Safety of Testosterone-Replacement Therapy in Older Men

Circulating levels of testosterone decline with age in men,1 and some clinical consequences of hypogonadism resemble those of normal aging: fatigue, weakness, and impaired sexual function. These outcomes have led to the reasonable hypothesis that age-related decreases in testosterone levels may cause these symptoms and that quality of life could be improved by testosterone supplementation. Although the number of older men with testosterone levels below the normal range is small,2 the past several decades have seen large increases in the number of prescriptions for testosterone, mainly for middle-aged and older men.3

Despite the large number of men receiving testosterone supplementation, data that support its efficacy and safety in treating hypogonadism have accumulated slowly. The landmark Testosterone Trials, a series of well-designed, placebo-controlled trials, provided much-needed clarity about what benefits could be expected from testosterone treatment.4 In symptomatic men who were 65 years of age or older and who had a low testosterone level (<275 ng per deciliter), 1 year of testosterone supplementation resulted in modest but significant improvements in sexual function, bone mineral density, 6-minute walking distance, depressive symptoms, and hemoglobin levels, but did not improve vitality or cognitive function. However, the Testosterone Trials were not designed to assess important safety issues. In particular, there has been concern about possible adverse effects of testosterone therapy with respect to the risk of cardiovascular events.5 The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, the results of which are now reported by Lincoff et al.6 in this issue of the Journal, was conducted primarily to address that concern.

The TRAVERSE trial was a rigorously conducted, randomized, placebo-controlled trial of transdermal testosterone in men 45 to 80 years of age who reported symptoms compatible with hypogonadism, had serum testosterone levels of less than 300 ng per deciliter, and were at high risk for cardiovascular events. The primary end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, and tertiary end points included death from any cause, hospitalization or an urgent visit for heart failure, peripheral arterial revascularization, and venous thromboembolic events. A total of 5246 men underwent randomization and were included in the analyses, with a mean duration of therapy of approximately 22 months.

A principal finding was that testosterone-replacement therapy was noninferior to placebo with respect to the primary composite safety end point; there was no appreciable difference in the incidence of major adverse cardiac events between the testosterone and placebo groups (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Moreover, there were no apparent differences in the incidence of secondary and most tertiary end-point events. However, among the men who received testosterone, there was a higher incidence of pulmonary embolism (0.9% vs. 0.5%), nonfatal arrhythmias warranting intervention (5.2% vs. 3.3%), atrial fibrillation (3.5% vs. 2.4%), and acute kidney injury (2.3% vs. 1.5%). The incidence of prostate cancer was approximately 0.4% in both groups.

The TRAVERSE trial provides strong evidence that testosterone replacement over a period of 2 years did not increase the incidence of major adverse cardiac events among older men, but questions can be raised about several aspects of the trial. First, the men enrolled were somewhat unusual because they had preexisting or a high risk of cardiovascular disease, most had obesity (the mean body-mass index [the weight in kilograms divided by the square of the height in meters] was 35.0 in the testosterone group and 34.8 in the placebo group), and the majority had diabetes. These characteristics are typical of men with low testosterone levels and cardiovascular disease, but they raise the issue of generalizability to a broader population. Second, atherosclerotic cardiovascular disease evolves over decades, and the duration of therapy in the TRAVERSE trial was relatively short. In the Testosterone Trials, 1 year of testosterone therapy was associated with an increased volume of noncalcified coronary-artery plaque, and it remains uncertain whether a longer duration of testosterone therapy would eventually elevate the risk of cardiovascular events through that mechanism or through another slowly developing effect.

Third, in the TRAVERSE trial, the increase in testosterone levels during therapy was modest; the median testosterone level in the testosterone group ranged from 326 to 386 ng per deciliter (Table S3 in the Supplementary Appendix, available with the full text of the article at NEJM.org). The Endocrine Society7 and American Urological Association8 guidelines suggest that supplementation in hypogonadal men should lead to testosterone levels in the normal range (the American Urological Association recommends a testosterone level of 450 to 600 ng per deciliter). Would supplementation to achieve these higher levels have led to different outcomes? Finally, estradiol levels were also increased by testosterone supplementation in the current trial. In the Testosterone Trials, several effects of treatment were attributed primarily to the change in estradiol levels,9 and in women, estrogen-replacement therapy has been linked to an increased risk of thrombosis.10 It will be important to examine the relationship between estradiol levels and outcomes in the TRAVERSE trial as well.

This trial fills a major gap in knowledge concerning testosterone supplementation in older men with hypogonadism who are at high risk for cardiovascular events, and it provides critical safety information for patients and providers who are faced with making decisions about testosterone replacement. At least over a 2-year treatment period, testosterone-replacement therapy appeared to impart no additional risk of major adverse cardiac events. However, the safety of longer-term therapy, the implications of supplementation to reach higher testosterone levels, and the adverse effects that appeared to be associated with this therapy must be better understood.