Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Objective: Glucocorticoids (GCs) serve a variety of important functions thr oughout the body. The synthesis and secretion of GCs are under the strict i nfluence of the hypothalamo-pituitary-adrenal axis. The mechanisms of actio n of GCs are mediated by the intracellular glucocorticoid receptor (GR). Ov er the years, many studies have been performed concerning the regulation of GR expression by GC concentrations. Methods: In the present study, we determined the characteristics of the GR in peripheral mononuclear blood leukocytes (PBML) from thirteen patients wi th endogenous Gushing's syndrome and fifteen control subjects, using a whol e cell dexamethasone binding assay. Furthermore, cortisol concentrations we re determined in order to investigate a possible relationship between serum cortisol levels and receptor characteristics. Results: There were no differences in mean receptor number between patients and controls. On the other hand, a significantly lower ligand affinity was identified in cells from patients with Gushing's syndrome compared with co ntrols. A complete normalisation of the ligand affinity was observed after treatment in the only patient tested in this respect, whereas the receptor number was not affected. In patients. there was a statistically significant negative correlation between cortisol concentrations and ligand affinity w hich was not found in controls. Conclusion: Receptor down-regulation does not occur in PBML from patients w ith endogenous Gushing's syndrome. On the other hand, there seems to be a d iminished ligand affinity which possibly reflects receptor modification in response to exposure to the continuously high cortisol levels in patients w ith Gushing's syndrome. This assumption is substantiated by the fact that i n one patient a normalisation of the ligand affinity after complete remissi on of the disease was seen.