How should a female patient with elevated testosterone be evaluated and managed?

Evaluation and Management of Elevated Testosterone in Women

A female patient with elevated testosterone requires systematic evaluation to distinguish polycystic ovary syndrome (PCOS)—the most common cause—from rarer but serious conditions including androgen-secreting tumors, non-classical congenital adrenal hyperplasia (NCCAH), and medication effects, particularly valproate therapy. 1, 2

Initial Clinical Assessment

Key Historical Features to Elicit

• Onset and tempo of symptoms: Gradual onset after menarche with persistent anovulation suggests PCOS, while rapid onset of severe virilization (clitoromegaly, voice deepening, male-pattern baldness) raises concern for androgen-secreting tumor 2, 3
• Menstrual pattern: Document cycle length over 6 months—oligomenorrhea (>35 days), amenorrhea (>6 months), or polymenorrhea (<23 days) 1
• Medication history: Valproate causes hyperandrogenism and polycystic ovaries in 60-64% of women taking it as monotherapy 1
• Weight changes: Antiepileptic drug-related weight gain can trigger PCOS in predisposed women 1

Physical Examination Priorities

• Hirsutism assessment: Use Ferriman-Gallwey scoring or document male escutcheon pattern 1
• Body habitus: Calculate BMI and waist-to-hip ratio (WHR >0.9 indicates truncal obesity associated with PCOS) 1
• Signs of virilization: Clitoromegaly, voice deepening, increased muscle mass, or male-pattern baldness mandate urgent tumor evaluation 2, 3
• Pelvic examination: Palpable adnexal mass requires immediate imaging 3

Laboratory Evaluation Algorithm

First-Line Hormonal Testing (Day 3-6 of Cycle)

Total testosterone (TT) and calculated free testosterone (cFT) are the recommended first-line tests for biochemical hyperandrogenism, ideally measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) rather than immunoassay. 1

• Testosterone >2.5 nmol/L (>72 ng/dL): Abnormal, suggests PCOS or valproate effect 1
• Testosterone >5 nmol/L (>144 ng/dL): Warrants tumor evaluation, though PCOS remains possible in obese women 3
• Free androgen index (FAI): Calculate using total testosterone/SHBG × 100; FAI >4.97 has 71.4% sensitivity and 85.2% specificity for PCOS 4
• Bioavailable testosterone >0.78 nmol/L: Has 75.9% sensitivity and 83.3% specificity for PCOS 4

Additional Androgen Measurements

• Androstenedione >10.0 nmol/L: Raises concern for adrenal or ovarian tumor 1
• DHEAS: Age-adjusted cutoffs (age 20-29: >3800 ng/mL; age 30-39: >2700 ng/mL) suggest NCCAH or adrenal tumor 1

Gonadotropins and Ovulatory Function

• LH, FSH: Measure as average of three samples 20 minutes apart on days 3-6; LH/FSH ratio >2 supports PCOS 1
• Mid-luteal progesterone <6 nmol/L: Indicates anovulation, common in PCOS 1
• Prolactin >20 μg/L: Exclude hyperprolactinemia (ensure not postictal measurement in epilepsy patients) 1

Metabolic Assessment

• Fasting glucose and insulin: Glucose >7.8 mmol/L or glucose/insulin ratio >4 suggests insulin resistance associated with PCOS 1

Diagnostic Decision Points

When Testosterone is Mildly Elevated (2.5-5 nmol/L)

This range most commonly represents PCOS, particularly with menstrual irregularity, LH/FSH ratio >2, and polycystic ovaries on ultrasound. 1, 4

• Perform pelvic ultrasound (transvaginal preferred, days 3-9 of cycle): >10 peripheral cysts 2-8 mm diameter with thickened stroma confirms polycystic ovaries 1
• If on valproate: Consider medication as causative; discontinuation reverses hyperandrogenism within one year 1
• Rule out NCCAH with basal 17-hydroxyprogesterone or ACTH stimulation test if DHEAS elevated 2

When Testosterone is Markedly Elevated (>5 nmol/L)

Despite traditional teaching, testosterone >2 ng/mL (>5.8 nmol/L) has poor predictive value for androgen-secreting tumors, especially in obese women with chronic anovulation. 3

However, proceed with tumor evaluation if:

• Rapid onset of virilization 2, 3
• Palpable adnexal mass 3
• Mean testosterone from three daily samples >2.5 times upper limit of normal 3

Imaging approach:

• Pelvic ultrasound first-line for ovarian masses 1
• Consider MRI pelvis if ultrasound equivocal 3
• Adrenal CT if DHEAS markedly elevated 1

Critical Pitfall: Laboratory Interference

When testosterone levels are extremely high without virilization signs, suspect laboratory interference from heterophile antibodies or other assay artifacts. 5

• Repeat measurement using different assay method or after diethyl-ether extraction 5
• Discordance between laboratory values and clinical presentation demands rigorous re-evaluation 5

Management Based on Etiology

PCOS Management

• Lifestyle modification: Weight loss improves insulin sensitivity and hyperandrogenism 1
• Hormonal contraceptives: First-line for menstrual regulation and hirsutism 1
• Metformin: Consider for insulin resistance, particularly if glucose/insulin ratio >4 1
• Fertility: Refer to reproductive endocrinology if pregnancy desired after >12 months unprotected intercourse 1

Valproate-Associated Hyperandrogenism

Discontinuation of valproate reverses hyperinsulinemia, hyperandrogenism, and polycystic ovaries within one year. 1

• Discuss medication switch with neurology, weighing seizure control risk 1
• If valproate continuation necessary, treat metabolically like PCOS 1

Tumor Management

• Ovarian steroid cell tumors: Surgical resection; testosterone normalizes within 24 hours post-operatively 5
• Adrenal tumors: Surgical referral based on imaging characteristics 1

NCCAH Management

• Refer to endocrinology for glucocorticoid therapy consideration 2
• Dexamethasone suppression test confirms diagnosis (significant decrease in testosterone and DHEAS) 2

Monitoring and Referral Indications

Refer to endocrinology and/or gynecology for:

• Persistently abnormal hormone levels despite initial management 1
• Infertility after 12 months of regular unprotected intercourse 1
• Suspected tumor requiring surgical evaluation 1, 3
• Complex cases requiring specialized hormonal manipulation 1

Common pitfall to avoid: Do not routinely obtain testosterone levels in women outside of specific clinical indications (hirsutism, menstrual irregularity, infertility), as this leads to overdiagnosis and unnecessary interventions. 1