Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Corona G, Maseroli E, Rastrelli G, et al. Expert opinion on drug safety. Oct 2014;13(10):1327-1351.

Accumulating evidence shows beneficial effects of testosterone therapy on a wide range of health outcomes, including inflammation, insulin sensitivity, muscle mass, body fat mass, lipid profiles, endothelial function, bone mineral density, energy and vitality, mood, sexual function and overall quality of life.^1-9 Despite this, concerns have been raised that testosterone therapy could have detrimental effects on cardiovascular disease.

This editorial summarizes results from a comprehensive systematic review and meta-analysis, the largest to date, of all placebo-controlled randomized clinical trials (RCTs) on the effect of testosterone therapy on cardiovascular-related problems.¹⁰

The notion that testosterone is "bad for the heart" arose from the well documented simple observation that heart diseases are more prevalent in men than in women.^11-18 Acute coronary heart disease and ischaemic stroke events appear approximately 10 years earlier in men than in women, and these rates remain higher in men than in women in all age groups.¹¹ More men are living with and dying of coronary heart disease than women, and have more hospital discharges for cardiovascular diseases, and the prevalence of coronary heart disease is higher in men within each age stratum.¹⁹ These observations contributed to the perception that heart disease is a “man’s disease”.¹⁹

A recent analysis found that the age-standardized risk of death from cardiovascular diseases is 80% higher for men (442/100 000) than for women (246/100 000).¹² Because men have higher testosterone, it was automatically assumed that testosterone may be the culprit. Further support for this notion comes from case reports of sudden cardiovascular death amongst male athletes abusing anabolic steroids (which are synthetic compounds similar to testosterone)^20-24, and observations that testosterone dose-dependently increases hematocrit^25,26 and reduces HDL-cholesterol at supra-physiological levels.^27-29

However, longitudinal observational studies demonstrate that it is reduced, rather than increased testosterone levels, which are associated with elevated risk of cardiovascular disease, cardiovascular mortality and all-cause mortality.^30,31 This can be explained by the well documented strong associations of hypogonadism with a number of cardiovascular risk factors, including adiposity and increased waist circumference, insulin resistance and type 2 diabetes mellitus, hypertension and inflammation.^32-37
In line with this, androgen deprivation therapy for prostate cancer causes worsening of these risk factors and co-morbidities³⁸, and a growing body of research demonstrates that testosterone therapy improves them.^1-9,39 This indicates that hypogonadism is causally related to disease development and progression.

The results from the comprehensive systematic review and meta-analysis presented here show that testosterone therapy is not related to any increase in cardiovascular risk, and that it may have a protective effect on cardiovascular risk in men with metabolic derangements.¹⁰ This conclusion is based on an analysis of the largest number of studies collected so far, which clearly refutes the previously purported causal role between testosterone therapy and cardiovascular events.

A strength of this meta-analysis is that its principal outcome was the effect of testosterone therapy, as compared with placebo, on the incidence of new major adverse cardiovascular events (MACE).¹⁰ A previous meta-analysis, which concluded that testosterone therapy increased the risk of cardiovascular-related events⁴⁰, included many events which are not typically considered for the assessment of cardiovascular risk (e.g., peripheral edema, self-reported syncope etc.). This can be grossly misleading due to the limited reliability of diagnostic criteria used to attribute these events as drug-related. It should be recognized that the use of MACE, instead of a broader ambiguous definition of cardiovascular side effects, has the advantage of a clearer diagnostic definition and precise diagnosis, which is less dependent on investigators’ subjective opinions. Therefore, the assessments of cardiovascular safety of any therapy should be based on the incidence of MACE, which are easier to detect and less controversial in diagnosis. It should be underscored that regulatory agencies assessing the safety of drugs require analyses of MACE and not of broadly defined cardiovascular side effects.⁴¹

This meta-analysis also did not observe any sponsorship bias, because no difference in cardiovascular risk was found when the analysis was performed according to the presence or absence of drug company funding.¹⁰ This is also in contrast to the meta-analysis just mentioned, which reported that the effects of testosterone on cardiovascular-related events varied with source of funding.⁴⁰

Comparison to previous meta-analyses

As of this writing, only one previous meta-analysis concluded that testosterone therapy increases the risk of cardiovascular-related events.⁴⁰ However, this meta-analysis has been criticized on several grounds. The authors specifically included only studies in which cardiovascular events were reported; therefore studies without any cardiovascular events were excluded. Importantly, two studies were included that were performed with off-label use of the respective testosterone preparation^42,43 and one study used a non-approved preparation of testosterone (oral micronised testosterone) which resulted in supraphysiologic serum testosterone levels reaching as high as 745 nmol/L (21 486 ng/dl), which is about 20 times the upper limit of normal.⁴⁴ Since oral forms of testosterone may cause liver toxicity (comment: this only proven for the 7α-methylated testosterone preparations) it is no surprise that such markedly supraphysiologic testosterone would be harmful, especially in a study population of patients with liver cirrhosis.⁴⁴

These three studies accounted for 39% of events in the testosterone treated group and 18% in the placebo group.⁴⁴ After excluding them from the analysis, there would have been a similar rate of events among testosterone and placebo groups; 70/1570 (4.5%) events in the testosterone group and 53/1001 (5.3%) events in the placebo group.

Notably, results from three other large meta-analyses which included a more representative set of studies, and that specifically focused on identifying potential adverse effects of testosterone treatment, are in line with the conclusions from the most recent meta-analysis reported here; none of them found increased cardiovascular risks with testosterone therapy versus placebo.^45-47 More specifically, their conclusions were:

• The frequency of cardiovascular events, sleep apnea or death is not significantly different between the testosterone and placebo treated groups.⁴⁵
• Currently (as of 2007) available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects.⁴⁷
• There is no significant negative effect of testosterone therapy on mortality, prostate, or cardiovascular outcomes.⁴⁶

Supporting data from other studies

Multiple other lines of evidence concur with the conclusions in this meta-analysis. Two notable studies demonstrated that testosterone therapy decreases mortality compared with no testosterone treatment⁴⁸, and improves survival in hypogonadal men with type 2 diabetes.⁴⁹ Further support comes from The MrOS (Osteoporotic Fractures in Men) study which after a 5-year follow-up found that an apparent threshold of ≥550 ng/dL (approximately 19 nmol/L) needs to be reached in order to reduce risk of cardiovascular events.⁵⁰ In this study, men in the highest quartile of testosterone (≥550 ng/dL) had a 30% lower risk of cardiovascular events (hazard ratio: 0.70) compared with men in the 3 lower quartiles, where no protective effect was noted.⁵⁰ This association remained after adjustment for traditional cardiovascular risk factors and was not materially changed in analyses excluding men with known cardiovascular disease at baseline.⁵⁰

Additional support refuting the notion that testosterone therapy would be pro-atherogenic comes from a notable recent dose-response study which assessed the effects of graded doses of testosterone on serum markers of oxidative stress, chemotaxis, adhesion, and inflammation in healthy younger and older men.51 Weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate were administered for 20 weeks in 121 eugonadal men (n = 61, 18-35 years of age and n = 60, 60-75 years of age). No significant linear associations were observed between testosterone dose and MCP-1 (chemokine monocyte chemotactic protein-1), sICAM-1 (soluble intracellular adhesion molecule-1), or hs-CRP (high-sensitivity C-reactive protein) (all p-trend >0.20).⁵¹ Also, levels of the oxidative stress marker 8-isoprostane PGF2-alpha (8-iso-PGF2-alpha) were not negatively impacted.⁵¹ As MCP-1⁵², sICAM-1⁵³ and hs-CRP⁵⁴ are atherogenic markers which independently predict risk of cardiovascular disease or acute myocardial infarction, the results from this study are strongly congruent with the conclusions that testosterone therapy does not increase atherosclerosis.

Reflections

A few flawed studies of epidemiological observations induced an epidemic of sensational and misleading media coverage and false claims alleging potential dangerous effect of testosterone therapy on the cardiovascular system.^55,56 Over the past year popular press headlines have purported that testosterone therapy is associated with serious cardiac hazards. However, as outlined here, results from RCTs, which are gold standard in medical research, show that testosterone therapy does not increase cardiovascular events, and to the contrary, that it is protective against cardiovascular events in hypogonadal men.¹⁰ According to expert opinion, testosterone therapy in hypogonadal men can be a valuable strategy to improve metabolic profile, reduce body fat and increase lean muscle mass, which would ultimately reduce the risk of heart disease.¹⁰