corticotropin-like-intermediate-lobe-peptide and ACTH-Syndrome--Ectopic

The remarkable conservation of the primary structures and anatomical location of dogfish α-melanocyte-stimulating hormone (MSH), corticotrophin-like intermediate lobe peptide (CLIP) and adrenocorticotrophic hormone (ACTH) compared with mammals reinforced the tissue-specific processing hypothesis of ACTH peptides in the pituitary gland. The cloning of dogfish pro-opiomelanocortin (POMC) led to the identification of δ-MSH and simultaneously revealed the high conservation of the γ-MSH sequence during evolution. These studies have also shown that β-MSH is much less conserved during evolution and in some species is not even processed from β-LPH. Human pro-γ-MSH potentiates the corticosteroidogenic activity of ACTH and peptides generated from its N-terminal, in particular big-γ-MSH, appear to have adrenal mitogenic activity. Human big-γ-MSH (from the zona intermedia) may also cause the adrenache. The review finishes with a cautionary note with regard to the misdiagnosis of the ectopic ACTH syndrome in which partial processing of ACTH can result in large concentrations of α-MSH and CLIP, which can interfere in the performance of two-site immunoassays, and the problem of the correct disulphide bridge arrangement in synthetic N-POMC peptides is also discussed.

Topics: ACTH Syndrome, Ectopic; Adrenal Glands; Adrenocorticotropic Hormone; alpha-MSH; Animals; beta-Endorphin; Corticotropin-Like Intermediate Lobe Peptide; History, 20th Century; Humans; Melanocyte-Stimulating Hormones; Pituitary ACTH Hypersecretion; Pituitary Gland; Pro-Opiomelanocortin; Protein Isoforms

In order to evaluate which of human (h) corticotrophin-like intermediary lobe peptide (CLIP) or h beta-melanocyte stimulating hormone5-22 (h beta MSH5-22) was the better marker of alternate pro-opiomelanocortin (POMC) processing, both peptides were simultaneously sought in the same tissue extracts from a normal human pituitary, six corticotrophic adenomas, and four non-pituitary tumours responsible for an ectopic ACTH syndrome. Human CLIP was detected using a combination of gel exclusion chromatography and two different radioimmunoassays (RIAs): a mid-ACTH RIA which recognized ACTH but not CLIP, and a COOH-ACTH RIA which recognized both molecules. Human beta MSH5-22 had been measured previously. Neither hCLIP nor h beta MSH5-22 were detected in the normal or tumoural pituitaries. The four non-pituitary tumours, in contrast, contained both peptides; the hCLIP and h beta MSH5-22 ratios (CLIP/CLIP + ACTH and h beta MSH5-22/h beta MSH5-22 + h gamma LPH) ranged from 40 to 94% and from 24 to 46%, respectively. In a given tissue the hCLIP ratio was always higher than the h beta MSH5-22 ratio. hCLIP is therefore the better marker of alternate POMC processing.

Topics: ACTH Syndrome, Ectopic; Adenoma; Adrenocorticotropic Hormone; Biomarkers, Tumor; Bronchial Neoplasms; Carcinoid Tumor; Chromatography, Gel; Corticotropin-Like Intermediate Lobe Peptide; Humans; Melanocyte-Stimulating Hormones; Paraneoplastic Endocrine Syndromes; Peptide Fragments; Pituitary Neoplasms; Pro-Opiomelanocortin; Radioimmunoassay; Thymus Neoplasms

Adrenocorticotrophin, lipotrophin and the related peptides alpha-MSH, CLIP, beta-endorphin and met-enkephalin have been measured, and characterized chromatographically in tumour extracts from seven patients with the ectopic ACTH syndrome. Four of the seven tumours contained the complete family of peptides, although the proportion of one to another varied between tumours. In addition, large molecule weight forms of ACTH and met-enkephalin were seen. The potential clinical importance of these observations is discussed.

Topics: ACTH Syndrome, Ectopic; Adrenocorticotropic Hormone; beta-Lipotropin; Chromatography, Gel; Corticotropin-Like Intermediate Lobe Peptide; Endorphins; Enkephalins; Humans; Melanocyte-Stimulating Hormones; Paraneoplastic Endocrine Syndromes; Peptide Fragments