Endocrine Abstracts

Objective: Genetic variation in the glucocorticoid receptor (GR) gene may be related to the clinical heterogenety and severity of the Cushing’s syndrome. BclI, N363S and ER22/23EK polymorphisms are the three most investigated polymorphisms within the GR gene, however, the importance and magnitude of their effect in hypercortisolemic states are unclear. The BclI and the N363S variants are associated with increased, while the ER22/23EK variant is associated with reduced glucocorticoid sensitivity.

Methods: The allele frequencies of the BclI, N363S and ER22/23EK polymorphisms were investigated in 74 patients with endogenous or exogenous hypercortisolism and 172 healthy control subjects. The patient population included 31 patients with pituitary ACTH producing adenoma, 24 patients with adrenal Cushing’s syndrome, 2 patients with ectopic Cushing’s syndrome and 17 patients with glucocorticoid induced osteoporosis (GIO) caused by exogenously administered corticosteroids. DNA was extracted from peripheral blood leucocytes. The BclI and the N363S variants were detected by allele-specific polymerase chain reaction, and PCR-RFLP method was used to determine the ER22/23EK polymorphism. Bone mineral density was measured by DEXA at the lumbar spine and the left femoral neck (FN). This study was approved by local ethics committee, and written informed consent was obtained from all subjects.

Results: The frequency of the N363S polymorphism was significantly higher in patients with GIO than in the healthy control subjects (allele frequency 14.7% vs. 3.8%; P<0.05). Patients with the homozygous polymorph variant of the BclI polymorphism had significantly reduced mean FN z-score compared to patients with the wild-type variant (−1.803±0.07 vs. −0.508±0.944; P<0.001).

Conclusion: These results suggest that both of the N363S and the BclI polymorphisms of the GR gene may have an impact on the glucocorticoid sensitivity of bones.