Studies on the role of ACTH in the regulation of adrenal responsiveness and the timing of parturition in the ovine fetus

Abstract

A dramatic late-gestation increase in fetal plasma cortisol concentrations is critical for the timing of parturition in the sheep. This increase appears to depend upon an intact hypothalamo-pituitary unit and is characterised by increasing responsiveness of the fetal adrenal gland to ACTH. ACTH has been postulated as the critical determinant of the late-gestation cortisol increase; however, recent evidence has suggested that other factors, including the ACTH precursor, pro-opiomelanocortin, may also be involved. To further define the role of ACTH in determining the timing of parturition and the responsiveness of the fetal adrenal gland, intact (INT/ACTH) and hypophysectomised (HX/ACTH) fetuses received a continuous infusion of ACTH from the time of surgery (115 days gestational age (GA)) at a rate we have previously shown to generate normal fetal cortisol concentrations and term parturition in HX fetuses. A third group of saline-infused intact fetuses (INT/SAL) served as the control group. Adrenal responsiveness was assessed by cortisol responses to ACTH challenges at 120, 130 and 140 days GA.There were no differences between the three groups of fetuses in the timing of parturition, the late-gestation increase in cortisol concentrations or the size of the adrenal cortex. In both INT/SAL and INT/ACTH fetuses, there were significant increases in basal immunoreactive-ACTH concentrations with advancing GA, although no such increase was observed in HX/ACTH fetuses. The proportion of total ACTH immunoreactivity present in low molecular weight (LMW) forms in INT/ACTH fetuses was greater than that in INT/SAL fetuses, while the level of LMW ACTH in HX/ACTH fetuses was intermediate. Both ACTH (1-24) -infused groups of fetuses had dramatically enhanced adrenal responsiveness to ACTH at all GAs tested when compared with INT/SAL fetuses and there was a correlation (in rank order) between the proportion of LMW ACTH immunoreactivity and adrenal responsiveness.From these observations it appears that there is a separate regulation of adrenal responsiveness from basal cortisol concentrations and that an increase in basal cortisol concentrations can occur in the absence of an increase in basal ACTH concentrations. Furthermore, an increase in adrenal responsiveness does not appear to predict the timing of parturition nor basal cortisol concentrations. Taken together with previous studies it appears that ACTH plays an essential role in maintaining the growth of the fetal adrenal and enhancing its responsiveness, but a late-gestation increase in ACTH concentrations is not required to regulate basal cortisol concentrations or the timing of parturition.

Leptin receptor antagonist treatment ameliorates the effects of long-term maternal hypoxia on adrenal expression of key steroidogenic genes in the ovine fetus

“…The relatively constant concentrations of ACTH 1-39 during the infusion period are consistent with those previously reported during this window of gestation (21) and are also consistent with the concept that adrenocortical maturation in fetal sheep largely takes place in the presence of relatively steady basal levels of ACTH during late gestation (32). The lack of effect of the leptin antagonist on ACTH 1-39 , compared with the inhibitory actions of exogenous leptin previously noted in fetal sheep, may relate to the gestational age of the animals in the present study and the mode of administration (peripheral vs. central) of the leptin antagonist.…”

Lipopolysaccharide-Induced Tumor Necrosis Factor-Alpha Release Is Controlled by the Central Nervous System

“…LPS-induced tumor necrosis factor (TNF)-· and interleukin (IL)-1 can signal the central nervous system and stimulate corticotrophinreleasing hormone release into the hypophyseal portal veins that transport it to the anterior pituitary gland where it stimulates the release of adrenocorticotropic hormone from the corticotropes [1]. Adrenocorticotropic hormone circulates to the adrenal cortex and stimulates the release of glucocorticoids [9]. LPS also alters the secretion of other pituitary hormones, increasing prolactin (PRL) release and decreasing growth hormone and luteinizing hormone release [5].…”

Effect of Antalarmin, a Novel Corticotropin-Releasing Hormone Antagonist, on the Dynamic Function of the Preterm Ovine Fetal Hypothalamo-Pituitary-Adrenal Axis

“…The presence of immunoreactive, ACTH-related peptides with corticotropic, unchanged or anticorticotropic biological activity has been demonstrated in plasma and pituitaries of intact fetuses [10, 23, 34, 35, 36, 37, 38, 39, 40, 41]and it has been speculated that this immunoreactivity may correspond to high molecular weight (MW) ACTH precursors [20, 38, 42, 43]. We have previously demonstrated that the HPD fetus has normal concentrations of both low and high MW ACTH-containing peptides by chromatography [13]and by two site immunoradiometric assays at days 130–140 GA [38, 44]and we now report an apparently identical biological scenario in intact fetuses using a radioimmunoassay that appears to preferentially bind low MW ACTH-immunoreactive species (our unpublished data based on assay of gel chromatography eluates from fetal plasma). The presence of immunoreactive, but not bioactive, ACTH in the intact fetal sheep circulation could explain the apparent lack of congruence of ir-ACTH and cortisol concentrations that has been reported in fetal sheep in this and many other studies.…”

“…The secretory dynamics of ir-ACTH and cortisol were assessed by deconvolution analysis [27]at day 138 GA using samples drawn 5 min apart over 3 h [15]. At day 140 GA the adrenal response to a standard dose of ACTH 1–24 (2.5 µg/kg) was determined [13, 14]. …”

“…In addition, the fetal HPA axis exhibits unique features not in keeping with our understanding of the adult HPA axis. These include the presence in the plasma of multiple corticotropin (ACTH)-containing peptides [10, 11], an ambiguous role of ACTH in regulating basal glucocorticoid secretion [12, 13, 14, 15], the phenomenon of the exponential increase in plasma glucocorticoid in the ovine fetus [16], and the possibility that placentally-derived agonists may act at the hypothalamic and adrenal levels of the axis [12, 17, 18]. …”