Tissue-selective
androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for
androgen suppression in the treatment of benign prostate
hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of
hydroxyflutamide (
antiandrogen) and
finasteride (5alpha-reductase inhibitor), two major drugs used for
androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to
finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of
testosterone, LH, and FSH.
Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma
hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5alpha-reductase (Ki, >20 microm) during in vitro assays. Therefore, although S-1 and
finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as
androgen receptor partial agonist, whereas
finasteride inhibited prostatic 5alpha-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination
therapy for BPH.