Differential effects of natural and synthetic glucocorticoids on cytochrome 17 alpha-hydroxylase (P-450(17 alpha),) and cytochrome P-450 side-chain cleavage (P-450(scc)) messenger ribonucleic acid in the sheep placenta

OBJECTIVE: Our purpose was to determine differential effects of natural and synthetic glucocorticoids on cytochrome 17 alpha-hydroxylase and cytochrom e P-450 side-chain cleavage messenger ribonucleic acid in the sheep placent a and to determine whether feed-forward effects during labor are involved i n further inducing placental cytochrome 17 alpha-hydroxylase. STUDY DESIGN: Sheep underwent placement of myometrial electromyogram electr odes while they were under general anesthesia at 117 days' gestation. At 12 5 days' gestation either saline solution (early control animals not in labo r, n = 5), 0.48 mg betamethasone during 48 hours (n = 7), 0.48 mg dexametha sone during 48 hours (n = 7), or 55 mg cortisol during a maximum of 96 hour s (n = 4) was directly administered intravenously to the fetus. Necropsies were performed at 127 to 129 days' gestation. We also studied 6 awes in spo ntaneous term labor at 143-147 days' gestation, 6 term control animals not in labor at 140 to 147 days' gestation, and 6 sheep in which myometrial act ivity was inhibited by intravenous infusion to the ewe of the selective cyc looxygenase 2 inhibitor nimesulide 9 hours after the onset of labor beginni ng at 147 to 148 days' gestation. Total fetal placental ribonucleic acid wa s analyzed by Northern blot with complementary deoxyribonucleic acid probes for cytochrome 17 alpha-hydroxylase, cytochrome P-450 side-chain cleavage, and 185 ribosomal ribonucleic acid to correct for loading. RESULTS: Placental cytochrome 17 alpha-hydroxylase messenger ribonucleic ac id was detectable neither in term control animals not in labor nor in early control animals not in labor. Placental cytochrome 17 alpha-hydroxylase me ssenger ribonucleic acid was induced in spontaneous term labor and all cort isol-infused sheep in labor with respect to term control animals not in lab or and early control animals not in labor (P <.01). All betamethasone-infus ed sheep had myometrial contraction activity; however, only 4 of 7 had dete ctable placental cytochrome 17 alpha-hydroxylase messenger ribonucleic acid . Placental cytochrome 17 alpha-hydroxylase messenger ribonucleic acid was not detected in dexamethasone-infused sheep, even the 2 that had myometrial contractions. After reversal of the progression of spontaneous labor with nimesulide placental cytochrome 17 alpha-hydroxylase messenger ribonucleic acid was significantly lower than the spontaneous term labor group (without nimesulide treatment). The placentas from all animals expressed cytochrome P-450 side-chain cleavage messenger ribonucleic acid, but no changes were associated with either gestational age studied (130 versus > 140 days' gest ation) or glucocorticoid-induced premature labor and spontaneous term labor . CONCLUSIONS: (1) In sheep the expression of placental cytochrome 17 alpha-h ydroxylase is tightly associated with spontaneous term labor, and active sy nthesis of placental cytochrome 17 alpha-hydroxylase is required during the progression of labor. (2) Cortisol is a more potent stimulator of placenta l cytochrome 17 alpha-hydroxylase messenger ribonucleic acid in sheep than are synthetic glucocorticoids. (3) Betamethasone has a greater effect in in ducing labor in sheep than does dexamethasone, possibly mediated through pl acental cytochrome 17 alpha-hydroxylase. (Am J Obstet Gynecol 1999;180:1215 -21.).