LY207320 (6-METHYLENE-4-PREGNENE-3,20-DIONE) INHIBITS TESTOSTERONE BIOSYNTHESIS, ANDROGEN UPTAKE, 5-ALPHA-REDUCTASE, AND PRODUCES PROSTATICREGRESSION IN MALE-RATS

LY207320 is an in vitro inhibitor (estimated IC50 = 0.06 mu M) of ster oid 5 alpha-reductase that catalyzes the conversion of testosterone (T ) to dihydrotestosterone (DHT). In contrast, LY207320 was only moderat ely active against rat prostatic Sa-reductase in vivo (32% inhibition at 50.0 mg/kg single dose). LY207320 did, however, inhibit the in vivo uptake of [H-3]-T by the prostate. The antiprostatic and endocrine ef fects of this agent were evaluated following daily (21 days) administr ation to castrated, androgen-supplemented castrate, and intact rats. L Y207320, which has modest progestational competitive binding activity, does not bind to rat prostatic androgen or uterine estrogen cytosolic receptors. In the castrated male rat, subcutaneously (s.c.) administe red LY207320 had no androgen agonist activity, as evidenced by a lack of accessory sex organ weight gains. Administration of s.c. LY207320 t o intact rats for 21 days at doses greater than 5.0 mg/kg-day produced significant (P <0.05) reductions of seminal vesicle and ventral prost atic weights (maximal regression = -65% and -40% from control values, respectively at 50.0 mg/kg-day). The compound had no regressive activi ty on male accessory sex organs when administered orally. LY207320 did not alter circulating prolactin, LH, or corticosterone levels, but at high doses (greater than or equal to 50.0 mg/kg-day), lowered circula ting T[-67% from intact control levels (P <0.05)]. Histological analys is of the rat ventral prostates (RVPs) in LY207320-treated rats was co nsistent with an androgen-deprived state. Decreased circulating androg ens and prostatic regression are associated with inhibition of testicu lar 17 alpha-hydroxy/C17,20-lyase enzyme activity (IC50 = 0.06 mu M). These findings support the contention that LY207320 is a physiological antagonist of androgen action in male rats, and that its effects are mediated primarily through inhibition of testicular androgen productio n rather than accessory sex organ 5 alpha-reductase. (C) 1993 Wiley-Li ss, Inc.