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ACTH and Cortisol responses to ghrelin and desmopressin in patients with Cushing’s disease and adrenal enlargement

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Abstract

Background: Overexpression of ghrelin and vasopressin (V3) receptors demonstrated on corticotrophe adenomas accounts for exaggerated ACTH and cortisol responses to ghrelin and desmopressin (DDAVP) in patients with Cushing’s disease (CD). Aim: In this study we have compared ACTH and cortisol responsiveness to DDAVP and ghrelin in CD patients with and without adrenal enlargemenent. Subjects and methods: Ghrelin and DDAVP tests were performed in 15 patients with CD (7 with and 8 without signs of adrenal enlargement) with CRH test in 8 patients. In 7 ageand sex-matched healthy subjects, ghrelin test was performed. Plasma ACTH and serum cortisol concentrations were measured after ghrelin, DDAVP and CRH. Growth hormone was measured after stimulation with ghrelin. Results: Significantly higher baseline and peak ACTH and cortisol concentrations after ghrelin were observed in all patients with CD compared to healthy control subjects. Patients with CD and adrenal enlargement had significantly lower baseline and peak ACTH concentrations after stimulation with ghrelin compared to CD patients without adrenal enlargement, while cortisol levels at baseline and after ghrelin administration were similar. Three out of seven patients with CD and adrenal enlargement did not respond to DDAVP while they responded well to CRH and ghrelin. Conclusion: Patients with CD and adrenal enlargement pose special diagnostic problems. They may have lower baseline ACTH levels and may not respond to DDAVP while they respond to ghrelin and CRH. Despite increased endogenous cortisol levels in CD, cortisol responses to ghrelin and CRH are preserved in patients with CD and adrenal enlargement.

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References

  1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth hormone releasing acylated peptide from stomach. Nature 1999, 402: 656–60.

    Article  PubMed  CAS  Google Scholar 

  2. Arvat E, Maccario M, Di Vito L, et al. 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 2001, 86: 1169–74.

    PubMed  CAS  Google Scholar 

  3. Leal-Cerro A, Torres E, Soto A, et al. Ghrelin is no longer able to stimulate growth hormone secretion in patients with Cushing’s syndrome but instead induces exaggerated corticotropin and cortisol responses. Neuroendocrinology 2002, 76: 390–6.

    Article  PubMed  CAS  Google Scholar 

  4. Correa de Silva SR, Nascif SO, Lengyel AM. Decreased GH secretion and enhanced ACTH and cortisol release after ghrelin administration in Cushing’s disease: comparison with GH-releasing pep-tide-6 (GHRP-6) and GHRH. Pituitary 2006, 9: 101–7.

    Article  PubMed  CAS  Google Scholar 

  5. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor GHS-R in humans. J Clin Endocrinol Metab 2002, 87: 2988.

    Article  PubMed  CAS  Google Scholar 

  6. Skinner MM, Nass R, Lopey B, Laws ER, Thorner MO. Growth hormone secretagogue receptor expression in human pituitary tumors. J Clin Endocrinol Metab 1998, 83: 4314–20.

    PubMed  CAS  Google Scholar 

  7. Barlier A, Zamora AJ, Grino M, et al. Expression of functional growth hormone secretagogue receptors in human pituitary adenomas: polymerase chain reaction, triple in-situ hybridization and cell culture studies. J Neuroendocrinol 1999, 11: 491–502.

    Article  PubMed  CAS  Google Scholar 

  8. Kim K, Arai K, Sanno N, Osamura RY, Teramoto A, Shibasaki T. Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas. Clin Endocrinol 2001, 54: 759–68.

    Article  CAS  Google Scholar 

  9. Korbonits M, Bustin SA, Kojima M, et al. The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. J Clin Endocrinol Metab 2001, 86: 881–7.

    PubMed  CAS  Google Scholar 

  10. Arnaldi G, Mancini T, Kola B, et al. Cyclical Cushing’s syndromein a patient with a bronchial neuroendocrine tumor (typical carcinoid) expressing ghrelin and growth hormone secretagogue receptors. J Clin Endocrinol Metab 2003, 88: 5834–40.

    Article  PubMed  CAS  Google Scholar 

  11. Korbonits M, Kaltsas G, Perry LA, et al. The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary adrenal axis via arginine vasopressin. J Clin Endocrinol Metab 1999, 84: 2489–95.

    Article  PubMed  CAS  Google Scholar 

  12. Malerbi DA, Mendonca BB, Liberman B, et al. The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol 1993, 38: 463–72.

    Article  CAS  Google Scholar 

  13. Newell-Price J, Perry L, Medbak S, et al. A combined test using desmopressin and corticotropin-releasing hormone in the differential diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 1997, 82: 176–81.

    PubMed  CAS  Google Scholar 

  14. Moro M, Putignano P, Losa M, Invitti C, Maraschini C, Cavagnini F. The desmopressin test in the differential diagnosis between Cushing’s disease and pseudo-Cushing’s states. J Clin Endocrinol Metab 2000, 85: 3569–74.

    PubMed  CAS  Google Scholar 

  15. Tsagarakis S, Tsigos C, Vasiliou V, et al. The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab 2002, 87: 1646–53.

    PubMed  CAS  Google Scholar 

  16. Thibonnier M, Conarty DM, Preston JA, Wilkins PL, Berti-Mattera L, Mattera R. Molecular pharmacology of human vasopressin receptors. Adv Exp Med Biol 1998, 449: 251–76.

    Article  PubMed  CAS  Google Scholar 

  17. Dahia PLM, Ahmed-Shuaib A, Jacobs RA, et al. Vasopressin receptor expression and mutation analysis in corticotropin-secreting tumors. J Clin Endocrinol Metab 1996, 81: 1768–71.

    PubMed  CAS  Google Scholar 

  18. De Keyzer Y, René P, Beldjord C, Lenne F, Bertagna X. Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumors. Clin Endocrinol 1998, 49: 475–82.

    Article  Google Scholar 

  19. De Keyzer Y, Lenne F, Auzan C, et al. The pituitary v3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome. J Clin Invest 1996, 97: 1311–8.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Arlt W, Dahia PLM, Callies JP, et al. Ectopic ACTH production by a bronchial carcinoid tumor responsive to desmopressin in vivo and in vitro. Clin Endocrinol 1997, 47: 623–7.

    Article  CAS  Google Scholar 

  21. Oliviera JH, Vieira JG, Abucham J, Lengyel AM. GHRP-6 is able to stimulate cortisol and ACTH release in patients with Cushing’s disease: comparison with DDAVP. J Endocrinol Invest 2003, 26: 230–5.

    Article  Google Scholar 

  22. Clark AJ, Metherell LA. Mechanisms of disease: the adrenocorticotropin receptor and disease. Nat Clin Pract Endocrinol Metab 2006, 2: 282–90.

    Article  PubMed  CAS  Google Scholar 

  23. Imai T, Sarkar D, Shibata A, et al. Expression of adrenocorticotropin receptor gene in adrenocortical adenomas from patients with Cushing syndrome: possible contribution for the autonomous production of cortisol. Ann Surg 2001, 234: 85–91.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Petersenn S, Rasch AC, Penshorn M, Beil FU, Schulte HM. Genomic structure and transcriptional regulation of the human growth hormone secretagogue receptor. Endocrinology 2001, 142: 2649–59.

    PubMed  CAS  Google Scholar 

  25. Tsagarakis S, Vasiliou V, Kokkoris P, Stavropoulous G, Thalassinos N. Assessment of cortisol and ACTH responses to the desmopressin test in patients with Cushing’s syndrome and simple obesity. Clin Endocrinol 1999, 51: 473–7.

    Article  CAS  Google Scholar 

  26. Terzolo M, Reimondo G, Alì A, et al. The limited value of the desmopressin test in the diagnostic approach to Cushing’s syndrome. Clin Endocrinol 2001, 54: 609–16.

    Article  CAS  Google Scholar 

  27. Tsagarakis S, Tsigos V, Vasiliou P, et al. The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab 2002, 87: 1646–53.

    PubMed  CAS  Google Scholar 

  28. Suda T, Kageyama K, Nigawara T, Sakihara S. Evaluation of diagnostic tests for ACTH-dependent Cushing’s syndrome. Endocr J 2009, 56: 469–76. doi 10.1507/endocrj. K08E-353.

    Article  PubMed  CAS  Google Scholar 

  29. Marova E, Goncharov N, Kolesnikova G, Arapova SD, Lapshina AM. The response of corticotropin and adrenal steroids to desmopressin stimulation in patients with various forms of hypercortisolism. Hormones 2008, 7: 243–50.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Endocrinology, University Clinical Center of Serbia, Belgrade, Serbia

    D. Miljic, M. Doknic, M. Ivovic, M. Djurovic, S. Pekic, M. Tancic, M. Stojanovic, Dj. Macut, S. Damjanovic &  V. Popovic

  2. Clinic for Neurosurgery, University Clinical Center of Serbia, Belgrade, Serbia

    M. Joksimovic

  3. Medical Statistics, Medical Faculty, Belgrade

    I. Soldatovic

  4. Institute of Urology, University Clinical Center of Serbia, Belgrade, Serbia

    Dj. Nale

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  1. D. Miljic
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  2. M. Joksimovic
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  3. M. Doknic
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  4. M. Ivovic
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  5. M. Djurovic
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  6. S. Pekic
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  9. M. Stojanovic
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  12. S. Damjanovic
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  13. V. Popovic
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Correspondence to V. Popovic.

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Miljic, D., Joksimovic, M., Doknic, M. et al. ACTH and Cortisol responses to ghrelin and desmopressin in patients with Cushing’s disease and adrenal enlargement. J Endocrinol Invest 33, 526–529 (2010). https://doi.org/10.1007/BF03346641

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  • DOI: https://doi.org/10.1007/BF03346641

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