No abstract

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 glucocorticoid receptor (GR) is crucial for the effects of glucocorticoids (GCs). Several polymorphisms of the GR are associated with altered sensitivity to GCs. For the ER22/23EK polymorphism, a relative GC resistance has been demonstrated. In vivo, this was suggested by a smaller response to a dexamethasone suppression test (DST), whereas in vitro experiments showed a diminished transactivational activity. The associated features of ER22/23EK carriers consist of favorable metabolic and body compositional conditions. In elderly subjects this polymorphism was associated with longevity and decreased risk of dementia. Interestingly, recent studies also showed an increased risk of major depression. In contrast, the N363S polymorphism was reported to be associated with an enhanced sensitivity to GCs, as was demonstrated by a DST. This polymorphism has also been associated with increased body mass index (BMI) and LDL-cholesterol levels, as well as increased risk of cardiovascular disease. However, additional studies yielded conflicting results, showing no associations with being overweight. The BclI polymorphism is also associated with increased GC sensitivity. In addition, associations with increased abdominal fat mass, Crohn's disease and, remarkably, major depression have been reported. Another GR polymorphism, located in exon 9beta, is associated with increased expression and stabilization of the dominant negative splice variant GR-beta. Carriers of this polymorphism displayed a relative GC resistance in vitro as evidenced by diminished transrepressional activity, which is important for the immune system and inflammation. Associations have been found with increased inflammatory parameters, cardiovascular disease, and rheumatoid arthritis. In this article, studies concerning these clinically relevant GR variants are discussed.

Elevated long-term cortisol levels are associated with a history of cardiovascular disease. The increased cardiovascular risk we found is equivalent to the effect of traditional cardiovascular risk factors, suggesting that long-term elevated cortisol may be an important cardiovascular risk factor.