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Familial/Sporadic Glucocorticoid Resistance: Clinical Phenotype and Molecular Mechanisms
EVANGELIA CHARMANDARI,
TOMOSHIGE KINO AND
GEORGE P. CHROUSOS
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
Address for correspondence: Evangelia Charmandari, M.D., National Institutes of Health, Building 10, Room 9D42, 10 Center Drive MSC 1583, Bethesda, MD 20892-1583. Voice: 301- 496-5800; fax: 301-402-0884. charmane{at}mail.nih.gov
Ann. N.Y. Acad. Sci. 1024: 168-181 (2004).
Glucocorticoids regulate a variety of biologic processes and exert profound influences on many physiologic functions. Their actions are mediated by the glucocorticoid receptor (GR), which belongs to the nuclear receptor family of ligand-dependent transcription factors. Alterations in tissue sensitivity to glucocorticoids may manifest as states of resistance or hypersensitivity. Glucocorticoid resistance is a rare, familial or sporadic, condition characterized by generalized, partial target-tissue resistance to glucocorticoids. Compensatory elevations in circulating adrenocorticotropic hormone (ACTH) concentrations lead to increased production of adrenal steroids with mineralocorticoid and/or androgenic activity and their corresponding clinical manifestations, as well as increased urinary free-cortisol excretion in the absence of symptomatology suggestive of hypercortisolism. The molecular basis of the condition has been ascribed to mutations in the GR gene, which impair normal glucocorticoid signal transduction, altering tissue sensitivity to glucocorticoids. The present review focuses on the mechanisms of GR action and the clinical manifestations and molecular mechanisms of familial/sporadic glucocorticoid resistance.
Key Words: glucocorticoid receptor • glucocorticoid resistance • tissue sensitivity to glucocorticoids • mutations in the GR gene
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