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

Front Endocrinol (Lausanne). 2023 Mar 29:14:1124646. doi: 10.3389/fendo.2023.1124646. eCollection 2023.

Abstract

Objective: Pituitary neuroendocrine corticotroph tumors commonly cause Cushing's disease (CD) that results from increased adrenocorticotropic hormone (ACTH) secretion by the pituitary tumor and consequent increase of cortisol levels in blood. However, in some patients, corticotroph tumors remain clinically non-functioning. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis and includes a negative feedback between cortisol and ACTH secretion. Glucocorticoids reduce ACTH level both by hypothalamic regulation and acting on corticotrophs via glucocorticoid (GR) and mineralocorticoid (MR) receptors. The aim of the study was to determine the role of GR and MR expression at mRNA and protein levels in both functioning and silent corticotroph tumors.

Methods: Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry.

Results: Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8-mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors.

Conclusions: Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics.

Keywords: Cushing’s disease (CD); NR3C1; NR3C2; glucocorticoid receptor; hypothalamic - pituitary - adrenal axis; mineralocorticoid receptor; pituitary neuroendocrine tumor (PitNET); silent corticotroph adenoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma* / complications
  • Adenoma* / genetics
  • Adenoma* / metabolism
  • Adrenocorticotropic Hormone / metabolism
  • Corticotrophs / metabolism
  • Glucocorticoids / metabolism
  • Humans
  • Hydrocortisone
  • Hypothalamo-Hypophyseal System / metabolism
  • Pituitary ACTH Hypersecretion* / surgery
  • Pituitary Neoplasms* / complications
  • Pituitary Neoplasms* / genetics
  • Pituitary Neoplasms* / metabolism
  • Pituitary-Adrenal System / metabolism
  • Receptors, Mineralocorticoid / genetics

Substances

  • Glucocorticoids
  • Hydrocortisone
  • Receptors, Mineralocorticoid
  • Adrenocorticotropic Hormone

Grants and funding

This research was funded by National Science Centre, Poland, grant number 2021/05/X/NZ5/01874. Publication fee was covered by the subvention for the maintenance and development of research potential of the Maria Sklodowska-Curie National Research Institute of Oncology.