Glucocorticoids regulate many physiological processes and have an essential role in the systemic response to stress. For example, gene transcription is modulated by the glucocorticoid–glucocorticoid receptor complex via several mechanisms. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Differences in sensitivity to glucocorticoids in healthy individuals are partly genetically determined by functional polymorphisms of the gene that encodes the glucocorticoid receptor. Hereditary syndromes have also been identified that are associated with increased and decreased sensitivity to glucocorticoids. As a result of their anti-inflammatory properties, glucocorticoids are widely used in the treatment of allergic, inflammatory and haematological disorders. The variety in clinical responses to treatment with glucocorticoids reflects the considerable variation in glucocorticoid sensitivity between individuals. In immune-mediated disorders, proinflammatory cytokines can induce localized resistance to glucocorticoids via several mechanisms. Individual differences in how tissues respond to glucocorticoids might also be involved in the predisposition for and pathogenesis of the metabolic syndrome and mood disorders. In this Review, we summarize the mechanisms that influence glucocorticoid sensitivity in health and disease and discuss possible strategies to modulate glucocorticoid responsiveness.
The biologic effects of glucocorticoids are determined by not only the concentrations of glucocorticoids but also individual and tissue sensitivity to glucocorticoids
Differences between individuals in sensitivity to glucocorticoids can be demonstrated in both health and disease
Glucocorticoid sensitivity is modulated by genetic and acquired disease-related factors
Genetic factors that affect glucocorticoid sensitivity are involved in the predisposition for certain diseases, the phenotype of inflammatory and mood disorders and the clinical response to glucocorticoid therapy
In immune disorders, proinflammatory cytokines induce tissue resistance to glucocorticoids by interfering with local glucocorticoid availability, the glucocorticoid receptor and its signalling pathway and the interaction of glucocorticoid receptor with target genes
Pharmacological modulation of glucocorticoid sensitivity might be an innovative strategy to improve the treatment outcome of inflammatory diseases and the metabolic syndrome
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The authors declare no competing financial interests.
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Quax, R., Manenschijn, L., Koper, J. et al. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol 9, 670–686 (2013). https://doi.org/10.1038/nrendo.2013.183
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