What is the best approach to test for hyperandrogenism (high androgen levels)?

Best Approach to Test for Hyperandrogenism

Total testosterone (TT) and free testosterone (FT) should be used as first-line laboratory tests to assess biochemical hyperandrogenism, with TT measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and FT either measured by equilibrium dialysis or calculated using Free Androgen Index (FAI). 1

Initial Clinical Assessment

• Document timing of symptom onset
• Assess severity of symptoms
• Look for clustering of symptoms:
  • Hirsutism
  • Acne
  • Menstrual irregularities
  • Androgenic alopecia
  • Body odor changes
  • Virilization (clitoromegaly, deepening voice)
  • Truncal obesity 1, 2

First-Line Laboratory Testing

1. Total Testosterone (TT)

   • Preferably measured by LC-MS/MS (highest accuracy)
   • Avoid direct immunoassays due to lower accuracy
   • Morning collection preferred

2. Free Testosterone (FT)

   • Gold standard: Equilibrium dialysis or ammonium sulfate precipitation
   • Alternative: Calculate using Free Androgen Index (FAI)
   • FAI = Total testosterone (nmol/L) × 100 / SHBG (nmol/L)

These tests have the highest diagnostic accuracy with:

• TT: Sensitivity 0.74, Specificity 0.86, AUC 0.87
• cFT: Sensitivity 0.89, Specificity 0.83, AUC 0.85
• FAI: Sensitivity 0.78, Specificity 0.85, AUC 0.87 1

Second-Line Laboratory Testing

If TT or FT are not elevated but clinical suspicion remains high, consider:

1. Androstenedione (A4)

   • Sensitivity 0.75, Specificity 0.71, AUC 0.80

2. Dehydroepiandrosterone sulfate (DHEAS)

   • Sensitivity 0.75, Specificity 0.67, AUC 0.77
   • Particularly useful for adrenal hyperandrogenism 1, 3

Additional Testing Based on Clinical Presentation

For suspected PCOS:

• LH:FSH ratio (>2 suggests PCOS)
• Pelvic ultrasound (to assess for polycystic ovaries) 2, 4

For suspected non-classical congenital adrenal hyperplasia (NCCAH):

• 17-hydroxyprogesterone (17-OHP) - basal or ACTH-stimulated
• Two-day dexamethasone suppression test 3, 4

For suspected Cushing's syndrome:

• 1mg overnight dexamethasone suppression test
• 24-hour urinary free cortisol 1, 3

For suspected androgen-secreting tumors:

• Comprehensive androgen panel including:
  • 17β-estradiol
  • 17-OH progesterone
  • Androstenedione
  • 17-OH pregnenolone
  • 11-deoxycorticosterone
  • Progesterone 1

Important Considerations

• Routine endocrinologic testing is not indicated for most patients with acne alone 1
• Testing should be performed when clinical signs/symptoms of hyperandrogenism are present (hirsutism, oligomenorrhea, androgenic alopecia, infertility, virilization) 1
• Severe or rapid-onset hyperandrogenism with virilization should prompt investigation for androgen-secreting tumors 3, 5
• LC-MS/MS is strongly preferred over immunoassay methods for all androgen measurements due to superior accuracy 1

Common Pitfalls to Avoid

• Relying solely on direct immunoassay methods, which have lower accuracy
• Testing without considering clinical context
• Failing to recognize that isolated acne rarely warrants hormonal testing
• Not considering potential causes beyond PCOS (adrenal disorders, tumors)
• Overlooking the need for specialized testing in cases of virilization

By following this systematic approach to testing for hyperandrogenism, clinicians can accurately diagnose the underlying cause and implement appropriate treatment strategies to improve patient outcomes.