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

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 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.

Effects of periconceptional undernutrition on the initiation of parturition in sheep

“…(9 -11) and with the hypothesis currently favored in the literature suggesting that the surge in fetal adrenal cortisol production at the end of gestation resulting from sustained activation of the fetal HPAA leads to increased placental trophoblast PGHS-2 expression and PGE 2 production (31). The alternative hypothesis, not supported by our data, suggests that placental PGE 2 production might play a key role in mediating fetal HPAA activation in late-gestation sheep fetuses (18,20,28). This does not exclude the possibility that placental PGE 2 may directly stimulate the fetal adrenal, sustaining the activation of the fetal HPAA at the end of gestation via a feed forward loop (1,18).…”

“…The alternative hypothesis suggests that placental PGE 2 production might play a key role in mediating fetal HPAA activation, as fetal PGE 2 infusion increased cortisol and ACTH concentrations (18,28), and specific inhibition of PGH synthase (PGHS)-2 blocked the increase in fetal plasma cortisol and ACTH concentrations in late-gestation sheep (20). Hence placental PGE 2 may directly stimulate the fetal adrenal gland, sustaining the activation of the fetal HPAA at the end of gestation via a feed forward loop (1,18).…”

Dose-Dependent Effects of Meloxicam Administration on Cyclooxygenase-1 and Cyclooxygenase-2 Protein Expression in Intrauterine Tissues and Fetal Tissues of a Sheep Model of Preterm Labor

“…15,16 Blood samples (1.5 mL) for MEL measurement and various blood analyses (0.5 mL) were also collected at the same times. Maternal gastrointestinal activity was assessed by the observation of fecal consistency.…”

“…MEL administration has been shown to decrease PG production and uterine activity in the sheep model. 15,16 Since it has been previously shown that other nonsteroidal anti-inflammatory drugs (NSAIDs) can affect not only enzyme activity but also expression of the enzyme, this led us to evaluate the effect of MEL on protein expression of COX-1, COX-2, and PGDH. 17,18 Thus, nimesulide has been shown to downregulate COX-2 mRNA expression in ovine endometrium, myometrium, and placenta, 17 while indomethacin treatment has been shown to increase PGDH mRNA expression in tumor C cells.…”

Role of the Low‐Affinity Glucocorticoid Receptor in the Regulation of Behavior and Energy Metabolism in the Migratory Red KnotCalidris canutus islandica

“…Birds were divided into three treatment groups consisting of 10 animals each: (1) vehicle-injected controls, (2) birds administered with 10 mg/kg of RU486 (mifepristone; Sigma), and (3) birds administered with 50 mg/kg of RU486. Dose was determined from previous studies conducted in mammals (Hinz and Hirschelman 2000;McKeown et al 2000). RU486 was suspended in vehicle (peanut oil; Hain Celestial) via sonication and was administered by subcutaneous injection.…”