Fetal Programming of Hypothalamic-Pituitary-Adrenal Axis by Synthetic Glucocorticoids

Abstract

Major physiological systems, such as the hypothalamic-pituitary-adrenal (hpa) axis, are susceptible to certain intrauterine exposures of the fetus. These exposures may lead to long-term programming, with potential consequences for the individual throughout life. One such exposure is the administration of synthetic glucocorticoids that are commonly used in different medical fields. This chapter focuses on fetal programming of hpa axis by synthetic glucocorticoids. It introduces the pharmacological and physiological background of this topic, summarizes major findings from human and animal studies, and addresses potential biological mechanisms and the clinical relevance of such programming. In humans, exposure to synthetic glucocorticoids in utero reduces fetal and, in some cases, postnatal hpa activity under basal conditions, and following stress. Data from animal studies indicate that lifelong hpa axis dysregulation, rather than either static hypoactivity or hyperactivity of hpa axis, is a common consequence of early exposure to synthetic glucocorticoids. The mechanisms of glucocorticoid-induced changes in hpa axis function are complex, including possible alterations at subcortical and cortical levels of the brain. Emerging evidence indicates that early dysregulation of hpa axis is adverse, possibly leading to compromised development and health in the short term. It is as yet unclear as to whether long-term health disturbances are to be expected. More randomized human follow-up studies are needed to better understand the short- and long-term effects of intrauterine exposure to synthetic glucocorticoids on hpa axis and potential short- and long-term consequences on health and development.