LY207320 is an in vitro inhibitor (estimated IC50 = 0.06 microM) of
steroid 5 alpha-reductase that catalyzes the conversion of
testosterone (T) to
dihydrotestosterone (DHT). In contrast,
LY207320 was only moderately active against rat prostatic
5 alpha-reductase in vivo (32% inhibition at 50.0 mg/kg single dose).
LY207320 did, however, inhibit the in vivo uptake of [3H]-T by the prostate. The antiprostatic and endocrine effects of this agent were evaluated following daily (21 days) administration to castrated,
androgen-supplemented castrate, and intact rats.
LY207320, 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.) administered
LY207320 had no
androgen agonist activity, as evidenced by a lack of accessory sex organ
weight gains. Administration of s.c.
LY207320 to 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 prostatic weights (maximal regression = -65% and -40% from control values, respectively at 50.0 mg/kg-day). The compound had no regressive activity on male accessory sex organs when administered orally.
LY207320 did not alter circulating
prolactin, LH, or
corticosterone levels, but at high doses (> or = 50.0 mg/kg-day), lowered circulating T[-67% from intact control levels (P < 0.05)]. Histological analysis of the rat ventral prostates (RVPs) in LY207320-treated rats was consistent with an
androgen-deprived state. Decreased circulating
androgens and prostatic regression are associated with inhibition of testicular 17 alpha-hydroxy/C17,20-
lyase enzyme activity (IC50 = 0.06 microM). 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 production rather than accessory sex organ
5 alpha-reductase.