Glucocorticoid Resistance and Hypersensitivity

Abstract

GC resistance and hypersensitivity syndromes may be generalized or localized to specific tissues. Mechanisms of altered GC sensitivity include mutations or deletions of the GRα gene, decreased GRα cofactors, alterations in cortisol binding globulin, and perturbations of local cortisol concentrations. GRα gene mutations and deletions produce GGR. Polymorphisms of the GRα may contribute to mild syndromes of GGR and hypersensitivity. GRα gene deletions localized to ACTH-secreting pituitary tumors may contribute to pituitary GC resistance of some patients with Cushing's disease. Similarly, GRα gene abnormalities may contribute to GC resistance of a small number of hematologic malignancies. Decreased expression of the C/EBPα GRα cofactor in bronchial smooth muscle has been implicated in the development of asthma. Altered tissue concentrations of cortisol by increased or decreased interconversion of cortisol and cortisone cause apparent GC resistance and hypersensitivity syndromes. Best described is the syndrome of apparent mineralocorticoid excess that is caused by decreased 11β-HSD2 activity in the kidney. Cortisone reductase converts cortisone to active cortisol in local tissues. Decreased cortisone reductase activity may cause local resistance, while increased cortisone reductase activity may cause a local cortisol hypersensitivity syndrome. Finally, apparent GGR and sensitivity may be caused by increases and decreases in circulating CBG concentrations. © 2005 Elsevier Inc. All rights reserved.