ANDROGEN METABOLISM IN THE PROSTATE OF THE FINASTERIDE-TREATED, ADULT-RAT - A POSSIBLE EXPLANATION FOR THE DIFFERENTIAL ACTION OF TESTOSTERONE AND 5-ALPHA-DIHYDROTESTOSTERONE DURING DEVELOPMENT OF THE MALE UROGENITAL TRACT

Previous work has clearly demonstrated that inhibition of 5 alpha-dihy drotestosterone (DHT) formation in vivo is not as effective as total a ndrogen ablation (castration) in causing involution of the prostate. I t is likely that this is due to the fact that testosterone is partiall y effective in maintaining androgen action. To provide insight into th is observation, the androgenic metabolites of testosterone, androstene dione, and 5 alpha-DHT, were measured in prostate tissue and in blood of 5 alpha-reductase inhibitor (finasteride)-treated adult male rats. Finasteride treatment caused a significant decrease in prostatic DHT l evels and a profound increase in prostatic testosterone and androstene dione levels. Similarly, circulating DHT levels were decreased in fina steride-treated rats (0.02 ng/ml compared with 0.05 ng/ml seen in cont rol rats), and circulating androstenedione and testosterone levels wer e significantly elevated in finasteride-treated animals compared with controls. The in vitro effects of finasteride were assessed on the met abolism of [H-3]testosterone in a tissue-slice assays. In the prostate , the inhibition of 5 alpha-reductase activity resulted not only in th e decreased formation of 5 alpha-reduced metabolites (primarily DHT an d 5 alpha-androstanedione), but also an increase in the 17-ore metabol ite androstenedione. In contrast, the tissues derived from the embryon ic wolffian duct (seminal vesicle and epididymis) formed relatively lo w amounts of 17-keto steroids. Because DHT is a high affinity ligand f or the androgen receptor and androstenedione shows very little, if any , affinity for the receptor, these studies suggest that 5 alpha-reduct ion of testosterone may be a mechanism to amplify androgen action in u rogenital tissues such as the prostate by preventing catabolism of tes tosterone to the inactive androgen, androstenedione, at the site of ho rmone action.