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Primary Generalized Glucocorticoid Resistance and Hypersensitivity

Context: The human glucocorticoid receptor (hGR) is a ubiquitously expressed intracellular, ligand-dependent transcription factor, which mediates the action of glucocorticoids and influences physiological functions essential for life. Alterations in the molecular mechanisms of hGR action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms and clinical aspects of primary generalized glucocorticoid resistance (PGGR) and hypersensitivity (PGGH). Evidence Acquisition: A systematic review of the published, peer-reviewed medical literature (PubMed: 1975 through May 2011) was conducted to identify original articles and reviews on this topic. Evidence Synthesis: Evidence synthesis was relied upon the experience of a number of experts in the field, including our extensive personal experience. Conclusions: The molecular basis of PGGR and PGGH has been ascribed to mutations in the hGR gene, which alter tissue sensitivity to glucocorticoids. The stochastic nature of glucocorticoid signaling pathways in association with the variable effect that hGR gene mutations/polymorphisms might have on glucocorticoid signal transduction indicates that alterations in hGR action may have important implications for many critical biological processes, such as the behavioral and physiological responses to stress, the immune and inflammatory reaction, as well as growth and reproduction.