Search

Background —Male 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/μg total RNA; P 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, there was no significant effect of androgen on lipid loading in female-donor macrophages ( P >0.2 versus controls). Conclusions —Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men.