Endocrine Abstracts

Epidemiological evidence suggests that an adverse fetal environment permanently programmes physiology leading to increased risks of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. Prenatal glucocorticoid excess might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress or exposure to synthetic glucocorticoid which cross the placenta reduces birth weight and causes permanent hypertension, hyperglycaemia, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behaviour resembling of anxiety. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. Severe maternal stress in human pregnancy also affects the offspring HPA axis and associates with neuropsychiatric disorders. Maternal glucocorticoid therapy alters offspring cognitive and affective behaviours.

Physiologically, 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) in fetal tissues and the placental labyrinth forms a ‘barrier’ to maternal glucocorticoids. Administration of inhibitors of 11ß-HSD during pregnancy in rodents recapitulates the effects of non-substrate synthetic glucocorticoids. Moreover, in humans and rodents, 11ß-HSD2 gene mutations cause low birth weight and placental 11ß-HSD2 activity correlates directly with birth weight and inversely with infant blood pressure. Recent studies in mice bearing null alleles of the 11β-HSD2 gene show that the effects of 11β-HSD2 loss reflects actions upon the fetus and/or placenta rather than any maternal action. Curiously, some of these effects appear to be ‘inherited’ into a further generation, itself unexposed to exogenous glucocorticoids at any point in the lifespan from fertilization, implying epigenetic marks persist into subsequent generation(s). Overall, the data suggest that prenatal exposure to excess glucocorticoids due to bypass or lack of placental 11β-HSD2 programmes peripheral and CNS functions in adult life, predisposing to pathologies some of which may be transmitted into subsequent generations.