, Volume 7, Issue 4, pp 243–248 | Cite as

Ghrelin, Hypothalamus-Pituitary-Adrenal (HPA) Axis and Cushing's Syndrome

  • Roberta Giordano
  • Andreea Picu
  • Fabio Broglio
  • Lorenza Bonelli
  • Matteo Baldi
  • Rita Berardelli
  • Ezio Ghigo
  • Emanuela ArvatEmail author


Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS. Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts pleiotropic actions that are explained by the widespread distribution of ghrelin and GHS-R expression. Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a. However, GHS-R subtypes are likely to exist; they also bind unacylated ghrelin that is, in fact, the most abundant circulating form and exerts some biological actions. Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction. The role of glucocorticoids on ghrelin synthesis and secretion is still unclear although morning ghrelin levels have been found reduced in some patients with Cushing's syndrome; this, however, would simply reflect its negative association to body mass. Ghrelin, like synthetic GHS, stimulates ACTH and cortisol secretion in normal subjects and this effect is generally sensitive to the negative glucocorticoid feedback. It is remarkable that, despite hypercortisolism, ghrelin as well as synthetic GHS display marked increase in their stimulatory effect on ACTH and cortisol secretion in patients with Cushing's disease. This is even more intriguing considering that the GH response to ghrelin and GHS is markedly reduced by glucocorticoid excess. It has been demonstrated that the ACTH-releasing effect of ghrelin and GHS is purely mediated at the central level in physiological conditions; its enhancement in the presence of ACTH-secreting tumours is, instead, likely to reflect direct action on GHS receptors present on the neoplastic tissues. In fact, peculiar ACTH hyperresponsiveness to ghrelin and GHS has been observed also in ectopic ACTH-secreting tumours.

Key Words

ghrelin GHS HPA axis Cushing's syndrome 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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;402:656–660.CrossRefPubMedGoogle Scholar
  2. 2.
    Van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004;25:426–457.CrossRefPubMedGoogle Scholar
  3. 3.
    Broglio F, Benso A, Gottero C, Prodam F, Gauna C, Filtri L, Arvat E, van der Lely AJ, Deghenghi R, Ghigo E. Non-acylated ghrelin does not possess the pituitaric and pancreatic endocrine activity of acylated ghrelin in humans. J Endocrinol Invest 2003;26:192–196.PubMedGoogle Scholar
  4. 4.
    Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K. Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chemistry 2003;278:64–70.Google Scholar
  5. 5.
    Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002;87:2988.CrossRefPubMedGoogle Scholar
  6. 6.
    Volante M, Allia E, Gugliotta P, Funaro A, Broglio F, Deghenghi R, Muccioli G, Ghigo E, Papotti M. Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab 2002;87:1300–1308.CrossRefPubMedGoogle Scholar
  7. 7.
    Muccioli G, Papotti M, Locatelli V, Ghigo E, Deghenghi R. Binding of 125I-labeled ghrelin to membranes from human hypothalamus and pituitary gland. J Endocrinol Invest 2001;24:RC7–RC9.PubMedGoogle Scholar
  8. 8.
    Horvath TL, Diano S, Sotonyi P, Heiman M, Tschop M. Minireview: Ghrelin and the regulation of energy balance-a hypothalamic perspective. Endocrinology 2001;142:4163–4169.CrossRefPubMedGoogle Scholar
  9. 9.
    Choi K, Roh SG, Hong YH, Shrestha YB, Hishikawa D, Chen C, Kojima M, Kangawa K, Sasaki S. The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis. Endocrinology 2003;144:754–759.PubMedGoogle Scholar
  10. 10.
    Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Comm 2004;313: 635–641.CrossRefPubMedGoogle Scholar
  11. 11.
    Smith RG, Van der Ploeg LHT, Howard AD, Feighner SD, Cheng K, Hickey GJ, Wyvratt MJ, Fisher MH, Nargund RP, Patchett AA. Peptidomimetic regulation of growth hormone secretion. Endocr Rev 1997;18:621–645.CrossRefPubMedGoogle Scholar
  12. 12.
    Korbonits M, Grossman AB. Growth hormone-releasing peptide and its analogues. Novel stimuli to growth hormone release. Trends Endocrinol Metab 1995;6:43–49.Google Scholar
  13. 13.
    Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. Eur J Endocrinol 1997;136:445–460.PubMedGoogle Scholar
  14. 14.
    Chanoine JP, Wong AC. Ghrelin gene expression is markedly higher in fetal pancreas compared to fetal stomach: Effect of maternal fasting. Endocrinology 2004;145:3813–3820.CrossRefPubMedGoogle Scholar
  15. 15.
    Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA 2004;101:2924–2929.CrossRefPubMedGoogle Scholar
  16. 16.
    Tortorella C, Macchi C, Spinazzi R, Malendowicz LK, Trejter M, Nussdorfer GG. Ghrelin, an endogenous ligand for the growth hormone-secretagogue receptor, is expressed in the human adrenal cortex. In J Mol Medicine 2003;12:213–217.Google Scholar
  17. 17.
    Andreis PG, Malendowicz LK, Trejter M, Neri G, Spinazzi R, Rossi GP, Nussdorfer GG. Ghrelin and growth hormone secretagogue receptor are expressed in the rat adrenal cortex: Evidence that ghrelin stimulates the growth but not the secretory activity of adrenal cells. FEBS Letters 2003;536:173–179.CrossRefPubMedGoogle Scholar
  18. 18.
    Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC Melillo DG, Van der Ploeg LH. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996;273:974–977.PubMedGoogle Scholar
  19. 19.
    Smith RG, Leonard R, Bailey AR, Palyha O, Feighner S, Tan C, McKee KK, Pong SS, Griffin P, Howard A. Growth hormone secretagogue receptor family members and ligands. Endocrine 2001;14:914.CrossRefGoogle Scholar
  20. 20.
    Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamura H, Kamegai J, Sugihara H, Oikawa S, Wakabayashi I. Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 2002;109:1429–1436.CrossRefPubMedGoogle Scholar
  21. 21.
    Cassoni P, Papotti M, Ghe C, Catapano F, Sapino A, Graziani A, Deghenghi R, Reissmann T, Ghigo E, Muccioli G. Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. J Clin Endocrinol Metab 2001;86:1738–1745.CrossRefPubMedGoogle Scholar
  22. 22.
    Korbonits M, Bustin SA, Kojima M, Jordan S, Adams EF, Lowe DG, Kangawa K, Grossman AB. 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;86:881–887.PubMedGoogle Scholar
  23. 23.
    Arnaldi G, Mancini T, Kola B, Appolloni G, Freddi S, Concettoni C, Bearzi I, Masini A, Boscaro M, Mantero F. Cyclical Cushing's syndrome in a patient with a bronchial neuroendocrine tumor (typical carcinoid) expressing ghrelin and growth hormone secretagogue receptors. J Clin Endocrinol Metab 2003;88:5834–5840.PubMedGoogle Scholar
  24. 24.
    Thomas GB, Bennett PA, Carmignac DF, Robinson IC. Glucocorticoid regulation of growth hormone (GH) secretagogue-induced growth responses and GH secretagogue receptor expression in the rat. Growth Horm IGF Res 2000;10:45–52.PubMedGoogle Scholar
  25. 25.
    Tamura H, Kamegai J, Sugihara H, Kineman RD, Frohman LA, Wakabayashi I. Glucocorticoids regulate pituitary growth hormone secretagogue receptor gene expression. J Neuroendocrinol 2000;12:481–485.PubMedGoogle Scholar
  26. 26.
    Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623–1630.CrossRefPubMedGoogle Scholar
  27. 27.
    Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. American J Physiol Endocrinol Metab 2004;287:E297–E304.Google Scholar
  28. 28.
    Barkan AL, Dimaraki EV, Jessup SK, Symons KV, Ermolenko M, Jaffe CA. Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J Clin Endocrinol Metab 2003;88:2180–2184.CrossRefPubMedGoogle Scholar
  29. 29.
    Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50:707–709.PubMedGoogle Scholar
  30. 30.
    Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum J, Estour B. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab 2003;88:109–116.CrossRefPubMedGoogle Scholar
  31. 31.
    Goldstone AP, Thomas EL, Brynes AE, Castroman G, Edwards R, Ghatei MA, Frost G, Holland AJ, Grossman AB, Korbonits M, Bloom SR, Bell JD. Elevated fasting plasma ghrelin in PraderWilli syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance. J Clin Endocrinol Metab 2004;89:1718–1726.CrossRefPubMedGoogle Scholar
  32. 32.
    Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001;50:1714–1719.PubMedGoogle Scholar
  33. 33.
    Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R, Folwaczny C. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest 2001;24:RC19–RC21.PubMedGoogle Scholar
  34. 34.
    Doucet E, Pomerleau M, Harper ME. Fasting and postprandial total ghrelin remain unchanged after short-term energy restriction. J Clin Endocrinol Metab 2004;89:1727–1732.CrossRefPubMedGoogle Scholar
  35. 35.
    Lucidi P, Murdolo G, Di Loreto C, De Cicco A, Parlanti N, Fanelli C, Santeusanio F, Bolli GB, De Feo P. Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia. Diabetes 2002;51:2911–2914.PubMedGoogle Scholar
  36. 36.
    Nakagawa E, Nagaya N, Okumura H, Enomoto M, Oya H, Ono F, Hosoda H, Kojima M, Kangawa K. Hyperglycaemia suppresses the secretion of ghrelin, a novel growth-hormone-releasing peptide: Responses to the intravenous and oral administration of glucose. Clin Science 2002;103:325–328.Google Scholar
  37. 37.
    Flanagan DE, Evans ML, Monsod TP, Rife F, Heptulla RA, Tamborlane WV, Sherwin RS. The influence of insulin on circulating ghrelin. Am J of Physiol Endocrinol Metab 2003;284:E313–E316.Google Scholar
  38. 38.
    Broglio F, Prodam F, Gottero C, Destefanis S, Me E, Riganti F, Giordano R, Picu A, Balbo M, van der Lely AJ, Ghigo E, Arvat E. Ghrelin does not mediate the somatotroph and corticotroph responses to the stimulatory effect of glucagon or insulin-induced hypoglycaemia in humans. Clin Endocrinol 2004;60:699–704.Google Scholar
  39. 39.
    Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002;87:240–244.CrossRefPubMedGoogle Scholar
  40. 40.
    Schaller G, Schmidt A, Pleiner J, Woloszczuk W, Wolzt M, Luger A. Plasma ghrelin concentrations are not regulated by glucose or insulin: A double-blind, placebo-controlled crossover clamp study. Diabetes 2003;52:16–20.PubMedGoogle Scholar
  41. 41.
    Erdmann J, Lippl F, Schusdziarra V. Differential effect of protein and fat on plasma ghrelin levels in man. Reg Pep 2003;116:101–107.Google Scholar
  42. 42.
    Broglio F, Koetsveld PP, Benso A, Gottero C, Prodam F, Papotti M, Muccioli G, Gauna C, Hofland L, Deghenghi R, Arvat E, van der Lely AJ, Ghigo E. Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans. J Clin Endocrinol Metab 2002;87:4829–4832.PubMedGoogle Scholar
  43. 43.
    Arosio M, Ronchi CL, Gebbia C, Cappiello V, Beck-Peccoz P, Peracchi M. Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels. J Clin Endocrinol Metab 2003;88:701–704.CrossRefPubMedGoogle Scholar
  44. 44.
    Gualillo O, Caminos JE, Kojima M, Kangawa K, Arvat E, Ghigo E, Casanueva FF, Dieguez C. Gender and gonadal influences on ghrelin mRNA levels in rat stomach. Eur J Endocrinol 2001;144:687–690.CrossRefPubMedGoogle Scholar
  45. 45.
    Caminos JE, Nogueiras R, Blanco M, Seoane LM, Bravo S, Alvarez CV, Garcia-Caballero T, Casanueva FF, Dieguez C. Cellular distribution and regulation of ghrelin messenger ribonucleic acid in the rat pituitary gland. Endocrinology 2003;144:5089–5097.PubMedGoogle Scholar
  46. 46.
    Otto B, Tschop M, Heldwein W, Pfeiffer AF, Diederich S. Endogenous and exogenous glucocorticoids decrease plasma ghrelin in humans. Eur J Endocrinol 2004;151:113–117.CrossRefPubMedGoogle Scholar
  47. 47.
    Libe R, Morpurgo PS, Cappiello V, Maffini A, Bondioni S, Locatelli M, Zavanone M, Beck-Peccoz P, Spada A. Ghrelin and adiponectin in patients with Cushing's disease before and after successful transsphenoidal surgery. Clin Endocrinol 2005;62:30–36.CrossRefGoogle Scholar
  48. 48.
    Tannenbaum GS, Epelbaum J, Bowers CY. Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion. Endocrinology 2003;144:967–974.CrossRefPubMedGoogle Scholar
  49. 49.
    Tassone F, Broglio F, Destefanis S, Rovere S, Benso A, Gottero C, Prodam F, Rossetto R, Gauna C, van der Lely AJ, Ghigo E, Maccario M. Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity. J Clin Endocrinol Metab 2003;88:5478–5483.CrossRefPubMedGoogle Scholar
  50. 50.
    Broglio F, Gianotti L, Destefanis S, Fassino S, Abbate DG, Mondelli V, Lanfranco F, Gottero C, Gauna C, Hofland L, van der Lely AJ, Ghigo E. The endocrine response to acute ghrelin administration is blunted in patients with anorexia nervosa, a ghrelin hypersecretory state. Clin Endocrinol 2004;60:592–599.Google Scholar
  51. 51.
    Ghigo E, Arvat E, Ramunni J, Colao A, Gianotti L, Deghenghi R, Lombardi G, Camanni F. Adrenocorticotropin- and cortisol-releasing effect of hexarelin, a synthetic growth hormone-releasing peptide, in normal subjects and patients with Cushing's syndrome. J Clin Endocrinol Metab 1997;82:2439–2944.CrossRefPubMedGoogle Scholar
  52. 52.
    Arvat E, Giordano R, Ramunni J, Arnaldi G, Colao A, Deghenghi R, Lombardi G, Mantero F, Camanni F, Ghigo E. Adrenocorticotropin and cortisol hyperresponsiveness to hexarelin in patients with Cushing's disease bearing a pituitary microadenoma, but not in those with macroadenoma. J Clin Endocrinol Metab 1998;83:4207–4211.CrossRefPubMedGoogle Scholar
  53. 53.
    Leal-Cerro A, Torres E, Soto A, Dios E, Deghenghi R, Arvat E, Ghigo E, Dieguez C, Casanueva FF. 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;76:390–396.CrossRefPubMedGoogle Scholar
  54. 54.
    Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin a hormone with multiple functions. Front Neuroendocrinology 2004;25:2768.Google Scholar
  55. 55.
    Arvat E, Ramunni J, Maccagno B, Giordano R, Broglio F, Deghenghi R, Boscaro M, Ghigo E. Corticotropin-releasing effect of hexarelin, a peptidyl GH secretagogue, in normal subjects pretreated with metyrapone or RU-486, a glucocorticoid receptor antagonist, and in patients with Addison's disease. Neuroendocrinology 1999;70:200–206.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Roberta Giordano
    • 1
  • Andreea Picu
    • 1
  • Fabio Broglio
    • 1
  • Lorenza Bonelli
    • 1
  • Matteo Baldi
    • 1
  • Rita Berardelli
    • 1
  • Ezio Ghigo
    • 1
  • Emanuela Arvat
    • 1
    Email author
  1. 1.Division of Endocrinology and Metabolism, Department of Internal MedicineUniversity of TurinItaly

Personalised recommendations