Glucocorticoid receptor and molecular chaperones in the pathogenesis of adrenal incidentalomas: potential role of reduced sensitivity to glucocorticoids.

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 9ß) 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 9ß (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 9ß, 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.

Relationship between basal metabolic rate and cortisol secretion throughout pregnancy.

The role of cortisol in mediating basal metabolic rate (BMR) changes that accompany the adjustment of maternal body weight (BW) and body composition during pregnancy is unknown. We tested whether increase in BMR during pregnancy is explained by variations in cortisol secretion. Longitudinal changes in BW, fat mass (FM), fat-free mass (FFM), BMR, hormonal, and metabolic parameters in 31 parous Caucasian women at gestational weeks 12, 26, and 36 were examined. Individual differences (Delta) between the last and the first measurement occasions for each variable were calculated. By gestational week 36, BW and BMR increased while both FFM/FM and BMR/BW ratio decreased (P < 0.001 for all) suggesting higher proportion of FM accretion. Cortisol, leptin, and insulin-like growth factor-1 (IGF-1) concentration rose, whereas non-placental growth hormone (GH) and thyroid hormones declined (P < 0.001 for all). Insulin resistance changed; basal glucose (P < 0.001) and ghrelin (P < 0.014) declined, whereas insulin (P < 0.001), homeostatic model index (HOMA-IR) (P = 0.041), and free fatty acid (FFA) concentration (P = 0.007) increased. The elevation in BMR showed inverse correlations with DeltaBW (r = 0.37, P = 0.047) and Deltacortisol (r = -0.53, P = 0.004). Significant portion (51.6%) of the variation in BMR change was explained by increases of cortisol (27.1%), FFA (13.4%), and free triiodothyronine (11.1%). In conclusion, the changes in maternal cortisol concentration are in relationship with changes in BMR and BW, further suggesting that increased cortisol secretion during pregnancy could be linked with the maintenance of maternal BW and body composition.