Jordan V C, Gosden B
J Steroid Biochem. 1983 Sep;19(3):1249-58. doi: 10.1016/0022-4731(83)90147-4.
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.
非甾体类抗雌激素药物LY117018和单羟基他莫昔芬在3日龄未成熟大鼠子宫重量试验中为部分激动剂。两种化合物均刺激子宫孕酮受体浓度增加（通过葡聚糖包被活性炭法和蔗糖密度梯度离心分析测定）以及腔上皮细胞高度增加。然而，LY117018的雌激素活性比单羟基他莫昔芬低得多。该研究还表明，增加雌二醇剂量可在体内逆转LY117018和单羟基他莫昔芬的抗雌激素作用。高剂量的LY117018以大约1:24（w/w）的剂量比抑制了单羟基他莫昔芬的部分子宫营养作用和雌二醇的完全子宫营养作用。这一结果提示了雌二醇和羟基化抗雌激素作用的共同机制。由于LY117018在体内逆转了大鼠子宫中[3H]雌二醇的结合以及雌激素可竞争的[3H]单羟基他莫昔芬的结合，非甾体类抗雌激素对子宫总湿重的影响可以通过雌激素受体机制与雌二醇的竞争性相互作用来解释。然而，弱雌激素性抗雌激素LY117018无法抑制雌激素刺激的腔上皮细胞高度增加和孕酮受体水平升高。这些数据提示LY117018在大鼠子宫中存在差异性相互作用，以至于只有特定的雌激素刺激效应，即子宫湿重，会被该特定“抗雌激素”剂量的药物所拮抗。
