Identification of Adrenocorticotropin Receptor Messenger Ribonucleic Acid in the Human Pituitary and Its Loss of Expression in Pituitary Adenomas

Damian G. Morris, Blerina Kola, Ninetta Borboli, Gregory A. Kaltsas, Maria Gueorguiev, Anne Marie McNicol, Roderick Ferrier, T. Hugh Jones, Stephanie Baldeweg, Michael Powell, Sándor Czirják, Zoltan Hanzély, Jan Ove Johansson, Márta Korbonits, Ashley B. Grossman

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35 Citations (Scopus)

Abstract

The ACTH receptor (ACTH-R) is the second member of the melanocortin (MC-2) receptor family that includes five seven-transmembrane G protein-coupled receptors and has been shown to be predominantly expressed in the adrenal cortex. It has been postulated that ACTH may regulate its own secretion through ultra-short-loop feedback within the pituitary. ACTH-secreting adenomas are characterized by resistance to glucocorticoid feedback, and they may have dysregulated ACTH feedback. We therefore investigated the ACTH-R in normal and adenomatous human pituitary tissue. We report here the identification of ACTH-R mRNA in the human pituitary gland, which was confirmed by direct sequencing. We studied the expression of the ACTH-R in 23 normal pituitary specimens and 53 pituitary adenomas (22 ACTH-secreting, nine GH-secreting, eight prolactin-secreting, one TSH-secreting, one FSH-secreting, 10 nonfunctioning, and two silent corticotroph adenomas), using the sensitive technique of real-time quantitative PCR. Contamination of ACTH-secreting adenomas and nonfunctioning pituitary adenomas with nonadenomatous tissue was excluded by lack of Pit-1 expression. ACTH-R mRNA was detected in all normal pituitary specimens, and in situ hybridization colocalized expression to ACTH staining cells only. However, ACTH-R mRNA levels were undetectable in 16 of 22 ACTH-secreting tumors and in both silent corticotroph tumors. Diagnostic preoperative plasma ACTH levels were significantly lower in the ACTH-R positive ACTH-secreting tumors, compared with those who were ACTH-R negative (P = 0.0006). Direct sequencing of the coding region of the ACTH-R in cDNA from three ACTH-secreting tumors positively expressing the receptor showed no mutations, as did sequencing of genomic DNA in three receptor negative ACTH-secreting tumors and the two silent corticotrophs. These results provide further evidence compatible with an ACTH feedback loop in the pituitary and suggest that loss of expression of the ACTH-R in corticotroph adenomas of patients with Cushing's disease may play a role in the resistance to feedback of the pituitary-adrenal axis seen in these patients.

Original languageEnglish
Pages (from-to)6080-6087
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume88
Issue number12
DOIs
Publication statusPublished - Dec 2003

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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    Morris, D. G., Kola, B., Borboli, N., Kaltsas, G. A., Gueorguiev, M., McNicol, A. M., Ferrier, R., Jones, T. H., Baldeweg, S., Powell, M., Czirják, S., Hanzély, Z., Johansson, J. O., Korbonits, M., & Grossman, A. B. (2003). Identification of Adrenocorticotropin Receptor Messenger Ribonucleic Acid in the Human Pituitary and Its Loss of Expression in Pituitary Adenomas. Journal of Clinical Endocrinology and Metabolism, 88(12), 6080-6087. https://doi.org/10.1210/jc.2002-022048