The modern testosterone-and-heart controversy starts with one 2010 paper in the New England Journal of Medicine, titled simply "Adverse Events Associated with Testosterone Administration."[1] The Testosterone in Older Men with Mobility Limitations trial was stopped before completion after more cardiovascular events accumulated in the treated group than in the placebo group.
That result launched a decade of alarm, regulatory action and eventually the largest testosterone trial ever run. It is worth understanding what the study was and was not.
What it was designed to answer
TOM was a trial in older men with limited mobility — a frail population with a high burden of existing disease. Its purpose was to see whether testosterone improved physical function.
It was not powered as a cardiovascular outcomes trial. The cardiovascular events that halted it were adverse events observed during a trial of something else — which is exactly what the title says.
Why a small imbalance carries so little certainty
In a trial of this size, a difference of a handful of events between arms can produce an alarming-looking ratio while remaining entirely compatible with chance. That is not a criticism of the investigators, who reported what they found and stopped the study — the responsible action when a safety signal appears.
It is a caution about what the finding could support. A signal is a reason to investigate. It is not an answer.
What it set in motion
TOM did not stay a single paper. It became the anchor for a body of concerning evidence that accumulated over the following three years — including a 2013 JAMA analysis reporting an association between testosterone therapy and mortality, myocardial infarction and stroke in men with low testosterone,[2] and a 2013 systematic review and meta-analysis of placebo-controlled randomised trials examining testosterone therapy and cardiovascular events.[3]
Together these drove regulatory action, and the story of how that evidence was weighed is the flawed meta-analysis and the FDA warning.
How it was eventually resolved
By running the trial that TOM was not. TRAVERSE enrolled 5,204 men aged 45 to 80 with hypogonadism and either cardiovascular disease or increased cardiovascular risk, and was designed specifically to assess major adverse cardiac events.[4]
That is roughly the study the 2010 signal demanded, and it took thirteen years to report. The answer is in TRAVERSE, the definitive answer.
Frequently asked questions
Was the TOM trial wrong? It reported what it observed. The limitation is what a small, early-terminated trial in a frail population can establish about cardiovascular risk — which is: a signal worth investigating.
Does this mean testosterone is dangerous for the heart? The question was addressed directly by TRAVERSE more than a decade later.[4] See what TRAVERSE means for TRT today.
Why did one trial have such an outsized effect? Because it was the first credible randomised signal, it appeared in a leading journal, and no adequately powered trial existed to contradict it for thirteen years.
Next in this series
The 2010 signal did not act alone. What turned it into an FDA warning was the evidence assembled around it.
Continue with the flawed meta-analysis and the FDA warning.
References
4 sources
- Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med. 2010;363(2):109–122. doi:10.1056/NEJMoa1000485 · PMID 20592293
- Vigen R, O'Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829–1836. doi:10.1001/jama.2013.280386 · PMID 24193080
- Xu L, Freeman G, Cowling BJ, et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013;11:108. doi:10.1186/1741-7015-11-108 · PMID 23597181
- Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107–117. doi:10.1056/NEJMoa2215025 · PMID 37326322
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