The effects of estradiol-17 beta infusion into fetal sheep in late gestation

Activation of the hypothalamic-pituitary-adrenal (HPA) axis of fetal sheep during late gestation is associated with increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol, and ultimately results in parturition. However, the mechanisms contributing to the concurrent increases in ACTH and cortisol are unclear. Plasma estradiol-17 beta (E-2) concentrations increase progressively in the prepartum ovine fetus, and we hypothesized that E-2 may influence HPA activity by affecting either basal and/or hypoxemia-stimulated ACTH release. We examined potential mechanisms, including altered expression of pro-opiomelanocortin (POMC) in fetal pituitary corticotrophs, and changes in corticosteroid binding globulin (CBC) and/or the enzymes 11 beta hydroxy steroid dehydrogenase (11 beta HSD)-1 or 11 beta HSD-2 in liver and placenta, that could alter negative feedback control. We infused fetal sheep at 127 d of gestation with either E-2 (100 mu g/24 h) or saline for 100 h. Fetal arterial blood samples were collected at 8 h intervals during the infusion of E-2 or saline (n = 4), for measurement of basal plasma ACTH and cortisol concentrations, as well as plasma corticosteroid binding capacity (CBC). Placenta and fetal liver samples were collected at 100 h for measurement of placental 11 beta HSD-1 and 11 beta HSD-2 mRNA and hepatic CBC and 11 beta HSD-1 mRNA, by Northern blotting. Fetal pituitary samples were collected for measurement of POMC mRNA by in situ hybridization. In a separate experiment, fetuses were exposed to 2 h of hypoxemia at 75 h of E-2 or saline infusion (n = 4), and fetal arterial blood samples were collected during the period of hypoxemia for measurement of plasma ACTH and cortisol concentrations. E-2 infusion had no effect on basal plasma concentrations of ACTH or total cortisol, or on the stimulated levels of ACTH or total cortisol achieved in response to hypoxemia. Basal fetal pituitary POMC mRNA also did not change significantly with E-2 infusion. No significant increases were observed in plasma CBC during E-2 administration. However, hepatic CBC and 11 beta HSD-1 mRNA were significantly elevated in the livers of E-2-treated fetuses. Placental 11 beta HSD-1 mRNA; but not 11 beta HSD-2 mRNA was increased by E-2 treatment. These data do not support a direct effect of exogenous E-2 at the level of basal or hypoxemia-stimulated ACTH output, but suggest that elevated E-2 concentrations may alter the expression of genes encoding proteins implicated in tonic regulation of fetal HPA function.