Epidemiological studies in many distinct human populations have associated low weight or
thinness at birth with a substantially increased risk of cardiovascular and metabolic disorders, including
hypertension and
insulin resistance/
type 2 diabetes, in adult life. The concept of fetal "programming" has been advanced to explain this phenomenon. Prenatal
glucocorticoid therapy reduces
birthweight, and
steroids are known to exert long-term organizational effects during specific "windows" of development. Therefore, we hypothesized that fetal overexposure to endogenous
glucocorticoids might underpin the link between early life events and later disease. In rats,
birthweight is reduced following prenatal exposure to the synthetic
glucocorticoid dexamethasone, which readily crosses the placenta, or to
carbenoxolone, which inhibits
11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental "barrier" to endogenous
glucocorticoids. Although the offspring regain the weight deficit by weaning, as adults they exhibit permanent
hypertension,
hyperglycemia, and increased hypothalamic-pituitary-adrenal axis activity. Moreover, physiological variations in placental
11beta-HSD2 activity near term correlate directly with
fetal weight. In humans,
11beta-HSD2 gene mutations produce a low
birthweight, and some studies show reduced placental
11beta-HSD2 activity in association with
intrauterine growth retardation. Moreover, low
birthweight babies have higher plasma
cortisol levels throughout adult life, indicating that hypothalamic-pituitary-adrenal axis programming also occurs in humans. The molecular mechanisms of
glucocorticoid programming are beginning to be unraveled and involve permanent and tissue-specific changes in the expression of key genes, notably of the
glucocorticoid receptor itself. Thus,
glucocorticoid programming may explain, in part, the association between fetal events and subsequent disorders in adult life.