Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

Abstract

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

Association between vitamin D deficiency and heart failure risk in the elderly

“…Of equal importance in this context of higher risk of HF in men is the strong association of andropause with vitamin D deficiency, which can justify this high risk, considering the positive relationship between vitamin D and testosterone levels, as reported in the literature 29. Especially important is the protective effect that testosterone plays on the myocardium, reducing the risk of heart disease and mortality 30. Thus, male seniors in this study are significantly at increased risk of vitamin D deficiency, HF, and higher prevalence of andropause.…”

Adaptation to acute coronary syndrome-induced stress with lowering of testosterone: a possible survival factor

“…Even if there is some supportive exprimental data (19), the causality between testosterone levels and CVD remains elusive. During the past 4 years, several independent studies, published in prestigious journals, have shown men treated with testosterone to have increased amount of cardiovascular symptoms (2, 3, 4, 5, 6), which has created heated debate around the testosterone vs CVD issue (20,21).…”

Testosterone and the Heart

“…11 The severity of CAD has also been investigated as a function of serum T concentrations. Four studies have noted an inverse relationship between serum T levels and CAD severity, 6 with lower levels of serum T associated with more severe CAD and higher serum T levels associated with reduced severity. 11 However, these results should be interpreted with caution due to the relatively small sample size included in each study.…”

“…Many studies have indicated that low serum T concentrations are associated with increased CV risk and mortality and that TRT may have clinically relevant CV benefits. 6 Two recent observational studies reported increased CV risks in men who received testosterone prescriptions. 17,18 Although they gained a significant amount of media attention, neither study provided credible evidence of increased CV risk.…”

“…Interpretation of total T concentrations is confounded by variation between individuals, variation in serum SHBG, and variation in androgen sensitivity. 6 Furthermore, considerable controversy has arisen regarding the accuracy of currently available commercial testosterone assays, especially those showing T levels at the lower end of the "normal" range. 4 Free testosterone level may be a more reliable indicator of androgen status, but more studies are needed to confirm this.…”