Activation of pituitary-adrenal function in fetal sheep by corticotrophin-releasing factor and arginine vasopressin

In sheep, birth is preceded by an increase in fetal plasma concentrations of ACTH and cortisol. Activation of the fetal pituitary-adrenal axis is pivotal to the onset of parturition in this species and may be regulated, at least in part, by corticotrophin-releasing factor (CRF). Pulsed administration of CRF has been shown to activate the fetal pituitary-adrenal axis in immature fetal sheep. However, pituitary ACTH responsiveness declined after continued administration of CRF, as a result of increasing negative feedback effects of increased concentrations of endogenous cortisol. To test the hypothesis that arginine vasopressin (AVP) is required, in addition to CRF, to produce the necessary trophic stimulus to the pituitary-adrenal axis, we administered saline, CRF (1 μg), AVP (200 ng) or CRF plus AVP as pulses every 4 h for 7 days to fetal sheep beginning at days 117-120 of pregnnacy (term = 145 days). Pituitary-adrenal responses were assessed by measuring plasma concentrations of immunoreactive (ir) ACTH and cortisol in response to one of the pulses on each of the 7 days of treatment. On day 1, CRF and AVP significantly increased plasma concentrations of ir-ACTH and there was a synergistic interaction when the two peptides were given together (P <0.05). However, as pulsed treatment continued there was a decline in the pituitary ir-ACTH response to all treatments (P <0.05). This decline in pituitary response occurred over a much longer period of time when CRF and AVP were given together when compared with the two peptides given separately. In contrast, the cortisol response to endogenously released ir-ACTH after administration of CRF, AVP or CRF plus AVP was small on day 1 but gradually increased as treatment progressed. This was particularly apparent when the two peptides were given together. A significant inverse correlation (r = 0.781, P <0.01) between basal cortisol concentrations and the ir-ACTH response to CRF plus AVP was observed over the 7 days of treatment. Premature delivery was not induced by any of the treatments despite significant increases in fetal adrenal weight. Furthermore, there were no changes in the circulating maternal plasma concentrations of progesterone or oestrone during the 7 days of the experiment. We conclude that a combination of CRF and AVP administered as pulses to immature fetal sheep results in a greater degree of pituitary-adrenal activation when compared with the two peptides given independently. However, even after this combined treatment regimen pituitary responsiveness eventually declines, an effect which may be due to increased negative feedback effects of increased endogenous cortisol.