, increased muscularity, severe hirsutism, or male-pattern baldness—requires urgent evaluation to exclude an androgen-secreting neoplasm, which is potentially life-threatening and occurs in approximately 0.2% of hyperandrogenic women with over 50% being malignant. 1, 2

Immediate Risk Stratification

Virilisation itself is a high-risk feature that dramatically increases the likelihood of an androgen-secreting tumor. 1, 2 The following clinical features further elevate concern:

• Sudden onset or rapid progression of androgenic symptoms over weeks to months 1, 2
• Clitoromegaly (clitoral enlargement) 1, 3
• Deepening of voice (reported in 85% of virilising ovarian tumors) 3, 4
• Increased muscle mass and masculine habitus 1, 5
• Palpable abdominal or pelvic mass 1, 2
• Severe hirsutism (Ferriman-Gallwey score >15) accompanying virilisation 1, 3

Essential Laboratory Evaluation

Obtain early-morning (8 AM) fasting blood samples, ideally on cycle days 4-10 if the patient is menstruating: 2

First-Line Hormonal Tests

• Total and free testosterone measured in a specialized reference laboratory 1, 2
• DHEAS (dehydroepiandrosterone sulfate) to assess adrenal androgen contribution 2, 6
• 17-hydroxyprogesterone (early morning, follicular phase) to exclude congenital adrenal hyperplasia 2, 6
• Prolactin to rule out hyperprolactinemia 2
• Pregnancy test in any patient with amenorrhea 2

Critical Testosterone Thresholds

• Testosterone >200 ng/dL strongly suggests an androgen-secreting neoplasm and mandates immediate imaging of both ovaries and adrenals 2
• Testosterone 2-5 times above normal (typically >150 ng/dL) with virilisation warrants urgent tumor work-up even if below 200 ng/dL 1, 3
• Median testosterone in confirmed virilising ovarian tumors is 5.6 ng/mL (560 ng/dL) with severe hyperandrogenemia but unsuppressed gonadotropins 3

Mandatory Imaging Studies

Pelvic ultrasonography is mandatory in all cases of virilisation to detect ovarian pathology, as steroid-cell tumors occur in ~0.2% of hyperandrogenic women with >50% being malignant. 2 Note that transabdominal ultrasonography detected virilising ovarian tumors in 92% of cases in one series, but small tumors (as small as 11 mm) can elude imaging. 3, 4

High-resolution adrenal CT is indicated when: 2

• Testosterone ≥200 ng/dL
• DHEAS >6,600 ng/mL (or >600 µg/dL in postmenopausal women)
• Clinical suspicion points to an adrenal source
• Elevated DHEAS (1.5-19.1 µmol/l) with non-suppressible androgens on dexamethasone testing 6

If initial imaging is negative but clinical suspicion remains high, proceed to: 4

• MRI of abdomen and pelvis
• Selective venous sampling (retrograde ovarian and adrenal vein sampling) to localize the androgen source, particularly when imaging fails to identify a tumor 4

Additional Endocrine Screening

Screen for other endocrinopathies that can present with virilisation: 1, 2

• Cushing's syndrome: 24-hour urinary free cortisol or overnight dexamethasone suppression test 2
• Thyroid dysfunction: TSH and free T4 2
• Acromegaly: IGF-1 if clinical features present 2

Medication and Exposure History

Systematically exclude exogenous androgen exposure: 1, 2

• Anabolic steroids (particularly in athletes) 1
• Androgenic supplements 2
• Danazol (used for endometriosis) 1, 2
• Valproic acid (the only anticonvulsant known to raise testosterone) 1, 2

Dynamic Testing When Initial Work-Up Is Inconclusive

If testosterone is moderately elevated but imaging is negative: 2, 6

• Dexamethasone suppression test (0.5 mg every 6 hours for 48 hours): Adrenarche and PCOS will suppress; tumors will not 6
• ACTH stimulation test (0.25 mg synacthen IM): Peak 17-OHP >50 nmol/L suggests congenital adrenal hyperplasia 6
• CYP21A2 genotyping if 17-OHP is elevated to confirm non-classic CAH 2

Diagnostic Algorithm Based on Findings

Scenario 1: Markedly Elevated Testosterone (>200 ng/dL) with Virilisation

• Perform both pelvic ultrasound and adrenal CT immediately 2
• If imaging is negative, proceed to selective venous sampling to localize occult tumor 4
• Consider bilateral oophorectomy in postmenopausal women with severe recent-onset virilisation, normal adrenal imaging, and no Cushing's syndrome, as this avoids delays in definitive management 4

Scenario 2: Moderately Elevated Testosterone with Negative Imaging

• Repeat total and free testosterone in a specialty laboratory 2
• Perform dexamethasone suppression test to distinguish tumor (non-suppressible) from adrenal hyperplasia or PCOS (suppressible) 6
• Consider MRI and selective venous sampling if suspicion remains high 4

Scenario 3: Virilisation with Normal or Mildly Elevated Testosterone

• Consider disorders of sex development (DSD), particularly if presenting at puberty with primary amenorrhea 5
• Karyotype and genetic testing (including SRY, DMRT1) may reveal cryptic Y-chromosome material or gonadal dysgenesis 5
• Pelvic MRI to evaluate for dysgenetic gonads that may harbor gonadoblastoma risk 5

Critical Pitfalls to Avoid

• Do not assume ovarian origin solely because testosterone is high with normal DHEAS; rare pure testosterone-secreting adrenal adenomas exist 2
• Do not assume adrenal origin solely on elevated DHEAS; ovarian tumors can co-secrete DHEAS 2
• Do not delay imaging or surgery based on "normal" initial ultrasound; virilising tumors can be as small as 11 mm and occult on standard imaging 4
• Do not attribute virilisation to PCOS without excluding neoplasm first; PCOS rarely causes true virilisation 1, 7
• Do not overlook pregnancy luteoma in pregnant patients with new-onset virilisation, as this benign condition regresses spontaneously postpartum 8

Surgical Management

Surgery is the definitive treatment for androgen-secreting tumors: 3, 4

• Unilateral salpingo-oophorectomy for confirmed ovarian tumors in reproductive-age women 3
• Total abdominal hysterectomy with bilateral salpingo-oophorectomy for peri- or postmenopausal women 3, 4
• All patients achieve normalization of testosterone after tumor excision with slow regression of hirsutism over months (due to the 4-month anagen phase of terminal hair) 1, 3

Histological Subtypes of Virilising Ovarian Tumors

Sertoli-Leydig cell tumor is the most common (54% in one series), followed by steroid cell tumor (23%) and Leydig cell tumor (15%). 3

Post-Exclusion of Neoplasm: PCOS Management

Once malignancy is excluded and PCOS is diagnosed (testosterone elevation, anovulation, polycystic ovarian morphology): 2

• Regulate menstrual cycles with combined oral contraceptives or progestins to reduce endometrial hyperplasia risk 2
• Address metabolic risk (fasting glucose, insulin, lipid profile, family history of diabetes) as PCOS increases risk for type 2 diabetes, metabolic syndrome, and cardiovascular disease 2
• Cosmetic management of hirsutism with anti-androgens (cyproterone acetate, spironolactone) and laser hair removal 7