What is the approach to diagnosing and treating hyperandrogenism?

Approach to Hyperandrogenism

For diagnosing hyperandrogenism, measure total testosterone (TT) and free testosterone (FT) as first-line tests using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and if these are not elevated but clinical suspicion remains high, proceed to second-line testing with androstenedione (A4) and DHEAS. 1, 2

Clinical Assessment

Key Clinical Signs to Identify

Dermatologic manifestations:

• Hirsutism (excessive terminal hair growth in male-pattern distribution) is the most sensitive clinical indicator, present in up to 80% of hyperandrogenic women 3
• Persistent or treatment-resistant acne, particularly truncal acne 2
• Androgenic alopecia (male-pattern hair loss) 2

Severe hyperandrogenism indicators:

• Clitoromegaly suggests significant androgen excess and warrants urgent evaluation for androgen-secreting tumors 2
• Rapid onset of virilization (deepening voice, increased muscle mass) indicates possible tumor 4, 5

Reproductive signs:

• Oligomenorrhea or amenorrhea 2
• Infertility 2

Metabolic indicators:

• Acanthosis nigricans (dark, velvety skin patches indicating insulin resistance) 2
• Central obesity with elevated BMI and waist-hip ratio >0.9 2, 6

Diagnostic Laboratory Testing

First-Line Tests (Mandatory)

Androgen measurement:

• Total testosterone (TT) measured by LC-MS/MS: sensitivity 74%, specificity 86% 1, 6
• Free testosterone (FT) by equilibrium dialysis or calculated using Free Androgen Index (FAI): sensitivity 89%, specificity 83% 1, 6
• Avoid direct immunoassays for FT due to poor accuracy at low concentrations 2
• Timing matters: measure in the morning due to diurnal variation 2

Critical point: LC-MS/MS demonstrates superior specificity (92%) compared to direct immunoassays (78%), reducing false positives 6

Second-Line Tests (If TT/FT Normal but Clinical Suspicion High)

• Androstenedione (A4): sensitivity 75%, specificity 71% 1, 6
• DHEAS: sensitivity 75%, specificity 67% 1, 6
• Note the poorer specificity of these markers compared to testosterone measurements 1

Essential Exclusionary Tests

Screen for secondary causes:

• TSH to exclude thyroid disease 2, 6
• Prolactin (morning resting levels) to exclude hyperprolactinemia 2, 6
• 17-hydroxyprogesterone if DHEAS elevated, to rule out non-classical congenital adrenal hyperplasia 6, 7

Metabolic screening (mandatory in all cases):

• 2-hour oral glucose tolerance test with 75g glucose load 2, 6
• Fasting lipid panel (total cholesterol, LDL, HDL, triglycerides) 2, 6
• BMI and waist-hip ratio calculation 6

Additional Tests for Specific Scenarios

If PCOS suspected:

• LH and FSH measured on days 3-6 of cycle; LH/FSH ratio >2 suggests PCOS (though only abnormal in 35-44% of cases) 6
• Mid-luteal progesterone <6 nmol/L confirms anovulation 6
• Transvaginal ultrasound (≥8 MHz transducer): ≥20 follicles per ovary and/or ovarian volume ≥10mL 8, 6
• Anti-Müllerian hormone (AMH) ≥35 pmol/L shows 92% sensitivity and 97% specificity, but should not replace ultrasound or serve as standalone test 8, 6

Red flags requiring urgent tumor workup:

• Testosterone >150-200 ng/dL 5
• Rapid symptom onset 6
• Severe virilization 4, 3
• Consider androstenedione >10.0 nmol/L indicating possible adrenal/ovarian tumor 6

If Cushing's syndrome suspected (buffalo hump, moon facies, hypertension, abdominal striae, easy bruising):

• 24-hour urinary free cortisol or overnight dexamethasone suppression test 6, 4

Differential Diagnosis by Prevalence

Most common causes (95% of cases):

• Polycystic ovary syndrome (PCOS) accounts for the vast majority, affecting 10-13% of women globally 1, 5, 3

Important secondary causes to exclude:

• Non-classical congenital adrenal hyperplasia 2, 7
• Hyperprolactinemia 4, 5
• Cushing's syndrome 4, 5
• Androgen-secreting tumors (ovarian or adrenal) 4, 5
• Thyroid disease 2
• Exogenous androgen use (medications, supplements) 2

Diagnostic Algorithm

Step 1: Assess clinical signs (hirsutism, acne, alopecia, menstrual irregularity, obesity)

Step 2: Measure TT and FT by LC-MS/MS in the morning 1, 2

• If elevated → confirms biochemical hyperandrogenism
• Calculate FAI if LC-MS/MS unavailable 1, 6

Step 3: If TT/FT normal but clinical suspicion high → measure A4 and DHEAS 1, 6

Step 4: Perform exclusionary testing: TSH, prolactin, 17-OHP (if DHEAS elevated) 2, 6, 7

Step 5: Metabolic screening: 2-hour OGTT, fasting lipids, BMI, waist-hip ratio 2, 6

Step 6: If PCOS suspected → LH/FSH, mid-luteal progesterone, transvaginal ultrasound 8, 6

Step 7: If tumor suspected (very high testosterone, rapid onset, virilization) → imaging (CT/MRI of adrenals and pelvis) 6, 5

Treatment Approach

First-line pharmacologic therapy:

• Combined oral contraceptives (COCs) effectively regulate menstrual cycles and reduce hyperandrogenism 2, 5
• Antiandrogens (cyproterone acetate, spironolactone, flutamide) for hirsutism, best used in combination with COCs 4, 5

Lifestyle modifications:

• Weight loss should be vigorously encouraged in overweight/obese patients to ameliorate metabolic consequences 5, 7
• Diet and exercise for insulin resistance 2

For fertility:

• Clomiphene citrate as first-line ovulation induction 5
• Human menopausal gonadotropins (hMG) or laparoscopic ovulation induction for clomiphene failures 5

Metabolic management:

• Metformin for insulin resistance in PCOS 7
• Screen and manage cardiovascular risk factors 2

Critical Pitfalls to Avoid

• Do not rely on direct immunoassays for testosterone measurement—they have 14% lower specificity than LC-MS/MS 6
• Do not use ultrasound as primary diagnostic criterion in adolescents <8 years post-menarche due to high false-positive rates 8
• Do not diagnose PCOS based solely on polycystic ovaries on ultrasound—requires clinical/biochemical hyperandrogenism plus ovulatory dysfunction 2
• Remember that 30% of women with confirmed PCOS have normal testosterone levels—clinical hyperandrogenism plus irregular cycles can establish diagnosis without biochemical confirmation 6
• Do not miss androgen-secreting tumors—any rapid onset, severe virilization, or very high testosterone requires urgent imaging 6, 5
• SHBG fluctuations (affected by age, weight, oral contraceptives) can alter TT and FAI results 2
• Address psychological impact of hyperandrogenism symptoms as part of comprehensive care 2