Testosterone down-regulates the levels of androgen receptor mRNA in smooth muscle cells from the rat corpora cavernosa via aromatization to estrogens.
Androgens down-regulate the levels of androgen receptors (AR) and AR mRNA in the penis and prostate of castrated rats, and are assumed to cause their decrease during sexual maturation in the penile smooth muscle of intact rats. In order to determine whether these effects occur directly at the target cell level, and to what extent they are due to testosterone (T) or to their metabolites, we have measured AR mRNA in cultures of smooth muscle cells from the adult rat corpora cavernosa treated in vitro with sex steroids. T at high concentrations (100 nM) acted like dihydrotestosterone (DHT) in increasing moderately the levels of AR mRNA in both proliferating and contact-inhibited cells. However, when conversion of T to DHT was blocked by the 5-alpha reductase inhibitor finasteride, the levels of AR mRNA were considerably down-regulated by T (10-500 nM), particularly in the contact-inhibited cells. Finasteride by itself was inactive. These effects in both types of cultures were inhibited by platelet derived growth factor (PDGF) (20 ng/ml), a growth factor that up-regulates AR mRNA levels, and by fadrozole (100 nM), an aromatase inhibitor of the T/estrogen conversion. Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels. With the exception of PDGF none of the treatments affected significantly cell growth, as measured by DNA synthesis and content. Our results indicate that it is possible to modulate in vitro AR mRNA levels in the penile smooth muscle cells, and that under normal conditions DHT and T act as moderate up-regulators. When DHT formation is inhibited, the aromatization pathway of T to estradiol will prevail and induce a pronounced down-regulation of AR mRNA levels. We assume that the in vivo AR down-regulation in the penile smooth muscle by androgens is an indirect effect mediated by a paracrine or endocrine mechanism elicited in another tissue.
Department of Surgery, UCLA School of Medicine, Torrance 90509.
M C
MC
Lin
J
J
Rajfer
R S
RS
Swerdloff
N F
NF
González-Cadavid
D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism*; D010413:Penis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology*
D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; D004247:DNA; D001141:Aromatase