BES2003 Poster Presentations Endocrine Tumours and Neoplasia (47 abstracts)
The ACTH receptor (ACTH-R) is the second member of the melanocortin 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, and as ACTH-secreting adenomas are characterised by resistance to glucocorticoid feedback, they may also have dysregulated ACTH feedback. We therefore investigated the ACTH-R in normal and adenomatous pituitary tissue. We report here for the first time identification of ACTH-R mRNA in the human pituitary gland, which is confirmed by direct sequencing. We studied the expression of the ACTH-R in 13 normal pituitary (NP) specimens and 40 pituitary adenomas (2 silent corticotroph, 14 ACTH-, 9 GH-, 3 PRL-, one TSH-, one FSH- secreting and 10 NFPA) using the sensitive technique of real-time quantitative PCR (RQ-PCR). ACTH-R mRNA was detected in all NP specimens, but levels were undetectable in 11 of 14 ACTH-secreting tumors (P=0.0003) and both silent corticotroph tumors. Pre-operative plasma ACTH levels were significantly lower in the ACTH-R positive ACTH-secreting tumours compared with those which were ACTH-R negative (P=0.03). There was also significantly reduced ACTH-R expression in GH-, PRL-, and NFPAs compared to normal pituitary (all P<0.05). Direct sequencing of the coding region of the ACTH-R in cDNA from tumors positively expressing the receptor showed no mutations, as did sequencing of genomic DNA in 3 receptor negative ACTH-secreting tumors and the 2 silent corticotrophs. These results provide further evidence for 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 HPA axis that these patients exhibit, but nonsense-mediated decay of abnormal mRNA is unlikely to underlie this change.