PROSTAGLANDIN E(2) ACTS VIA THE HYPOTHALAMUS TO STIMULATE ACTH-SECRETION IN THE FETAL SHEEP

Prostaglandin (PG) E(2) is secreted into the fetal circulation during late gestation in the sheep, Exogenous infusion of PGE, is associated with robust increases in the circulating concentrations of ACTH and co rtisol and it has therefore been proposed that endogenous PGE(2) modul ates the activity of the fetal HPA axis, which is the primary determin ant of parturition and essential for the maturation of vital organ sys tems, The sites of action of PGE, within the HPA axis have not been cl early established, We have compared the effects of PGE(2) infusion on ACTH and cortisol concentrations in intact fetuses and in those whose pituitaries were surgically disconnected from hypothalamic control (hy pothalamo-pituitary disconnected; HPD fetuses operated at 111-113 days gestational age), The effect of advancing gestational age on these re sponses was investigated by infusing PGE, at 121, 131, 141 and 148 day s of gestation, The functional integrity of the pituitary corticotroph s was tested by injecting CRH (1 mu g) into intact and HPD fetuses at day 125, This test was repeated for the HPD fetuses at 160 days. The r esponsiveness of the adrenal glands was also tested by injecting 2.5 m u g/kg synthetic ACTH(1-24) (Synacthen) into both groups of fetuses at day 135, with the HPD group retested at day 155. PGE(2) 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 d id not respond, except at day 148 when the response was small, Similar ly, cortisol concentrations were increased (P < 0.001) during PGE(2) i nfusion in intact fetuses but not in HPD fetuses, except for a minor i ncrease at 148 days.The response of irACtH to exogenous CRH was simila r in intact and HPD fetuses at 125 days and this response was maintain ed in HPD fetuses at day 160, The cortisol response of intact fetuses to ACTH(1-24) exceeded that of HPD fetuses at day 135 and, in HPD fetu ses, this response was unchanged when they were retested at 155 days, indicating that their adrenal responsiveness did not wane with time. W e conclude that the effects of PGE(2) on the fetal HPA axis are exerte d predominantly or exclusively at a level above the pituitary gland.