Testosterone Replacement Therapy

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New Data on Efficacy and Cardiovascular Safety

One of the most controversial questions in cardiovascular pharmacology is whether testosterone replacement therapy is safe for the cardiovascular system, especially in elderly men. There is little debate that as men age, their testosterone levels fall and low testosterone levels have an association with more atherosclerosis, coronary artery disease, and heart failure. A key debated question is whether the administration of exogenous testosterone to increase testosterone levels back to normal alters the incidence of adverse cardiovascular events. In recent papers in the Journal of the American Heart Association,1,2Journal of the American College of Cardiology,3 and Sexual Medicine Reviews,4 my colleagues and I have reviewed the numerous studies on this subject. This literature presents some of the most controversial group of papers that I have reviewed, with some studies suggesting that testosterone use is associated with an increase in adverse cardiac events including major adverse cardiac events (cardiovascular death, myocardial infarction, stroke), whereas others suggest just the opposite. The problem is that many of these studies are observational, the testosterone preparations vary, not all studies have followed up the testosterone levels once therapy is started, some studies included soft end points to describe the adverse cardiac events, the cardiac events were not prespecified as the primary outcome, the duration of follow-up was short, the baseline characteristics of the patients were very heterogeneous with varying degrees of underlying risk factors, and other issues that we have described. The only way this issue will ever truly be resolved is for a large prospective, randomized, blinded, long-term study to be carried out with major adverse cardiac events as the primary end point. It is my understanding that an industry consortium is developing such a protocol. However, it will be many years before data are available. In the meantime, the Food and Drug Administration has released new restrictions on the labeling for testosterone replacement therapy, as recently described.3

Although testosterone is known to be effective in patients with primary hypogonadism, the significance of the low testosterone associated with aging has been debated. There are mixed data suggesting that in these types of patients, testosterone replacement may improve sexual functioning (improved libido and erectile function), improve muscle mass, decrease fat mass, improve muscle strength, and perhaps improve mood and energy level.

The Testosterone Trials, sponsored by the National Institutes of Health, were conducted to help clarify the confusing literature on testosterone replacement therapy, and the data from these clinical trials are now emerging.5 These studies may answer some of the unresolved issues surrounding testosterone replacement therapy. They consist of 7 double-blinded, Placebo-controlled, interlinked multicenter studies in which men who were 65 years and older with serum testosterone levels that averaged <275 ng/dL were randomized to testosterone gel versus placebo gel for 1 year, with efficacy assessment at baseline and then every 3 months for 1 year. Results from 3 of these trials were recently reported. To be eligible for the Sexual Function Trial, men had to report decreased libido on questionnaires; to be eligible for the Physical Function Trial, men had to report difficulties walking or climbing stairs; and to be eligible for the Vitality Trial, men had to report low vitality on a questionnaire. The preparation of testosterone used was AndroGel at 5 g daily. Serum concentrations of testosterone were measured throughout the study. The primary outcome for the Sexual Function Trial was change from baseline on a questionnaire regarding sexual activity; secondary outcomes were changes in score in erectile function and sexual desire domains. For the Physical Function Trial, the primary outcome was percentage of men who improved their 6-minute walk tests by at least 50 m, and the secondary outcome was percentage of men who improved their physical function domain on a questionnaire. For the Vitality Trial, the primary outcome was percentage of men who improved their score for fatigue on a questionnaire by more than 4 points, and secondary outcomes were other improvements from baseline in questionnaires dealing with fatigue and depression. In addition, the patients were asked every 3 months about their own impressions regarding changes in sexual desire, ability to walk, and level of vitality. In the February 18, 2016 issue of the New England Journal of medicine, the first outcome paper from the Testosterone Trials Investigators was published by Snyder et al,5 which has provided important new information on the efficacy and safety of testosterone in 790 older men who participated in 1 of the 3 main Testosterone Trials as described above. Of note, at baseline, many of the men were obese, had hypertension, and 14.7% had histories of myocardial infarctions. The testosterone treatments did increase testosterone concentrations to the normal range for younger men. As determined by the Psychosexual Daily Questionnaire, question number 4, testosterone replacement therapy significantly increased sexual activity, and it also improved libido and erectile function. In the Physical Function Trial, men who took testosterone did not significantly increase their 6-minute walk time by at least 50 m. However, when combining men who participated in all 3 of the trials, testosterone replacement therapy was associated with a significant increase in the percentage of men who achieved an increase in their 6-minute walk times by at least 50 m (20.5% vs 12.6%; P = .003). The primary end point of an improvement in vitality on a questionnaire by more than 4 points was not achieved in the Vitality Trial; but when combining all 3 trials, testosterone was associated with an increase in score for vitality compared to baseline. Men on testosterone reported slightly better moods and less depression than those on placebo.

Importantly and in contrast to some of the recent reports that have caused concern about the use of testosterone,68 there was no signal for an increase in adverse cardiovascular events in the testosterone group. There was 1 myocardial infarction in the placebo group and 2 in the testosterone group; there were 5 strokes in each group; and there was 1 death from cardiovascular causes in the placebo group and 0 in the testosterone group. In total, there were 7 patients in the placebo group and 7 patients in the testosterone group who had a myocardial infarction, stroke, or death from cardiovascular causes. There were 7 deaths from any cause in the placebo group and 3 in the testosterone group. Although more men in the testosterone group had a prostate-specific antigen level of 1.0 ng/ml or higher during the study, only 1 participant, who was in the testosterone group, was diagnosed with prostate cancer during therapy; 3 more developed it during the following year (2 in the testosterone group and 1 in the placebo group). As expected and as seen in many other studies, the use of testosterone was associated with a hemoglobin level of 17.5 g/dL or more in 7 men but none in the placebo group. Although the authors conclude that the number of patients in the study was too low to draw conclusions about the risk of testosterone replacement therapy, it is at least reassuring that no signal for an increase in adverse cardiovascular events was detected. However, larger studies will be needed to definitively rule out any adverse effects of testosterone on the cardiovascular system. It is likely that additional safety data will emerge from the Testosterone Trials Investigators studies. These investigators are to be congratulated on a study that uses a well-designed systematic approach to assess and show the effectiveness of testosterone replacement therapy on multiple domains in a well-defined patient population. Hopefully, this will be one of several reports from this important group of studies, which helps to clarify the therapeutic role of testosterone replacement therapy.

Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr Kloner is a consultant to Abbvie, TesoRx, and Lipocine.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.