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.

The expression of glucocorticoid and mineralocorticoid receptors in pituitary tumors causing Cushing’s disease and silent corticotroph tumors

“…Targeting GR with receptor antagonist is one of the main pharmacological options in Cushing’s syndrome (CS) aimed to reduce cortisol-related complications ( 9 ). The efficacy of two GR modulators mifepristone and relacorilant were already tested and subjected to phase III clinical trials ( 9 ).…”

“…Targeting GR with receptor antagonist is one of the main pharmacological options in Cushing’s syndrome (CS) aimed to reduce cortisol-related complications ( 9 ). The efficacy of two GR modulators mifepristone and relacorilant were already tested and subjected to phase III clinical trials ( 9 ). In case of ACTH-related hypercortisolemia this therapeutical approach may provide both therapeutical benefit and adverse effect due to direct effect on corticotroph tumor.…”

“…The role of corticosteroid receptors in pituitary corticotroph tumors is relatively poorly understood ( 6 , 9 ). In CD-causing tumors, loss of heterozygosity (LOH) in the NR3C1 (encoding GR) locus was observed ( 10 ).…”

“…In CD-causing tumors, loss of heterozygosity (LOH) in the NR3C1 (encoding GR) locus was observed ( 10 ). More recently, somatic point mutations in NR3C1 were found in 6.4% of patients with CD ( 9 ). NR3C1 expression may be also downregulated by hsa-miR-124-3p miRNA in pituitary corticotroph tumors ( 11 ).…”