What causes elevated testosterone levels?

Causes of Elevated Testosterone Levels

Elevated testosterone results from either endogenous overproduction by tumors (adrenal, testicular, ovarian, or pituitary), enzyme deficiencies causing abnormal steroid metabolism (particularly congenital adrenal hyperplasia), or exogenous administration of testosterone or anabolic steroids. 1

Primary Endogenous Causes

Androgen-Producing Tumors

• Ovarian tumors are diagnosed in 1-3 per 1,000 patients presenting with hyperandrogenism and comprise less than 0.5% of all ovarian tumors 2
• Adrenal tumors (both benign adenomas and malignant carcinomas) are less common than ovarian tumors but cause significant testosterone elevation and virilization 2
• Testicular tumors can produce excess testosterone, requiring surgical evaluation 1
• Pituitary adenomas (both secreting and non-secreting) can disrupt normal hormonal regulation; men with testosterone levels combined with abnormal LH should undergo pituitary MRI regardless of prolactin levels 3, 1

Enzyme Deficiencies and Genetic Disorders

• 21-hydroxylase deficiency is the most common cause (>90% of cases) of congenital adrenal hyperplasia, leading to excessive androgen secretion as accumulated precursors are shunted into androgen synthesis pathways 4, 5
• 11β-hydroxylase deficiency (the second most frequent form of congenital adrenal hyperplasia) causes excessive secretion of both androgens and mineralocorticoids 4
• 3β-hydroxysteroid dehydrogenase deficiency affects synthesis of all steroid classes but can result in abnormal androgen accumulation 4
• In congenital adrenal hyperplasia, accumulated 17-hydroxyprogesterone is converted to androgens through multiple pathways, including the "backdoor pathway" to dihydrotestosterone and the 11-oxyandrogens pathway 5

Other Endogenous Conditions

• Ovarian hyperthecosis in postmenopausal women causes relative or absolute androgen excess 2
• Polycystic ovary syndrome (PCOS) can worsen after menopause, manifesting as hyperandrogenism 2
• Cushing syndrome should be excluded in patients with elevated testosterone and signs of glucocorticoid excess 2

Exogenous Causes

• Testosterone replacement therapy administered via intramuscular, transdermal, or patch formulations 3
• Anabolic-androgenic steroid abuse, particularly common among athletes seeking increased strength and recovery 6
• Iatrogenic hyperandrogenism from medications affecting steroid metabolism 2

Diagnostic Approach

Initial Laboratory Evaluation

• Measure serum LH levels to establish whether the testosterone elevation is primary (gonadal) or secondary (pituitary-driven) 3, 1
• Measure serum prolactin in patients with abnormal LH levels to screen for hyperprolactinemia and pituitary tumors 3, 1
• Measure dehydroepiandrosterone sulfate (DHEA-S) and androstenedione to help localize the source (adrenal vs. gonadal) 2
• Measure sex hormone-binding globulin (SHBG) as levels decrease with obesity, insulin resistance, and certain medications, affecting free testosterone interpretation 3, 2
• Measure serum estradiol in patients with breast symptoms or gynecomastia 3, 1
• Assess inhibin B in postmenopausal women with hyperandrogenism 2

Imaging Studies

• Pituitary MRI is mandatory for men with total testosterone levels <150 ng/dL combined with low or low-normal LH, regardless of prolactin levels, as non-secreting adenomas may be present 3, 1
• Adrenal MRI when DHEA-S is markedly elevated or adrenal tumor is suspected 2
• Pelvic ultrasound or MRI when ovarian source is suspected in women 2

Clinical Consequences

• Erythrocytosis develops as testosterone stimulates erythropoiesis; hematocrit >54% warrants intervention 3, 1
• Metabolic disturbances including hypercholesterolemia, insulin resistance, and hypertension 2
• Cardiovascular disease risk increases with prolonged elevation 2
• Virilization in women, including terminal hair growth in androgen-dependent areas, acne, and alopecia 2
• Fertility impairment as elevated testosterone suppresses the hypothalamic-pituitary-gonadal axis, causing chronic anovulation in women and suppressed spermatogenesis in men 1, 5

Important Clinical Pitfalls

• Confirm abnormal results before initiating extensive workup, as hormone levels fluctuate and spurious elevations occur 1, 2
• Measure morning fasting testosterone on at least two occasions for accurate assessment 3
• Avoid testing during acute illness as stress conditions can alter testosterone levels 3
• Consider SHBG alterations that affect total testosterone interpretation: SHBG increases with aging, hyperthyroidism, and certain medications (anticonvulsants, estrogens), while it decreases with obesity, hypothyroidism, and insulin resistance 3
• Screen for Cushing syndrome with appropriate tests (24-hour urinary free cortisol, overnight dexamethasone suppression test) when clinical features suggest glucocorticoid excess 2