Background Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRα, of which two splice variants involving the hormone-binding domain exist, GRβ and GR-P. Objective To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. Design and methods We assessed mRNA expression of the GRα, GRβ and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. Results GRα and GR-P mRNA constituted 87 ± 8% and 13 ± 2%, respectively, of total GR mRNA in liver. GRβ mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (α = 96 ± 11%, P = 3·9 ± 0·4%, β = 0·010 ± 0·002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0·001 for all). Serum cortisol levels were negatively associated with liver GRα and muscle GR-P expression (P < 0·05). mRNA expression of both liver GRα and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0·01). Conclusion We demonstrate the presence of GRα and GR-P mRNA in liver and of GRα, GRβ and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.

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Journal Clinical Endocrinology
Peeters, R.P, Hagendorf, A, Vanhorebeek, I, Visser, T.J, de Jong, F.H, Klootwijk, W, … van den Berghe, G. (2009). Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clinical Endocrinology, 71(1), 145–153. doi:10.1111/j.1365-2265.2008.03443.x