What are the etiologies of elevated serum testosterone in a male?

Causes of High Testosterone in Males

Exogenous Androgen Administration

The most common cause of elevated testosterone in males is exogenous testosterone therapy or anabolic steroid use. 1

• Testosterone replacement therapy at excessive doses directly raises serum testosterone levels and should be the first consideration when evaluating elevated testosterone 1
• Anabolic-androgenic steroid abuse for athletic performance or bodybuilding is a frequent cause, particularly in younger males 2
• Illicit use of androgenic herbal supplements can also contribute to elevated testosterone levels 2

Endocrine Disorders

Androgen-Secreting Tumors

• Testicular tumors (Leydig cell tumors) can autonomously produce testosterone, leading to markedly elevated levels 1
• Adrenal tumors or carcinomas may secrete androgens, causing elevated testosterone 1

Congenital Adrenal Hyperplasia

• Enzyme deficiencies (particularly 21-hydroxylase or 11β-hydroxylase deficiency) result in shunting of steroid precursors toward androgen production 1
• This condition typically presents with elevated DHEA-S and androstenedione in addition to testosterone 1

Pituitary Disorders

• Prolactin-secreting adenomas (prolactinomas) can paradoxically cause elevated testosterone in rare cases through disruption of normal feedback mechanisms 1
• Non-functioning pituitary adenomas may alter gonadotropin secretion patterns 3

Diagnostic Evaluation Algorithm

Initial Laboratory Assessment

• Obtain a comprehensive hormonal panel including LH, FSH, prolactin, and estradiol to determine the source of elevation 1
• Measure hematocrit/hemoglobin at baseline, as elevated testosterone commonly causes polycythemia (hematocrit >50% warrants investigation) 1
• Check PSA in men over 40 years to exclude occult prostate pathology 1
• Obtain liver function tests to assess for hepatic complications 1

Imaging Studies Based on Laboratory Results

• If LH is low or prolactin is elevated: Order pituitary MRI to investigate for adenomas or other sellar masses 1
• If DHEA-S is markedly elevated: Obtain adrenal CT or MRI to evaluate for adrenal tumors 1
• If testicular examination is abnormal: Perform testicular ultrasound to identify Leydig cell tumors 1

Interpretation of Gonadotropin Levels

• Low LH/FSH with high testosterone: Suggests exogenous androgen use (negative feedback suppression) or androgen-secreting tumor 1
• Elevated LH/FSH with high testosterone: Rare pattern that may indicate androgen resistance or receptor abnormalities 3
• Normal LH/FSH with high testosterone: May represent physiologic variation at the upper end of normal or early tumor development 4

Clinical Significance and Complications

Cardiovascular Risk

• Elevated testosterone increases atherosclerosis risk and causes adverse lipid profile changes 1
• Thrombotic events may occur due to increased blood viscosity from polycythemia 1

Reproductive Effects

• Suppression of natural hormone production through negative feedback on the hypothalamic-pituitary axis 1
• Fertility impairment due to suppressed spermatogenesis when LH/FSH are suppressed 1, 5
• Gynecomastia may develop from aromatization of excess testosterone to estradiol 1

Hematologic Complications

• Polycythemia (hematocrit >54%) requires intervention with phlebotomy or dose adjustment 1
• Regular monitoring of complete blood count is essential 1

Management Approach

If Exogenous Testosterone is Identified

• Discontinue exogenous testosterone or anabolic steroids with gradual tapering to prevent withdrawal symptoms 1
• Adjust dosing regimen to achieve testosterone levels within normal range if therapeutic testosterone is medically indicated 1
• Recovery of normal spermatogenesis typically requires 6 months or longer after cessation 1, 2

If Endocrine Disorder is Identified

• Refer to endocrinology for management of underlying disorders 1
• Treatment depends on specific etiology (surgical resection for tumors, dopamine agonists for prolactinomas, glucocorticoid replacement for congenital adrenal hyperplasia) 1

Monitoring Requirements

• Check testosterone levels every 3-6 months initially, then annually once stable 1
• Monitor hematocrit regularly, with intervention required if exceeds 54% 1
• Perform cardiovascular risk assessment including blood pressure and lipid profiles 1
• Conduct digital rectal examination and PSA testing at baseline and during follow-up, with low threshold for prostate biopsy if PSA rises substantially 1

Important Caveats

• Naturally elevated endogenous testosterone (>800 ng/dL) in men not on therapy is rare (only 4% of males) and is not associated with significant clinical morbidity, sleep disorders, urinary symptoms, or depression 4
• The hematocrit elevation seen with naturally high testosterone is typically not clinically significant 4
• This challenges assumptions about "safe" testosterone targets and suggests that physiologically elevated endogenous testosterone may be better tolerated than exogenous administration 4