What are the evaluation and treatment options for a younger to middle-aged individual, possibly with a history of polycystic ovary syndrome (PCOS) or anabolic steroid use, presenting with elevated testosterone levels?

Evaluation and Management of Elevated Testosterone Levels

For younger to middle-aged individuals with elevated testosterone, first determine the underlying cause through targeted testing: measure total testosterone (TT) and free testosterone (FT) using LC-MS/MS as first-line tests, followed by androstenedione (A4) and DHEAS if initial tests are equivocal, while immediately excluding androgen-secreting tumors if testosterone exceeds 2-3 standard deviations above normal. 1, 2

Initial Diagnostic Approach

Laboratory Testing Priority

• Measure TT and FT as first-line tests using liquid chromatography-tandem mass spectrometry (LC-MS/MS), which demonstrates superior sensitivity and specificity compared to direct immunoassay methods 1

• Calculate free testosterone (cFT) using equilibrium dialysis or ammonium sulfate precipitation, or use the free androgen index (FAI) as an alternative 1

• For PCOS diagnosis specifically, TT shows 74% sensitivity and 86% specificity, making it the most reliable single marker 3, 4

• If TT or cFT are not elevated but clinical suspicion remains high, measure androstenedione and DHEAS, though these have lower specificity (A4: 0.80 specificity; DHEAS: 0.67 specificity) 1

Critical Red Flags Requiring Urgent Investigation

• Testosterone levels >2-3 SD above normal reference range warrant immediate evaluation for androgen-secreting tumors, particularly ovarian steroid-cell tumors, even in the absence of virilization signs 2

• Rapid onset of virilization, severe hirsutism, or menstrual irregularities with markedly elevated testosterone require urgent imaging and tumor exclusion 2

• Consider diethyl-ether extraction if laboratory values seem discordant with clinical presentation, as this can identify laboratory interference 2

PCOS-Specific Evaluation

Diagnostic Accuracy of Androgen Markers

For women with suspected PCOS, the diagnostic hierarchy based on sensitivity and specificity is:

• Total testosterone: 70% of PCOS cases show elevation; most frequently abnormal biochemical marker 4
• Calculated free testosterone (cFT): Highest overall diagnostic accuracy 1
• Free androgen index (FAI): High sensitivity and specificity, particularly useful when combined with TT 1
• Androstenedione: 53% abnormal in PCOS; useful adjunct but lower specificity 5, 4
• DHEAS: Less discriminatory; no significant difference between PCOS and controls in some studies 6, 4

Combined Testing Strategy

A model combining testosterone, androstenedione, and FAI improves diagnostic efficiency, with androstenedione showing a Youden index of 0.65 (81.82% sensitivity, 83.16% specificity) 5

The combination of testosterone, androstenedione, or LH (either alone or together) identifies 86% of women with PCOS and should be the definitive hormonal testing approach 4

Anabolic Steroid Use Evaluation

Key Considerations

• Exogenous testosterone suppresses spermatogenesis and can cause severe oligospermia or azoospermia; recovery time is highly variable after cessation 1

• For individuals desiring future fertility, testosterone cessation must occur well in advance of conception attempts, with variable recovery periods ranging from months to over a year 1

• Baseline hemoglobin/hematocrit measurement is mandatory before any testosterone therapy consideration; withhold therapy if Hct >50% until etiology is investigated 1

Monitoring and Safety Considerations

For PCOS Patients on Anti-Androgen Therapy

If spironolactone is used for hyperandrogenism management:

• Monitor potassium levels at baseline, 1 week after initiation, and periodically thereafter due to risk of life-threatening hyperkalemia and cardiac arrhythmias 3

• Higher-risk patients (diabetes, kidney disorders, liver disorders, elderly) require more frequent monitoring 3

• Contraindications include concurrent potassium-sparing diuretics, potassium supplements, CYP3A4 inhibitors, or combined ACE inhibitor/ARB therapy 3

For Testosterone Replacement Therapy (if indicated)

• Measure PSA in men over 40 years before commencing therapy to exclude occult prostate cancer 1

• Monitor hematocrit during therapy; Hct >54% warrants dose reduction or temporary discontinuation 1

• Assess ASCVD risk factors (dyslipidemia, hypertension, diabetes, smoking) before initiating therapy 1

• Avoid testosterone therapy for 3-6 months following cardiovascular events 1

Common Pitfalls to Avoid

• Do not rely on LH/FSH ratio alone for PCOS diagnosis; it has low sensitivity (35-44% abnormal) and should be abandoned as a sole criterion 4

• Never use 17-alpha-alkylated oral testosterone preparations due to hepatotoxicity risk; use intramuscular or transdermal formulations instead 1

• Do not prescribe testosterone to individuals actively trying to conceive; it suppresses spermatogenesis and fertility 1

• Recognize that SHBG variations (affected by age, weight, medications) can influence TT and FAI results, making free testosterone measurement critical 1

• Adrenal androgen production capacity remains elevated throughout reproductive years in PCOS, so age-related decline seen in healthy women does not occur in PCOS patients 6