Context: The effects of cortisol are mediated by the -isoform of the glucocorticoid receptor (GR). GR- levels and activity are modulated by alternative splicing of the common pre-mRNA into mRNAs for the GR- and GR-P isoforms.

Objective: To investigate if chronic hypercortisolism, chronic hypocortisolism or acute, relative hypocortisolism influence the expression levels of the GR splice variants in mononuclear leukocytes.

Design: Case-control study.

Setting: University Hospital.

Participants: 18 patients with Cushing's syndrome, 5 patients with hypocortisolemia, 7 patients undergoing Metyrapone testing, and 14 controls.

Main outcome measures: mRNA levels, GR affinity and number per cell.

Results: All three GR mRNA isoforms were detected in participants from all groups at relative levels of :P:=1:0.25:0.001. There was a significant correlation between the expression levels of the 3 splice variants and between the mRNA levels and the number of receptors per cell. The GR in Cushing patients had an increased K_D (P < 0.05) preoperatively. GR number was not significantly different. Postoperatively, the K_D decreased. GR- mRNA expression was increased compared with controls (P < 0.05) and decreased after surgery (P < 0.05). In patients with chronic hypocortisolism, GR- mRNA expression was increased, and receptor numbers were increased (P < 0.05), whereas GR affinity was normal. No changes were observed in patients undergoing a Metyrapone test.

Conclusions: Cushing's syndrome is accompanied by a reversible decrease in GR affinity, possibly related to an increased GR- expression, which may be a compensatory mechanism to GC excess. In chronic hypocortisolism adaptive changes in GR status seem to occur at the level of GR number.