Early observations and pilot data that first suggested a new direction
Testosterone replacement therapy (TRT) for hypogonadism was widely prescribed, but cardiovascular safety remained uncertain. The TOM trial in 2010 raised significant concerns when it was stopped early after 209 older men (mean age 74) with mobility limitations showed an excess of cardiovascular adverse events in the testosterone group (23 events vs 5 in placebo). Although the trial was small and enrolled a high-risk population, the FDA issued a safety alert and subsequently mandated a large cardiovascular outcomes trial.
Landmark RCTs and pivotal trials that established the evidence base
The TRAVERSE trial, designed as an FDA-mandated post-marketing safety study, was the definitive cardiovascular outcomes trial. It randomized 5,246 men aged 45-80 with hypogonadism and preexisting or high risk of cardiovascular disease to transdermal testosterone gel or placebo for a mean of 27 months. The primary MACE endpoint occurred in 7.0% of the testosterone group versus 7.3% of placebo (HR 0.96; 95% CI 0.78-1.17), confirming cardiovascular noninferiority. This resolved the primary safety concern that had dominated the field for over a decade.
Follow-up studies, subgroup analyses, and real-world validation
Secondary analyses of TRAVERSE provided additional nuance. The trial confirmed that TRT modestly increased hematocrit but this did not translate into excess thromboembolic events. Prostate safety data were reassuring in the short term, though longer-term follow-up was considered necessary. The Testosterone Trials (TTrials) had previously established modest benefits of TRT on sexual function, physical function, bone density, and anemia in older men with low testosterone, providing the efficacy context alongside TRAVERSE safety data.
Integration into clinical practice guidelines and recommendations
The Endocrine Society 2018 guidelines and subsequent updates recommended TRT for men with unequivocally low testosterone levels and consistent symptoms, with monitoring of hematocrit, PSA, and cardiovascular risk factors. Post-TRAVERSE, the FDA removed its 2015 boxed warning about cardiovascular risk, and European expert panels issued position statements supporting the cardiovascular safety of appropriately prescribed TRT.
Endocrine Society
TRT recommended for men with symptomatic hypogonadism and unequivocally low testosterone; monitor hematocrit, PSA, and cardiovascular risk
European Expert Panel
TRAVERSE confirms cardiovascular safety of TRT when used as indicated; supports treatment in appropriately selected hypogonadal men
Now
Current standard of care and ongoing research directions
The TRAVERSE trial resolved the decade-long cardiovascular safety debate, confirming that TRT is noninferior to placebo for MACE in men with hypogonadism and cardiovascular risk. The field has shifted from safety concerns to appropriate patient selection and monitoring. Remaining considerations include long-term prostate safety, optimal testosterone formulations and targets, and whether TRT has genuine cardiovascular or metabolic benefits beyond symptom relief.
Is testosterone replacement therapy safe for the heart?+
The TRAVERSE trial (5,246 men, NEJM 2023) demonstrated that transdermal testosterone was noninferior to placebo for major cardiovascular events (HR 0.96; 95% CI 0.78-1.17) in hypogonadal men with or at high risk of cardiovascular disease. This resolved the concern raised by the smaller TOM trial in 2010.
What monitoring is needed during testosterone therapy?+
Per Endocrine Society guidelines: hematocrit at 3-6 months then annually (stop if >54%), PSA and digital rectal exam per screening guidelines, testosterone levels to ensure therapeutic range, and assessment for sleep apnea symptoms. TRAVERSE showed modest hematocrit increases without excess thromboembolic events.
