Differential effects of natural and synthetic glucocorticoids on cytochrome 17α-hydroxylase (P-45017α,) and cytochrome P-450 side-chain cleavage (P-450scc) 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 cytochrome P-450 side-chain cleavage messenger ribonucleic acid in the sheep placenta and to determine whether feed-forward effects during labor are involved in further inducing placental cytochrome 17 alpha-hydroxylase. STUDY DESIGN: Sheep underwent placement of myometrial electromyogram electrodes while they were under general anesthesia at 117 days' gestation. At 125 days' gestation either saline solution (early control animals not in labor, n = 5), 0.48 mg betamethasone during 48 hours (n = 7), 0.48 mg dexamethasone during 48 hours (n = 7), or 55 mg cortisol during a maximum of 96 hours (n = 4) was directly administered intravenously to the fetus. Necropsies were performed at 127 to 129 days' gestation. We also studied 6 awes in spontaneous 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 activity was inhibited by intravenous infusion to the ewe of the selective cyclooxygenase 2 inhibitor nimesulide 9 hours after the onset of labor beginning at 147 to 148 days' gestation. Total fetal placental ribonucleic acid was 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 acid was detectable neither in term control animals not in labor nor in early control animals not in labor. Placental cytochrome 17 alpha-hydroxylase messenger ribonucleic acid was induced in spontaneous term labor and all cortisol-infused sheep in labor with respect to term control animals not in labor and early control animals not in labor (P <.01). All betamethasone-infused sheep had myometrial contraction activity; however, only 4 of 7 had detectable 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' gestation) or glucocorticoid-induced premature labor and spontaneous term labor. CONCLUSIONS: (1) In sheep the expression of placental cytochrome 17 alpha-hydroxylase is tightly associated with spontaneous term labor, and active synthesis of placental cytochrome 17 alpha-hydroxylase is required during the progression of labor. (2) Cortisol is a more potent stimulator of placental cytochrome 17 alpha-hydroxylase messenger ribonucleic acid in sheep than are synthetic glucocorticoids. (3) Betamethasone has a greater effect in inducing labor in sheep than does dexamethasone, possibly mediated through placental cytochrome 17 alpha-hydroxylase. (Am J Obstet Gynecol 1999;180:1215-21.).