Divergent changes in plasma ACTH and pituitary POMC mRNA after cortisol administration to late-gestation ovine fetus

Abstract

Plasma concentrations of cortisol and adrenocorticotropic hormone (ACTH) rise in the late-gestation sheep fetus at approximately the same time as there is an increase in the plasma levels of corticosteroid- binding globulin (CBG). We hypothesized that intrafetal cortisol infusion during late pregnancy would stimulate an increase in fetal plasma CBG, which in turn would bind cortisol and diminish glucocorticoid negative-feedback regulation of the fetal pituitary, leading to an increase in plasma ACTH concentrations. Cortisol was infused into chronically catheterized fetal sheep beginning at 126.1 ± 0.5 days of gestation and continued for 96 h. Control fetuses were infused with saline. In cortisol-infused fetuses, the plasma cortisol concentrations rose significantly from control levels (4.4 ± 0.6 ng/ml) to 19.3 ± 3.1 ng/ml within 24 h and remained significantly elevated throughout the infusion period. Plasma immunoreactive (ir) ACTH concentrations were significantly elevated in cortisol-infused fetuses within 24–48 h and remained significantly higher than in controls throughout the 96-h experimental period. Plasma free cortisol concentrations increased 10-fold and remained significantly elevated in cortisol-infused animals, despite a rise in plasma corticosteroid-binding capacity. Levels of pituitary proopiomelanocortin (POMC) mRNA in the fetal pars distalis and pars intermedia were 96 and 38% lower, respectively, after 96 h of cortisol infusion. Therefore physiological elevations of plasma cortisol, in the late-gestation ovine fetus, lead to increases in mean plasma irACTH concentrations, but this is not associated with increases in fetal pituitary POMC mRNA levels.

Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term

“…Less staining was observed, however, in the pars distalis of treated pituitaries. These observations are consistent with those of Jeffray et al (1998), who reported a decrease in the number of ir-ACTH-positive corticotrophs in the fetal pars distalis after 96 h of fetal cortisol infusion, but no change in the pars intermedia. Content of ACTH(1-39) in the pars distalis was similar in 146-day fetuses of both groups.…”

“…Hypothalamic sections were incubated with -35 Slabelled, 45-mer oligonucleotide antisense probes complementary to bases 503-547 of the ovine CRH gene (Matthews et al 1991), bases 146-191 of the GR gene (Yang et al 1992), bases 1-45 of the bovine PENK gene (Noda et al 1982), and to bases 771-816 of the ovine oxytocin-neurophysin gene (Ivell et al 1990). All probes have been characterised and used previously (Matthews et al 1991, Broad et al 1993, Matthews & Challis 1995a, Jeffray et al 1998. Control slides were incubated with -35 S-labelled, 45-mer oligonucleotide random sequences, which did not correspond to the antisense probes.…”

Effect of maternal nutrient restriction in early gestation on development of the hypothalamic-pituitary-adrenal axis in fetal sheep at 0.8-0.9 of gestation

“…Pituitary POMC levels may be downregulated by an increase in the efficacy of glucocorticoid-mediated negative feedback mechanisms. This effect could be mediated by exposure to elevated plasma glucocorticoid concentrations ( Jeffray et al 1998), or by an increase in pituitary glucocorticoid receptor number. Pituitary responsiveness could also be reduced by downregulation of CRH receptor numbers, and experiments have shown that this type of effect is associated with an attenuation of ACTH secretion (Lu et al 1994).…”

Impact of maternal undernutrition on the hypothalamic–pituitary–adrenal axis responsiveness in sheep at different ages postnatal

“…Plasma ACTH levels were measured by a commercial RIA kit that detects ACTH 1-24 (DiaSorin Inc., Stillwater, MN, USA) and that has previously been validated for use in the sheep (Jeffray et al 1998). The sensitivity of the assay was 15 pg/ml.…”