Androgen receptor expression is greater in macrophages from male than from female donors - A sex difference with implications for atherogenesis

background sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. Methods and Results-Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64+/-0.06 versus 0.15+/-0.02 amol/mu g total RNA; P<0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (P=0.16). The functional consequence of this sex difference was then explored, Lipid-loading studies were performed on male (n=9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109+/-10%, 117+/-3%, and 120+/-4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, P=0.002; 95+/-8% for DHT with hydroxyflutamide, P=0.58 versus controls). By contrast, then was no significant effect of androgen on lipid lending in female-donor macrophages (P>0.2 versus controls). Conclusions-Sex differences in androgen-mediated macrophage lipid lending may contribute to the greater prevalence and severity of atherosclerosis in men.