Context: Some variants of the glucocorticoid receptor (GR) gene have been found to alter glucocorticoid sensitivity and have been associated with altered metabolic profiles.

Objective: To examine whether N363S and ER22/23K variants of the GR gene may be associated with the development of adrenal incidentalomas and whether these variants may contribute to metabolic abnormalities frequently present in these patients.

Design, Setting and Patients: The study included 99 patients with unilateral and 44 patients with bilateral adrenal incidentalomas, 102 population-matched control subjects and 100 patients with type 2 diabetes mellitus.

Main Outcome Measures: Metabolic, hormonal parameters and GR gene variants were determined.

Results: When compared with control subjects, the carrier frequency for the N363S variant was markedly and significantly higher in patients with bilateral (7.1% vs. 20.4%, P < 0.05) but not in those with unilateral incidentalomas (7.8%) or in patients with type 2 diabetes (13.0%). Type 2 diabetes occurred more frequently in patients with bilateral compared with those with unilateral incidentalomas (40.9 vs. 22.2%, P < 0.05). In patients with bilateral incidentalomas, a significant association of the N363S variant with impaired glucose homeostasis, but not with BMI, hypertension, hyperlipidemia, or history of coronary artery disease was found. The carrier frequency of the ER22/23EK variant was similar in all groups and this variant failed to show any association with metabolic abnormalities.

Conclusion: These results suggest, that the N363S variant of the GR gene may play a role in the pathogenesis of bilateral adrenal incidentalomas, although the mechanism still remains to be investigated.