The fetal hypothalamic–pituitary–adrenal axis: relevance to developmental origins of health and disease

Introduction A clear relationship exists between intrauterine development and predisposition to postnatal disease. It is now understood that pre- and periconceptional nutritional status, glucocorticoid exposure and immediate postnatal development including catch-up growth may all contribute to these influences of early development on later-life disease. Barker and colleagues have described in detail the potential influence that an adverse intrauterine environment could play in the risk of developing particular diseases later in life (Barker 1994a, 1994b, 1995). It has been proposed that resetting of endocrine axes controlling growth and development could be one pathway for the developmental programming of later health and wellbeing. The fetal hypothalamic–pituitary–adrenal (HPA) axis in particular is highly vulnerable to changes in the intrauterine environment. Fetal HPA axis activity increases with gestation in most species and contributes to increased fetal levels of circulating glucocorticoids (Fowden et al. 1998). Even subtle changes in the intrauterine environment can disrupt the delicate balance of fetal HPA development and glucocorticoid production and can therefore alter long-term HPA activity and function. HPA hyperactivity has been demonstrated in animals after prenatal undernutrition (Lingas et al. 1999), prenatal stress (Takahashi and Kalin 1991) and maternal synthetic glucocorticoid administration (Uno et al. 1990, Sloboda et al. 2000). Programming of the fetal HPA axis during development appears to play a central role in the link between fetal growth and long-term disease in adulthood. Prenatal programming of HPA axis function may increase the risk of developing cardiovascular and metabolic diseases.