Safety of Testosterone Replacement Questioned
Abstract & Commentary
By Rahul Gupta, MD, MPH, FACP
Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
Synopsis: In a study of men in the Veterans Affairs health care system with low serum testosterone levels, the use of testosterone therapy was associated with an increased risk of mortality, myocardial infarction, or ischemic stroke.
Source: Vigen R, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
Testosterone replacement therapy is widely prescribed to help reverse the effects of hypogonadism. However, the research is uncertain whether testosterone therapy would have any benefit for older men who are otherwise healthy. Widespread marketing for a condition named as "Low T" has led to a recent rapid expansion in the market for demand of testosterone replacement therapy and has often led men to believe that taking testosterone replacement may help them feel younger and more vigorous as they age. As a result, the prescribing rates of testosterone therapy have increased approximately five times over the past decade or so in the United States. Along with this booming business has been a trend to take advantage of the various pharmacokinetic properties of the drug to increase the range of testosterone preparations in the market and provide for a consumer choice as well as competition. Various marketed preparations include transdermal delivery (patches and gels), as well as oral (including buccal tablets) and parenteral (subcutaneous pellets, intramuscular) formulations. While it is recommended that patients who are treated with testosterone should be monitored regularly to determine that normal serum testosterone concentrations are being achieved, it is not always done in the clinical setting due to a variety of reasons. Similarly, it is recommended that certain other tests (such as hematocrit, and prostate cancer screening) also be conducted in most or selected patients. When administered to a hypogonadal male patient, the principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range. As a result, the patient's symptoms improve, including increases in libido, muscle strength, fat-free mass, and bone density.1 In addition to beneficial effects, testosterone replacement therapy can also have potential adverse effects, including increases in hemoglobin and hematocrit, increases in serum prostate specific antigen, and worsening of sleep apnea among others. Whether the use of testosterone replacement therapy is associated with an increased risk of cardiovascular adverse events has not been conclusively proven since little research has been done in this area and the most recent data demonstrate a varied picture.
In their study, Vigen et al conducted a retrospective cohort study of 8709 men with low testosterone levels (< 300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011. These veterans had a high existing burden of disease, with approximately 20% having a prior history of myocardial infarction (MI), 50% diabetes, and more than 80% having coronary artery disease (CAD). These 8709 patients were divided into two groups, one was placed on testosterone therapy and the other was not on such therapy. Approximately 14% (1223 veterans) were initiated on testosterone therapy. Patients who were initiated on testosterone therapy tended to be younger and have lower rates of comorbidities compared with those in the control population. These patients were prescribed varying forms of testosterone treatments, including gel, injections, and patches. The primary outcome of the study was a composite of all-cause mortality, MI, and ischemic stroke. After an average follow-up of 840 days (27.5 months), a total of 1710 events in the entire cohort was noted, including 748 deaths, 443 MIs, and 519 strokes. Of these total events at 3 years after coronary angiography, 19.9% of events occurred in the group not on testosterone therapy vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% (95% confidence interval [CI], -1.4% to 13.1%). In further analysis adjusting for the presence of CAD, testosterone therapy use as a time-varying covariate was associated with an increased risk of adverse outcomes (hazard ratio, 1.29; 95% CI, 1.04-1.58). The authors conclude their observations by stating that the use of testosterone therapy in their study cohort — which included veterans with significant medical comorbidities — was associated with an increased risk of mortality, MI, or ischemic stroke, and the findings were not modified by the presence of CAD.
The discussion surrounding the population subgroup in which testosterone replacement therapy can be used safely and appropriately is far from being concluded. While several prior studies have shown that testosterone therapy may protect against heart disease and improve mortality, they have typically been of short duration or included a smaller sample size.2 The current finding is relatively new, since only a handful of research data may have shown that the use of testosterone treatment could be associated with an increased risk of cardiovascular adverse events while a number of studies have shown either no impact or being beneficial.3 In the current study by Vigen et al, several possible mechanisms by which testosterone therapy may raise cardiovascular risk are suggested, including increasing platelet thromboxane A2 receptor density and platelet aggregation, stimulating smooth muscle proliferation and expression of vascular cell adhesion molecule 1, and worsening obstructive sleep apnea, a risk factor for atherosclerosis. However, several design weaknesses also are associated with this research, including being a retrospective study. For this reason, it is difficult to generalize the study findings or even recommend a particular patient population to whom the study results would apply. However, it is clear that prospective data from large, well-designed, long-term trials of testosterone treatment are lacking and will be required to verify the cardiovascular efficacy and safety of chronic treatment practices. However, in the interim, it is essential that prescribers take every precaution possible to be punctilious in the manner in which we prescribe these long-term medications.
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