Glucocorticoid Programming

Authors

  • JONATHAN R. SECKL,

    Corresponding author
    1. Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK and Douglas Hospital Research Center, McGill Program for the Study of Behavior, Genes & Environment, Department of Psychiatry, Verdun H4H 1R3, Canada
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  • MICHAEL J. MEANEY

    1. Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK and Douglas Hospital Research Center, McGill Program for the Study of Behavior, Genes & Environment, Department of Psychiatry, Verdun H4H 1R3, Canada
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Address for correspondence: Professor Jonathan Seckl, Edinburgh University, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK. Voice: (44) 131-651-1035; fax: (44) 131-651-1085. J.Seckl@ed.ac.uk

Abstract

Abstract: Epidemiological evidence suggests that an adverse fetal environment permanently programs physiology, leading to increased risks of cardiovascular, metabolic, and neuroendocrine disorders in adulthood. Prenatal glucocorticoid excess or stress might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal glucocorticoid exposure or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the fetoplacental “barrier” to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis (HPA) activity and behavior resembling anxiety. In humans, 11β-HSD2 gene mutations cause low birth weight and reduced placental 11β-HSD2 activity associated with intrauterine growth retardation. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors; key is the glucocorticoid receptor itself. Differential programming of the glucocorticoid receptor in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the glucocorticoid receptor gene. Overall, the data suggest that either pharmacological or physiological exposure to excess glucocorticoids prenatally programs pathologies in adult life.

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