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Altered Fetal Pituitary-Adrenal Function in the Ovine Fetus Treated with RU486 and Meloxicam, an Inhibitor of Prostaglandin Synthase-II¹

^a MRC Group in Fetal and Neonatal Health and Development, ^b Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 ^c Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada M5G 1X5 ^d University of Western Ontario and Lawson Research Institute, London, Ontario, Canada N6A 5B8 ^e MRC Group in Development and Fetal Health, Department of Obstetrics and Gynecology, University of British Columbia, British Columbia, Canada V6T 1Z3 ^{f g} Faculty of Pharmaceutical Sciences, University of British Columbia, British Columbia, Canada V6T 1Z3

ABSTRACT

Term and preterm labor are associated with increased fetal hypothalamic-pituitary-adrenal (HPA) activation and synthesis of prostaglandins (PGs) generated through the increased expression of prostaglandin H synthase-II (PGHS-II) in the placenta. Inhibition of PGHS-II has been advocated as a means of producing uterine tocolysis, but the effects of such treatment on fetal endocrine functions have not been thoroughly examined. Because PGE₂ is known to activate the fetal HPA axis, we hypothesized that administration of meloxicam, a PGHS-II inhibitor, to sheep in induced labor would suppress fetal HPA function. Chronically catheterized pregnant ewes were treated with RU486, a progesterone receptor antagonist, to produce active labor, and then treated with either high-maintenance-dose meloxicam, graded-maintenance-dose meloxicam, or a saline infusion. Maternal uterine contraction frequency increased 24 h after the RU486 injection and the animals were in active labor by 48 ± 4 h. RU486 injection led to increased concentrations of PGE₂, ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F₂ (PGFM) in the maternal circulation. Uterine activity was inhibited within 12 h of beginning meloxicam infusion at both infusion regimes. During meloxicam infusion there were significant decreases in fetal plasma PGE₂, ACTH, and cortisol concentrations, and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE₂, ACTH, and cortisol concentrations increased after RU486 administration, and continued to rise during saline infusion until delivery occurred. We conclude that RU486-provoked labor in sheep is associated with activation of fetal HPA function, and that this is attenuated during meloxicam treatment to a level considered compatible with pregnancy maintenance.

FOOTNOTES

First decision: 16 May 2000.

¹ We gratefully acknowledge the support of the Medical Research Council of Canada (Operating Grant MT-14395; Group Grant in Development and Fetal Health; Group Grant in Fetal and Neonatal Health and Development).

² Correspondence: Kevin McKeown, Department of Physiology, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8. FAX: 416 978 4940; kevin.mckeown{at}utoronto.ca

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