title: Postcoital administration of RU486 induces a hormonally under-stimulated rat endometrium.
abstract: RU486 is a partial progesterone and estrogen receptor antagonist, functioning to actively silence progesterone receptor gene-associated transcription. For this reason, it has been used as both a contraceptive and an abortive agent. In the present study, cellular and gene specific effects of RU486 were investigated in a rat model of early pregnancy, including key phases of the window of receptivity and early implantation. As these stages are hormonally regulated by progesterone and estrogens, the focus here was to elucidate the mechanism of action of a single dose of RU486, used as a postcoital contraceptive, to successfully prevent implantation of a viable blastocyst. Immunofluorescent techniques were used to examine the change in protein levels of PR in RU486-treated endometria at days 4.5, 5.5 and 6.5 of pregnancy. Changes in the Pgr gene expression level as a consequence of RU486 administration was evaluated using quantitative real-time reverse transcription polymerase chain reaction. The progesterone receptor gene and protein expression was ubiquitously decreased throughout pregnancy as a direct consequence of RU486 administration. The overall effects of postcoital RU486 administration during early pregnancy indicate highly effective inhibition of progesterone and estrogen effects on the endometrium, mediated by their receptors. More specifically, the expression and localization of the progesterone receptor mirrors that described in ovariectomized animal models, suggesting a hormonally under-stimulated endometrium. Clearly from the present study, the precise priming of the endometrium by progesterone, in preparation for blastocyst implantation, is severely impaired by RU486, thus predisposing the uterus to pregnancy failure.
authors.affiliation: School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa; Department of Medical Sciences, Public Health and Health Promotion, School of Health Sciences, Faculty of Health Sciences, University of Limpopo, Private Bag X1106, Sovenga 0727, South Africa. Electronic address: kathrine.theron@ul.ac.za.
authors.forename: Kathrine E
authors.initials: KE
authors.lastname: Theron
authors.affiliation: Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa.
authors.forename: Clement B
authors.initials: CB
authors.lastname: Penny
authors.affiliation: School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa; Newcastle University Medicine Malaysia, No. 1 Jalan Sarjana 1, Kota Ilmu, EduCity@Iskandar, 79200 Nusajaya, Johor, Malaysia.
authors.forename: Margot J
authors.initials: MJ
authors.lastname: Hosie
mesh_terms: D000818:Animals; D003283:Contraceptives, Postcoital, Synthetic / Q000008:administration & dosage; D010064:Embryo Implantation / Q000187:drug effects*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D065171:Estrogen Receptor Antagonists / Q000008:administration & dosage; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007279:Injections, Subcutaneous; D015735:Mifepristone / Q000008:administration & dosage; D011247:Pregnancy; D011374:Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D017208:Rats, Wistar; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D003283:Contraceptives, Postcoital, Synthetic; D065171:Estrogen Receptor Antagonists; D011980:Receptors, Progesterone; D015735:Mifepristone; D011374:Progesterone
keywords: Early pregnancy; Estrogen; Implantation; Progesterone; RU486