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      Prenatal glucocorticoids and long-term programming.

      1
      European journal of endocrinology
      Bioscientifica

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          Abstract

          Epidemiological evidence suggests that low birth weight is associated with an increased risk of cardiovascular, metabolic and neuroendocrine disorders in adult life. Glucocorticoid administration during pregnancy reduces offspring birth weight and alters the maturation of the lung and other organs. We hypothesised that prenatal exposure to excess glucocorticoids or stress might represent a mechanism linking foetal growth with adult pathophysiology. In rats, birth weight is reduced following prenatal exposure to the synthetic steroid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental 'barrier' to maternal glucocorticoids. As adults, the offspring exhibit permanent hypertension, hyperglycaemic, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behaviour reminiscent of anxiety. Physiological variations in placental 11beta-HSD2 activity correlate directly with foetal weight. In humans, 11beta-HSD2 gene mutations cause low birth weight. Moreover, low-birth-weight babies have higher plasma cortisol levels throughout adult life, indicating HPA axis programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, key among which is the glucocorticoid receptor (GR) itself. The differential programming of the GR in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. Overall, the data suggest that both pharmacological and physiological exposure prenatally to excess glucocorticoids programmes cardiovascular, metabolic and neuroendocrine disorders in adult life.

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          Author and article information

          Journal
          Eur J Endocrinol
          European journal of endocrinology
          Bioscientifica
          0804-4643
          0804-4643
          Nov 2004
          : 151 Suppl 3
          Affiliations
          [1 ] Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. J.Seckl@ed.ac.uk
          Article
          10.1530/eje.0.151u049
          15554887
          f8b5b5f8-9759-40fa-8f45-609bcb44a599
          History

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