Abstract
Glucocorticoid (GC) sensitivity depends on glucocorticoid receptor (GR) and heat shock proteins (Hsps). We investigated whether common GR genes (ER22/23EK, N363S, Bcl I, and 9β) and adrenocorticotropin receptor promoter polymorphisms influence susceptibility for unilateral adrenal incidentaloma (AI), plus GR and Hsp expression in tumorous (n = 19), peritumorous (n = 13) and normal adrenocortical (n = 11) tissues. Patients (n = 112), population-matched controls (n = 100) and tumor tissues (n = 32) were genotyped for these polymorphisms. Postdexamethasone serum cortisol was higher in patients (p < 0.001). GR gene variants, larger allele of Bcl I (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.7-5.1; p < 0.001] and minor allele of 9β (OR 3.0; 95% CI 1.6-5.7; p < 0.001) were independent predictors of AI. In patients, the first allele is linked with larger tumors (p = 0.002) and the latter with higher postdexamethasone cortisol levels (p = 0.025). Both allele carriers had lesser waist circumference (p = 0.02), similar adrenocorticotropin and higher basal (p = 0.024) and postdexamethasone cortisol concentrations (p < 0.001). Tumorous and constitutional genotypes were similar. GR-D is the major receptor isoform in normal adrenal cortex by Western blotting. Loss of other receptor isoforms, decrease in immunostaining for GR (p < 0.0001), underexpression of chaperones (p ≤ 0.01) and the presence of inducible Hsp70 were found in adenomas. In conclusion, GR gene variants, C allele of Bcl I and minor allele of 9β, are associated with AIs. Their concurrent presence in patients reduces GC sensitivity. Normal adrenal cortex preferentially expresses GR-D. In adenomas, the lack of other GR isoforms and underexpression of heat shock proteins perhaps permanently impair GC signaling, which could promote dysregulated cortisol production and tumor growth. The innate GC sensitivity probably modifies these effects.
Highlights
Adrenal tumors are common and reported in 3–7% of autopsy and radiological series [1]
We investigate the expression of glucocorticoid receptor (GR) and molecular chaperons in the tissue samples of adrenocortical adenomas and corresponding adjacent and normal adrenal cortex
There was no difference in morning cortisol concentration between patients and control subjects, but postdexamethasone values were significantly lower in controls
Summary
Adrenal tumors are common and reported in 3–7% of autopsy and radiological series [1]. Most of adrenal lesions found incidentally during imaging evaluation (so-called “incidentalomas” [AIs]) in patients with no known malignancy are presumed to be benign adenomas. The prevalence of adrenal masses increases from 3% in middle-age patients to as much as 10% in the elderly [2]. Patients with functional adrenal tumors are offered surgery. Almost 10% of adrenocortical carcinomas lie within the size range of 3–5 cm [4]. Most of adrenocortical masses are considered nonhypersecretory adenomas, 5–25% of them secrete cortisol autonomously [5,6] and high incidence of obesity, diabetes and hypertension is detected among patients with these tumors [6,7]
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