Altered fetal pituitary-adrenal function in the ovine fetus treated with RU486 and meloxicam, an inhibitor of prostaglandin synthase-II.
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 PGE(2) 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 PGE(2), ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F(2 alpha) (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 PGE(2), ACTH, and cortisol concentrations, and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE(2), 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.
McKeown
K J
KJ
MRC Group in Fetal and Neonatal Health and Development, Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8. kevin.mckeown@utoronto.ca
Challis
J R
JR
Small
C
C
Adamson
L
L
Bocking
A D
AD
Fraser
M
M
Rurak
D
D
Riggs
K W
KW
Lye
S J
SJ
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006854:Hydrocortisone / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007751:Labor, Induced; D000077239:Meloxicam; D015735:Mifepristone / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000196:embryology* / Q000502:physiology*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012756:Sheep; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D015149:Tocolytic Agents / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013843:Thiazines; D013844:Thiazoles; D015149:Tocolytic Agents; D015735:Mifepristone; D015121:6-Ketoprostaglandin F1 alpha; D000324:Adrenocorticotropic Hormone; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D000077239:Meloxicam; D006854:Hydrocortisone