Differential Effect of 5α-Reductase Inhibition and Castration on Androgen-Regulated Gene Expression in Rat Prostate

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5α-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5α-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5α-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intrapros-tatic DHT levels and a 10-fold increase in intrapros-tatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 ± 53 in control rats, 171 ± 10 in finasteride-treated rats (P < 0.001 compared to controls), 115 ± 2 in castrated rats (P < 0.05 compared to finasteride), and 107 ± 43 in finaster-ide-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged. Castration decreased the average content of PSBP mRNA per cell by 85 ± 3% on day 4. Finaster-ide produced no decrease in relative PSBP mRNA expression on any day. The combination of finaster-ide and castration, however, caused a greater decrease in PSBP mRNA per cell on day 4 than did castration alone. TRPM-2 mRNA was very low or undetectable in prostates from intact rats. Castration caused a marked rise in TRPM-2 mRNA, as expected, but no increase in this message was seen with finasteride treatment of intact rats. The combination of finasteride and castration resulted in the same degree of TRPM-2 expression as castration alone. We conclude that prostate growth is DHT dependent and is not stimulated by the rise in intraprostatic T levels that occurs with 5α-reductase inhibition. PSBP gene induction and TRPM-2 gene repression, however, appear to be responsive to elevated intraprostatic T levels. TRPM-2 is considered to be a marker of apoptosis (programmed cell death) in the prostate and is maximal on day 4 after castration. The failure of finasteride to induce TRPM-2 mRNA in intact rats after 4 days of treatment in spite of a marked decrease in prostatic DNA content suggests that 5α-reductase inhibition can induce cell loss through a mechanism independent of apoptosis.