Premium
LY207320 (6‐methylene‐4‐pregnene‐3,20‐dione) inhibits testosterone biosynthesis, androgen uptake, 5α‐reductase, and produces prostatic regression in male rats
Author(s) -
Neubauer Blake Lee,
Best Kevin L.,
Blohm Thomas R.,
Gates Cynthia,
Goode Robin L.,
Hirsch Kenneth S.,
Laughlin Marie E.,
Petrow Vladimir,
Smalstig E. Barry,
Stamm Nancy B.,
Toomey Richard E.,
Hoover Dennis M.
Publication year - 1993
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.2990230302
Subject(s) - endocrinology , medicine , androgen , testosterone (patch) , dihydrotestosterone , seminal vesicle , prolactin , in vivo , prostate , estrogen , castration , hormone , biology , cancer , microbiology and biotechnology
LY207320 is an in vitro inhibitor (estimated IC 50 = 0.06 μM) of steroid 5α‐reductase that catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT). In contrast, LY207320 was only moderately active against rat prostatic 5α‐reductase in vivo (32% inhibition at 50.0 mg/kg single dose). LY207320 did, however, inhibit the in vivo uptake of [ 3 H]‐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 (>m50.0 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 17α‐hydroxy/C17,20‐lyase enzyme activity (IC 50 = 0.06 μM). 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 5α‐reductase. © 1993 Wilcy‐Liss, Inc.