The T Trials, 2016: Seven Coordinated Trials in 790 Older Men

In 2016, seven coordinated trials in 790 men aged 65 and over reported together. Testosterone gel for one year produced a moderate benefit for sexual function, some benefit for mood and depressive symptoms, and no benefit for vitality or walking distance.[1] The T Trials are the closest thing the field had to a definitive answer before TRAVERSE, and their most useful feature is that they did not return a single verdict.

What the trials were

The design is the part worth understanding, because it explains why the results are quoted so inconsistently.

• Population: 790 men, 65 years of age or older, with a serum testosterone concentration below 275 ng/dL and symptoms suggesting hypoandrogenism.[1]
• Intervention: testosterone gel or placebo gel, for one year.
• Structure: each man took part in one or more of three trials — the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. Each had its own primary outcome, and each primary outcome was also evaluated across all participants.[1]

That structure is unusual, and it is why "the T Trials" is plural. There was no single primary endpoint for the programme. There were three, plus a set of further trials examining cognition, bone, anaemia and cardiovascular measures.

Treatment worked as pharmacology: testosterone raised serum levels into the mid-normal range for men aged 19 to 40.[1] Whatever the trials found, they did not fail for lack of exposure.

What improved

Sexual function was the clearest positive. The increase in testosterone was associated with significantly increased sexual activity on the Psychosexual Daily Questionnaire (P<0.001), along with significantly increased sexual desire and erectile function.[1]

Mood moved slightly. Men receiving testosterone reported modestly better mood and lower severity of depressive symptoms than men on placebo.[1]

What did not

Vitality — the trial's own word for the thing most men actually want — did not improve. On the Functional Assessment of Chronic Illness Therapy–Fatigue scale, testosterone had no significant benefit.[1]

Walking distance is the result most often misreported. In the Physical Function Trial itself, the percentage of men achieving an increase of at least 50 metres in six-minute walking distance did not differ significantly between groups. It did differ when men from all three trials were pooled — 20.5% on testosterone versus 12.6% on placebo, P=0.003.[1]

Those two sentences describe the same data and support different headlines. The trial designed to answer the physical-function question answered it negatively. A larger pooled analysis, not the trial's primary comparison, was positive. Reporting the second without the first is the standard error.

What the authors concluded

In symptomatic men 65 years of age or older, raising testosterone concentrations for one year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function, some benefit with respect to mood and depressive symptoms, but no benefit with respect to vitality or walking distance.[1]

They added a limitation that matters more in hindsight than it did at the time: the number of participants was too few to draw conclusions about the risks of testosterone treatment.[1]

That sentence is why TRAVERSE had to happen. The T Trials could characterise benefit. They could not settle safety.

The cognition result

A companion analysis published the following year examined men from the T Trials who also had age-associated memory impairment, testing whether treatment improved cognitive function.[2] It is worth reading alongside the main paper for anyone who arrived at testosterone hoping for a memory effect — and it is covered in brain fog and low testosterone.

Why the T Trials still matter

Three reasons.

1. They set the benefit expectation honestly. A treatment that reliably improves sexual function, modestly improves mood, and does nothing measurable for fatigue or walking is a narrower proposition than the marketing of the same period suggested. That framing survives into the current Endocrine Society guidance.
2. They demonstrated the pooling problem. The walking-distance result is a teaching case in why the primary endpoint of the trial that was designed for the question outranks a pooled analysis that was not.
3. They defined the gap TRAVERSE filled. Underpowered for risk, by the authors' own statement — which is exactly what the 5,246-man cardiovascular trial was built to address seven years later.

Bottom line

The T Trials are neither the vindication nor the debunking they get quoted as. In symptomatic older men with genuinely low testosterone, one year of treatment moved sexual function meaningfully, mood slightly, and vitality and walking not at all.

Anyone being told that testosterone will restore energy in an older man is making a claim the largest trial of that question, in exactly that population, tested and did not find.

References

2 sources

1. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611–624. doi:10.1056/NEJMoa1506119 · PMID 26886521
2. Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA. 2017;317(7):717–727. doi:10.1001/jama.2016.21044 · PMID 28241356