ENDOCRINE AND ANTIPROSTATIC EFFECTS OF RALOXIFENE (LY156758) IN THE MALE-RAT

The benzothiophene anti-estrogen, raloxifene [LY156758; (6-hydroxy-2-( 4-hydroxyphenyl) nzo(b)thien-3-yl)(4-(2-1-piperidinyl)ethoxy)phenyl me thanone hydrochloride] has selective estrogen pharmacological antagoni st activity in female rats. The present studies were done in the male rat to assess activity of raloxifene related to inhibition of prostati c growth and effects on the hypothalamic-pituitary-gonadal axis. Ralox ifene did not compete for binding of the androgen, [H-3]-methyltrienol one (R1881) in cytosolic extracts of ventral prostate. Similarly, the compound did not inhibit prostatic 5 alpha-reductase or testicular 17 alpha-hydroxy/C17,20-lyase activities. Raloxifene had no effect on the ventral prostatic uptake of [H-3]-R1881 in vivo. Administration of es tradiol to castrated male rats stimulated fourfold increases of in vit ro ventral prostatic binding of [H-3]-R1881. Raloxifene was devoid of agonist activity in castrated animals, because the compound had no sti mulatory effect on prostatic androgen receptor binding activity. When raloxifene was coadministered with estradiol, the compound markedly an tagonized the estrogen-induced increase of prostatic [H-3]-R1881 bindi ng, confirming its antiestrogenic properties in male rats. Serum prola ctin was also elevated significantly (P <0.05) with a single injection of raloxifene (20.0 mg/kg). In these same animals, serum FSK was sign ificantly (P <0.05) decreased by one dose (10.0 mg/kg) of the compound . Luteinizing hormone levels in castrated male rats were unaffected by raloxifene administration. Raloxifene treatment of castrated males si gnificantly (P <0.05) antagonized the stimulatory response of the vent ral prostate (VP) to exogenous androgens in a dose-dependent manner. R aloxifene treatment of intact male rats for 14 and 28 days produced si gnificant (P <0.05) dose-dependent regression of the VP and seminal ve sicles (SV). The VP regressive responses to raloxifene were associated with a decline in serum testosterone levels. Histological analysis of the VPs in raloxifene-treated rats was consistent with an androgen-de prived state. These findings support the contention that raloxifene is a pure estrogen antagonist and a physiological antagonist of androgen action in male rats. These pharmacological properties provide support for further structure-activity and mechanistic investigations with be nzothiophenes in the medical management of prostatic neoplasia. (C) 19 93 Wiley-Liss, Inc.