Ovine uteroplacental and fetal metabolism during and after fetal cortisol overexposure in late gestation

Cortisol modifies fetal metabolism in preparation for delivery, but whether preterm cortisol exposure programs persisting changes in fetoplacental metabolism remains unknown. This study infused fetal sheep with saline (n = 36) or cortisol (n = 27) to raise fetal plasma cortisol to normal prepartum concentrations for 5 days from day 125 of gestation (term: ≈145 days). Fetal uptake and uteroplacental metabolism of glucose, oxygen, and lactate, together with fetal hepatic glucogenic capacity, were measured on the final day of infusion or 5 days later. Cortisol reduced adrenal weight and umbilical glucose uptake during infusion but increased fetal glucose concentrations, hepatic glycogen content, and hepatic glucogenic enzyme activity (fructose-1,6-bisphosphatase and glucose-6-phosphatase) and gene expression (PC and G6PC) compared with saline infusion. Postcortisol infusion, umbilical glucose uptake, and hepatic glucose-6-phosphatase activity remained low and high, respectively, whereas fetal glucose levels normalized and hepatic glycogen was lower with higher adrenal weights than in controls. Cortisol infusion increased the proportion of total uterine glucose uptake consumed by the uteroplacental tissues, irrespective of age. Placental tracer glucose transport capacity was also increased after, but not during, cortisol infusion, without changes in placental glucose transporter gene expression. Blood lactate concentration and P_CO2were higher, whereas pH and O₂content were lower in cortisol-infused than saline-infused fetuses, although uteroplacental metabolism and fetal uptake of oxygen and lactate were unaltered. The results suggest that preterm cortisol overexposure alters fetoplacental metabolism and adrenal function subsequently with persisting increases in uteroplacental glucose consumption at the expense of the fetal supply.