Why is understanding the relationship of testosterone to cardiovascular risk so important?

Epidemiological studies hint at a beneficial influence of endogenous circulating testosterone (T), or its metabolite dihydrotestosterone (DHT), such that men with lower concentrations of T or DHT appear to have poorer health outcomes including frailty, diabetes, cardiovascular disease, and mortality.1 Small interventional studies of T have shown favorable effects on surrogate outcome measures, but a large randomized controlled trial (RCT) with the prespecified outcome of cardiovascular events has not been performed and would be logistically demanding.2 In the absence of such a definitive RCT, there is a controversy about the cardiovascular risks of T-therapy fuelled by contradictory findings from retrospective analyses of insurance databases of men prescribed T.345 The US Testosterone Trials (T-Trials) are the largest published RCTs of T-therapy in older men with symptoms or signs of hypogonadism and circulating T <9.54 nmol l−1 at baseline.6 The T-Trials showed a modest benefit of T-therapy over a 12-month period on sexual function, a significant benefit in bone density and for anemia and neutral effect on cognition.789 The T-Trials cardiovascular sub-study was designed to determine the effects of T in these older men, and there was a statistically significant difference in the increase in noncalcified plaque volume in the T-treated group compared to placebo, but it is difficult to interpret these results due to differences in baseline coronary plaque burden (>50% difference) between the treatment and placebo arms of the subset involved.10 Therefore, there continues to be ongoing uncertainty over the effect of T-therapy on the cardiovascular system in men.

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[16]  B. Dawn,et al.  Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. , 2015, European heart journal.

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[19]  G. Grunwald,et al.  Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. , 2013, JAMA.

[20]  David Handelsman Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse , 2013, The Medical journal of Australia.

[21]  A. Araujo,et al.  Do low testosterone levels contribute to ill-health during male ageing? , 2012, Critical reviews in clinical laboratory sciences.