Androgens

Importance Male hypogonadism is a clinical syndrome of signs and symptoms of testosterone deficiency and consistently low morning serum testosterone concentrations. The prevalence of hypogonadism due to hypothalamus, pituitary, or testes pathology is less than 1%, and the prevalence due to obesity (body mass index ≥30) is from 2% to 8%.

Observations The most common signs and symptoms of hypogonadism are decreased libido, decreased spontaneous erections, and small testes. Primary hypogonadism is characterized by deficient testicular production of testosterone despite elevated luteinizing hormone (LH) concentrations. The most common cause of primary hypogonadism is Klinefelter syndrome (≥2 X chromosomes and 1 Y chromosome), which affects 2 in 1000 men and is frequently undiagnosed. Secondary hypogonadism is caused by hypothalamic or pituitary dysfunction and is characterized by low testosterone concentrations and low or inappropriately normal LH and follicle-stimulating hormone (FSH) concentrations. The most common permanent causes of secondary hypogonadism are head and neck radiation and severe head trauma. The most common potentially reversible causes of secondary hypogonadism are obesity, severe illness, and medication use (opioids, corticosteroids, checkpoint inhibitors, and medications that cause hyperprolactinemia). Testing for hypogonadism is reserved for men with signs and symptoms of androgen deficiency. Hypogonadism is confirmed if an individual’s serum testosterone concentration is less than 264 to 300 ng/dL in at least 2 fasting samples collected between 7 and 10 am and measured with an accurate and external quality-controlled assay. Assessment of calculated free testosterone concentration derived using total testosterone and sex hormone–binding globulin (SHBG) concentrations is necessary for men with obesity, diabetes, and other conditions that cause low serum SHBG concentrations. Patients diagnosed with hypogonadism should have serum FSH and LH concentrations measured to distinguish primary from secondary hypogonadism. For men with obesity-induced hypogonadism, the recommended first-line management is weight loss. In men with obesity, weight loss of at least 5% typically increases serum total testosterone concentration significantly, and weight loss is associated with improved physical function, libido, and erectile function. Men with permanent hypogonadism, or those unable to discontinue medications that cause hypogonadism, may be treated with testosterone. The testosterone formulation (injection, gel, or pill) and dosage should be individualized with monitoring of serum testosterone concentration, hematocrit percentage, and possibly prostate-specific antigen concentration.

Conclusions and Relevance Primary hypogonadism affects less than 1% of men, whereas secondary hypogonadism due to obesity (body mass index ≥30) occurs in 2% to 8%. First-line treatment for obesity-induced hypogonadism is weight loss. Testosterone therapy should be initiated for men with permanent hypogonadism or those who are unable to discontinue medications that cause hypogonadism.