Testosterone concentrations in men decrease with increasing age. Many symptoms and conditions similar to those that are caused by low testosterone levels in men with pituitary or testicular disease become more common with increasing age. Such symptoms include decreases in mobility, sexual function, and energy. These parallels suggest that the lower testosterone levels in older men may contribute to these conditions. Snyder et al. report the findings of the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial — the three main trials in the Testosterone Trials — in the February 18, 2016, issue of the New England Journal of Medicine.
In this study, men 65 years of age or older with low serum testosterone and symptoms of hypoandrogenism received testosterone or placebo for a year. Testosterone had a moderate benefit in sexual function and some benefit in mood but no benefit in vitality or walking distance. A new Original Article summarizes.
• What findings led to the Testosterone Trials?
Previous trials of testosterone treatment in men 65 years of age or older have yielded equivocal results. Although testosterone treatment consistently increased muscle mass and decreased fat mass, effects on physical performance, sexual function, and energy have been inconsistent. In 2003, an Institute of Medicine panel concluded that there was insufficient evidence that testosterone treatment was beneficial in older men and recommended a coordinated set of clinical trials to determine whether testosterone would benefit older men who had low testosterone levels for no known reason other than age and who had clinical conditions to which low testosterone might contribute. The Testosterone Trials are a coordinated set of seven double-blind, placebo-controlled trials designed to implement this recommendation.
• Are the results of the Testosterone Trials widely generalizable?
In the studies by Snyder et al., eligibility criteria included an age of 65 years or older and serum testosterone levels that averaged less than 275 ng per deciliter. The participants had relatively high rates of coexisting conditions: 62.9% were obese, 71.6% had hypertension, and 14.7% had a history of myocardial infarction. A major limitation of these trials, albeit intentional, is that the results apply only to men 65 years of age or older whose testosterone levels averaged less than 275 ng per deciliter.
Morning Report Questions
Q: What does testosterone treatment improve in older men?
A: In the trials by Snyder et al., men who received testosterone reported better sexual function, including activity, desire, and erectile function, than those who received placebo. Although the effect sizes were low to moderate, men in the testosterone group were more likely than those in the placebo group to report that their sexual desire had improved, which suggests that this effect was of clinical relevance. The percentage of men whose 6-minute walking distance increased by at least 50 m did not differ significantly between the two study groups in the Physical Function Trial. Among men enrolled in the Vitality Trial, testosterone treatment showed no significant benefit over placebo with respect to vitality, as determined by an increase of at least 4 points in the Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score (primary outcome) (odds ratio, 1.23; P=0.30). However, testosterone was associated with small but significant benefits with respect to mood and depressive symptoms.
Table 1. Sexual Function Trial Outcomes.
Table 2. Physical Function Trial Outcomes.
Table 3. Vitality Trial Outcomes.
Q: What was concluded from the Testosterone Trials about the risks associated with testosterone treatment in older men?
A: In the Testosterone Trials, the number of participants was too few to draw conclusions about the risks of testosterone treatment. The authors observed four cases of prostate cancer, three of which were in men treated with testosterone, and there was no significant difference in urinary symptoms (as assessed by means of the IPSS) between the study groups. The generalizability of these results is limited, however, because the study excluded men with a high risk of prostate cancer and men with moderately severe urinary tract symptoms. Furthermore, the sample size was inadequate to assess reliably the effect of testosterone on the risk of these conditions. Some studies have suggested that testosterone treatment is associated with increased cardiovascular risk, although others have not. The authors did not observe a pattern of increased risk, but this trial was too small to exclude other than a large increase.