Inhibition of the Estradiol-Mediated Endometrial Gland Formation by the Antigestagen Onapristone in Rabbits: Relationship to Uterine Estrogen Receptors
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.