Increased maternal nighttime cortisol concentrations in late gestation alter glucose and insulin in the neonatal lamb

Abstract

Previous studies in our laboratory have shown that a modest chronic increase in maternal cortisol concentrations impairs maternal glucose metabolism and increases the incidence of perinatal stillbirth. The dramatic outcomes prevented our ability to study the effects of maternal hypercortisolemia on neonatal growth, glucose metabolism, and hypothalamo–pituitary–adrenal axis response. Therefore, we developed a model in which pregnant ewes are infused for 12 h/day at 0.5 mg·kg–1·day–1 from day 115 of gestation until delivery (˜145), elevating nighttime plasma cortisol concentrations. This pattern of elevation of cortisol mimics that in patients with elevated evening cortisol concentrations, as in Cushing’s syndrome or chronic depression. Plasma cortisol, glucose, insulin, and electrolytes were measured during pregnancy and postpartum in control and cortisol-infused ewes and their postnatal lambs for the first 14 days after delivery. Neonatal growth and plasma ACTH, aldosterone, renin activity, and electrolytes, and organ weights at 14 days of age were also measured. Infusion of cortisol increased maternal plasma cortisol during pregnancy but not postpartum, and did not alter neonatal ACTH or cortisol. Although maternal glucose and insulin concentrations were not changed by the maternal infusion of cortisol, neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group. Neonatal ponderal index and kidney weight were reduced, left ventricular wall thickness was increased, and plasma sodium and creatinine were increased after maternal cortisol infusion. These results suggest that excess maternal cortisol concentrations in late gestation alter growth, glucose and insulin regulation, and organ maturation in the neonate.

A Transcriptomic Model of Postnatal Cardiac Effects of Prenatal Maternal Cortisol Excess in Sheep

“…Although morning maternal cortisol concentrations were increased in the ewes prior to birth, plasma cortisol concentrations were not different postpartum in the ewes or between the two groups of lambs. There was an overall effect of CORT to increase plasma glucose and decrease plasma insulin concentrations in the postnatal lambs, and therefore average glucose to insulin ratio was increased in the CORT lambs, as previously reported (Antolic et al, 2015).…”

“…The in vivo data and morphometrics at 2 weeks of age in the control and cortisol-treated ewes and their lambs has been previously reported (Antolic et al, 2015). The average morning cortisol concentration during the infusion was 22.0 ± 4.0 ng/ml in CORT ewes and 9.5 ± 2.6 ng/ml in the Control ewes.…”

“…Ewes were of similar body condition and were fed a diet of pelleted feed at a weight within NRC standards for the ewe’s body weight, fetal number and gestational age, with supplementation with alfalfa hay from 140 day onward. Ewes were prepared with chronic indwelling femoral arterial and venous catheters at approximately day 115 of pregnancy under isoflurane anesthesia as previously described (Antolic et al, 2015). Ewes were randomly assigned at surgery to one of two groups: control with no infusion (Control; n = 7 ewes), or cortisol- infused (CORT, n = 10 ewes; Cortisol (Solu-Cortef, Pfizer, Inc.).…”

“…The heart is one of the organs in which cortisol appears to play a vital role in maturation (Rog-Zielinska et al, 2013). However, excess glucocorticoids or repeated exogenous glucocorticoid treatments, have been found to reduce birth weight (Newnham and Moss, 2001; Davis et al, 2009), increase postnatal blood pressure (Dodic et al, 1998, 2001, 2002a,b), and alter postnatal glucose metabolism (Moss et al, 2001; Sloboda et al, 2002; Antolic et al, 2015).…”

Adverse Intrauterine Environment and Cardiac miRNA Expression

“…Maternal stress during pregnancy has been extensively studied in relation to the development of the fetal brain and the hypothalamo–pituitary–adrenal (HPA) axis. These studies demonstrate changes in molecular and behavioral differences in offspring of chronically stressed mothers [ 123 , 125 , 126 , 127 ]. The major stress hormone, cortisol, increases in the maternal circulation two to four fold over the course of gestation.…”