Adrenocorticotrophin (ACTH) is derived by cleavage from the precursor, pro-opiomelanocortin (POMC), and depending on the degree of processing by the tissue or tumor, there is the potential for a number of ACTH-related peptides to be secreted from POMC expressing cells. Previous chromatographic approaches have indicated the presence of high molecular weight forms of ACTH in the human peripheral circulation. However a quantitative assessment of the degree of processing requires two-site immunoradiometric assays which distinguish ACTH precursors and ACTH. Using this approach, we have previously identified the precursors of ACTH (POMC and proACTH) in the circulation of normal subjects in the range 5–40 pmol/l, which suggests that processing in the normal pituitary cell is incomplete.
This study aimed to examine the extent of POMC processing by tumors that give rise to Cushing's Syndrome as a means of evaluating its usefulness as a diagnostic marker. In a retrospective analysis of 86 patients with Cushing's Syndrome, 34/35 patients with pituitary tumors had low levels of ACTH precursors (below 100 pmol/l) and the mean ratio of ACTH precursors:ACTH was 5:1 which indicates that these tumors do process POMC to ACTH relatively efficiently. In ectopic Cushing's Syndrome, it is unlikely that the extra-pituitary tumor cells, process POMC as efficiently. Therefore increased prevalence of ACTH precursors in the circulation would be expected and this was substantiated by the large excess of ACTH precursors (139–18,000 pmol/l) in the circulation of the 51 patients with the ectopic ACTH Syndrome.
The diagnostic accuracy of the measurement of ACTH precursors was then prospectively compared with a group of 62 patients undergoing the current “gold standard” test of inferior petrosal sinus sampling (IPSS). All those patients with ACTH precursors below a diagnostic cut-off of 100 pmol/l were subsequently shown to have pituitary tumors, whereas levels of >100 pmol/l were seen in the four patients with ectopic tumors. In comparison the IPSS had a specificity of 100% but a sensitivity of 93% and for these false negative results the ACTH precursors proved diagnostically useful. Therefore measurement of ACTH precursors offers a simple non-invasive diagnostic test for the differential diagnosis of Cushing's Syndrome which compares favourably with IPSS.
Unable to display preview. Download preview PDF.
- 10.White A, Clark AJ. The cellular and molecular basis of the ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1993;39:131–141.Google Scholar
- 15.Stewart PM, Gibson S, Crosby SR, Penn R, Holder R, Ferry D, Thatcher N, Phillips P, London DR, White A. ACTH precursors characterize the ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1994;40:199–204.Google Scholar
- 16.White A, Smith H, Hoadley M, Dobson SH, Ratcliffe JG. Clinical evaluation of a two-site immunoradiometric assay for adrenocorticotrophin in unextracted human plasma using monoclonal antibodies. Clin Endocrinol (Oxf) 1987;26:41–51.Google Scholar
- 17.Hinnie J, Gray CE, McNicol AM, Carter R, Thomson JA, White A, Campbell IW, McBain A. Cushing's syndrome in a 16 year old girl due to ectopic ACTH precursor production from a pancreatic tumour. Clin Endocrinol (Oxf) 2000;53:539–540.Google Scholar
- 19.Ratter SJ, Gillies G, Hope J, Hale AC, Grossman A, Gaillard R, Cook D, Edwards CR, Rees LH. Pro-opiocortin related peptides in human pituitary and ectopic ACTH secreting tumours. Clin Endocrinol (Oxf) 1983;18:211–218.Google Scholar
- 21.Loli P, Vignati F, Grossrubatscher E, Dalino P, Possa M, Zurleni F, Lomuscio G, Rossetti O, Ravini M, Vanzulli A, Bacchetta C, Galli C, Valente D. Management of occult adrenocorticotropin-secreting bronchial carcinoids: Limits of endocrine testing and imaging techniques. J Clin Endocrinol Metab 2003;88:1029–1035.PubMedGoogle Scholar
- 23.Vieau D, Massias JF, Girard F, Luton JP, Bertagna X. Corticotrophin-like intermediary lobe peptide as a marker of alternate pro-opiomelanocortin processing in ACTH-producing non-pituitary tumours. Clin Endocrinol (Oxf) 1989;31:691–700.Google Scholar
- 26.Kaltsas GA, Giannulis MG, Newell-Price JD, Dacie JE, Thakkar C, Afshar F, Monson JP, Grossman AB, Besser GM, Trainer PJ. A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1999;84:487–492.PubMedGoogle Scholar
- 28.Giraldi FP, Invitti C, Cavagnini F. The corticotropin-releasing hormone test in the diagnosis of ACTH-dependent Cushing's syndrome: A reappraisal. Clin Endocrinol (Oxf) 2001;54:601–607.Google Scholar
- 30.Wiggam MI, Heaney AP, McIlrath EM, McCance DR, Sheridan B, Hadden DR, Atkinson AB. Bilateral inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropindependent Cushing's syndrome: A comparison with other diagnostic tests. J Clin Endocrinol Metab 2000;85:1525–1532.PubMedGoogle Scholar
- 31.Reimondo G, Paccotti P, Minetto M, Termine A, Stura G, Bergui M, Angeli A, Terzolo M. The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing's syndrome. Clin Endocrinol (Oxf) 2003;58:718–724.Google Scholar
- 32.White A, Gibson S. ACTH precursors: Biological significance and clinical relevance. Clin Endocrinol (Oxf) 1998;48:251–255.Google Scholar