Testosterone and its metabolites: differential associations with cardiovascular and cerebrovascular events in men

Abstract

As men grow older, circulating testosterone declines while the incidence of cardiovascular disease increases. Thus, the role of sex hormones as biomarkers, and possibly contributing factors to clinical manifestations of cardiovascular disease in the increasing demographic of aging men, has attracted considerable interest. This review focuses on observational studies of endogenous androgens, namely circulating testosterone and dihydrotestosterone, which have examined their associations with cardiovascular events such as myocardial infarction and stroke. Studies which have examined the associations of endogenous estrogens, namely circulating estradiol, with these outcomes are also discussed. In large prospective cohort studies of predominantly middle-aged and older men, lower circulating testosterone consistently predicts higher incidence of cardiovascular events. Of note, both lower circulating testosterone and lower dihydrotestosterone are associated with higher incidence of stroke. These associations are less apparent when myocardial infarction is considered as the outcome. Results for estradiol are inconsistent. Lower circulating testosterone has been shown to predict higher cardiovascular disease-related mortality, as has lower circulating dihydrotestosterone. It is possible that the relationship of circulating androgens to cardiovascular events or mortality outcomes may be U-shaped rather than linear, with an optimal range defining men at lowest risk. Epidemiological studies are observational in nature and do not prove causality. Associations observed in studies of endogenous androgens need not necessarily translate into similar effects of exogenous androgens. Rigorous randomized controlled trials are needed to clarify the effects of testosterone treatment on cardiovascular risk in men.

Keywords: cardiovascular disease; cardiovascular-related mortality; dihydrotestosterone; estradiol; male aging; myocardial infarction; stroke; testosterone.

Figure 1

Nelson–Aalen plots showing the cumulative incidence of nonfatal or fatal stroke according to (a) quartiles of T, (b) calculated free T, (c) DHT, and (d) E2 in 3690 community dwelling men aged 70–89 years. T, DHT, and E2 were measured using liquid chromatography-mass spectrometry. Figure reproduced with the permission of the publisher. DHT: dihydrotestosterone; E2: estradiol; T: testosterone.