THE EFFECTS OF ESTRADIOL-17-BETA INFUSION INTO FETAL SHEEP IN LATE-GESTATION

Activation of the hypothalamic-pituitary-adrenal (HPA) axis of fetal s heep during late gestation is associated with increases in plasma conc entrations of adrenocorticotropic hormone (ACTH) and cortisol, and ult imately results in parturition. However, the mechanisms contributing t o the concurrent increases in ACTH and cortisol are unclear. Plasma es tradiol-17 beta (E-2) concentrations increase progressively in the pre partum ovine fetus, and we hypothesized that E-2 may influence HPA act ivity by affecting either basal and/or hypoxemia-stimulated ACTH relea se. We examined potential mechanisms, including altered expression of pro-opiomelanocortin (POMC) in fetal pituitary corticotrophs, and chan ges in corticosteroid binding globulin (CBC) and/or the enzymes 11 bet a hydroxy steroid dehydrogenase (11 beta HSD)-1 or 11 beta HSD-2 in li ver and placenta, that could alter negative feedback control. We infus ed fetal sheep at 127 d of gestation with either E-2 (100 mu g/24 h) o r 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 measureme nt of basal plasma ACTH and cortisol concentrations, as well as plasma corticosteroid binding capacity (CBC). Placenta and fetal liver sampl es 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 Nort hern blotting. Fetal pituitary samples were collected for measurement of POMC mRNA by in situ hybridization. In a separate experiment, fetus es 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 pe riod of hypoxemia for measurement of plasma ACTH and cortisol concentr ations. E-2 infusion had no effect on basal plasma concentrations of A CTH or total cortisol, or on the stimulated levels of ACTH or total co rtisol achieved in response to hypoxemia. Basal fetal pituitary POMC m RNA also did not change significantly with E-2 infusion. No significan t increases were observed in plasma CBC during E-2 administration. How ever, hepatic CBC and 11 beta HSD-1 mRNA were significantly elevated i n 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 concen trations may alter the expression of genes encoding proteins implicate d in tonic regulation of fetal HPA function.