The Controversy Years: How TRT Went From Boom to Boxed Warning and Back

Testosterone prescribing more than tripled in the decade to 2011. Within four years the same therapy carried a cardiovascular warning on every label in the United States. Nothing about the underlying biology changed in between — what changed was three studies, none of which was designed to answer the question everyone used it to answer.

This article is the timeline. The individual studies each have their own page; the point here is the sequence, because the sequence is what produced the outcome.

2010 — a trial stopped early

The TOM trial randomised older men with limited mobility to testosterone gel or placebo. It was halted before completion after more cardiovascular events accumulated in the treated group.[1]

Three things about it are usually left out. It was small. It was designed to measure mobility, not cardiovascular risk. And its population — older men with pre-existing limitations in mobility and a high burden of chronic disease — was not the population being prescribed testosterone in the community.

A halted trial is alarming by construction. It is also, on its own, weak evidence about a risk it was not powered to detect. The full account is in the 2010 study that scared everyone.

2013 — an observational analysis and a meta-analysis

Vigen and colleagues published a retrospective analysis of men in the Veterans Affairs system with low testosterone, reporting an association between testosterone therapy and mortality, myocardial infarction and stroke.[2]

The same year, Xu and colleagues published a systematic review and meta-analysis of placebo-controlled randomised trials of testosterone and cardiovascular events.[3]

Neither is a randomised trial of cardiovascular outcomes. An observational cohort can show that treated men had more events without establishing that treatment caused them — the men who get prescribed a drug differ from the men who do not, in ways that are never fully measurable. A meta-analysis inherits the limitations of everything it pools, and what it pooled were trials designed for other endpoints.

Vigen 2013 is treated in detail separately, including the methodological criticism it attracted.

2015 — the warning

Three studies, none decisive, were together enough to move a regulator. The FDA required class-wide labeling changes carrying a cardiovascular warning, and the warning applied to every testosterone product regardless of formulation.[5]

This is the moment the story stops being scientific and becomes regulatory. A label change is binary — a warning is either on the product or it is not — while the evidence behind it was anything but. How contested evidence became a label change covers that transition.

The same period produced evidence in the other direction

The convenient version of this history has the evidence running one way until 2023. It did not.

Sharma and colleagues analysed 83,010 male veterans and reported that normalisation of testosterone level was associated with reduced incidence of myocardial infarction and mortality.[4] It is an observational cohort with the same class of limitation as Vigen — it cannot establish causation either — but it points the opposite way, in a larger population, using the same kind of data.

Two observational analyses of veterans, opposite conclusions. That is the state the field was actually in, and it is a fair description of why a randomised outcome trial became unavoidable. Both are examined in the 83,010-veteran study.

2023 — TRAVERSE

TRAVERSE randomised men with hypogonadism and either pre-existing cardiovascular disease or high cardiovascular risk to testosterone or placebo, and measured major adverse cardiac events as the primary endpoint.[6]

It is the trial the previous thirteen years lacked: randomised, powered for the cardiovascular question, and deliberately enrolled in the men most likely to have an event. Its findings and its limits are set out in the TRAVERSE main trial, and the nested sub-studies — bone, prostate, anaemia, sexual function — carry results that do not all point the same way.

2025 and 2026 — the label changes again, twice

In February 2025 the FDA issued class-wide labeling changes for testosterone products.[5] The warning that went on in 2015 on the strength of contested evidence came off following a trial built to test it.

That was not the end of it. February 2025 kept the limitation of use saying safety and efficacy in men with age-related hypogonadism had not been established — the sentence separating men with a known cause from men whose testosterone is simply low with age. In June 2026 the FDA requested a further round of updates that removed it, and revised the prostate cancer and benign prostatic hyperplasia information.[7] Anyone working from a 2025-vintage summary is reading a superseded position. The two steps are set out in what the 2025 label change did.

What this history is actually good for

It is tempting to read the arc as vindication — scare, investigation, exoneration. That reading is too clean, and it misses the useful lessons.

1. Evidence that is individually weak can be collectively decisive in practice. No single study from 2010–2013 would have moved a label. Three in sequence did.
2. Population matters more than most summaries admit. TOM studied men with limited mobility. TRAVERSE studied men at cardiovascular risk. Neither result transfers cleanly to a healthy 45-year-old, in either direction.
3. The question was never fully symmetrical. Removing a warning is not the same as demonstrating benefit. TRAVERSE tested safety, not whether testosterone should be prescribed more widely — and the T Trials had already shown the benefit profile is narrower than the market implied.

Bottom line

The testosterone controversy was not resolved by anyone proving the sceptics wrong. It was resolved by someone finally running the trial that should have preceded the argument.

The practical implication has not changed across the whole arc: whether testosterone is appropriate depends on a confirmed diagnosis and an individual risk picture, which is why what happens before the first prescription is the part of this that should be strict.

References

7 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. Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706–15. doi:10.1093/eurheartj/ehv346 · PMID 26248567
5. U.S. Food and Drug Administration. FDA issues class-wide labeling changes for testosterone products. February 28, 2025. fda.gov
6. 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
7. U.S. Food and Drug Administration. Testosterone Information — postmarket drug safety information for patients and providers, including the TRAVERSE results and the June 2026 requested prescribing-information updates. fda.gov