Diagnostic Workup for Idiopathic Hyperandrogenism
The initial workup for idiopathic hyperandrogenism must include high-quality androgen measurements using LC-MS/MS to rule out other causes of hyperandrogenism, followed by targeted testing to exclude specific disorders like PCOS, adrenal disorders, and androgen-secreting tumors. 1
Initial Laboratory Assessment
First-Line Testing
- Total Testosterone (TT) using LC-MS/MS (sensitivity 0.74, specificity 0.86)
- Free Testosterone (FT) by equilibrium dialysis or calculation using Free Androgen Index (FAI) (sensitivity 0.89, specificity 0.83)
- Sex Hormone Binding Globulin (SHBG) to calculate FAI
- Morning collection is preferred for all androgen measurements 1
Second-Line Testing
- Androstenedione (A4) and Dehydroepiandrosterone sulfate (DHEAS) if first-line tests are normal but clinical suspicion remains high 1, 2
- 17α-hydroxyprogesterone (17-OHP) in early morning (follicular phase) to rule out non-classic congenital adrenal hyperplasia (NCCAH) 1, 3
Differential Diagnosis Workup
Rule Out PCOS
- Assess for oligo/anovulation (menstrual history)
- Pelvic ultrasound to evaluate for polycystic ovarian morphology
- LH:FSH ratio 1
Rule Out Adrenal Disorders
- ACTH stimulation test with measurement of 17-OHP to definitively rule out NCCAH 3
- 1mg overnight dexamethasone suppression test and/or 24-hour urinary free cortisol to rule out Cushing's syndrome 1, 3
- Two-day dexamethasone suppression test to assess for significant decrease in serum testosterone and DHEA-S 3
Rule Out Androgen-Secreting Tumors
- Consider if there are signs of virilization (clitoromegaly, deepening voice, male pattern baldness, increased muscle mass)
- Adrenal and ovarian imaging (CT or MRI) if clinical suspicion exists 2, 4
Diagnosis of Idiopathic Hyperandrogenism
Idiopathic hyperandrogenism is diagnosed when:
- Clinical signs of hyperandrogenism are present (hirsutism, acne, androgenic alopecia)
- Normal ovulatory menstrual cycles are documented
- Normal androgen levels are found (though may be in the upper normal range - "relative hyperandrogenemia") 5, 6
- Normal ovarian morphology on ultrasound 5
- Other causes of hyperandrogenism have been excluded
Management Considerations
Pharmacological Options
- Spironolactone - FDA approved for primary hyperaldosteronism but commonly used off-label for hirsutism 7, 4
- Cyproterone acetate or flutamide as alternative antiandrogens 4
- Avoid exogenous testosterone in patients interested in fertility, as it can suppress spermatogenesis 2
Monitoring
- Annual assessment of health and well-being
- Monitor for development of new autoimmune disorders
- Assess for complications of therapy 2
Clinical Pearls and Pitfalls
- Pitfall: Relying on direct androgen immunoassays, which have limited accuracy. Always use LC-MS/MS for androgen measurements 1, 2
- Pitfall: Assuming "idiopathic" means no androgen excess. Recent research suggests these patients may have "relative hyperandrogenemia" (higher but still within normal range) or increased local androgen production in skin 6
- Pearl: Consider that "idiopathic hirsutism" may represent an early stage of hyperandrogenic disorders like PCOS 6
- Pearl: Virilization is uncommon in idiopathic hyperandrogenism and should prompt investigation for androgen-producing tumors 4, 8
Remember that idiopathic hyperandrogenism is ultimately a diagnosis of exclusion after ruling out other specific causes of hyperandrogenism. The term "idiopathic" may be misleading, as these patients likely have subtle alterations in androgen metabolism that are not detected by standard testing.