Testosterone Replacement Therapy – cpt.sagepub.com

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

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.

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