Relative Effectiveness of Alternative Androgen Withdrawal Therapies in Initiating Regression of Rat Prostate

Abstract

From a large number of potentially effective androgen withdrawal regimens including bilateral orchiectomy, estrogens, antiandrogens and LHRH agonists alone or in combinations, we compared the ability of 12 different treatment options to mimic the acute results of surgical castration on the rat prostate. Agents were administered s.c. in clinical doses to groups of male rats daily for three days. On day 4 the prostatic tissue was removed and analyzed by conventional methods for whole-tissue and nuclear concentrations of dihydrotestosterone, nuclear androgen receptor and cytoplasmic androgen receptor. Castration-like changes were most pronounced with the synergistic combinations of cyproterone acetate + low-dose diethylstilbestrol, and megestrol acetate + low-dose diethylstil-bestrol. Comparing the effectiveness of single agents, low-dose diethylstilbestrol was superior to cyproterone acetate, megestrol acetate, flutamide, leuprolide and RU23908. Leuprolide combined with flutamide was superior to leuprolide + cyproterone acetate, leuprolide + cyproterone acetate + low-dose diethylstilbestrol or leuprolide + RU23908 after three days of administration; however, this advantage disappeared when the treatments were extended to seven days. The observations indicate that the most potent androgen withdrawal therapies such as cyproterone acetate + low-dose diethylstilbestrol and megestrol acetate + low-dose diethylstilbestrol at best approximate but do not surpass the early effects of surgical castration. During the same time course, other regimens are characterized by a slower onset of action and a lesser degree of suppression of androgenic mechanisms within the cell.