The role of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins essential for adrenal steroidogenesis in the late-gestation ovine fetus

Abstract

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.

Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep

“…This may have enhanced our ability to detect a treatment effect. Another investigation undertaken by Simmonds et al (44), in which fetuses were infused for a maximum of 18 days (from 115 dGA) at 14.7 pmol⅐kg Ϫ1 ⅐h Ϫ1 , also failed to demonstrate an increase in expression of ACTH-R mRNA. The relatively low sensitivity of the slot blot technique used for quantifying ACTH-R mRNA in this study may have precluded the detection of a treatment effect.…”

“…Findings from numerous in vitro studies support the notion that ACTH is a positive regulator of ACTH-R mRNA expression (23,24,27,30,31,35). Conversely, the two in vivo studies undertaken to date have not demonstrated a positive influence of ACTH on receptor expression in the fetus (6,44). Recently, our investigative group (48) reported that HPD at around 120 days of gestational age (dGA) prevented not only the late-gestation cortisol surge but also the increase in fetal plasma ACTH levels, adrenal ACTH-R mRNA and protein expression, and, indeed, adrenal responsiveness.…”

Antenatal glucocorticoids reset the level of baseline and hypoxemia-induced pituitary-adrenal activity in the sheep fetus during late gestation

“…Other results of the present study show no effect of dexamethasone on adrenocortical mass. Therefore, any maturational effects on steroidogenic capacity of dexamethasone could be mediated via effects on the activities of adrenal steroidogenic enzymes (10,11,39,45). Furthermore, Ross et al (42) showed that premature elevations in circulating cortisol, before the normal prepartum surge in fetal cortisol, suppressed the expression of 11␤-HSD type 2 mRNA in the adrenal of the sheep fetus.…”

Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis

“…The HPA axis, through regulation of glucocorticoid biosynthesis (138,157), dictates differentiation and maturation of key organ systems, including lung, liver, and kidney, and regulation of metabolism, including lipolysis, glycogenolysis, and protein catabolism (37,108,115). Acutely, activation of the HPA axis leads to a significant increase in cortisol (2,23,24,80,87), a glucocorticoid that plays a critical role in governing metabolism by influencing plasma glucose, lipid, and protein concentrations as well as immune regulation, inflammation, and cardiovascular function.…”

“…Therefore, the ability of the fetal HPA axis to adapt to limit cortisol production under conditions of chronic stress is crucial for maintaining normal development during gestation. The HPA axis must mature to permit the normal ontogenic rise in cortisol in preparation for birth (19,76,105,126,138,157) while allowing for an acute response to a secondary stressor.…”