Open Access Review

Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor

Nicolas C Nicolaides12*, Evangelia Charmandari12, George P Chrousos123 and Tomoshige Kino4

Author Affiliations

1 Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens 11527, Greece

2 Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece

3 Saudi Diabetes Study Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

4 Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 2089, USA

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BMC Endocrine Disorders 2014, 14:71  doi:10.1186/1472-6823-14-71

Published: 25 August 2014


Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor.

Glucocorticoid receptor; Glucocorticoid resistance; Glucocorticoid hypersensitivity; Glucocorticoid signal transduction