Estrogenic effects of the antiprogestin onapristone (ZK98.299) in the rodent uterus.
OBJECTIVE
Our purpose was to assess the estrogenic action of onapristone (ZK299).


METHODS
Three rodent models of estrogen action in the uterus were used. Deoxyribonucleic acid synthesis in the uterine epithelium of neonatal mice was determined by thymidine autoradiography. In adult ovariectomized mice uterine wet weight and progesterone receptor and estrogen receptor concentrations were determined. In immature rats uterine deoxyribonucleic acid synthetic activity was determined by thymidine autoradiography, epithelial hypertrophy and stromal edema were assessed histomorphometrically, and complement C3 protein synthesis was assessed by metabolic labeling in vitro. The effects of ZK299 were challenged with the antiestrogens ICI164,384 and tamoxifen. The ability of ZK299 to displace tritiated estradiol from the estrogen receptor was assessed in cytosolic preparations from mouse uterus.


RESULTS
In the neonatal mouse ZK299 stimulated epithelial deoxyribonucleic acid synthesis; two other antiprogestins, RU486 and ZK98.734, had no effect. Three daily injections of ZK299 at 10 micrograms/gm body weight to 6-week-old ovariectomized mice increased uterine progesterone receptor 42%; this effect was blocked by ICI164,384. In another experiment three daily doses of ZK299 (20 micrograms/gm) to 10-week-old ovariectomized mice increased progesterone receptor concentration by 63% and uterine wet weight by 42%. In 21-day-old rats a single injection of ZK299 increased uterine epithelial deoxyribonucleic acid synthesis; this effect was blocked by tamoxifen. Both ZK299 and tamoxifen increased epithelial cell height and thymidine labeling in the stroma. ZK98.734 had no effect on epithelium or stroma. ZK299 also stimulated synthesis of complement C3 by uteri of immature rats. In competitive binding assays ZK299 exhibited weak relative binding affinity (0.05%) for mouse uterine estrogen receptor.


CONCLUSIONS
ZK299 can act as a weak estrogen in the rodent uterus, most likely through a direct, low-affinity interaction with the estrogen receptor. Because estrogens may increase the risk for endometrial, breast, and liver cancer, caution is warranted in long-term administration of this drug to women.
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis 46202-5196.
R M
RM
Bigsby
P C
PC
Young
D000818:Animals; D000831:Animals, Newborn; D015932:Complement C3c / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006067:Gonanes / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011374:Progesterone / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000032:analysis / Q000378:metabolism; D011980:Receptors, Progesterone / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology; D014599:Uterus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
D006067:Gonanes; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D011374:Progesterone; D004958:Estradiol; D015932:Complement C3c; D004247:DNA; C053238:onapristone