How Three Years of Contested Evidence Became a Warning on Every Label

Three pieces of evidence, none of them definitive, combined into a regulatory position that shaped a decade of prescribing.

• 2010 — the TOM trial, stopped early after more cardiovascular events in the treated arm.[1]
• 2013 — a JAMA analysis reporting an association between testosterone therapy and mortality, myocardial infarction and stroke in men with low testosterone levels.[2]
• 2013 — a systematic review and meta-analysis of placebo-controlled randomised trials of testosterone therapy and cardiovascular events.[3]

Each has real limitations. The composite was treated as more solid than any part of it.

Why each piece was contestable

TOM was small, terminated early, and conducted in older men with mobility limitations — a frail population. It was a trial of physical function that reported cardiovascular events as adverse events.[1]

The 2013 JAMA analysis was observational. Men prescribed testosterone differ systematically from men who are not — in symptoms, comorbidity and health-seeking behaviour — and observational designs can adjust for measured differences but not unmeasured ones. An association is not an effect.

The meta-analysis pooled placebo-controlled randomised trials.[3] Pooling is only as good as the inputs: trials of differing size, population, formulation, duration and outcome definition. A meta-analysis of studies never designed to measure cardiovascular outcomes inherits that limitation and adds precision it has not earned.

What the warning did

It changed the default. Prescribers became cautious, patients became frightened, and testosterone therapy acquired a cardiovascular reputation that persisted long after the evidence base changed.

The reputational lag is the interesting part. TRAVERSE reported in 2023 that testosterone was non-inferior to placebo for major adverse cardiac events in men with hypogonadism and either cardiovascular disease or increased cardiovascular risk.[4] The FDA issued class-wide labeling changes for testosterone products in February 2025.[5]

So the regulatory correction arrived roughly a decade after the regulatory caution — and public understanding is still catching up with the second event.

The lesson that generalises

Weak evidence pointing consistently in one direction feels like strong evidence. It is not, and the tell is whether any individual study was designed to answer the question being asked.

That test is worth applying in both directions. It is also the reason this hub cites primary literature for every clinical claim: a summary of a summary loses exactly the information — design, population, endpoint — that decides whether a finding means anything.

Frequently asked questions

Was the FDA wrong to act? Acting on a safety signal is reasonable regulatory behaviour. The subsequent evidence changed the picture, and the labelling was updated in 2025.[5]

Is the 2013 JAMA paper discredited? It is observational, with the limits that carry. It is one input into a question later addressed by a dedicated randomised trial.[4]

What does the current label say? The FDA issued class-wide labeling changes in February 2025.[5] Your prescriber works from current labelling.

Next in this series

The trial that was actually designed for the question took thirteen years and 5,204 men.

Continue with TRAVERSE, the definitive answer.

References

5 sources

1. 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
2. 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
3. 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
4. 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
5. U.S. Food and Drug Administration. FDA issues class-wide labeling changes for testosterone products. February 28, 2025. fda.gov