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Glucorticoid programming of development during early life
Human epidemiological studies have shown that low birthweight is associated with an increased incidence of adult metabolic disease. Similarly, in experimental animals, induction of fetal growth restriction alters adult metabolic phenotype. Collectively, these studies have led to the concept that sub-optimal environmental conditions during early development program later metabolic dysfunction. Glucocorticoid stress hormones may mediate many of these environmental programming effects as they inhibit fetal growth and their maternal administration is known to alter metabolic and endocrine function of the adult offspring in several species. Normally, glucocorticoids only act as prepartum maturational signals but, earlier in development, they can also act as signals of environmental adversity. However, relatively little is known about the programming effects of neonatal glucocorticoid overexposure when tissues are particularly glucocorticoid-sensitive.
In horses unlike other species, the fetal hypothalamic-pituitary-adrenal (HPA) axis develops late in gestation with the main cortisol increment after not before birth. Indeed, in preterm and dysmature foals, cortisol concentrations can be high for several days after birth. Thus, horses may be more susceptible to glucocorticoid programming in the neonatal rather than fetal period of development. Administration of synthetic glucocorticoids to pregnant mares near term (≥300 days) causes both stillbirth and early delivery of viable foals depending on the exact gestational age at treatment (4). In ponies in late gestation (≥270 days), this treatment causes maternal hyperinsulinaemia and hyperglycaemia, indicative of insulin resistance, but has little effect on gestational length or foal birth weight and size, although it does have minor actions on foal HPA function in the first 2-3 weeks after birth. In contrast, raising cortisol concentrations endogenously in the foal for 5 days after birth by ACTH administration had little effect on HPA function in the young foal (≤15 weeks) but did alter basal ACTH concentrations and hypoglycaemia-induced ACTH secretion in the adult ponies at 1 and 2 years of age in association with sex-linked differences in adreno-cortical growth at 2 years. In addition, neonatal cortisol overexposure reduced glucose-stimulated insulin secretion in the young foals but not in the adults while increasing insulin sensitivity in the young foals and yearlings but not in the 2 year olds. However, the extent to which these changes persist, resolve or exacerbate with increasing age remains unknown. Cortisol overexposure of equine neonates, therefore, programs their subsequent endocrine and metabolic phenotype with implications for their adult health and potential athletic performance.
Keywords: Glucocorticoid programming