The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

Abstract

Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing's disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic-pituitary-adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth.

Keywords: Cushing’s disease; HSP90; corticotroph adenomas; glucocorticoid receptor; relacorilant.

Figure 1

Graphical representation of glucocorticoid receptor (GR) action in ACTH-secreting pituitary cells and regulation of POMC expression. GR resides in the cytoplasm inactive in a multimeric complex with heat shock proteins (HSP90) and immunophilins (FKBP51 and/or FKBP52). After cortisol binding, GR dissociates from HSP90, and nuclear localization signal activates. Associated with cortisol (F), GR translocates into the nucleus and combines with other two COR/GR complexes, binding to nGRE (negative Glucocorticoid Receptor Element) in the POMC promoter. GR downregulates POMC expression not by directly binding nGRE but via transrepression, antagonizing the binding of orphan nuclear receptors Nur77 and Nurr1. This mechanism also requires the recruitment of BRG1 protein and Histone deacetylase 2 (HDAC2), decreasing histone acetylation of the POMC gene and, consequently, its expression. NBRE: Nur77-binding response element; P: phosphorylated; other factors possibly involved in GC resistance: TR4 (Nuclear Receptor Subfamily 2 Group C Member 2) and HSD11B2 (Hydroxysteroid 11-Beta Dehydrogenase 2), which converts F to the inactive cortisone (CRT).