Pituitary

, Volume 6, Issue 3, pp 119–126 | Cite as

Characterisation of ACTH Related Peptides in Ectopic Cushing's Syndrome

  • Robert L. Oliver
  • Julian R.E. Davis
  • Anne White
Article

Abstract

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.

POMC pro-opiomelanocortin Cushing's syndrome ACTH ectopic IPSS 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mains RE, Eipper BA. Biosynthesis of adrenocorticotropic hormone in mouse pituitary tumor cells. J Biol Chem 1976;251:4115–4120.PubMedGoogle Scholar
  2. 2.
    Mains RE, Eipper BA, Ling N. Common precursor to corticotropins and endorphins. Proc Natl Acad Sci USA 1977;74:3014–3018.PubMedGoogle Scholar
  3. 3.
    Orth DN, Nicholson WE, Mitchell WM, Island DP, Shapiro M, Byyny RL. ACTH and MSH production by a single cloned mouse pituitary tumor cell line. Endocrinology 1973;92:385–393.PubMedGoogle Scholar
  4. 4.
    Orth DN, Guillemin R, Ling N, Nicholson WE. Immunoreactive endorphins, lipotropins and corticotropins in a human nonpituitary tumor: Evidence for a common precursor. J Clin Endocrinol Metab 1978;46:849–852.PubMedGoogle Scholar
  5. 5.
    Roberts JL, Herbert E. Characterization of a common precursor to corticotropin and beta-lipotropin: Cell-free synthesis of the precursor and identification of corticotropin peptides in the molecule. Proc Natl Acad Sci USA 1977;74:4826–4830.PubMedGoogle Scholar
  6. 6.
    Smith AI, Funder JW. Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues. Endocr Rev 1988;9:159–179.PubMedGoogle Scholar
  7. 7.
    Dumermuth E, Moore HP. Analysis of constitutive and constitutive-like secretion in semi-intact pituitary cells. Methods 1998;16:188–197.PubMedGoogle Scholar
  8. 8.
    Wakamatsu K, Graham A, Cook D, Thody AJ. Characterisation of ACTH peptides in human skin and their activation of the melanocortin-1 receptor. Pigment Cell Res 1997;10:288–297.PubMedGoogle Scholar
  9. 9.
    Pritchard LE, Turnbull AV, White A. Pro-opiomelanocortin processing in the hypothalamus: Impact on melanocortin signalling and obesity. J Endocrinol 2002;172:411–421.PubMedGoogle Scholar
  10. 10.
    White A, Clark AJ. The cellular and molecular basis of the ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1993;39:131–141.Google Scholar
  11. 11.
    Crosby SR, Stewart MF, Ratcliffe JG, White A. Direct measurement of the precursors of adrenocorticotropin in human plasma by two-site immunoradiometric assay. J Clin Endocrinol Metab 1988;67:1272–1277.PubMedGoogle Scholar
  12. 12.
    Gibson S, Crosby SR, Stewart MF, Jennings AM, McCall E, White A. Differential release of proopiomelanocortin-derived peptides from the human pituitary: Evidence from a panel of two-site immunoradiometric assays. J Clin Endocrinol Metab 1994;78:835–841.PubMedGoogle Scholar
  13. 13.
    Bertagna X, Camus F, Lenne F, Girard F, Luton JP. Human joining peptide: A proopiomelanocortin product secreted as a homodimer. Mol Endocrinol 1988;2:1108–1114.PubMedGoogle Scholar
  14. 14.
    Yalow RS, Berson SA. Size heterogeneity of immunoreactive human ACTH in plasma and in extracts of pituitary glands and ACTH-producing thymoma. Biochem Biophys Res Commun 1971;44:439–445.PubMedGoogle Scholar
  15. 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. 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. 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
  18. 18.
    Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, Cutler GB, Jr, Loriaux DL. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome.N Engl J Med 1991;325:897–905.PubMedGoogle Scholar
  19. 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
  20. 20.
    Hirata Y, Yamamoto H, Matsukura S, Imura H. In vitro release and biosynthesis of tumor ACTH in ectopic ACTH producing tumors. J Clin Endocrinol Metab 1975;41:106–114.PubMedGoogle Scholar
  21. 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
  22. 22.
    Raffin-Sanson ML, Massias JF, Dumont C, Raux-Demay MC, Proeschel MF, Luton JP, Bertagna X. High plasma proopiomelanocortin in aggressive adrenocorticotropin-secreting tumors. J Clin Endocrinol Metab 1996;81:4272–4277.PubMedGoogle Scholar
  23. 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
  24. 24.
    Beuschlein F, Hammer GD. Ectopic pro-opiomelanocortin syndrome. Endocrinol Metab Clin North Am 2002;31:191–234.PubMedGoogle Scholar
  25. 25.
    Colao A, Faggiano A, Pivonello R, Giraldi FP, Cavagnini F, Lombardi G. Inferior petrosal sinus sampling in the differential diagnosis of Cushing's syndrome: Results of an Italian multi-center study. Eur J Endocrinol 2001;144:499–507.PubMedGoogle Scholar
  26. 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
  27. 27.
    Doppman JL, Chang R, Oldfield EH, Chrousos G, Stratakis CA, Nieman LK. The hypoplastic inferior petrosal sinus: A potential source of false-negative results in petrosal sampling for Cushing's disease. J Clin Endocrinol Metab 1999;84:533–540.PubMedGoogle Scholar
  28. 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
  29. 29.
    Newell-Price J, Morris DG, Drake WM, Korbonits M, Monson JP, Besser GM, Grossman AB. Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab 2002;87:1640–1645.PubMedGoogle Scholar
  30. 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. 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. 32.
    White A, Gibson S. ACTH precursors: Biological significance and clinical relevance. Clin Endocrinol (Oxf) 1998;48:251–255.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Robert L. Oliver
    • 1
  • Julian R.E. Davis
    • 1
  • Anne White
    • 1
  1. 1.Endocrine Sciences Research Group, Schools of Medicine and Biological SciencesUniversity of ManchesterManchesterUK

Personalised recommendations