EFFECTS OF ESTRADIOL-17-BETA AND 5-ALPHA-DIHYDROTESTOSTERONE ON GUINEA-PIG PROSTATE SMOOTH-MUSCLE CELL-PROLIFERATION AND STEROID-RECEPTOR EXPRESSION IN-VITRO

Smooth muscle cells (SMCs) are the major cellular component of the pro static stroma. The aim of this study was to examine the effects of oes tradiol-17 beta(OE(2)) and 5 alpha-dihydrotestosterone (DHT) on the pr oliferation of guine-pig prostate SMCs in vitro. OE(2) stimulated SMC DNA synthesis at all concentrations examined. At a plating density of 3.0 x 10(4)cells/cm(2), maximal incorporation of [H-3]thymidine (136%o f control) was observed after 36 h of treatment with 1 nmol OE(2)/1. A t the same plating density, DHT had an inhibitory effect on SMC DNA sy nthesis, with maximal effects (73% of control) being observed 24 h aft er treatment with 1 nmol DHT/1. These effects OE(2) and DHT were preve nted by co-incubation with specific steroid receptor antagonists. At a threefold lower plating density (1.0 x 10(4) cells/cm(2)), the maxima l stimulatory and inhibitory effects of OE(2) and DHT were delayed by approximately 24 and 12 h respectively. At the lower plating density, a biphasic effectof DHT was observed on DNA synthesis; DHT was both in hibitory and stimulatory. Maximal inhibition (71% of control) and maxi mal stimulation (168% of control) were observed after 36 and 134 h tre atment with DHT respectively. At the lower plating density, longer ter m treatment of SMC cultures with OE(2) and DHT also resulted in an inc rease in cell number. After 7 days of treatmentwith OE(2) and DHT, cel l number increased by 13% and 12% respectively. When OE(2) and DHT wer e added in combination, the short-term inhibitory effect of DHT on SMC DNA synthesis was dominant over the stimulatory effect of OE(2). Trea tment with DHT for 24 h significantly inhibited OE(2)-induced stimulat ion of [H-3]thymidine incorporation, irrespective of the prior duratio n of OE(2) treatment. At the lower plating density, OE(2) also decreas ed oestrogen receptor (ER) mRNA levelsto 38% of control levels after 2 4 h of treatment. ER mRNA levels remained repressed until 72 h after t reatment with OE(2), and returned to controlvalues following 96 h of t reatment. Both the androgen-induced inhibition and stimulation of DNA synthesis observed following treatment of SMCs with 1 nmol DHT/1 were associated with a reduction in androgen receptor (AR) mRNA levels. At an intermediate time (i.e. 48 h after commencement of treatment with D HT) AR mRNA levels were increased more than twofold over control level s. The increase in Ali mRNA levels at 48 h after DHT treatment only oc curred in cells plated at the lower density, suggesting that this is a n essential requirement for the longer term stimulation of prostatic S MC proliferation by DHT.