Hypogonadism and Testosterone Therapy

Abstract

Testosterone replacement therapy (TRT) use is increasing, primarily in men with symptomatic hypogonadism. There are many benefits associated with TRT use, including improved sexual function, improved bone mineral density, and increased free fat mass and strength. As TRT use increases, its role on cardiovascular health must be explored. While previous evidence identified no adverse cardiovascular risks associated with TRT use, more recent studies suggest that there may be an associated risk, especially in elderly men and younger men with cardiac disease. Care must be taken with TRT use in these groups of men by careful monitoring for cardiac dysfunction. While testosterone therapy has many benefits and may generally be well tolerated, those prescribing the therapy must be cognizant of the potential adverse cardiovascular risks and advise men on the potential risks versus benefits.

Introduction

Testosterone therapy is being used for patients who suffer from symptomatic testosterone deficiency. The Food and Drug Administration defines hypogonadism as testosterone levels <300 ng/dL. The American Society of Andrology recommends that men with testosterone levels <230 ng/dL with symptoms may require replacement therapy (Mehta & Paduch, 2013). Symptomatic hypogonadism is defined as the presence of low libido, erectile dysfunction, osteoporosis, or two or more of the following symptoms: sleep disturbance, depressed mood, lethargy, or diminished physical performance (Mehta & Paduch, 2013). Testosterone replacement in these men has several beneficial effects including improved sexual function, improved bone mineral density, and increased free fat mass and strength (Vigen et al., 2013). The prescription of testosterone for men has been increasing worldwide. In fact, prescription totals have increased 12 fold globally from 2000 to 2011 (Handelsman, 2013).

The prevalence of low testosterone levels in men is gradually increasing from 20% to 50% in the sixth to ninth decades of life (Fernández-Balsells et al., 2010). As testosterone use becomes more widespread, it raises concern regarding the effects of testosterone replacement therapy (TRT) on cardiovascular health. While there are currently no Food and Drug Administration warnings regarding TRT’s use and adverse cardiovascular events, recent evidence suggests that adverse side effects may exist. It is even more worrisome given that some prescriptions for testosterone are written without levels being checked. In fact, up to one quarter of prescriptions are issued without any determination of the testosterone level (O’Conner, 2014). As testosterone becomes more widespread, it is important to determine the true risks to patients.

Low Endogenous Testosterone Increases Cardiovascular Risk

Early studies of testosterone therapy in men did not demonstrate adverse cardiovascular outcomes. In fact, several studies have suggested that a low level of endogenous testosterone is associated with cardiovascular disease (English, Mandour et al., 2000; Hak et al., 2002). Multiple studies have shown that the severity of coronary artery disease (CAD; English, Mandour et al., 2000; Zhao & Li, 1998), congestive heart failure (Jankowska et al., 2006), type 2 diabetes, and obesity are associated with lower levels of endogenous testosterone compared with healthy controls (Oskui et al., 2013). In a case-control study with 11,606 men, Khaw et al. (2007) prospectively examined the relationship between endogenous testosterone concentrations and mortality due to all causes, including cardiovascular disease and cancer. They reported that endogenous testosterone concentrations were inversely related to mortality due to all causes. In another prospective analysis of 794 men between ages 50 and 91 years, Laughlin, Barrett-Connor, and Bergstrom (2008) reported increased cardiovascular risk associated with low testosterone with hazard ratio 2.29 (1.25-4.20) after 11.8 years’ follow-up.

TRT Is Associated With Decrease in Cardiovascular Risk

The effects of exogenous testosterone, or TRT, have been reported to be beneficial. TRT in men with hypogonadism and CAD has been reported to increase time to 1mm ST-segment depression with stress testing (Webb, Adamson, de Zeigler, & Collins, 1999) and has been reported to cause coronary artery vasodilation (Webb, McNeill, Hayward, de Zeigler, & Collins, 1999). A double-blinded randomized placebo-controlled trial by English, Seeds, Jones, Diver, and Channer (2000), reported reduction in exercise-induced myocardial ischemia with no significant changes in lipid or coagulation profile with TRT. A retrospective Veterans Affairs study by Shores, Smith, Forsberg, Anawalt, and Matsumoto (2012) concluded that those treated with testosterone had a lower mortality rate compared with those who were not (10.3% vs. 20.7%, p < .0001). And lastly, those men with diabetes, a known risk factor for life expectancy, with lower serum testosterone levels had worse all-cause mortality (Muraleedharan, Marsh, Kapoor, Channer, & Jones, 2013). In a randomized, double-blinded, placebo-controlled parallel trial of 76 men with heart failure, men treated with TRT (5 mg Androdrem) had an improvement in exercise capacity and symptoms from baseline compared with placebo (p = .006; Malkin et al., 2006).

Meta-analyses following these studies recapitulated similar conclusions and reported no significant increase in cardiovascular risk with TRT (Calof et al., 2005; Fernández-Balsells et al., 2010; Haddad et al., 2007). One such meta-analysis studied 51 comparative, randomized and nonrandomized trials and reported no significant effect on cardiovascular outcomes, including myocardial infarction, coronary revascularization procedures, or arrhythmias. However, they did note that it was associated with increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein (Fernández-Balsells et al., 2010). Another meta-analysis by Calof et al. (2005) analyzed 19 randomized placebo-controlled trials, which included 651 men older than 45 years undergoing treatment with TRT or placebo for greater than 90 days. The authors did not find any statistically significant differences in rates of myocardial infarction, chest pain, atrial fibrillation, coronary artery bypass grafts, and vascular, cerebrovascular events between TRT and placebo groups. However, the study reported that there was a significant rise in hematocrit (>50%) in the testosterone treated group with odds ratio (OR) of 3.69 (1.82-7.51). Haddad et al. (2007) analyzed six placebo-controlled randomized trials of 308 men undergoing treatment with placebo or TRT. Adverse cardiac events included death, myocardial infarction, angina, arrhythmia, revascularization, and stroke (Haddad et al., 2007; Oskui et al., 2013). They reported no significant difference in rates of events between TRT and placebo-treated groups, with OR 1.82 (.78-4.23).

While these early studies seem to indicate that TRT does not cause adverse cardiac events, there are several criticisms. The quality of the evidence included in these meta-analyses was variable. There was marked heterogeneity in terms of what constituted cardiovascular events in the studies. Additionally, the duration of the trials was often short, and therefore lacks long-term insight into the safety of the treatment (Vigen et al., 2013).

TRT Can Be Associated With Adverse Cardiovascular Events

Contrary to the previous studies, more recent studies seem to suggest there is an increase in adverse cardiovascular events associated with TRT. A study by Basaria et al. (2010), Testosterone in Older Men with Mobility Limitations (TOM trial), was a placebo-controlled randomized trial that enrolled older men with lower levels of testosterone to evaluate the effects of testosterone administration on lower extremity strength and physical function. It is currently the only randomized controlled trial evaluating the cardiovascular risks associated with TRT. The trial enrolled 209 men to evaluate the safety of a 100-mg testosterone gel patch. The trial was stopped early because 23 patients in the testosterone group suffered more than one adverse cardiovascular event in comparison with the 7 in the placebo group. The adverse events reported include acute coronary syndrome, chest pain, syncope, myocardial infarction, angioplasty, coronary artery bypass graft, atrial fibrillation, and stroke. During the course of the study, the testosterone-treated group had higher risk of cardiovascular-related events after 6 months of treatment. However, the study was small and the population was unique, making it difficult to make broad inferences. The men had a mean age of 74 years, and a majority of them suffered from chronic diseases, such as diabetes, hypertension, hyperlipidemia, and heart disease. While the majority of baseline characteristics were similar, there were a greater proportion of men in the testosterone-treated group that had a diagnosis of hyperlipidemia compared with placebo.

While the generalizability of the TOM trial is questionable, its early termination still raises concern regarding the association between cardiovascular risk and TRT. A recent retrospective analysis by Vigen et al. (2013) studied cardiovascular events with TRT in a national cohort of veterans with hypogonadism who underwent coronary angiography. The men were older than 60 years, and 80% of them had documented coronary disease. The study assessed the association between TRT and all-cause mortality, myocardial infraction, and stroke (Vigen et al., 2013). Among the 8,709 participants, the study concluded that there was an absolute risk increase of 5.8% (p < .05) of adverse cardiovascular events in the TRT group compared with placebo. The researchers did note several limitations of their study, including the retrospective design, lack of randomization, possible variability in testosterone level measurements, and small group of patients with extended follow-up. Additionally, it is unclear whether or not testosterone was prescribed appropriately and why some men with low testosterone level were treated while others were not. This raises the issue of whether the men treated with testosterone were more symptomatic and therefore more likely to have an underlying cardiovascular condition. Furthermore, the largest issue is the generalizability of the study. Most of the men were elderly and had documented CAD and therefore were already at a high risk for cardiovascular events. This makes it difficult to apply the results of this study to other groups of men and determine whether the increased risk applies to them and whether the benefits of TRT outweigh these risks.

While the previous meta-analyses did not report significant increases in cardiovascular risk, they did note nonsignificant increases in risk (Calof et al., 2005; Fernández-Balsells et al., 2010; Haddad et al., 2007). A more recent meta-analysis by Xu, Freeman, Cowling, and Schoolin (2013) et al. of placebo-controlled randomized trials included a larger number of participants (2994), mostly elderly men, compared with the previous meta-analyses. This study concluded that there was a statistically significant increase in cardiovascular-related events in men with TRT lasting 12 or more weeks, with OR 1.54 (p < .05; Xu et al., 2013). Interestingly, they identified that the risk of adverse events with testosterone therapy was higher in studies not funded by the pharmaceutical industry compared with those that were.

A recent cohort study by Finkle et al. (2014) examined the risk of myocardial infarction following the initiation of testosterone therapy in 55,593 young and old men. They determined that there was a significant increased risk of myocardial infarction following TRT in older men (>65 years) with a relative risk increase of 2.19 (1.27-3.77) and in younger men (<65 years) with prediagnosed heart disease, with relative risk 2.9 (p < .05), within the 90 days following initiation of TRT. They reported no increased risk in men less than 65 without heart disease. One particular limitation of this study was that serum testosterone was not collected, making it difficult to determine whether or not patients were eugonadal while on the therapy. Additionally, the control group in this study consisted of patients who were prescribed phophodiesterase inhibitors for erectile dysfunction. Recent data suggest that these drugs, given their vasodilatory action, may have cardioprotective effects and may serve as potential therapy for myocardial infarction, ischemic injury, and heart failure (Kukreja et al., 2011). Therefore, it is possible that the control group’s risk of cardiovascular events was reduced by the drug.

While the Vigen et al. (2013) and Finkle et al. (2014) studies have suggested increased risk associated with TRT, several issues should be considered before accepting this conclusion. Neither of the studies measured levels of estrogen, which could have increased because of aromatase-mediated conversion of testosterone. Some subgroups of men, primarily those with increased abdominal fat, may have increased aromatase activity, causing increased conversion of testosterone to estrogen. Estrogen itself is known to increase cardiovascular risk (Lerchbaum et al., 2011; Sudhir & Komesaroff, 1999). Testosterone itself can increase hematocrit levels, which can increase risk of thrombosis, and neither study measured hematocrit levels of the patients (Marchioli et al., 2013). As previously mentioned, not all patients had follow-up testing in either of the two studies, making it difficult to determine if testosterone levels were therapeutic. This is a concern because supraphysiologic levels of testosterone can induce oxidative damage and endothelial dysfunction. Finally, dihydrotestosterone, a potent testosterone derivative, was not measured in either of the studies, which itself has been shown to contribute to atherosclerosis (Death et al., 2004). If dihydrotestosterone levels were too high, patients may have benefited from a 5-alpha reductase inhibitor (Smith, n.d.). Other than the TOM trial, there are still no other randomized clinical trials with a primary end point of establishing adverse cardiovascular outcomes of TRT. Definitive assessment of the long-term effects of TRT on cardiovascular health will require larger randomized clinical trials in which cardiovascular events are the primary outcomes. However, based on the studies previously discussed, it is possible that cardiovascular risk may be associated with testosterone therapy. A current, large, ongoing trial, Effects of Testosterone Replacement on Atherosclerosis Progressions in Older Men with Low Testosterone Levels, will be crucial in providing this much needed data.

Conclusion

Administration of testosterone therapy may prove to be a careful balancing act. There is a large body of evidence from earlier studies that have demonstrated low testosterone is associated with adverse cardiovascular risk factors, and that TRT is associated with cardiovascular benefits. Several recent studies are suggesting that testosterone supplementation may in fact be associated with adverse events. While these recent studies certainly do not disprove prior data, their conclusions warrant caution when prescribing testosterone and emphasize the need for additional investigation. Clearly the role of testosterone in men remains to be further defined.