Evidence of a role for endogenous estrogens in men
Evidence of a role for endogenous estrogens in men
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Endogenous estrogens, lipoproteins, and glucose metabolism. There is now compelling evidence that endogenous production of estrogens in men plays an important role in cardiovascular health and disease. Physiological levels of estrogen have been reported to play a role in influencing plasma lipoprotein concentrations in men. When selective estrogen deficiency was induced in young men by administration of combined drug therapy with a GnRH antagonist (to suppress endogenous steroid hormones), testosterone (to restore testosterone levels to baseline), and testolactone (an aromatase inhibitor that prevents conversion of testosterone to estrogens), plasma high density lipoprotein (HDL) and apolipoprotein A-1 decreased, while plasma low density lipoprotein (LDL) and triglyceride levels did not change (7). Shono et al. ( investigated the relationships of plasma sex hormones to lipid and glucose metabolism in a cross-sectional study on 212 apparently healthy men ranging in age from 18 to 59 yr. They showed that the estradiol level was negatively related to both LDL cholesterol and fasting blood glucose, suggesting that the levels of estradiol within the physiological range for healthy men may help maintain a desirable profile of lipid and glucose metabolism.
Lessons from "experiments of nature". Recent evidence from a 28-yr-old man with estrogen insensitivity caused by a disruptive mutation in the estrogen receptor (ER) gene suggests that estrogen may play an important role not only in bone metabolism but also in cardiovascular function. This individual presented with tall stature, normal masculinization, incomplete epiphyseal closure, and decreased bone mineral density. His serum estradiol and estrone, FSH, and LH concentrations were elevated, while testosterone was normal. Direct sequencing of exon 2 of his ER gene revealed a cytosine-to-thymine transition at codon 157 of both allelles, resulting in a premature stop codon and expression of a truncated nonfunctional ER protein (9). Peripheral vascular studies in this individual revealed an intact rapid nongenomic vasodilator response to sublingual estradiol; however, he demonstrated marked endothelial dysfunction evidenced by absence of flow-mediated vasodilation in the brachial artery (10), an observation consistent with the impaired basal nitric oxide release in the aorta of the male estrogen- receptor knockout mouse (11). Electron beam computed tomography scanning of the heart in this individual showed calcium deposition in his left anterior descending coronary artery, indicating early atherosclerosis (12). Lipoprotein analysis showed relatively low levels of HDL, but total and LDL cholesterol concentrations were also low, as were apolipoprotein A-1 and lipoprotein(a), while triglyceride concentrations were normal (12). Overall, these observations suggest that some actions of estrogen likely to be protective against the development of premature vascular disease in men.
Further evidence for a role for endogenously produced estrogen in normal male cardiovascular health comes from a condition in which a deficiency occurs in the enzyme responsible for the conversion (aromatization) of C19 androgenic steroids to the corresponding estrogens, involving the conversion of the delta 4–3-1 A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Recently, a number of mutations of the aromatase gene have been described that give rise to complete estrogen deficiency. In females this estrogen deficiency results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men (13). Such patients also have low HDL and increased total and LDL cholesterol concentrations and triglycerides, and hyperinsulinemia (14). Thus, as has been suggested in menstruating women, it is possible that part of a putative protective role for endogenous estrogens in men is by maintenance of normal HDL concentrations and possibly by reducing LDL cholesterol.
Aromatase inhibition in men: vascular effects. In a recent preliminary study (15), we have demonstrated a potential role for endogenous sex hormones in vascular reactivity in elderly men taking the aromatase inhibitor testolactone for benign conditions for prolonged periods. Cessation of testolactone therapy was associated with a fall in serum testosterone, a trend to an increase in estrogens, and significant improvement in forearm endothelium-dependent vasorelaxation. However, norepinephrine-induced vasoconstriction was enhanced, and arterial compliance decreased, suggesting a complex interaction between sex hormones and vascular function. In addition, because the presence of aromatase has been demonstrated in the vasculature (16), local changes in steroid concentrations resulting in vascular effects cannot be excluded. Of note, variations in endogenous estrogen levels are observed in men in conditions such as obesity (17). The degree of obesity appears to have a direct effect on estradiol levels, probably through transformation of androgens in adipose tissue to estrogens (17). Moderate to high ethanol intake is also reported to influence sex hormone levels in men; in particular, plasma testosterone levels decrease, probably via alcohol-induced inhibition of testosterone (1. In addition, ethanol induces an increase in cytosolic ER in the human male liver, a possible explanation for feminization in chronic liver disease due to alcohol (19). However, the influence of such variations in endogenous sex hormone levels and ER on cardiovascular physiology in men with obesity or chronic liver disease is unknown.
