Hormonal regulation of normal vascular tone in males.

The presence of steroid hormone receptors in the vasculature of male animals has been recognized for more than two decades,1,2 and the ability of vascular estrogen receptors (ERs) to activate gene expression in vascular smooth muscle and endothelial cells from both sexes is now well established.3 We know now that normal ER function is required for skeletal development in the human male,4 male fertility,5 and normal cardiovascular development and function in males as well as females.6 – 8 In men, circulating estrogen levels are quite low and substantially lower than androgen levels. How do cardiovascular tissues in men become exposed to estrogen? Males generate estrogen by synthesizing it directly from testosterone in target tissues. The enzyme aromatase, a member of the P450 superfamily of enzymes, is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the A-ring of androgens to the corresponding phenolic A-ring characteristic of estrogens (Figure). Aromatase is widely expressed in ovary, placenta, hypothalamus, liver, muscle, adipose tissue, and of note, in vascular smooth muscle and endothelial cells.9 –12 Estradiol is therefore generated directly in the male vasculature, where it can activate ERs in both the cells in which it arises and in neighboring vascular smooth muscle and endothelial cells. Two new studies contribute substantially to our understanding of the autocrine and paracrine effects of aromatase-derived estrogen in the male vasculature.13,14 In the last issue of Circulation Research, Lew and colleagues13 report studies in healthy young men of the effect of aromatase inhibition on endothelial function. Study subjects were given anastrozole, a nonsteroidal inhibitor of aromatase used widely in the treatment of postmenopausal women with hormone receptor–positive breast cancer, to suppress local estrogen production. Anastrazole caused a significant decrease in flow-mediated brachial dilatation compared with placebo in these healthy subjects.13 In this issue of Circulation Research, Kimura and coworkers14 present animal studies complementary to these human studies. They report that endothelium-dependent vasodilatation is significantly blunted in blood vessels from the male aromatase knockout (ArKO) mice. These studies thus both support the hypothesis that aromatization of testosterone to estrogen is required for the maintenance of normal endothelial function and vascular tone in males.