What is the appropriate evaluation and management for a patient with elevated testosterone?

Evaluation and Management of Elevated Testosterone

The first priority is to determine whether elevated testosterone is endogenous or exogenous, then identify the underlying cause through comprehensive hormonal evaluation including LH, FSH, prolactin, and estradiol levels, followed by appropriate imaging studies if indicated. 1

Initial Diagnostic Workup

Essential Laboratory Testing

• Measure LH and FSH levels to distinguish between primary gonadal disorders versus central causes of androgen excess 1, 2
• Check prolactin levels, particularly if LH is low or low-normal, as this may indicate a pituitary tumor causing secondary hormonal dysregulation 1, 2
• Obtain estradiol levels to assess for aromatization of excess androgens and evaluate gynecomastia risk 3, 1
• Measure 17-hydroxyprogesterone (17-OHP) early morning levels to screen for congenital adrenal hyperplasia, specifically 21-hydroxylase deficiency 2
• Check ACTH levels to determine if excess androgen production originates from the adrenal gland versus ectopic sources 2

Baseline Safety Assessments

• Measure hemoglobin/hematocrit at baseline, as elevated testosterone can cause polycythemia; levels above 50% warrant investigation before any intervention 3, 1
• Check PSA in men over 40 years to exclude occult prostate pathology, as testosterone elevation may unmask or promote prostate disease 3, 1
• Obtain lipid profile and blood pressure for cardiovascular risk assessment, as elevated testosterone increases atherosclerosis risk and causes adverse lipid changes 1
• Measure liver function tests if pharmacologic therapy is anticipated 1

Imaging Studies When Indicated

• Order pituitary MRI if LH is low or prolactin is elevated to investigate for pituitary adenomas or other sellar masses 1
• Obtain adrenal imaging if androgen-secreting tumors are suspected, particularly if testosterone is severely elevated 1, 2

Common Etiologies to Investigate

Exogenous Sources

• Testosterone replacement therapy at excessive doses is a common iatrogenic cause 1
• Anabolic steroid use should be specifically queried, as patients may not volunteer this information 1, 2

Endocrine Disorders

• Congenital adrenal hyperplasia presents with elevated androgens and requires 17-OHP screening 1, 2
• Androgen-secreting tumors (adrenal or testicular) should be suspected if testosterone is severely elevated, particularly with tumors >5 cm, inhomogeneous appearance, irregular margins, or local invasion 1, 2
• Polycystic ovary syndrome in females causes hyperandrogenism, though typically with mild elevations 4
• Ovarian steroid-cell tumors in females can cause extremely high testosterone without virilization signs 4

Management Approach

If Exogenous Testosterone Identified

• Immediately discontinue all exogenous testosterone or anabolic steroids with gradual tapering to prevent withdrawal symptoms 1, 2
• Adjust dosing regimen to achieve testosterone levels within normal range if continuation is medically indicated 1
• Counsel on cardiovascular risks and potential complications 2

If Endocrine Disorder Identified

• Refer to endocrinology for management of underlying disorders, with treatment depending on specific etiology 1
• Initiate glucocorticoid therapy to suppress excessive ACTH-driven androgen production in congenital adrenal hyperplasia 2
• Consider surgical intervention for androgen-secreting tumors: open adrenalectomy for suspected malignant tumors, laparoscopic adrenalectomy for benign adenomas when feasible, with postoperative corticosteroid supplementation required until HPA axis recovery 2
• Treat hyperprolactinemia with dopamine agonists for prolactinomas, or address medication-induced causes 1

Metabolic Considerations

• Evaluate for insulin resistance and metabolic syndrome, which are commonly associated with hyperandrogenism 5
• Implement lifestyle modifications including weight loss and increased physical activity to reduce testosterone levels in patients with metabolic causes 5
• Consider metformin if insulin resistance is present 5

Fertility Considerations

Discuss the impact on spermatogenesis with all patients interested in future fertility, as elevated testosterone suppresses natural hormone production through negative feedback on gonadotropins 3, 1

• Recovery of normal spermatogenesis typically requires 6 months or longer after cessation of exogenous testosterone or anabolic steroids 1
• Testosterone cessation should occur in advance of any effort to conceive 3
• Counsel patients about the highly variable time course to recover sperm in the ejaculate 3

Monitoring and Follow-Up

Laboratory Surveillance

• Recheck testosterone, DHEA, and DHEA-S levels at 1-2 months after intervention to assess treatment efficacy 2
• Monitor testosterone levels every 3-6 months initially, then annually once stable 1
• Check hematocrit regularly, with intervention required if Hct exceeds 54% (phlebotomy, dose adjustment if on any therapy) 3, 1
• Monitor complete blood count for polycythemia, as elevated androgens increase hemoglobin/hematocrit 1, 2
• Assess lipid profile and blood pressure regularly for cardiovascular risk, particularly in patients with prolonged androgen excess 1, 2
• Measure liver function tests to assess treatment effectiveness 1, 2

Prostate Monitoring

• Perform digital rectal examination and PSA testing at baseline and during follow-up, with low threshold for prostate biopsy if PSA rises substantially or examination becomes abnormal 1
• Screen for metabolic complications, including lipids and glucose tolerance 5

Potential Complications of Untreated Elevated Testosterone

Cardiovascular Risks

• Increased risk of atherosclerosis and adverse lipid profile changes 1
• Thrombotic events may occur with prolonged elevation 1

Reproductive and Hormonal Effects

• Suppression of natural hormone production through negative feedback 1
• Fertility issues due to suppressed spermatogenesis 1
• Gynecomastia from aromatization to estradiol, though symptomatic breast symptoms are uncommon 3

Important Clinical Pitfalls

Any discrepancy between laboratory tests and clinical scenario deserves rigorous evaluation to minimize misinterpretation and diagnostic errors 4. In women with very elevated testosterone levels and absence of clinical manifestations, laboratory interference should be suspected, and diethyl ether extraction is a useful technique when other methods fail to detect it 4.

Avoid measuring random testosterone levels; obtain early morning samples on at least two separate occasions for accuracy 2. Research suggests that naturally elevated endogenous testosterone levels (>800 ng/dL) are not associated with significant clinical morbidity in men not receiving testosterone therapy, though they do have higher hematocrit levels that remain clinically insignificant 6.