In sheep an increase in fetal pituitary–adrenal function, reflected in rising concentrations of plasma ACTH and cortisol, is important in relation to fetal organ maturation and the onset of parturition. This review presents evidence that implicates the hypothalamic–pituitary–adrenal axis in the control of parturition and describes recent experiments that explore in detail the maturation of the fetal hypothalamus and pituitary in relation to fetal adrenal function. Recent improvements for the measurement of ACTH in unextracted plasma and the ability to maintain vascular catheters in chronically catheterized fetal sheep have enabled subtle changes in fetal ACTH concentrations to be detected. As a result of these advances it has now been established that the terminal rise in cortisol, which is responsible for the onset of parturition in sheep, is preceded by an increase in fetal plasma ACTH concentrations. This has led to the hypothesis that birth results from the sequential development of the fetal hypothalamic–pituitary–adrenal axis with the signal originating from the fetal brain. This increase in trophic drive to the fetal adrenal may result from changes in the responsiveness of the fetal pituitary gland to factors that stimulate the release of ACTH. Corticotropin releasing factor (CRF) and arginine vasopressin are two such factors that stimulate the secretion of ACTH and cortisol secretion in the chronically catheterized fetal sheep. The response to these factors increases with gestational age and is sensitive to glucocorticoid feedback. Furthermore, repeated administration of CRF to immature fetal sheep results in pituitary and adrenal activation and in some cases may lead to premature parturition. Until recently, little was known of the controls of CRF secretion from the fetal hypothalamus. However, CRF has now been detected in the fetal sheep hypothalamus by radioimmunoassay and with immunohistochemistry, during the last third of pregnancy. The CRF material detected by radioimmunoassay co-elutes with synthetic ovine CRF on Sephadex G75 chromatography and also stimulates the release of ACTH from adult sheep pituitary cells maintained in culture. Furthermore at d100 of pregnancy (term of 145 days), CRF is released from fetal sheep hypothalami perifused in vitro both under basal conditions and in response to potassium-induced nerve terminal depolarization. Dexamethasone does not affect the release of CRF under these conditions. At d140, the hypothalamus contains similar quantities of immunoreactive and bioactive CRF which are released at a higher rate during in vitro perifusion. Potassium causes a similar release of CRF compared with d100 and again is unaffected by the presence of dexamethasone. However, at d140, dexamethasone does reduce basal CRF release. These results provide evidence for maturation of glucocorticoid feedback mechanisms at the level of the fetal hypothalamus and, together with the additional data presented in this review, illustrate the complexity of neuroendocrine control of the hypothalamic–pituitary–adrenal axis in birth.
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