Differential antiestrogen action in the immature rat uterus: a comparison of hydroxylated antiestrogens with high affinity for the estrogen receptor.
The non-steroidal antiestrogens LY117018 and monohydroxytamoxifen are partial agonists in the 3-day immature rat uterine weight test. Both compounds stimulated increases in uterine progesterone receptor concentration (as determined by DCC assay and SDG analysis) and luminal epithelial cell height. However, LY117018 was much less estrogenic than monohydroxytamoxifen. The study also showed that the antiestrogenic effects of LY117018 and monohydroxytamoxifen could be reversed in vivo by increasing doses of estradiol. The partial uterotrophic effect of monohydroxytamoxifen and full uterotrophic effects of estradiol were both inhibited by high doses of LY117018 at an approximate dosage ratio of 1:24, w/w. This result suggests a common mechanism for the action of estradiol and the hydroxylated antiestrogens. Since LY117018 reversed the binding of [3H]estradiol and estrogen-competable [3H]monohydroxytamoxifen binding in the rat uterus in vivo, the effects of nonsteroidal antiestrogens on gross uterine wet weight can be explained by competitive interaction with estradiol via the estrogen receptor mechanism. However, the weakly estrogenic antiestrogen LY117018 was unable to inhibit estrogen-stimulated rises in luminal epithelium cell height and progesterone receptor levels. These data suggest a differential interaction by LY117018 in the rat uterus so that only selected estrogen stimulated effects i.e.: uterine wet weight, are antagonized by this particular "antiestrogenic" dose of the drug.
D000818:Animals; D001667:Binding, Competitive; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D009929:Organ Size / Q000187:drug effects; D011397:Promegestone / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000378:metabolism*; D012741:Sexual Maturation; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects / Q000502:physiology*
D004965:Estrogen Antagonists; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013876:Thiophenes; D013629:Tamoxifen; C016601:afimoxifene; C025430:LY 117018; D011397:Promegestone