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Objective The hypothalamic–pituitary–adrenal axis setpoint and the glucocorticoid sensitivity of various tissues are at least partially genetically determined. We investigated the impact of glucocorticoid receptor (GR) gene polymorphisms, including the BclI, N363S, ER22/23EK and A3669G variants on bone turnover and/or mineral density (BMD) in patients with endogenous glucocorticoid excess. Design Sixty patients including 35 patients with ACTH producing pituitary adenoma (CD) and 25 patients with adrenal Cushing's syndrome (ACS) as well as 129 healthy subjects were genotyped. Analysis of the GR gene polymorphisms were determined using allele specific PCR, PCR-RFLP and Taqman allelic discrimination assays. Hormonal evaluation, BMD and bone marker measurements were carried out. Results No significant differences were found in allelic frequencies of the four polymorphisms between patients with ACS, CD and healthy controls. Patients with endogenous hypercortisolism carrying the BclI polymorphism in a homozygous form had reduced BMD at femoral subregions compared to patients with the wild-type variant; femoral neck Z-score (–1·44 ± 0·73 vs. –0 ·39 ± 0·91; P < 0·05), trochanteric Z-score (–1·89 ± 0·47 vs.–0·54 ± 0·98; P < 0·05). Patients with homozygous BclI polymorphism had significantly higher β-CrossLaps Z-scores compared to those with the heterozygous and wild-type variants (+4·42 ± 2·37 vs. +0·79 ± 1·67 and +0·11 ± 1·47; P < 0·01). Conclusions The BclI, N363S, ER22/23EK and A3669G polymorphisms of the GR gene probably do not modify the risk for the development of CD or ACS. Contrary to healthy subjects, however, the BclI polymorphism may modify the skeletal sensitivity to glucocorticoids in patients with endogenous glucocorticoid excess. [ABSTRACT FROM AUTHOR]