ACTIVITY OF RALOXIFENE IN IMMATURE AND OVARIECTOMIZED RAT UTEROTROPHIC ASSAYS

Raloxifene is generally regarded as a tissue-selective? estrogen agoni st, being capable of selectively counteracting both the loss of bane d ensity and the increase in serum cholesterol that occur in rats follow ing ovariectomy, without the induction Of a trophic effect on the rat uterus. An implication of this activity profile is that reliance canno t be placed on the rat uterotrophic assay for the detection and assess ment; of xenobiotic estrogens. Within that context the estrogenic acti vity of raloxifene has been reevaluated in immature and ovariectomized rat uterotrophic assays. Four separate experiments were conducted. In the first two a reproducible increase (1.7-fold) was observed in the uterus wet weights of immature rats administered three daily doses of raloxifene. The maximum uterotrophic response observed over the dose r ange 0.01-2 mg/kg was for 0.1 mg/kg raloxifene. Further experiments ut ilized three daily doses of 0.1 mg/kg raloxifene. In the third experim ent the uterotrophic response elicited by raloxifene in immature rats was abolished by coadministration of the estrogen receptor blocking ag ent Faslodex (ICI 182,780). This confirmed the direct involvement of e strogen receptors in the uterotrophic response elicited by raloxifene. Two further indications of the estrogenicity of raloxifene were obtai ned in this experiment. First. dry uterus weights were also shown to b e increased by raloxifene administration, thereby eliminating water re tention as the sole cause of the observed increases in uterus weights. Second, the height of the surface epithelium was increased by 1.7-fol d in the raloxifene-treated animals, an effect that was accompanied by increases in mitotic activity and glandular formation in the stromal endometrium. The endometrial epithelium of the treated rats also showe d evidence of vacuolation and, occasionally, the presence of degenerat ing cells. Raloxifene, did not, however, cause premature vaginal openi ng in immature rats, unlike estradiol. In the fourth experiment the ut erotrophic activity of raloxifene was confirmed in ovariectomized rats , although the response was less (1.2-fold) than in immature rats. In contrast to the effects seen for the positive control agent estradiol, the uterotrophic responses observed for raloxifene in ovariectomized animal were not accompanied by cornification of the vaginal cornificat ion may be less sensitive markers of estrogenic activity than the uter otrophic response. These collected observations confirm that raloxifen e exerts a genuine trophic effect on the rat uterus, and as a conseque nce, the uterotrophic assay can be relied upon to detect estrogens wit h only a marginal effect on the uterus. (C) 1997 Academic Press.