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


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/microgram 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, 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.
McCrohon
J A
JA
Heart Research Institute, Department of Cardiology, Royal Prince Alfred Hospital in Missenden Road, University of Sydney, Australia.
Death
A K
AK
Nakhla
S
S
Jessup
W
W
Handelsman
D J
DJ
Stanley
K K
KK
Celermajer
D S
DS
D000328:Adult; D000368:Aged; D001161:Arteriosclerosis / Q000209:etiology*; D002788:Cholesterol Esters / Q000032:analysis; D013196:Dihydrotestosterone / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000032:analysis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors
D002788:Cholesterol Esters; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D005485:Flutamide