The impact of prenatal glucocorticoid administration on the development and long term activity of the hypothalamic-pituitary-adrenal and metabolic axes
grantor:
University of TorontoFew studies have examined the effects of clinically relevant doses of glucocorticoids on HPA and metabolic function. Moreover, there is little information available regarding differential effects based on the route of administration. Repeated administration of betamethasone in the pregnant sheep resulted in reduced fetal weight and increases in cord plasma adrenocorticotropin (ACTH) and cortisol and a rise in cord plasma corticosteroid binding capacity (CBC), which was associated with an increase in fetal hepatic corticosteroid binding globulin (CBG) mRNA levels. This increase in CBC may result in a decrease in free circulating cortisol levels, thereby reducing negative feedback at the hypothalamus or the pituitary. Local availability of glucocorticoids is regulated by the enzyme 11ßHSD1, responsible for the conversion of cortisone to cortisol. Maternal betamethasone administration resulted in an increase in fetal hepatic 11ßHSD1 mRNA and protein levels. Alterations in 11ßHSD1 could generate increased levels of local cortisol in the fetal liver, and affect expression of glucocorticoid sensitive hepatic enzymes involved in the regulation of glucose production. To investigate postnatal effects of prenatal glucocorticoid administration, single or multiple doses of betamethasone were administered to the mother or fetus and lambs were challenged at 6 months and one year with CRH + AVP and glucose. One dose of maternal betamethasone resulted in elevations in basal and stimulated cortisol concentrations, without associated changes in ACTH responses at one year. Fetal betamethasone administration resulted in attenuated ACTH responses to CRH + AVP at one year not associated with alterations in cortisol levels. Both single and multiple doses of maternal betamethasone resulted in elevated insulin responses to glucose at 6 months, which may indicate the onset of insulin resistance. At one year, this effect was only present in animals that received multiple doses. Furthermore, animals that received one dose of maternal betamethasone demonstrated elevated basal glucose levels at one year. At 6 months offspring treated with maternal betamethasone are able to maintain normal glucose tolerance through an increased insulin response. Therefore, antenatal glucocorticoid exposure altered HPA and metabolic function and these changes persisted into adult life.Ph.D
