McKeown K J, Challis J R, Small C, Adamson L, Bocking A D, Fraser M, Rurak D, Riggs K W, Lye S J
MRC Group in Fetal and Neonatal Health and Development, Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Biol Reprod. 2000 Dec;63(6):1899-904. doi: 10.1095/biolreprod63.6.1899.
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.
足月分娩和早产与胎儿下丘脑-垂体-肾上腺（HPA）轴激活增加以及胎盘内通过前列腺素H合酶-II（PGHS-II）表达增加而产生的前列腺素（PGs）合成有关。抑制PGHS-II已被提倡作为一种实现子宫抑制宫缩的方法，但这种治疗对胎儿内分泌功能的影响尚未得到充分研究。由于已知前列腺素E2（PGE2）可激活胎儿HPA轴，我们推测在诱导分娩的绵羊中给予PGHS-II抑制剂美洛昔康会抑制胎儿HPA功能。对长期插管的怀孕母羊用孕激素受体拮抗剂RU486进行处理以引发活跃分娩，然后分别用高维持剂量美洛昔康、分级维持剂量美洛昔康或生理盐水输注进行治疗。注射RU486后24小时，母羊子宫收缩频率增加，48±4小时时动物进入活跃分娩期。注射RU486导致胎儿循环中PGE2、促肾上腺皮质激素（ACTH）和皮质醇浓度升高，母羊循环中13,14-二氢-15-酮前列腺素F2α（PGFM）浓度升高。在两种输注方案下，开始输注美洛昔康后12小时内子宫活动均受到抑制。在输注美洛昔康期间，胎儿血浆中PGE2、ACTH和皮质醇浓度以及母羊血浆中PGFM浓度均显著降低。在对照动物中，给予RU486后子宫收缩频率、母羊血浆PGFM、胎儿血浆PGE2、ACTH和皮质醇浓度均升高，并在输注生理盐水期间持续上升直至分娩。我们得出结论，RU486引发的绵羊分娩与胎儿HPA功能激活有关，而在美洛昔康治疗期间这种激活作用减弱至被认为与维持妊娠相容的水平。
