Androgen-induced regrowth in the castrated rat ventral prostate: role of 5alpha-reductase.
Testosterone (T), the major circulating androgen, must be converted to dihydrotestosterone (DHT) by the enzyme 5alpha-reductase (5alpha-R) to be maximally 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 5alpha-R in the growing prostate. To create dose-response curves for intraprostatic T or DHT, rats were castrated for 2 weeks to allow their prostates to fully regress and then given T implants of various sizes in the presence or absence of the 5alpha-R inhibitor, finasteride. Markers for androgen effects on regrowth of the prostate were prostate weight, duct mass (a measure of secretory activity) and DNA content (a measure of cell number). To assess the relative uptake of T and DHT by the prostate, 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 half-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 for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5alpha-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 circulating androgen, although the rate of DHT production would have to be considerably higher to counter the apparent rapid clearance from serum. In addition, we hypothesize that T has arisen as the major circulating androgen instead of DHT because it can be aromatized to estradiol, which itself has important roles in male reproductive function and bone physiology.
Wright
A S
AS
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. aswright@is2.dal.ca
Douglas
R C
RC
Thomas
L N
LN
Lazier
C B
CB
Rittmaster
R S
RS
D000728:Androgens / Q000502:physiology*; D000818:Animals; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D004343:Drug Implants; D008297:Male; D009919:Orchiectomy; D010088:Oxidoreductases / Q000502:physiology*; D011467:Prostate / Q000254:growth & development* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
D000728:Androgens; D004343:Drug Implants; D013196:Dihydrotestosterone; D013739:Testosterone; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase