Testosterone replacement therapy in middle-aged and older men with hypogonadism was noninferior to placebo for major cardiovascular events but produced a higher rate of nonfatal arrhythmias, according to the TRAVERSE trial, a multicenter, randomized, double-blind, placebo-controlled study of 5,246 men published by Lincoff and colleagues in the New England Journal of Medicine in 2023. The finding, from the largest cardiovascular outcomes trial ever conducted in testosterone therapy, closes one longstanding safety question while opening others, and it lands in a market where prescriptions rose sharply during the 2000s before regulators, journals, and clinical societies began pushing back.
Testosterone does more than support libido and muscle
Testosterone is the primary male sex hormone. It supports muscle mass and strength, bone density, red blood cell production, libido, and, to a smaller and more contested degree, mood and cognition. Circulating levels fall gradually with age, typically about 1 to 2% per year from the mid-30s onward. This age-related decline is called late-onset hypogonadism, though many men whose numbers drop remain asymptomatic and do not meet clinical criteria for treatment.
Hypogonadism in its clinical sense is not defined by low numbers alone. Endocrine Society and American Urological Association guidelines require both consistently low serum testosterone, generally below 300 ng/dL on two morning samples, and symptoms plausibly caused by testosterone deficiency: reduced libido, erectile dysfunction, loss of muscle mass, reduced bone density, or unexplained fatigue. The distinction matters. Men who meet both criteria stand to benefit from treatment; men who meet only one are being treated for an incidental laboratory finding.
Prescriptions rose sharply in the 2000s, then reversed
US testosterone prescriptions tripled between 2001 and 2011, expanding fastest in men without a clear indication (Baillargeon et al., JAMA 2018). The rise coincided with direct-to-consumer television advertising for “low T” and the emergence of chains of dedicated hormone clinics. Prescriptions turned down in 2013 and 2014 after two studies reported increased cardiovascular events with testosterone use, and after the FDA issued a safety bulletin in January 2014 requiring updated labeling to warn about possible increased risk of heart attack and stroke. The reversal was visible across regions and age groups.
The TRAVERSE trial was designed to settle the cardiovascular question
The FDA required a definitive cardiovascular outcomes trial as a condition of continued marketing. That trial was TRAVERSE, run at 316 US sites and enrolling 5,246 men aged 45 to 80 with hypogonadism and either preexisting cardiovascular disease or high cardiovascular risk. Men received either transdermal 1.62% testosterone gel titrated to maintain levels of 350 to 750 ng/dL, or placebo gel, and were followed for a median of about 33 months.
The primary endpoint, a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, occurred in 7.0% of the testosterone group and 7.3% of the placebo group. That met the prespecified criterion for noninferiority. Testosterone did not increase major cardiovascular events over the trial’s duration in this population.
The trial also identified new safety signals. Nonfatal arrhythmias, particularly atrial fibrillation, occurred more often in the testosterone group. Pulmonary embolism, acute kidney injury, and a modest increase in fractures were also more common on testosterone, the last of which was a striking result given testosterone’s known bone-building effect and warrants further investigation. The trial’s co-principal investigator, A. Michael Lincoff, concluded that the findings “provide reassurance about the cardiovascular safety of testosterone therapy over the typical duration of treatment in men in whom it is indicated.”
Vague symptoms do not mean testosterone deficiency
The commercial “low T” pitch conflates the specific clinical syndrome with symptoms shared by many other conditions: fatigue, low motivation, weight gain, reduced libido. Poor sleep, obesity, insulin resistance, depression, and thyroid dysfunction can produce the same picture. Endocrine and urology guidelines are consistent that these possibilities should be evaluated before, or alongside, a testosterone workup, and that treatment should not be started without a documented deficiency and a symptom pattern consistent with it.
Fertility, sperm count, and dependence deserve explicit discussion
Exogenous testosterone suppresses the pituitary signals that drive testicular testosterone and sperm production. In practice this means most men on TRT will have substantially reduced sperm counts, and some will become azoospermic. Men who may want to father children should discuss preservation options before starting therapy. Testicular size typically decreases as well. When TRT is stopped, natural production often takes months to recover, and in some men does not fully recover. These are not reasons to avoid appropriate therapy, but they are reasons to be sure it is appropriate before starting.
What the evidence cannot yet answer
TRAVERSE followed men for a median of about 33 months. Whether the arrhythmia signal reflects a real cardiac risk from longer exposure, or a shorter-term effect that plateaus, is not yet resolved. The trial was conducted in men with existing or high cardiovascular risk, and its findings do not extend cleanly to younger, otherwise healthy men who make up much of the commercial market. Cognitive and mood benefits remain modest and inconsistent in randomized trials. And the appropriate lower threshold of testosterone for treatment in symptomatic men is still debated between endocrinology and urology society guidelines.
References
- Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy (TRAVERSE). New England Journal of Medicine, 2023; 389: 107-117. DOI: 10.1056/NEJMoa2215025
- Baillargeon J, Kuo YF, Westra JR, Urban RJ, Goodwin JS. Testosterone Prescribing in the United States, 2002-2016. JAMA, 2018; 320: 200-202. DOI: 10.1001/jama.2018.7999
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism, 2018; 103: 1715-1744. DOI: 10.1210/jc.2018-00229
- Snyder PJ, Bauer DC, Ellenberg SS, et al. Testosterone Treatment and Fractures in Men with Hypogonadism. New England Journal of Medicine, 2024; 390: 203-211. DOI: 10.1056/NEJMoa2308836