Prostaglandin E2 Acts via the Hypothalamus to Stimulate ACTH Secretion in the Fetal Sheep

Abstract

Prostaglandin (PG) E2 is secreted into the fetal circulation during late gestation in the sheep. Exogenous infusion of PGE2 is associated with robust increases in the circulating concentrations of ACTH and cortisol and it has therefore been proposed that endogenous PGE2 modulates the activity of the fetal HPA axis, which is the primary determinant of parturition and essential for the maturation of vital organ systems. The sites of action of PGE2 within the HPA axis have not been clearly established. We have compared the effects of PGE2 infusion on ACTH and cortisol concentrations in intact fetuses and in those whose pituitaries were surgically disconnected from hypothalamic control (hypothalamo-pituitary disconnected; HPD fetuses operated at 111-113 days gestational age). The effect of advancing gestational age on these responses was investigated by infusing PGE2 at 121, 131, 141 and 148 days of gestation. The functional integrity of the pituitary corticotrophs was tested by injecting CRH (1 microgram) into intact and HPD fetuses at day 125. This test was repeated for the HPD fetuses at 160 days. The responsiveness of the adrenal glands was also tested by injecting 2.5 micrograms/kg synthetic ACTH1-24 (Synacthen) into both groups of fetuses at day 135, with the HPD group retested at day 155. PGE2 infusion was associated with a robust increase (P < 0.001) in plasma immunoreactive (ir) ACTH in intact fetuses at all gestational ages while HPD fetuses did not respond, except at day 148 when the response was small. Similarly, cortisol concentrations were increased (P < 0.001) during PGE2 infusion in intact fetuses but not in HPD fetuses, except for a minor increase at 148 days. The response of irACTH to exogenous CRH was similar in intact and HPD fetuses at 125 days and this response was maintained in HPD fetuses at day 160. The cortisol response of intact fetuses to ACTH1-24 exceeded that of HPD fetuses at day 135 and, in HPD fetuses, this response was unchanged when they were retested at 155 days, indicating that their adrenal responsiveness did not wane with time. We conclude that the effects of PGE2 on the fetal HPA axis are exerted predominantly or exclusively at a level above the pituitary gland.