BackgroundUncertainty exists whether glucocorticoid receptor (GCR) polymorphisms play a role in steroid-related side effects in Addison's disease (AD) patients on hydrocortisone. The polymorphismsBcll and N363S appear to increase sensitivity to cortisol, while the ER22/23EK polymorphism has been associated with resistance to cortisol.MethodOne hundred and forty seven AD patients, and gender, and ethnicity-matched controls were recruited in South Africa. Three polymorphisms in the GCR were studied, using PCR followed by restriction fragment length analysis. Associations with BMI, lipids, glucose and inflammatory markers were investigated.ResultsIn both patients and controls, theBcll polymorphism occurred more frequently in whites than in other ethnic groups studied but was not associated with any of the metabolic parameters tested. The ER22/23EK polymorphism was associated with an increased BMI in both patients (29.4 vs 24.7 kg/m²) and control subjects (26.3 vs 24.2 kg/m²). The ER22/23EK polymorphism was also associated with lower LDL cholesterol in control subjects (3.46 vs 3.93 mmol/l) and in patients (3.52 vs 4.10 mmol/l). N363S was associated with increased BMI in controls 29.9 kg/m²vs wild type 24.8 kg/m². Median hydrocortisone doses were greater in patients heterozygous for either ER22/23EK 30.0 mg or N363S 25.0 mg polymorphisms than in wild type patients 20.0 mg (both comparisons).ConclusionAlterations in lipids, BMI and hydrocortisone dose were associated with two polymorphisms. Further larger studies are warranted to corroborate these findings.