Testosterone Replacement Therapy in Aging Men: A Critical Appraisal of Evidence, Risks, and Benefits

Abstract

Testosterone replacement therapy (TRT) use has increased substantially over the past two decades. This narrative review evaluates the evidence for TRT in aging men and finds that age-related decline in testosterone concentrations frequently reflects accumulated comorbidity rather than primary testicular failure. Obesity-related and functional hypogonadism are potentially reversible conditions, and lifestyle modification, principally weight reduction and structured exercise, can restore endogenous testosterone production and should be offered first. Randomized trials demonstrate domainspecific and generally modest benefits. Sexual function improves consistently, but by less than the minimum clinically important difference in men with moderate-to-severe erectile dysfunction. Anemia correction is clinically meaningful, although it reflects the same erythropoietic effect that produces erythrocytosis. Bone mineral density increases without a corresponding reduction in fractures. Pre-specified primary outcomes for cognition and physical function were null, with small improvements on secondary measures of mood and vitality. The TRAVERSE trial established cardiovascular noninferiority for major adverse cardiac events over a mean of 21.7 months of treatment, and in February 2025, the United States Food and Drug Administration removed the cardiovascular boxed warning from testosterone products while retaining its limitation of use for age-related hypogonadism. Earlier adverse signals, including coronary plaque progression, an early-terminated trial in men with mobility limitation, and a non-industry-funded meta-analysis, derive from small or short studies and are best interpreted alongside TRAVERSE rather than in place of it. Confirmatory diagnostic testing remains uncommon in practice. Notwithstanding the absence of definitive comparative trials, lifestyle modification, addressing the causes rather than the consequences of testosterone deficiency, should precede TRT, which is best reserved for men with unequivocally and persistently low testosterone concentrations and consistent symptoms, particularly unexplained anemia or reduced libido, following shared decision-making.