Testosterone therapy improved sexual function, not energy. Then it broke more bones.

The largest randomised trials of testosterone treatment in men with low levels found a moderate benefit for sexual function, some benefit for mood, and no benefit for vitality or walking distance. A later trial of 5,246 men designed specifically to test cardiovascular safety found no excess of heart attacks, strokes or cardiovascular deaths — and, in its fracture subtrial, more broken bones in the men taking testosterone than in those taking placebo. That combination is the whole picture, and it is not the one the marketing describes.

What the treatment did

The Testosterone Trials, published in the New England Journal of Medicine in 2016, assigned 790 men aged 65 or older with a serum testosterone concentration below 275 ng/dL and symptoms suggesting hypoandrogenism to receive testosterone gel or placebo gel for one year [s1]. Each man took part in one or more of three trials — the Sexual Function Trial, the Physical Function Trial and the Vitality Trial — and each trial's primary outcome was also assessed in all participants [s1].

Treatment raised serum testosterone to the mid-normal range for men aged 19 to 40 [s1]. That increase was associated with significantly increased sexual activity on a daily questionnaire (P < 0.001), along with increased sexual desire and erectile function [s1].

The other two questions came back differently. In the Physical Function Trial, the proportion of men achieving an increase of at least 50 metres in six-minute walking distance did not differ significantly between groups; the difference reached significance only when men from all three trials were pooled, at 20.5% on testosterone against 12.6% on placebo (P = 0.003) [s1]. On vitality, measured with a validated fatigue scale, there was no significant benefit at all [s1]. Men on testosterone reported slightly better mood and lower severity of depressive symptoms [s1].

The trial's own conclusion is worth reading exactly: raising testosterone from moderately low to the mid-normal range for a year gave a moderate benefit for sexual function, some benefit for mood and depressive symptoms, and no benefit for vitality or walking distance [s1]. The authors also state that the number of participants was too few to draw conclusions about the risks [s1].

The safety trial that was built to answer that

TRAVERSE enrolled 5,246 men aged 45 to 80 who had preexisting cardiovascular disease or were at high risk of it, reported symptoms of hypogonadism, and had two fasting testosterone measurements below 300 ng per decilitre [s3]. They were randomly assigned to daily transdermal 1.62% testosterone gel, dose-adjusted to keep levels between 350 and 750 ng per decilitre, or to placebo gel [s3]. Mean treatment duration was 21.7 months and mean follow-up 33.0 months [s3].

The primary endpoint — cardiovascular death, non-fatal myocardial infarction or non-fatal stroke — occurred in 182 men (7.0%) on testosterone and 190 (7.3%) on placebo, a hazard ratio of 0.96 (95% CI 0.78 to 1.17), meeting the trial's prespecified non-inferiority threshold [s3]. Secondary endpoints and the individual components looked similar between groups [s3].

That is a genuine reassurance on the question that had hung over the drug class for a decade, and it is bounded in ways worth naming. The trial tested one formulation, in men who met a specific biochemical and symptomatic definition, at doses titrated into a target range, for a mean of under two years. It was funded by AbbVie [s3]. And it was a non-inferiority trial: it was designed to show testosterone was not meaningfully worse than placebo, not that it was better.

TRAVERSE also recorded a higher incidence of atrial fibrillation, acute kidney injury and pulmonary embolism in the testosterone group [s3].

The fracture result nobody expected

Testosterone improves bone density, so a fracture subtrial was included on the reasonable assumption it would show fewer fractures. It showed the opposite. Among 5,204 men in the full-analysis population — 2,601 on testosterone and 2,603 on placebo — a clinical fracture occurred in 91 men (3.50%) on testosterone and 64 (2.46%) on placebo after a median 3.19 years, a hazard ratio of 1.43 (95% CI 1.04 to 1.97) [s2]. Fracture incidence appeared higher in the testosterone group for every other fracture endpoint measured as well [s2].

The paper does not claim to have found a mechanism, and its conclusion is stated carefully: testosterone treatment did not result in a lower incidence of clinical fracture than placebo, and the incidence was numerically higher [s2]. A hazard ratio whose lower bound is 1.04 is a result that would not survive much perturbation. But it is the direction of surprise that matters — a subtrial designed to confirm a benefit found the reverse.

Who this evidence is about

Every result above comes from men who met a definition. The American Urological Association's guideline sets a total testosterone below 300 ng/dL as a reasonable diagnostic cut-off, requires two measurements taken on separate occasions and both in the early morning, and states that the clinical diagnosis of testosterone deficiency is made only when low levels are combined with symptoms or signs [s4]. The guideline notes that a series of randomised trials it reviewed used a cut-off of below 350 ng/dL for entry, and that across those studies the median baseline total testosterone was 249 ng/dL, with an interquartile range of 233 to 283 ng/dL [s4].

None of these trials tested testosterone in men whose levels were normal. What the treatment does to a man with a testosterone of 500 ng/dL who feels tired is not a question the randomised literature has answered, because that man was excluded from it.

This article is informational and is not medical advice. Decisions about testing or treatment belong with a reader and their clinician.

Sources

• Effects of Testosterone Treatment in Older Men — New England Journal of Medicine, 2016-02-17
• Testosterone Treatment and Fractures in Men with Hypogonadism — New England Journal of Medicine, 2024-01-17
• Cardiovascular Safety of Testosterone-Replacement Therapy — New England Journal of Medicine, 2023-06-16
• Evaluation and Management of Testosterone Deficiency: AUA Guideline — American Urological Association, 2018