Testosterone and cardiovascular effects

Abstract

As men grow older, circulating testosterone (T) declines while the prevalence of ill health increases. T is metabolized by 5a-reductase (SRD5A2) to dihydrotestosterone (DHT, a more potent androgen) and by aromatase (CYP19A1) to estradiol (E2, an estrogen). Lower circulating T is associated with higher prevalence and incidence of cardiovascular disease (CVD) in middle-aged and older men. By contrast, higher T or higher DHT concentrations are independent predictors for reduced incidence of stroke in older men. Additionally, higher DHT is independently associated with reduced mortality from ischemic heart disease. Although the weight of epidemiologic evidence supports a beneficial influence of endogenous androgen to reduce risk of cardiovascular events, the role of exogenous T in this context remains controversial. A randomized controlled trial (RCT) of T in older men with limited mobility reported an increase in cardiovascular adverse effects associated with T. Another comparable study in frail or intermediate-frail older men found no such signal. The US Testosterone Trials found that T therapy in older men with low baseline T moderately improved sexual function, with no excess of cardiovascular adverse effects. Meta-analyses of T RCTs have generally not shown an association with cardiovascular adverse events. Retrospective analyses of insurance and prescription databases possess major methodologic limitations including lack of randomization, and other sources of bias and confounding, and have shown conflicting results associating T supplementation with either increased or reduced risk of CVD events or mortality. Of note, higher DHT or higher E2 are associated with longer leucocyte telomere length in men, a characteristic of slower biological aging. Mendelian randomization analysis suggests a possible causal link between E2 and telomere length, supporting the hypothesis that higher sex hormone concentrations could slow biological aging in men and thereby reduce the incidence of CVD. Men who are androgen deficient resulting from disease of the hypothalamus, pituitary, or testes should be considered for T replacement therapy. Further studies are needed to clarify the role of T supplementation to preserve health in men with low-normal circulating T in the absence of pathological hypogonadism.