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Acylated ghrelin as provocative test for the diagnosis of ACTH deficiency in patients with hypothalamus–pituitary disease

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Abstract

The insulin tolerance test (ITT) is the gold standard to evaluate adrenocorticotropic hormone (ACTH) insufficiency. However, alternative tests have been proposed such as metyrapone, glucagon, and ACTH stimulation test. We determined the diagnostic reliability of testing with ghrelin, the natural GH secretagogue that is a potent stimulus exploring the integrity of hypothalamic–pituitary–adrenal axis. We studied the ACTH and cortisol response to acylated ghrelin in 49 patients with history of pituitary disease. The best cortisol and ACTH cut offs to ghrelin test, defined as those with the best sensitivity (SE) and specificity (SP), were identified using the ROC analysis. We also compared accuracy of ghrelin test with that of a simple and cheap test like basal cortisol and ACTH levels. The best cortisol and ACTH cut offs to ghrelin test were ≤11.6 µg/dl (SE 86.4 %, SP 77.8 %) and ≤32.5 pg/ml (SE 72.7 %, SP 51.9 %), respectively; the best basal cortisol and ACTH cut offs were ≤10.7 µg/dl (SE 90.9 %, SP 70.4 %) and ≤25.0 pg/ml (SE 85 %, SP 37 %), respectively. The diagnostic accuracy was 81.6, 60.9, 79.6, and 57.4 %, respectively. A comparison between ROC AUC showed a great diagnostic power for cortisol, both stimulated and basal, versus ACTH, both stimulated and basal, but no difference between stimulated and basal cortisol evaluation. Our data show that testing with acylated ghrelin is not a useful diagnostic tool for the diagnosis of central hypocortisolism; particularly ghrelin test adds no more information that basal cortisol evaluation in the diagnosis of ACTH deficiency in patients with hypothalamus–pituitary disease.

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References

  1. Z. Karaca, F. Tanriverdi, H. Atmaca, C. Gokce, G. Elbuken, A. Selcuklu, K. Unluhizarci, F. Kelestimur, Can basal cortisol measurement be an alternative to the insulin tolerance test in the assessment of the hypothalamic-pituitary-adrenal axis before and after pituitary surgery? Eur. J. Endocrinol. 163, 377–382 (2010)

    Article  CAS  PubMed  Google Scholar 

  2. W.J. Inder, P.J. Hunt, Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J. Clin. Endocrinol. Metab. 87, 2745–2750 (2002)

    Article  CAS  PubMed  Google Scholar 

  3. W. Arlt, B. Allolio, Adrenal insufficiency. Lancet 361, 1881–1893 (2003)

    Article  CAS  PubMed  Google Scholar 

  4. R. Kazlauskaite, A.T. Evans, C.V. Villabona, T.A. Abdu, B. Ambrosi, A.B. Atkinson, C.H. Choi, R.N. Clayton, C.H. Courtney, E.N. Gonc, M. Maghnie, S.R. Rose, S.G. Soule, K. Tordjman, Consortium for evaluation of corticotropin test in hypothalamic-pituitary adrenal insufficiency: corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. J. Clin. Endocrinol. Metab. 93, 4245–4253 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. E. Yerlikaya, F. Akin, Misdiagnosis of hypocortisolemia based on early morning cortisol. Endocrine 43, 734–735 (2013)

    Article  CAS  PubMed  Google Scholar 

  6. K.C. Yuen, L.E. Chong, C.A. Koch, Adrenal insufficiency in pregnancy: challenging issues in diagnosis and management. Endocrine 44, 283–292 (2013)

    Article  CAS  PubMed  Google Scholar 

  7. A. Falorni, V. Minarelli, S. Morelli, Therapy of adrenal insufficiency: an update. Endocrine 43, 514–528 (2013)

    Article  CAS  PubMed  Google Scholar 

  8. E. Erturk, C.A. Jaffe, A.L. Barkan, Evaluation of the integrity of the hypothalamic–pituitary–adrenal axis by insulin hypoglycemia test. J. Clin. Endocrinol. Metab. 83, 2350–2354 (1998)

    CAS  PubMed  Google Scholar 

  9. S.K. Grinspoon, B.M. Biller, Clinical review 62: laboratory assessment of adrenal insufficiency. J. Clin. Endocrinol. Metab. 79, 923–931 (1994)

    CAS  PubMed  Google Scholar 

  10. L.K. Nieman, Dynamic evaluation of adrenal hypofunction. J. Endocrinol. Invest. 26, 74–82 (2003)

    CAS  PubMed  Google Scholar 

  11. R.I. Dorin, C.R. Qualls, L.M. Crapo, Diagnosis of adrenal insufficiency. Ann. Internal Med. 139, 194–204 (2003)

    Article  Google Scholar 

  12. S.L. Jones, P.J. Trainer, L. Perry, J.A. Wass, G.M. Bessser, A. Grossman, An audit of the insulin tolerance test in adult subjects in an acute investigation unit over one year. Clin. Endocrinol 41, 123–128 (1994)

    Article  CAS  Google Scholar 

  13. A. Tsatsoulis, S.M. Shalet, J. Harrison, W.A. Ratcliffe, C.G. Beardwell, L. Robinson, Adrenocorticotrophin (ACTH) deficiency undetected by standard dynamic tests of the hypothalamo–pituitary–adrenal axis. Clin. Endocrinol. 28, 225–232 (1988)

    Article  CAS  Google Scholar 

  14. M. Pfeifer, K. Kanc, R. Verhovec, A. Kocijancic, Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men. Clin. Endocrinol. 54, 17–22 (2001)

    Article  CAS  Google Scholar 

  15. J.J. Staub, B. Noelpp, J. Girard, J.B. Baumann, S. Graf, J.G. Ratcliffe, The short metyrapone test: comparison of the plasma ACTH response to metyrapone and insulin-induced hypoglycaemia. Clin. Endocrinol. 10, 595–601 (1979)

    Article  CAS  Google Scholar 

  16. T.M. Fiad, J.M. Kirby, S.K. Cunningham, T.J. McKenna, The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic–pituitary–adrenal axis. Clin. Endocrinol. 40, 603–609 (1994)

    Article  CAS  Google Scholar 

  17. H. Steiner, V. Bahr, P. Exner, P.W. Oelkers, Pituitary function tests: comparison of ACTH and 11-deoxy-cortisol responses in the metyrapone test and with the insulin hypoglycemia test. Exp. Clin. Endocrinol. 102, 33–38 (1994)

    Article  CAS  PubMed  Google Scholar 

  18. M. Spiger, W. Jubiz, A.W. Meikle, C.D. West, F.H. Tylor, Single-dose metyrapone test: review of a four-year experience. Arch. Inter. Med. 135, 698–700 (1975)

    Article  CAS  Google Scholar 

  19. K. Leong, A. Walker, I. Martin, D. Wile, J. Wilding, I. MacFarlane, An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic-pituitary disease. Clin. Endocrinol. 54, 463–468 (2001)

    Article  CAS  Google Scholar 

  20. M. Littley, S. Gibson, A. White, S. Shalet, Comparison of the ACTH and cortisol responses to provocative testing with glucagon and insulin hypoglycaemia in normal subjects. Clin. Endocrinol. 31, 527–533 (1989)

    Article  CAS  Google Scholar 

  21. W. Oelkers, Dose–response aspects in the clinical assessment of the hypothalamo–pituitary–adrenal axis, and the low-dose adrenocorticotropin test. Eur. J. Endocrinol. 135, 27–33 (1996)

    Article  CAS  PubMed  Google Scholar 

  22. E. Arvat, L. DiVito, F. Lanfranco, M. Maccario, C. Baffoni, R. Rossetto, G. Aimaretti, F. Camanni, E. Ghigo, Stimulatory effect of adrenocorticotropin on cortisol, aldosterone, and dehydroepiandrosterone secretion in normal humans: dose–response study. J. Clin. Endocrinol. Metab. 85, 3141–3146 (2000)

    CAS  PubMed  Google Scholar 

  23. D.H.P. Streeten, G.H. Anderson, M. Bonaventura, The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J. Clin. Endocrinol. Metab. 81, 285–290 (1996)

    CAS  PubMed  Google Scholar 

  24. T.A. Abdu, T.A. Elhadd, R. Neary, R.N. Clayton, Comparison of the low dose short synacthen test (1 mg), the conventional dose short synacthen test (250 mg), and the insulin tolerance test for assessment of the hypothalamo–pituitary–adrenal axis in patients with pituitary disease. J. Clin. Endocrinol. Metab. 84, 838–843 (1999)

    CAS  PubMed  Google Scholar 

  25. B. Ambrosi, L. Barbetta, T. Re, E. Passini, G. Faglia, The one microgram adrenocorticotropin test in the assessment of hypothalamic–pituitary–adrenal function. Eur. J. Endocrinol. 139, 575–579 (1998)

    Article  CAS  PubMed  Google Scholar 

  26. J. Mayenknecht, S. Diederich, V. Bahr, U. Plockinger, W. Oelkers, Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J. Clin. Endocrinol. Metab. 83, 1558–1562 (1998)

    Article  CAS  PubMed  Google Scholar 

  27. A.M. Suliman, T.P. Smith, M. Labib, T.M. Fiad, T.J. McKenna, The low-dose ACTH test does not provide a useful assessment of the hypothalamic–pituitary–adrenal axis in secondary adrenal insufficiency. Clin. Endocrinol. 56, 533–539 (2002)

    Article  CAS  Google Scholar 

  28. M. Maghnie, E. Uga, F. Temporini, N. Di Iorgi, A. Secco, C. Tinelli, A. Papalia, M.R. Casini, S. Loche, Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. Eur. J. Endocrinol. 152, 735–741 (2005)

    Article  CAS  PubMed  Google Scholar 

  29. R.N. Clayton, Short synacthen versus insulin stress test for assessment of the hypothalamo–pituitary–adrenal axis: controversy revisited. Clin. Endocrinol. 44, 147–149 (1996)

    Article  CAS  Google Scholar 

  30. H.K. Gleeson, B.R. Walker, J.R. Seckl, P.L. Padfield, Ten years on: safety of short synacthen tests in assessing adrenocorticotropin deficiency in clinical practice. J. Clin. Endocrinol. Metab. 88, 2106–2111 (2003)

    Article  CAS  PubMed  Google Scholar 

  31. A. Agha, J.W. Tomlinson, P.M. Clark, G. Holder, P.M. Stewart, The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic–pituitary–adrenal axis. J. Clin. Endocrinol. Metab. 91, 43–47 (2006)

    Article  CAS  PubMed  Google Scholar 

  32. L.K. Nieman, E.H. Oldfield, R. Wesley, G.P. Chrousos, D.L. Loriaux, G.B. Cutler Jr, A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome. J. Clin. Endocrinol. Metab. 77, 1308–1312 (1993)

    CAS  PubMed  Google Scholar 

  33. O.A. Muller, G.K. Stalla, K. von Werder, Corticotropin-releasing factor in humans. II. CRF stimulation in patients with diseases of the hypothalamo-pituitary-adrenal axis. Horm. Res. 25, 185–198 (1987)

    Article  CAS  PubMed  Google Scholar 

  34. R.P. Dullaart, S.H. Pasterkamp, J.A. Beentjes, W.J. Sluiter, Evaluation of adrenal function in patients with hypothalamic and pituitary disorders: comparison of serum cortisol, urinary free cortisol and the human-corticotrophin releasing hormone test with the insulin tolerance test. Clin. Endocrinol. 50, 465–471 (1999)

    Article  CAS  Google Scholar 

  35. M. Korbonits, A.P. Goldstone, M. Gueorguiev, A.B. Grossman, Ghrelin a hormone with multiple functions. Front. Neuroendocrinol. 25, 27–68 (2004)

    Article  CAS  PubMed  Google Scholar 

  36. E. Ghigo, E. Arvat, G. Muccioli, F. Camanni, Growth hormone releasing peptides. Eur. J. Endocrinol. 136, 445–460 (1997)

    Article  CAS  PubMed  Google Scholar 

  37. A.J. Van der Lely, M. Tschop, M.L. Heiman, E. Ghigo, Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr. Rev. 25, 426–457 (2004)

    Article  PubMed  Google Scholar 

  38. E. Arvat, M. Maccario, L. Di Vito, F. Broglio, A. Benso, C. Gottero, M. Papotti, G. Muccioli, C. Dieguez, F.F. Casanueva, R. Deghenghi, F. Camanni, E. Ghigo, Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J. Clin. Endocrinol. Metab. 86, 1169–1174 (2001)

    CAS  PubMed  Google Scholar 

  39. M.H. Zweig, G. Campbell, Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin. Chem. 39, 561–577 (1993)

    CAS  PubMed  Google Scholar 

  40. A. Beardsell, S. Bell, S. Robinson, H. Rumbold, MCEM Part A: MCQs (Royal Society of Medicine Press, London, 2009)

    Google Scholar 

  41. V. Gasco, G. Beccuti, C. Baldini, N. Prencipe, S. Di Giacomo, A. Berton, F. Guaraldi, I. Tabaro, M. Maccario, E. Ghigo, S. Grottoli, Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults. Eur. J. Endocrinol. 168, 23–30 (2012)

    Article  PubMed  Google Scholar 

  42. K. Blijdorp, L. Khajeh, G.M. Ribbers, E.M. Sneekes, M.H. Heijenbrok-Kal, H.J. van den Berg-Emons, A.J. van der Lely, F. van Kooten, S.J. Neggers, Diagnostic value of a ghrelin test for the diagnosis of GH deficiency after subarachnoid hemorrhage. Eur. J. Endocrinol. 169, 497–502 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. G. Aimaretti, C. Baffoni, F. Broglio, J.A. Janssen, G. Corneli, R. Deghenghi, A.J. van der Lely, E. Ghigo, E. Arvat, Endocrine responses to ghrelin in adult patients with isolated childhood-onset growth hormone deficiency. Clin. Endocrinol. 56, 765–771 (2002)

    Article  CAS  Google Scholar 

  44. V. Popovic, D. Miljic, D. Micic, S. Damjanovic, E. Arvat, E. Ghigo, C. Dieguez, F.F. Casanueva, Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level. J. Clin. Endocrinol. Metab. 88, 3450–3453 (2003)

    Article  CAS  PubMed  Google Scholar 

  45. Y. Hataya, T. Akamizu, K. Takaya, N. Kanamoto, H. Ariyasu, M. Saijo, K. Moriyama, A. Shimatsu, M. Kojima, K. Kangawa, K. Nakao, A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J. Clin. Endocrinol. Metab. 86, 4552–4555 (2001)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The present study was supported by University of Turin and SMEM Foundation.

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Authors declare that they have not any conflict of interest.

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, Città della Salute e della Scienza – Osp. San Giovanni Battista, C.so Dogliotti 14, 10126, Turin, Italy

    Valentina Gasco, Alessandro Berton, Mirko Parasiliti Caprino, Ioannis Karamouzis, Mauro Maccario, Ezio Ghigo & Silvia Grottoli

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  1. Valentina Gasco
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  2. Alessandro Berton
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Correspondence to Silvia Grottoli.

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Gasco, V., Berton, A., Caprino, M.P. et al. Acylated ghrelin as provocative test for the diagnosis of ACTH deficiency in patients with hypothalamus–pituitary disease. Endocrine 50, 474–482 (2015). https://doi.org/10.1007/s12020-014-0494-5

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