Effect of Cortisol Infusion on Basal and Corticotropin-eleasing Factor (CRF)-Stimulated Plasma ACTH Concentrations in the Sheep Fetus after Surgical Isolation of the Pituitary*

Abstract

Although it has been demonstrated that glucocorticoids can inhibit basal and stimulus-induced increase in fetal plasma ACTH concentrations, the site(s) of action of the glucocorticoids in the fetal hypothalamo-pituitary axis are unclear. We have investigated the ontogeny of the negative feedback effect of cortisol on basal and CRF-stimulated ACTH secretion in intact fetal sheep and in fetal sheep after surgical disconnection of the hypothalamus and pituitary (HPD). In saline-pretreated fetal sheep there was a significant increase in plasma ACTH concentrations in response to an ovine CRF (oCRF) bolus (1 microgram) in HPD and intact fetuses at 120-128 days and at 138-149 days gestation. In the intact group the ACTH response at 120-240 min after oCRF was significantly lower (P less than 0.01) after 138 days compared with before 128 days. In this group the cortisol response during the first hour after oCRF was significantly greater (P less than 0.005) after 138 days than in the younger fetuses. In the HPD group there was no significant difference between the two gestational age ranges in either the ACTH or cortisol responses to oCRF. Between 120 and 128 days gestation, increasing plasma cortisol concentrations (110-170 nmol/liter above baseline values) by exogenous infusion had no significant effect on the basal fetal plasma ACTH concentrations in HPD or in intact fetuses. In contrast, after 138 days gestation, the basal plasma ACTH concentrations were significantly decreased by 50% during the cortisol infusion period in the intact but not in the HPD group. It would appear therefore, that the development of the negative feedback action of cortisol to suppress basal fetal plasma concentrations of ACTH is dependent on the presence of a functional fetal hypothalamus. In HPD and intact fetuses cortisol infusion abolished the fetal ACTH response to the oCRF bolus from as early as 120 days gestation. Thus the negative feedback action of cortisol on the CRF-induced increases in fetal plasma ACTH concentrations can occur directly at the fetal pituitary.