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Effects of RU486 on Estrogen, Progesterone, Oxytocin, and Their Receptors in the Rat Uterus during Late Gestation¹

The Perinatal Research Centre, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada T5H 3V9

Address all correspondence and requests for reprints to: Dr. B. F. Mitchell, Department of Obstetrics and Gynecology, No. 205 CSC, 10240 Kingsway Avenue, Edmonton, Alberta, Canada T5H 3V9. E-mail: brymitch{at}gpu.srv.ualberta.ca

Oxytocin (OT) and its receptor (OTR) are synthesized in the endometrium and myometrium of the pregnant rat during late gestation. Both are regulated by estrogen and progesterone (P₄), and tissue concentrations of both increase markedly before parturition. The P₄ antagonist RU486 will induce parturition in the rat. The purpose of the present studies was to investigate changes in OT and OTR messenger RNA (mRNA) and peptide synthesis within the pregnant rat uterus during RU486-induced parturition.

Pregnant rats were given a single injection of RU486 (2.5 mg/rat in oil) on day 15 of pregnancy (normal delivery occurs on day 22). Control animals received injections of oil only. Groups of animals (n = 5 in each group) were euthanized at 0, 6, 12, 24, and 48 h after injection and during labor (immediately after delivery of the first pup). Maternal serum estradiol (E₂), P₄ and uterine OT, and PGE₂ concentrations were measured by RIA. Prostaglandin F₂ and estrogen receptor levels were measured by enzyme immunoassay (EIA). OTR and P₄ receptor (PR) were measured using radioligand-binding assays. OT, OTR, and estrogen receptor mRNAs were measured with ribonuclease protection assays.

The average time to delivery, after RU486 injection, was 27.0 ± 1.2 h. Serum E₂ and P₄ levels were increased slightly, but significantly, at 24 h after RU486. In controls, OT mRNA increased significantly, and this increase was blocked in the RU486 treatment group. OTR mRNA levels increased within 6 h of RU486 and remained elevated until delivery. OTR peptide was increased by 12 h. PGE₂ and PGF₂ were increased 3-fold and 16-fold, respectively, but not until after the increase in OTR had occurred.

We conclude that the mechanism of action of RU486 is to inhibit the P₄ suppression of OTR synthesis, allowing increased expression of OTR, which may directly stimulate myometrial contractions or act indirectly through increased synthesis of PGs.

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