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. 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. 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. 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. 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. 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. Therefore, there continues to be ongoing uncertainty over the effect of T-therapy on the cardiovascular system in men.
Age Factors ; Androgens/therapeutic use* ; Cardiovascular Diseases/metabolism* ; Dihydrotestosterone/metabolism* ; Hormone Replacement Therapy ; Humans ; Hypogonadism/metabolism* ; Male ; Protective Factors ; Risk Factors ; Testosterone/therapeutic use*

In this issue of Asian Journal of Andrology (AJA), several experts have reviewed the latest data on the potential and known effects of endogenous and exogenous testosterone (T) on cardiovascular risk. In the review by Meyer and Wittert, low endogenous serum T appears to be associated with higher risk of cardiovascular disease and overall mortality in certain populations such as Klinefelter syndrome and older men, but not in men with congenital hypogonadotropic hypogonadism. Whether this association is causal or whether low serum testosterone is a marker of other risk factors for cardiovascular disease such as obesity, diabetes mellitus, or other systemic disease is unknown. In Yeap's review of the relationship between circulating endogenous testosterone and its major metabolites, dihydrotestosterone, and estradiol, he raises the provocative hypotheses that there might be differential effects on cardiovascular and cerebrovascular risk related to endogenous testosterone and dihydrotestosterone concentrations. Based on the same epidemiological studies, Yeap postulates that there might be a U-shaped curve for circulating endogenous androgen concentrations such that lower and higher concentrations might confer greater risk of cardiovascular events and all-cause mortality than midrange concentrations. Shores demonstrates in a carefully done review of studies of large prescription databases (including >200 000 men) that testosterone therapy is not associated with overall mortality, myocardial infarction, stroke, or deep venous thrombosis events.
Cardiovascular Diseases ; Cardiovascular System ; Humans ; Hypogonadism ; Risk Factors ; Testosterone