Early-Life Glucocorticoid Exposure: The Hypothalamic-Pituitary-Adrenal Axis, Placental Function, and Long-term Disease Risk

An adverse early-life environment is associated with long-term disease consequences. Adversity early in life is hypothesized to elicit developmental adaptations that serve to improve fetal and postnatal survival and prepare the organism for a particular range of postnatal environments. These processes, although adaptive in their nature, may later prove to be maladaptive or disadvantageous if the prenatal and postnatal environments are widely discrepant. The exposure of the fetus to elevated levels of either endogenous or synthetic glucocorticoids is one model of early-life adversity that contributes substantially to the propensity of developing disease. Moreover, early-life glucocorticoid exposure has direct clinical relevance because synthetic glucocorticoids are routinely used in the management of women at risk of early preterm birth. In this regard, reports of adverse events in human newborns have raised concerns about the safety of glucocorticoid treatment; synthetic glucocorticoids have detrimental effects on fetal growth and development, childhood cognition, and long-term behavioral outcomes. Experimental evidence supports a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development and changes in placental function, and many of these alterations appear to be permanent. Because the placenta is the conduit between the maternal and fetal environments, it is likely that placental function plays a key role in mediating effects of fetal glucocorticoid exposure on hypothalamic-pituitary-adrenal axis development and long-term disease risk. Here we review recent insights into how the placenta responds to changes in the intrauterine glucocorticoid environment and discuss possible mechanisms by which the placenta mediates fetal hypothalamic-pituitary-adrenal development, metabolism, cardiovascular function, and reproduction.