In this study of older men with low testosterone levels and limitations in mobility, random assignment to daily application of a testosterone gel, as compared with a placebo gel, was associated with a greater frequency of adverse events, particularly cardiovascular, respiratory, and dermatologic events. The divergence between the groups in the incidence of cardiovascular adverse events was maintained over the 6-month intervention period and did not diminish during the 3-month observation phase that followed the intervention period. The increased cardiovascular risk in the testosterone group was seen with all three definitions of cardiovascular events, and the increase persisted after adjustment for baseline risk factors. The increased risk was also evident in sensitivity analyses adjusted for baseline mobility status and Short Physical Performance Battery score and in sensitivity analyses performed after the exclusion of subjects whose eligibility deviated from the planned criteria. The pattern of adverse cardiovascular events associated with testosterone therapy was considered by the data and safety monitoring board to be of sufficient concern to warrant termination of the trial.
The generalizability of our data about the safety of testosterone therapy is limited by several factors. First, cardiovascular events were not a planned primary or secondary outcome, and therefore, a structured evaluation of cardiovascular events was not performed, a factor that may have influenced the ascertainment of events. Most of the cardiovascular-related events were verified from medical records or by direct examination. Second, the sample, although larger than those in most previous trials, was small, and the number of adverse events was small. The results of individual small trials may not be confirmed in large trials,28
and trials that have been stopped early tend to overestimate treatment differences. Third, the clinical characteristics of our study population differ from those of most other populations in which testosterone therapy has been administered in a clinical setting or as part of a clinical trial. Men who were younger than 65 years of age and men with severe hypogonadism were excluded from the trial. Participants had substantial limitations in mobility and a high prevalence of chronic conditions, including preexisting heart disease, obesity, diabetes, and hypertension. Frail elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease than are those who do not have limitations in mobility.29,30
Previous studies provide very limited data to either reinforce or contradict the findings in this study with respect to the effects of testosterone therapy in older men with limited mobility. Meta-analyses of previous trials of testosterone therapy have not shown significant increases in cardiovascular risk with testosterone therapy, although nonsignificant increases have been noted among participants of all ages,31–33
as well as among older men.31,33
The trials in these meta-analyses were limited by inadequate methods of ascertaining adverse events or the poor quality of data on adverse events, by the small numbers of events or the small numbers of older participants, or by intervention periods that were shorter than the 6-month intervention in this trial. Some epidemiologic studies have shown that low testosterone levels are an independent risk factor for death from cardiovascular causes and from all causes.34–37
However, differences between the effects of endogenous hormones and those of pharmacologic hormonal therapy, as well as differences in the duration of exposure to testosterone, could contribute to the apparent discrepancies between these epidemiologic data and the results of our trial.
It is not likely that the adverse cardiovascular events seen in the TOM trial are a consequence of an unusual protocol for testosterone administration (Table 4 in the Supplementary Appendix
). The upper limit of the testosterone threshold used for inclusion in the trial is not dissimilar to that used in most other trials.16–19,38–47
The testosterone doses in this trial may have been higher than those that are typically used in clinical practice48
and were higher than the doses used in some previous trials17,18,39–42
but were similar to those in other trials.16,21,43–46
The average testosterone concentrations during the intervention period among men in our testosterone group were in the middle of the normal range for young men; these levels were higher than those in some testosterone trials17,18,39–42
but did not differ from levels reported in other trials.16,19,21,43–46
The cardiovascular adverse events reported in the TOM trial were diverse and may have variable clinical importance. The lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone. The results of several separate analyses were consistent with the initial observation of a significant difference, but these analyses were not entirely independent of one another. In interpreting these findings, it is essential to recognize the role that chance may have played in the outcomes we observed.
The diversity of cardiac adverse events also renders the events less susceptible to a single mechanistic explanation. Testosterone causes salt and water retention,49–51
particularly in older men,14
and this could contribute to edema, hypertension, and congestive heart failure, although there are some trials in which testosterone has been administered in men with congestive heart failure.39,40
Testosterone and associated increases in estradiol may promote inflammation, coagulation, and platelet aggregation.52
The use of anabolic steroids has been associated with left ventricular hypertrophy and systolic and diastolic dysfunction.53,54
Changes in plasma lipid levels would not account for the rapid divergence in rates of cardiovascular adverse events.
Testosterone therapy was associated with significant improvements in leg-press and chest-press strength and in stair-climbing power with a load. Inferences regarding efficacy are limited because of the attenuation of statistical power owing to the early termination of the trial.
In conclusion, we evaluated the effect of testosterone supplementation in men 65 years of age or older who had limitations in mobility and low serum levels of total or free testosterone. The trial was stopped before enrollment had been completed because of an incidence of adverse cardiovascular events that was higher in the testosterone group than in the placebo group. However, caution is warranted in interpreting this finding, because of the small numbers of events and because of limitations with respect to the ascertainment of adverse events. Caution is also warranted in extrapolating these findings to other doses and formulations of testosterone or to other populations, particularly young men who have hypogonadism without cardiovascular disease or limitations in mobility.