Maturation and activation of hypothalamic-pituitary adrenal function in fetal sheep

The progressive rise in the concentration of cortisol in the plasma of fetal sheep during late pregnancy arises from the sequential maturation of the fetal HPA axis. In addition, cortisol itself occupies a central role in accelerating this process through a series of feed-forward mechanisms. Before days 100-110 of pregnancy AVP appears to predominate over CRH as the major corticotropin-releasing factor in the fetus. Pituitary responsiveness to CRH increases progressively after day 100, and precedes maturation of fetal adrenal responsiveness to endogenous or exogenous ACTH. Cortisol accelerates the increase in the ratio of adult-fetal corticotropes in the fetal pituitary. In addition, cortisol modulates the mechanism by which ACTH activates fetal adrenal function, possibly through an action at the level of the ACTH receptor. Cortisol appears also to mediate the rise in fetal plasma CBG concentrations during late pregnancy, and may thereby alter the efficacy of the negative feedback process. In women, cortisol acts on the placenta to promote rather than to inhibit CRH output. CRH from the placenta may reach significant concentrations in the fetal circulation and augment the drive to fetal ACTH release. It may also act in a paracrine fashion to promote placental POMC gene expression. The importance of placental CRF and ACTH in the sheep is not yet apparent. These feed-forward loops establish a series of positive cascades that ensure concurrent rises in plasma ACTH and cortisol in the fetal circulation during late pregnancy. We suggest that this sequence leads to, and is broken by, the process of birth.