Androgen-induced regrowth in the castrated rat ventral prostate: Role of 5alpha-reductase

Testosterone (T), the major circulating androgen, must be converted to dihy drotestosterone (DHT) by the enzyme 5 alpha-reductase (5 alpha-R) to be max imally active in the prostate. The present study was designed to determine the relative potency of T and DHT on regrowth of the involuted prostate and to elucidate the role of 5 alpha-R in the growing prostate. To create dose -response curves for intraprostatic T or DHT, rats were castrated for 2 wee ks to allow their prostates to fully regress and then given T implants of v arious sizes in the presence or absence of the 5 alpha-R inhibitor, finaste ride. Markers for androgen effects on regrowth of the prostate were prostat e weight, duct mass (a measure of secretory activity) and DNA content (a me asure of cell number). To assess the relative uptake of T and DHT by the pr ostate, a comparison was made of intraprostatic DHT levels resulting from T and DHT implants. In the prostate, 1.6-1.9 times more T than DHT was required to achieve a ha lf-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold f or T was 2- to 3-fold greater than that for DHT. However, at high intrapros tatic concentrations, the effects of T mimicked those of DHT. When the rela tionship between serum T levels and prostate regrowth was considered, 13 ti mes more serum T was required for half-maximal prostate regrowth when its c onversion to DHT was blocked by finasteride. This is partly due to decrease d androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulte d in similar intraprostatic DHT levels, indicating that uptake of each seru m androgen into the prostate was similar. However, to achieve similar level s of DHT or T in serum, much larger DHT pellets were needed, suggesting mor e rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5 alpha-R is 2-fold: it converts testosterone into a modestly more potent androgen and enhances prostatic accumulation of androgen. DHT, in principle, could serve equally well as T as the circulat ing androgen, although the rate of DHT production would have to be consider ably higher to counter the apparent rapid clearance from serum. In addition , we hypothesize that T has arisen as the major circulating androgen instea d of DHT because it can be aromatized to estradiol, which itself has import ant roles in male reproductive function and bone physiology.