Loss of the pregnancy-induced rise in cortisol concentrations in the ewe impairs the fetal insulin-like growth factor axis

Abstract

Maternal cortisol levels increase during pregnancy. Although this change is important for optimal fetal growth, the mechanisms of the changes in growth remain unclear. We examined whether alterations in maternal plasma cortisol concentrations are associated with changes in the fetal insulin-like growth factor (IGF) axis. Pregnant ewes in late gestation (115 ± 0.4 days) were studied: six control animals, five ewes given 1 mg/kg/day cortisol (high cortisol), and five adrenalectomized ewes given 0.5-0.6 mg cortisol/kg/day (low cortisol). Blood samples were taken throughout the experiment and at necropsy (130 ± 0.2 days) and fetal liver was frozen for mRNA analysis. Fetal IGF-I and insulin plasma concentrations were lower and IGFBP-1 concentrations were higher in the low cortisol group compared with those in controls (p<0.05). Fetal liver IGF-II and IGFBP-3 (insulin-like growth factor binding protein 3) mRNA were decreased in low cortisol animals compared with those in controls (p<0.05). There were no significant changes in these parameters in the high cortisol group, and there were no changes in fetal liver IGF-I, growth hormone receptor, IGF-I receptor, IGF-II receptor, IGFBP-1 or IGFBP-2 mRNA levels between the groups. These data suggest that reduced fetal IGF availability contributes to reduced fetal growth when maternal cortisol secretion is impaired, but not during exposure to moderate increases in cortisol.

Chronic maternal hypercortisolemia in late gestation alters fetal cardiac function at birth

“…Similarly, in our studies, we have not found a decrease in fetal weight, although this may be a type II error resulting from low numbers of animals. However, as our laboratory did not find any change in concentrations of IGFs, nor changes in IGF expression in the heart in previous studies (27,47), the wellcharacterized effect of high-dose cortisol on growth appears not to be critical in the mechanism of cardiac dysfunction.…”

The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories

“…Maternal HPA axis activity and both maternal and foetal cortisol levels rise throughout pregnancy, reaching their zenith during birth ( 117 – 119 ). This rise plays an essential role in the terminal development of foetal lungs and initiating pulmonary surfactant production ( 120 ), as well as controlling hepatic ( 121 ), cardiac ( 122 ), cardiovascular ( 123 ), and G-I tract ( 124 ) maturation, as a coordinated series of events preparing the foetus for the transition to extra-uterine life.…”

SARS-CoV-2 (COVID-19) as a possible risk factor for neurodevelopmental disorders

“…Furthermore, they report that viral markers for SARS-CoV-2 were abundant in the hypothalamus of a 63-year-old male patient who died of COVID, but absent from the hypothalamus of controls (Nampoothiri et al, 2020). Very little work has been done on the possible neurodevelopmental consequences of low cortisol levels during pregnancy, but pregnancy is typically accompanied by substantial increases in cortisol (Mastorakos and Ilias, 2003;Jensen et al, 2011;Guardino et al, 2016). Several studies, conducted in sheep, indicate that lowering maternal cortisol during pregnancy alters placental morphology and reduces placental and uterine blood flow, which could result in restricted fetal growth (Jensen et al, 2005(Jensen et al, , 2007 and altered neurodevelopment, as previously discussed.…”