Chwalisz K, Hegele-Hartung C, Fritzemeier K H, Beier H M, Elger W
Research Laboratories of Schering AG, Berlin, Germany.
Endocrinology. 1991 Jul;129(1):312-22. doi: 10.1210/endo-129-1-312.
There is evidence from previous studies that progesterone antagonists (antigestagens) modify estrogen responses at endometrial and myometrial levels without having affinity to the estrogen receptor (ER). The purpose of the present study was to investigate the influence of the antigestagen onapristone (ZK 98 299) on the uterus in ovariectomized (OVX) estradiol (E2)-substituted rabbits (3.0 micrograms/animal.day). The animals were treated for 8 days with different doses of onapristone (3.0, 10.0, and 30.0 mg/animal.day, sc). Uterine growth was not influenced by onapristone compared to that in OVX E2-substituted controls. However, morphological (light microscopy, transmission electron microscopy) and morphometric criteria indicated that there was a significant dose-dependent inhibition of the estrogen-induced gland formation within the endometrium and degenerative changes in glandular epithelial cells. By contrast, there were morphological signs of activation of the endometrial stroma (proliferation, increased capillarization, and vascularization, edema) above the level of E2-treated animals. A dose-dependent increase in the concentration of uterine cytosolic ER, nuclear ER, and ER mRNA (ER mRNA) was measured in uterine homogenates after onapristone treatment compared to values in OVX E2-substituted controls. Immunocytochemical analysis of ER in uterine sections suggests that the increase in ER after onapristone treatment took place predominantly in the myometrium and surface epithelium. To examine whether the observed interference was mediated via the progesterone receptor (PR), E2-substituted rabbits were treated, in a separate experiment, with onapristone (10.0 mg/animal.day, sc) and various doses of progesterone (1.0, 3.0, and 10.0 mg/animal.day, sc). Progesterone reversed all onapristone-induced changes, indicating that the observed effects were mediated via the PR. The data indicate that the antigestagen onapristone interacts with estrogen action in the absence of the natural PR ligand. The increase in ER and ER mRNA concentrations after onapristone treatment in OVX E2-treated animals suggests that this antigestagen abolished an inhibitory action of the unoccupied PR on ER biosynthesis.
以往研究有证据表明，孕激素拮抗剂（抗孕激素）可在子宫内膜和子宫肌层水平改变雌激素反应，而对雌激素受体（ER）没有亲和力。本研究的目的是调查抗孕激素奥那司酮（ZK 98 299）对去卵巢（OVX）并用雌二醇（E2）替代的家兔（3.0微克/动物·天）子宫的影响。动物用不同剂量的奥那司酮（3.0、10.0和30.0毫克/动物·天，皮下注射）治疗8天。与OVX E2替代对照组相比，奥那司酮对子宫生长没有影响。然而，形态学（光学显微镜、透射电子显微镜）和形态测量标准表明，雌激素诱导的子宫内膜腺体形成受到显著的剂量依赖性抑制，腺上皮细胞出现退行性变化。相比之下，在高于E2处理动物的水平上，有子宫内膜基质激活的形态学迹象（增殖、毛细血管化和血管形成增加、水肿）。与OVX E2替代对照组的值相比，奥那司酮处理后子宫匀浆中子宫胞质ER、核ER和ER mRNA（ER mRNA）浓度呈剂量依赖性增加。子宫切片中ER的免疫细胞化学分析表明，奥那司酮处理后ER的增加主要发生在子宫肌层和表面上皮。为了检查观察到的干扰是否通过孕激素受体（PR）介导，在一项单独实验中，用奥那司酮（10.0毫克/动物·天，皮下注射）和不同剂量的孕激素（1.0、3.0和10.0毫克/动物·天，皮下注射）处理E2替代的家兔。孕激素逆转所有奥那司酮诱导的变化，表明观察到的效应是通过PR介导的。数据表明，抗孕激素奥那司酮在没有天然PR配体的情况下与雌激素作用相互影响。在OVX E2处理的动物中，奥那司酮处理后ER和ER mRNA浓度增加表明，这种抗孕激素消除了未占据的PR对ER生物合成的抑制作用。
