TESTOSTERONE DOWN-REGULATES THE LEVELS OF ANDROGEN RECEPTOR MESSENGER-RNA IN SMOOTH-MUSCLE CELLS FROM THE RAT CORPORA CAVERNOSA VIA AROMATIZATION TO ESTROGENS

Androgens down-regulate the levels of androgen receptors (AR) and AR m RNA in the penis and prostate of castrated rats, and are assumed to ca use their decrease during sexual maturation in the penile smooth muscl e of intact rats. In order to determine whether these effects occur di rectly at the target cell level, and to what extent they are due to te stosterone (T) or to their metabolites, we have measured AR mRNA in cu ltures of smooth muscle cells from the adult rat corpora cavernosa tre ated in vitro with sex steroids. T at high concentrations (100 nM) act ed 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 inhi bitor finasteride, the levels of AR mRNA were considerably down-regula ted by T (10-500 nM), particularly in the contact-inhibited cells. Fin asteride by itself was inactive. These effects in both types of cultur es were inhibited by platelet derived growth factor (PDGF) (20 ng/ml), a growth factor that up-regulates AR mRNA levels, and by fadrozole (1 00 nM), an aromatase inhibitor of the T/estrogen conversion. Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels. Wit h the exception of PDGF none of the treatments affected significantly cell growth, as measured by DNA synthesis and content. Our results ind icate that it is possible to modulate in vitro AR mRNA levels in the p enile smooth muscle cells, and that under normal conditions DHT and T act as moderate up-regulators. When DHT formation is inhibited, the ar omatization pathway of T to estradiol will prevail and induce a pronou nced down-regulation of AR mRNA levels. We assume that the in vivo AR down-regulation in the penile smooth muscle by androgens is an indirec t effect mediated by a paracrine or endocrine mechanism elicited in an other tissue.