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Generalized Glucocorticoid Resistance: Clinical Aspects, Molecular Mechanisms, and Implications of a Rare Genetic Disorder

Division of Endocrinology and Metabolism (E.C., G.P.C.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece; and Section on Pediatric Endocrinology (E.C., T.K., T.I., G.P.C.), Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892

Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, 4 Soranou tou Efessiou Street, Athens, 11527, Greece. E-mail: evangelia.charmandari{at}googlemail.com.

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: We have 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.

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