To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins that are essential for adrenal development, we investigated the effects of, first, an ACTH infusion and labour in intact fetuses and, secondly, the effect of an ACTH infusion to fetuses with and without a pituitary gland, on the relative abundance of the mRNA encoding for the ACTH receptor (MC2R), steroidogenic factor 1 (SF-1), cholesterol side-chain cleavage enzyme (P450 scc ), 3 -hydroxysteroid dehydrogenase (3 HSD) and 17 -hydroxylase (P450 C17 ) in the fetal adrenal gland. ACTH 1-24 infusion (14·7 pmol/kg per h) to intact fetuses was without effect on the abundance of mRNA encoding MC2R and SF-1, irrespective of whether the infusion was given for 18 (115-132 days of gestation) or 32 days (115 days to term (147 days of gestation)). Hypophysectomy (HX) did not alter the expression of MC2R mRNA; however, the abundance of SF-1 mRNA fell by approximately 50% following the removal of the pituitary gland. ACTH 1-24 infusion to HX fetuses failed to restore levels of SF-1 mRNA to that seen in intact animals. P450 scc and 3 HSD mRNAs were increased by ACTH 1-24 infusion for 18 days in intact animals, although no effects of the infusion were seen on P450 C17 mRNA levels. For all three of these mRNAs, there was a significant increase in their abundance between 132 days of gestation and term in intact fetuses. By term, ACTH 1-24 infusion was without any additional effect on their abundance. HX decreased the expression of P450 scc , 3 HSD and P450 C17 mRNAs, while ACTH 1-24 infusion to HX fetuses increased the expression of these mRNAs to levels seen in intact animals. There were significant correlations between the abundance of the mRNA for P450 scc , 3 HSD and P450 C17 , but not MC2R and SF-1, and premortem plasma cortisol concentrations. These results emphasise the importance of the pituitary gland and ACTH in the regulation of the enzymes involved in adrenal steroidogenesis. Factors in addition to ACTH may also play some role, as the infusion was not always effective in increasing the abundance of the mRNAs. Surprisingly, the mRNA for MC2R and SF-1 did not appear to be regulated by ACTH in the late-gestation ovine fetus, though a pituitary-dependent factor may be involved in the regulation of SF-1 mRNA abundance.
It is clear that the timing of parturition is dependent on a cascade of endocrine signals from an intact fetal hypothalamo-pituitary-adrenal axis. What is not known, however is the nature or source of the central neural stimulation which results in the stimulation of adrenocorticotrophic hormone (ACTH) synthesis and secretion in late gestation. The changes which occur in the synthesis and posttranslational processing of the ACTH precursor, proopiomelanocortin (POMC), in the fetal anterior pituitary before birth and the consequence of these changes for expression of the corticosteroidogenic enzymes in the fetal adrenal are described in this review. Evidence for the functional heterogeneity of corticotrophic cell types in the fetal sheep pituitary and the proposal that there is a maturational change in the populations of corticotrophic cells in late gestation are discussed. Finally, the development of cortisol negative feedback in the late gestation fetal hypothalamo-pituitary axis and the relevance of chronic stress to the timing of parturition are also discussed.
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