What are the differential diagnoses, evaluation steps, and management options for a female patient with an isolated elevation of dihydrotestosterone (DHT) and normal total and free testosterone?

Evaluation and Management of Isolated DHT Elevation in a Female Patient

Initial Clinical Assessment

The most likely explanation for isolated DHT elevation with normal total and free testosterone in a female patient is either increased peripheral 5α-reductase activity converting testosterone to DHT locally in target tissues, or laboratory interference requiring confirmation with alternative assay methods. 1, 2

Key Clinical Features to Evaluate

• Assess for signs of hyperandrogenism: hirsutism (facial/body hair), acne, androgenic alopecia (male-pattern baldness), and menstrual irregularities are the primary manifestations to document 3, 4
• Document menstrual history: oligomenorrhea, amenorrhea, or irregular cycles suggest ovarian dysfunction and possible PCOS 3
• Examine for virilization signs: clitoromegaly, deepening voice, increased muscle mass, and breast atrophy indicate severe androgen excess requiring urgent evaluation 3, 1
• Evaluate scalp hair density: women with elevated DHT commonly report decreased scalp hair density and androgenic alopecia 4

Differential Diagnosis

Most Common Causes

• Polycystic ovary syndrome (PCOS) remains the most common cause of androgen excess in women, affecting 4-6% of the general female population, though typically presents with elevated total or free testosterone rather than isolated DHT elevation 3, 5
• Increased peripheral 5α-reductase activity in skin and hair follicles can convert normal circulating testosterone to DHT locally, causing clinical hyperandrogenism without elevated serum testosterone 2, 4
• Laboratory interference should be suspected when DHT is markedly elevated without corresponding clinical manifestations; diethyl ether extraction prior to immunoassay can help detect interference 1

Less Common but Important Causes

• Ovarian steroid-cell tumors can produce androgens and present with very high DHT levels, though these typically also elevate testosterone and cause rapid virilization 1
• Non-classical congenital adrenal hyperplasia (NCAH) may present with mild enzyme deficiencies in adrenal steroidogenesis, though this usually affects multiple androgens 3, 5
• Adrenal tumors should be considered if DHEA-S is also elevated alongside DHT 5

Diagnostic Workup Algorithm

Step 1: Confirm DHT Elevation and Rule Out Laboratory Error

• Repeat DHT measurement using liquid chromatography with tandem mass spectrometry (LC-MS/MS) rather than direct immunoassay, as LC-MS/MS has superior sensitivity and specificity for androgen measurement 3, 1
• If DHT remains elevated, perform diethyl ether extraction prior to immunoassay to rule out laboratory interference from heterophile antibodies or other interfering substances 1

Step 2: Complete Androgen Panel

• Measure total testosterone and free testosterone by equilibrium dialysis or ammonium sulfate precipitation as first-line tests for biochemical hyperandrogenism 3
• Calculate free androgen index (FAI) using total testosterone divided by SHBG × 100 if equilibrium dialysis is unavailable 3
• Measure androstenedione (A4) if total testosterone and free testosterone are not elevated, noting its poorer specificity (71%) compared to testosterone measurements 3, 5
• Measure DHEA-S to assess adrenal androgen production, though it has the lowest diagnostic accuracy (sensitivity 75%, specificity 67%) for PCOS 3, 5
• Measure sex hormone-binding globulin (SHBG) to calculate FAI and assess for conditions affecting SHBG levels 3, 5

Step 3: Assess for PCOS Using Rotterdam Criteria

• Document oligo-anovulation: irregular menstrual cycles with intervals >35 days or <8 cycles per year 3
• Perform pelvic ultrasound to evaluate for polycystic ovary morphology (≥12 follicles measuring 2-9mm in diameter or ovarian volume >10mL) 3, 5
• PCOS diagnosis requires 2 of 3 criteria: clinical or biochemical hyperandrogenism, ovulatory dysfunction, or polycystic ovaries on ultrasound 3

Step 4: Rule Out Other Causes

• Measure morning cortisol and perform ACTH stimulation test if NCAH is suspected based on elevated 17-hydroxyprogesterone 3, 5
• Order adrenal CT or MRI if DHEA-S is very high (>700 μg/dL) or symptoms progress rapidly, to rule out adrenal tumor 5
• Perform pelvic ultrasound or MRI if testosterone or DHT levels are extremely elevated (>2-3 SD above normal) to evaluate for ovarian steroid-cell tumor 1
• Measure TSH and prolactin to exclude thyroid disease and hyperprolactinemia as differential diagnoses for PCOS 3, 5

Management Approach

For PCOS-Related DHT Elevation

• Initiate combined oral contraceptive pills as first-line therapy to regulate menstrual cycles and reduce androgen effects, including improvement in hirsutism and acne 3, 5
• Prescribe metformin 1500-2000mg daily if insulin resistance is present (elevated fasting insulin, HbA1c >5.7%, or metabolic syndrome features) 3, 5
• Recommend weight loss of 5-10% for overweight or obese patients, as this can significantly improve androgen levels and restore ovulation 5

For Cutaneous Hyperandrogenism from Increased 5α-Reductase Activity

• Consider finasteride 2.5-5mg daily as a competitive inhibitor of 5α-reductase to reduce peripheral conversion of testosterone to DHT, though this is off-label use in women 2
• Prescribe spironolactone 50-200mg daily as an androgen receptor blocker for hirsutism and acne, which are the most effective therapeutic modalities for cutaneous hyperandrogenism 3, 2
• Add topical eflornithine cream for facial hirsutism as adjunctive therapy 3

For Androgenic Alopecia

• Prescribe topical minoxidil 2-5% applied twice daily to the scalp as first-line therapy 3
• Consider oral finasteride 1-2.5mg daily for women with androgenic alopecia and elevated DHT, though pregnancy must be absolutely avoided due to teratogenic risk 2
• Prescribe spironolactone 100-200mg daily as an alternative anti-androgen for hair loss 3

If Ovarian or Adrenal Tumor Identified

• Refer immediately to gynecologic oncology or endocrine surgery for tumor resection 1
• Recheck DHT and testosterone levels 24 hours post-operatively to confirm biochemical resolution 1
• Monitor for return of menstruation within 1-2 months after tumor removal 1

Monitoring and Follow-Up

• Repeat DHT, total testosterone, and free testosterone every 3-6 months until normalized or stable on treatment 5
• Assess clinical symptoms of androgen excess (hirsutism, acne, alopecia) at each visit to evaluate treatment response 5
• Monitor for adverse effects of anti-androgen therapy, including hyperkalemia with spironolactone and sexual dysfunction with finasteride 3, 2
• Perform long-term follow-up for patients with persistent elevations to detect any changes suggesting developing pathology such as tumor 5

Critical Pitfalls to Avoid

• Do not dismiss isolated DHT elevation as laboratory error without confirming with LC-MS/MS and considering diethyl ether extraction, as true pathology may be missed 3, 1
• Do not assume PCOS based solely on elevated DHT without meeting Rotterdam criteria (2 of 3: hyperandrogenism, ovulatory dysfunction, polycystic ovaries) 3
• Do not overlook the possibility of selective peripheral tissue response where DHT elevation causes menstrual dysfunction and infertility without virilization signs 1
• Do not prescribe finasteride to women of reproductive age without strict contraception counseling due to severe teratogenic risk to male fetuses 2
• Do not fail to image the ovaries and adrenals when DHT is markedly elevated (>2-3 SD above normal) or symptoms progress rapidly, as this may indicate androgen-secreting tumor 1