The Role of Decreased Expression of Glucocorticoid Receptors in the Development of Itsenko-Cushing Syndrome

Abstract

Background: Itsenko-Cushing syndrome is caused by unregulated excessive cortisol incretion by the adrenal cortex. The causes of increased stimulation of cortisol incretion by the adrenal cortex, leading to hyperplasia and tumors (adenoma and cancer) of the adrenal cortex, as well as to adenoma of the pituitary gland itself, remain unclear to date. Materials and Methods: 6 patients with adrenal Itsenko-Cushing syndrome with adrenal cortex adenoma were under observation. The age of the patients ranged from 24 to 87 years. The patients underwent removal of the adrenal gland on the affected side. The control group consisted of 6 individuals who underwent surgical treatment of varicocele and hernias of various localization. In patients of the main group and control group, with their consent, a small fragment of skin from the edge of the surgical wound was taken for examination, which were fixed in a 10% formalin solution. Results: The presence of adrenal Itsenko-Cushing syndrome in patients of the main group was confirmed by laboratory and instrumental studies, as well as characteristic clinical manifestations. The average Histochemical score of the expression of glucocorticoid receptors (GR) of the skin in patients of the main group with Itsenko-Cushing adrenal syndrome was 2.7 times less than the same value in the control group. Conclusions: A decrease in the formation or absence of glucocorticoid receptors (congenital or acquired) blocks the negative feedback of cortisol suppression of corticoliberin production by the hypothalamus and ACTH-pituitary gland. The resulting excessive incretion of corticoliberin becomes the main link in pathogenesis of pituitary adenoma formation, and an excessive incretion of ACTH leads to the formation of cortical hyperplasia and tumors (adenomas, cancers) of the adrenal cortex. Unregulated excessive cortisol production by hyperplastic adrenal tissues or benign/malignant adrenal tumors leads to overcoming resistance to glucocorticoids and, according to the principle of negative feedback, suppresses the production of corticoliberin by the hypothalamus and ACTH-pituitary gland. As a result, the pituitary form of Itsenko-Cushing syndrome turns into an adrenal form with an unregulated increase in cortisol levels and a decrease in ACTH levels. Transfusion of the mononuclear fraction of peripheral blood obtained from healthy donors, which allows the pluripotent stem cells contained in it to partially replace the altered cells of all tissues of patients, is a promising method of treating patients with Itsenko-Cushing syndrome due to a hereditary decrease in the expression of glucocorticoid receptors.