Context: The effects of cortisol are mediated by the alpha-isoform of the glucocorticoid receptor (GR). GR-alpha levels and activity are modulated by alternative splicing of the common pre-mRNA into mRNAs for the GR-beta and GR-P isoforms.
Objective: The objective of this study was to investigate whether chronic hypercortisolism, chronic hypocortisolism, or acute, relative hypocortisolism influences the expression levels of the GR splice variants in mononuclear leukocytes.
Design: This was a case-control study.
Setting: The study was performed at a university hospital.
Participants: Eighteen patients with Cushing's syndrome, five patients with hypocortisolemia, seven patients undergoing metyrapone testing, and 14 controls were studied.
Main outcome measures: The main outcome measures were 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 alpha/P/beta = 1:0.25:0.001. There was a significant correlation between the expression levels of the three splice variants and between the mRNA levels and the number of receptors per cell. The GR in Cushing patients had an increased Kd (P < 0.05) preoperatively. GR number was not significantly different. Postoperatively, the Kd decreased. GR-beta mRNA expression was increased compared with controls (P < 0.05) and was decreased after surgery (P < 0.05). In patients with chronic hypocortisolism, GR-alpha 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-beta 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.