Progesterone and dexamethasone inhibition of estrogen-induced synthesis of DNA and complement in rat uterine epithelium: effects of antiprogesterone compounds.
Progesterone (P) blocks estrogen induction of cell proliferation and synthesis of complement C3 in the epithelium of the immature rat uterus. Here it is shown that dexamethasone (Dex) exerts a similar inhibitory effect on these two parameters. Furthermore, analysis of the newly synthesized, secreted proteins produced during a 20 h explant culture period showed that not only does the uterus synthesize complement C3 but it is capable of proteolytically cleaving complement into its biologically active peptides. Since large doses of P are required for its inhibitory effects and since P can interact with the glucocorticoid receptor (GR), the role of the GR in mediating the P effect was questioned. Two antiprogesterone compounds with reportedly differing antiglucocorticoid activity, ZK98.734 and RU486, were tested for their ability to antagonize the inhibitory actions of P and Dex. Attenuation of estrogen-induced epithelial DNA synthesis by either P or Dex was fully overcome by concurrent administration of either ZK98.734 or RU486. On the other hand, while either antagonist was effective against the inhibitory action of P on estrogen-induced complement C3 synthesis, only ZK98.734 was fully effective in blocking inhibition by Dex. Thus, unlike its activity in rat hepatic cells, ZK98.734 is a potent antiglucocorticoid in the immature rat uterus. Because of this antiglucocorticoid activity, differential antagonism of the P response was not possible using these two steroid analogs. Although these observations support the notion of GR mediated inhibition of estrogen action in the uterus, they do not answer the question of whether P might act through a GR mediated pathway.
Department of Obstetrics & Gynecology, Indiana University School of Medicine, Indianapolis 46202-5196.
R M
RM
Bigsby
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015932:Complement C3c / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000037:antagonists & inhibitors*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D004963:Estrenes; D011372:Progestins; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C048260:lilopristone; D011374:Progesterone; D004958:Estradiol; D003907:Dexamethasone; D015932:Complement C3c; D004247:DNA