Androgen Metabolism in the Prostate of the Finasteride-Treated, Adult Rat: A Possible Explanation for the Differential Action of Testosterone and 5 -Dihydrotestosterone during Development of the Male Urogenital Tract
Previous work has clearly demonstrated that inhibition of 5a- dihydrotestosterone(DHT)formationinvivoisnotaseffectiveastotal androgen ablation (castration) in causing involution of the prostate. It is likely that this is due to the fact that testosterone is partially effective in maintaining androgen action. To provide insight into this observation, the androgenic metabolites of testosterone, andro- stenedione, and 5a-DHT, were measured in prostate tissue and in blood of 5a-reductase inhibitor (finasteride)-treated adult male rats. Finasteride treatment caused a significant decrease in prostatic DHT levels and a profound increase in prostatic testosterone and andro- stenedionelevels.Similarly,circulatingDHTlevelsweredecreasedin finasteride-treated rats (0.02 ng/ml compared with 0.05 ng/ml seen in control rats), and circulating androstenedione and testosterone levels were significantly elevated in finasteride-treated animals compared with controls. The in vitro effects of finasteride were assessed on the metabolism of (3H)testosterone in a tissue-slice assays. In the pros- tate, the inhibition of 5a-reductase activity resulted not only in the decreased formation of 5a-reduced metabolites (primarily DHT and 5a-androstanedione), but also an increase in the 17-oxo metabolite androstenedione. In contrast, the tissues derived from the embryonic wolffian duct (seminal vesicle and epididymis) formed relatively low amounts of 17-keto steroids. Because DHT is a high affinity ligand for the androgen receptor and androstenedione shows very little, if any, affinity for the receptor, these studies suggest that 5a-reduction of testosterone may be a mechanism to amplify androgen action in uro- genital tissues such as the prostate by preventing catabolism of tes- tosterone to the inactive androgen, androstenedione, at the site of hormone action. (Endocrinology 138: 871-877, 1997)