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

Department of Endocrinology (D.G.M., B.K., N.B., G.A.K., M.G., M.K., A.B.G.), St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; Division of Cancer Sciences and Molecular Pathology (A.M.M., R.F.), Medical Faculty, University of Glasgow, Glasgow G4 0SF, United Kingdom; Academic Unit of Endocrinology (T.H.J.), Division of Genomic Medicine, University of Sheffield, Sheffield S10 2RX, United Kingdom; National Institute of Neurology and Neurosurgery (S.B., M.P.), Queen Square, London WC1N 3BG, United Kingdom; National Institute of Neurosurgery (S.C., Z.H.), 1145 Budapest, Hungary; and Research Centre for Endocrinology and Metabolism (J.-O.J.), Sahlgrenska University Hospital, 413 45 Göteborg, Sweden

Address all correspondence and requests for reprints to: Professor A. B. Grossman, Endocrine Oncology, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom. E-mail: a.b.grossman{at}qmul.ac.uk.

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.

D.G.M. and M.G. were supported by the Joint Research Board of St. Bartholomew’s Hospital. B.K. was supported by the Cancer Research Committee of St. Bartholomew’s Hospital. M.K. is a Medical Research Council Clinical Scientist.

Abbreviations: ACTH-R, ACTH receptor; DIG, digoxigenin; dNTP, deoxynucleotide triphosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; gDNA, genomic DNA; ISH, in situ hybridization; NFPA, nonfunctioning pituitary adenoma; POMC, proopiomelanocortin; PRL, prolactin; RQ-PCR, real-time quantitative PCR; RT, reverse transcription; SSC, saline sodium citrate; UTR, untranslated region.

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