Glucocorticoids and fetal programming.

Glucocorticoids Glucocorticoid hormones (cortisol in humans and most mammals, corticosterone in rats, mice and most lower vertebrates) are produced by the adrenal glands, predominantly under the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Receptors for glucocorticoids are members of the nuclear hormone receptor superfamily and, when activated by their hormone ligands, regulate (positively or negatively) the transcription of target genes, either by directly binding to palindromic DNA sequences or indirectly via interactions with other transcription factors, such as AP1 and the cyclic AMP response element binding protein, CREB. Glucocorticoids play a series of key roles in physiology, maintaining fuel metabolism under basal conditions and underpinning many of the body’s adjustments to stressful stimulation. During prenatal and early postnatal mammalian development, glucocorticoid levels are generally low, although towards term they rise in many species and effectively signal the onset of late fetal tissue maturation in preparation for extrauterine existence. Key targets for such late effects include the lung (surfactant secretion), gut, liver and brain. Indeed, when premature labour threatens, synthetic glucocorticoids, such as dexamethasone, are exploited to accelerate maturation of the lung and gut; such therapy efficaciously reduces the incidence of postnatal respiratory distress syndromes. But are all effects of prenatal glucocorticoids uniformly beneficial? From the earliest therapeutic exploitation of glucocorticoids in pregnancy, it became apparent that they caused reductions in birthweight. This was observed in experimental animals, including non-human primates, and in humans [l-51. However, the potential significance of birthweight reduction for later pathophysiology has only recently begun to be appreciated.