Androgens and Androgen Receptors as Determinants of Vascular Sex Differences Across the Lifespan

Androgens, including testosterone and its more potent metabolite dihydrotestosterone, exert multiple actions in the body. Physiologically, they play a critical role in male sex development. In addition, they influence vascular function, including arterial vasodilation and mediation of myogenic tone. Androgens are produced from 9 weeks' gestation in the human fetal testis, as well as in small amounts by the adrenal glands. Serum concentrations vary according to age and sex. The vasculature is a target for direct actions of androgens, which bind to various sex hormone receptors expressed in endothelial and vascular smooth muscle cells. Androgens exert both vasoprotective and vasoinjurious effects, depending on multiple factors including sex-specific effects of androgens, heterogeneity of the vascular endothelium, differential expression of androgen and sex hormone receptors in endothelial and vascular smooth muscle cells, and the chronicity of androgen administration. Long-term administration of androgens induces vasoconstriction and influences endothelial permeability, whereas acute administration may have opposite effects. At the cellular level, androgens stimulate endothelial cell production of nitric oxide and inhibit proinflammatory signalling pathways, inducing vasorelaxation and vasoprotection. However, androgens also activate endothelial production of vasoconstrictors and stimulate recruitment of endothelial progenitor cells. In humans, both androgen deficiency and androgen excess are associated with increased cardiovascular morbidity and mortality. This review discusses how androgens modulate vascular sex differences across the lifespan by considering the actions and production of androgens in both sexes and describes how cardiovascular risk is altered as levels of androgens change with aging.