Chapter 5. Generalized Glucocorticoid Insensitivity: Clinical Phenotype and Molecular Mechanisms

  1. Ian M. Adcock and
  2. Kian Fan Chung
  1. Evangelia Charmandari1,
  2. Tomoshige Kino2 and
  3. George P. Chrousos3

Published Online: 18 MAR 2008

DOI: 10.1002/9780470985731.ch5

Overcoming Steroid Insensitivity in Respiratory Disease

Overcoming Steroid Insensitivity in Respiratory Disease

How to Cite

Charmandari, E., Kino, T. and Chrousos, G. P. (2008) Generalized Glucocorticoid Insensitivity: Clinical Phenotype and Molecular Mechanisms, in Overcoming Steroid Insensitivity in Respiratory Disease (eds I. M. Adcock and K. F. Chung), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470985731.ch5

Editor Information

  1. Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK

Author Information

  1. 1

    Clarendon Wing, Leeds General Infirmary, Leeds, UK

  2. 2

    Section on Pediatric Endocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

  3. 3

    First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Athens, Greece

Publication History

  1. Published Online: 18 MAR 2008
  2. Published Print: 14 MAR 2008

ISBN Information

Print ISBN: 9780470058084

Online ISBN: 9780470985731

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Keywords:

  • Glucocorticoid receptor (GR);
  • Glucocorticoid resistance;
  • Mutations in the human glucocorticoid receptor (hGR) gene

Summary

Glucocorticoid resistance is a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. Compensatory elevations in circulating adrenocorticotropic hormone (ACTH) concentrations lead to increased secretion of cortisol and adrenal steroids with mineralocorticoid and/or androgenic activity, but no clinical evidence of hypercortisolism. The clinical spectrum of the condition is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction, thereby altering tissue sensitivity to glucocorticoids. The study of functional defects of natural hGR mutants enhances our understanding of the molecular mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.