Testosterone, Testosterone Replacement Therapy, and Cardiovascular Disease: A Contemporary Review

Whether low endogenous testosterone is causal for cardiovascular disease, and how the cardiovascular risk of testosterone replacement therapy should now be classified, remain contested, while US labeling has moved in 2 opposing directions within 16 months. We conducted a targeted narrative review reported in accordance with the Scale for the Assessment of Narrative Review Articles, searching MEDLINE and primary regulatory documents from January 2000 through July 2026. Evidence was graded with a prespecified 3-tier structured author-consensus rating separating established randomized findings, unresolved secondary signals, and evidentiary absence. Low endogenous testosterone is consistently associated with higher all-cause and cardiovascular mortality but most plausibly marks multimorbidity rather than causation. TRAVERSE established that physiologic transdermal testosterone replacement therapy was noninferior to placebo for 3-point major adverse cardiovascular events over ∼3 years, within a permissive margin and against a 61% discontinuation rate. Observational analyses linking normalization to lower mortality were not reproduced under randomization. Atrial fibrillation, pulmonary embolism, acute kidney injury, fracture, and noncalcified plaque progression remain unresolved. Blood pressure rises across the class; on ambulatory monitoring the magnitude differs by individual product rather than by route. Long-term exposure and nontransdermal formulations remain untested, and the age-related-hypogonadism limitation of use is now proposed for removal. Noninferiority over 3 years should not be read as long-term clinical equivalence. Safe use of testosterone replacement therapy requires appropriate patient selection, distinction between pathologic hypogonadism and functional or age-associated low testosterone, mapping of each recommendation to its evidentiary tier, and close multidisciplinary collaboration.