Generalized glucocorticoid resistance

Clinical aspects, molecular mechanisms, and implications of a rare genetic disorder

Evangelia Charmandari, Tomoshige Kino, Takamasa Ichijo, George P. Chrousos

Research output: Contribution to journalReview article

121 Citations (Scopus)

Abstract

Context: Primary generalized glucocorticoid resistance is a rare genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. We review the clinical aspects, molecular mechanisms, and implications of this disorder. Evidence Acquisition: We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through February 2008) to identify original articles and reviews on this topic. Evidence Synthesis:Wehave relied on the experience of a number of experts in the field, including our extensive personal experience. Conclusions: The clinical spectrum of primary generalized glucocorticoid resistance is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of the condition has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology. 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.

Original languageEnglish
Pages (from-to)1563-1572
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number5
DOIs
Publication statusPublished - May 2008
Externally publishedYes

Fingerprint

Inborn Genetic Diseases
Glucocorticoids
Glucocorticoid Receptors
Tissue
Hyperandrogenism
Mineralocorticoids
Peer Review
MEDLINE
Adrenocorticotropic Hormone
Fatigue
Signal Transduction
Signal transduction
Homeostasis
Physiology
Pathology
Mutation
Glucocorticoid Receptor Deficiency
Genes
Fatigue of materials
Defects

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Generalized glucocorticoid resistance : Clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. / Charmandari, Evangelia; Kino, Tomoshige; Ichijo, Takamasa; Chrousos, George P.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 5, 05.2008, p. 1563-1572.

Research output: Contribution to journalReview article

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