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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 Tract¹

Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-8857

Address all correspondence and requests for reprints to: F. W. George, Ph.D., Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8857. E-mail: george02{at}utsw.swmed.edu

Previous work has clearly demonstrated that inhibition of 5-dihydrotestosterone (DHT) formation in vivo is not as effective as total 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, androstenedione, and 5-DHT, were measured in prostate tissue and in blood of 5-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 androstenedione levels. Similarly, circulating DHT levels were decreased in 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 prostate, the inhibition of 5-reductase activity resulted not only in the decreased formation of 5-reduced metabolites (primarily DHT and 5-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 5-reduction of testosterone may be a mechanism to amplify androgen action in urogenital tissues such as the prostate by preventing catabolism of testosterone to the inactive androgen, androstenedione, at the site of hormone action.

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