Cardiovascular and metabolic actions of the androgens: Is testosterone a Janus-faced molecule?

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide and in the Western world, one-third of all deaths are attributed to CVD. A conspicuous characteristic of this healthcare epidemic is that most CVD is higher in men than in age-matched premenopausal women, yet reasons for these obvious sex differences remain poorly understood. Driven by clinical case and epidemiological studies and supported by animal experiments, a strong dogma emerged early on that testosterone (TES) exerts deleterious effects on cardiovascular health and exacerbates development of CVD and metabolic dysfunctions in men. In this review, earlier and more recent clinical and experimental animal evidence of cardiovascular and metabolic effects of androgens are discussed. The more recent evidence overwhelmingly suggests that it is progressive, age-dependent declines in TES levels in men that exacerbate CVD and metabolic dysfunctions, while TES exerts beneficial systemic hypotensive effects and protects against metabolic syndrome (MetS) and type2 diabetes mellitus (T2DM). Recent findings reveal existence of bi-directional modulation of glucose and fat homeostasis by TES in females vs males, such that age-dependent declines in TES levels in males and abnormal increases in normally low TES levels in females both result in similar dysfunction in glucose and fat homeostasis, resulting in development of MetS and T2DM, central risk factors for development of CVD, in men as well as women. These findings suggest that the long-held view that TES is detrimental to male health should be discarded in favor of the view that, at least in men, TES is beneficial to cardiovascular and metabolic health.