ACTH-Independent Macronodular Adrenal Hyperplasia

Livia M. Mermejo; Tânia L. Mazzuco; Solange Grunenwald; Maria Candida B. V. Fragoso; Isabelle Bourdeau; André Lacroix

doi:10.3803/EnM.2011.26.1.1

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Mermejo, Mazzuco, Grunenwald, Fragoso, Bourdeau, and Lacroix: ACTH-Independent Macronodular Adrenal Hyperplasia

Review Article

Endocrinol Metab 2011;26(1):1-11.

Published online: 10 March 2011

DOI: https://doi.org/10.3803/EnM.2011.26.1.1

ACTH-Independent Macronodular Adrenal Hyperplasia

Livia M. Mermejo, Tânia L. Mazzuco, Solange Grunenwald, Maria Candida B. V. Fragoso, Isabelle Bourdeau, André Lacroix

Division of Endocrinology, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal, Québec, H2W 1T8, Canada

Corresponding author: André Lacroix Professor of Medicine, Hôtel-Dieu du CHUM, 3840 Saint-Urbain street, Montréal, Québec, Canada H2W 1T8 Tel: +1-514-890-8042, Fax: +1-514-412-7128, E-mail: andre.lacroix@umontreal.ca

* This work was supported by grant MT-13–189 from the Canadian Institutes of Health Research. LMM and MCBVF were recipient of partial support from Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp), Brazil, SG from La Société Française d’Endocrinologie and CHU de Toulouse, and TLM from CHUM Foundation and Endocrine service.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an uncommon cause of Cushing's syndrome (CS). The pathophysiology of this disorder is heterogeneous in its molecular origin and also in its clinical presentation. AIMAH can present mainly as an incidental radiological finding with subclinical CS or rarely with overt CS. In a few familial cases reported with AIMAH, specific aberrant G-protein coupled receptors were expressed in the adrenals of all affected members, but sporadic cases are more common. The aberrant adrenal function of G-protein coupled receptors can lead to cell proliferation and abnormal regulation of steroidogenesis. Unilateral or bilateral adrenalectomy has been the most frequently used treatment for this adrenal disorder; alter-natively, the identification of aberrant receptors using in vivo protocol of investigation can offer specific pharmacological approach to control abnormal steroidogenesis and possibly prevent AIMAH progression.

Keywords: ACTH-independent macronodular adrenal hyperplasia (AIMAH), Aberrant adrenal G-protein coupled receptors, Cushing's syndrome, Familial forms

References

1. Lacroix A, Bourdeau I. Bilateral adrenal Cushing's syndrome: macronodular adrenal hyperplasia and primary pigmented nodular adrenocortical disease. Endocrinol Metab Clin North Am. 34:441–458. 2005.

2. Lieberman SA, Eccleshall TR, Feldman D. ACTH-independent massive bilateral adrenal disease (AIMBAD): a subtype of Cushing's syndrome with major diagnostic and therapeutic implications. Eur J Endocrinol. 131:6773. 1994.

3. Costa MH, Lacroix A. Cushing's syndrome secondary to ACTH-independent macronodular adrenal hyperplasia. Arq Bras Endocrinol Metabol. 51:1226–1237. 2007.

4. Stratakis CA, Kirschner LS. Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res. 30:456–463. 1998.

5. Doppman JL, Chrousos GP, Papanicolaou DA, Stratakis CA, Alexander HR, Nieman LK. Adrenocorticotropin-independent macronodular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism. Radiology. 216:797–802. 2000.

6. Swain JM, Grant CS, Schlinkert RT, Thompson GB, vanHeerden JA, Lloyd RV, Young WF. Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation. Arch Surg. 133:541–545. discussion 545–546. 1998.

7. Malchoff CD, Malchoff DM. Adrenocorticotropic hormone-independent adrenal hyperplasia. Endocrinologist. 6:79–85. 1996.

8. Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. Endocr Rev. 22:75–110. 2001.

9. Brown RJ, Kelly MH, Collins MT. Cushing syndrome in the McCune-Albright syndrome. J Clin Endocrinol Metab. 95:1508–1515. 2010.

10. Zeiger MA, Nieman LK, Cutler GB, Chrousos GP, Doppman JL, Travis WD, Norton JA. Primary bilateral adrenocortical causes of Cushing's syndrome. Surgery. 110:1106–1115. 1991.

11. Findlay JC, Sheeler LR, Engeland WC, Aron DC. Familial adrenocorticotropin-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 76:189–191. 1993.

12. Minami S, Sugihara H, Sato J, Tatsukuchi A, Sugisaki Y, Sasano H, Wakabayashi I. ACTH independent Cushing's syndrome occurring in siblings. Clin Endocrinol (Oxf). 44:483–488. 1996.

13. Nies C, Bartsch DK, Ehlenz K, Wild A, Langer P, Fleischhacker S, Rothmund M. Familial ACTH-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia clinically affecting only female family members. Exp Clin Endocrinol Diabetes. 110:277–283. 2002.

14. Miyamura N, Taguchi T, Murata Y, Taketa K, Iwashita S, Matsumoto K, Nishikawa T, Toyonaga T, Sakakida M, Araki E. Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines: detection of the aberrant hormone receptors on adrenal gland. Endocrine. 19:319–326. 2002.

15. Lee S, Hwang R, Lee J, Rhee Y, Kim DJ, Chung UI, Lim SK. Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia. Clin Endocrinol (Oxf). 63:625–630. 2005.

16. Vezzosi D, Cartier D, Regnier C, Otal P, Bennet A, Parmentier F, Plantavid M, Lacroix A, Lefebvre H, Caron P. Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors. Eur J Endocrinol. 156:21–31. 2007.

17. Bourdeau I, Boisselle A, Rioux D, Neculau M, Hamet P, Lacroix A. Systematic clinical screening of members of a family with hereditary cortisolsecreting B-adrenergic responsive ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH) reveals unsuspected subclinical Cushing's syndrome (CS) and aberrant B-adrenergic regulation of cortisol secretion. Program of the 89th Annual Meeting of the Endocrine Society. Toronto, CA. 148. (Abstract OR54–2). 2007.

18. Skogseid B, Larsson C, Lindgren PG, Kvanta E, Rastad J, Theodorsson E, Wide L, Wilander E, Oberg K. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 75:76–81. 1992.

19. Hsiao HP, Kirschner LS, Bourdeau I, Keil MF, Boikos SA, Verma S, Robinson-White AJ, Nesterova M, Lacroix A, Stratakis CA. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab. 94:2930–2937. 2009.

20. Matyakhina L, Freedman RJ, Bourdeau I, Wei MH, Stergiopoulos SG, Chidakel A, Walther M, Abu-Asab M, Tsokos M, Keil M, Toro J, Linehan WM, Stratakis CA. Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol Metab. 90:3773–3779. 2005.

21. Yamada Y, Sakaguchi K, Inoue T, Kubo M, Fushimi H, Sekii K, Itatani H, Tsujimura T, Kameyama M. Preclinical Cushing's syndrome due to adrenocorticotropin-independent bilateral adrenocortical macronodular hyperplasia with concurrent excess of gluco- and mineralocorticoids. Intern Med. 36:628–632. 1997.

22. Bourdeau I, D'Amour P, Hamet P, Boutin JM, Lacroix A. Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome. J Clin Endocrinol Metab. 86:5534–5540. 2001.

23. Goodarzi MO, Dawson DW, Li X, Lei Z, Shintaku P, Rao CV, Van Herle AJ. Virilization in bilateral macronodular adrenal hyperplasia controlled by luteinizing hormone. J Clin Endocrinol Metab. 88:73–77. 2003.

24. Ghayee HK, Rege J, Watumull LM, Nwariaku FE, Carrick KS, Rainey WE, Miller WL, Auchus RJ. Clinical, biochemical, and molecular characterization of macronodular adrenocortical hyperplasia of the zona reticularis: a new syndrome. J Clin Endocrinol Metab. 2010.

25. Mazzuco TL, Bourdeau I, Lacroix A. Adrenal incidentalomas and subclinical Cushing's syndrome: diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 16:203–210. 2009.

26. Ohashi A, Yamada Y, Sakaguchi K, Inoue T, Kubo M, Fushimi H. A natural history of adrenocorticotropin-independent bilateral adrenal macronodular hyperplasia (AIMAH) from preclinical to clinically overt Cushing's syndrome. Endocr J. 48:677–683. 2001.

27. Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone–dependent Cushing's syndrome. N Engl J Med. 341:1577–1581. 1999.

28. Lacroix A, Bolte E, Tremblay J, Dupre J, Poitras P, Fournier H, Garon J, Garrel D, Bayard F, Taillefer R, Flanagan RJ, Hamet P. Gastric inhibitory polypeptide-dependent cortisol hypersecretion-^ new cause of Cushing's syndrome. N Engl J Med. 327:974–980. 1992.

29. Antonini SR, Baldacchino V, Tremblay J, Hamet P, Lacroix A. Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing's syndrome. Clin Endocrinol (Oxf). 64:29–36. 2006.

30. Sasano H, Suzuki T, Nagura H. ACTH-independent macronodular adrenocortical hyperplasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes. Mod Pathol. 7:215–219. 1994.

31. Aiba M, Kawakami M, Ito Y, Fujimoto Y, Suda T, Demura H. Bilateral adrenocortical adenomas causing Cushing's syndrome. Report of two cases with enzyme histochemical and ultrastructural studies and a review of the literature. Arch Pathol Lab Med. 116:146–150. 1992.

32. Lampron A, Bourdeau I, Hamet P, Tremblay J, Lacroix A. Whole genome expression profiling of glucose-dependent insulinotropic peptide (GIP)- and adrenocorticotropindependent adrenal hyperplasias reveals novel targets for the study of GIP-dependent Cushing's syndrome. J Clin Endocrinol Metab. 91:3611–3618. 2006.

33. Aiba M, Hirayama A, Iri H, Ito Y, Fujimoto Y, Mabuchi G, Murai M, Tazaki H, Maruyama H, Saruta T, Suda T, Demura H. Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing's syndrome. Enzyme histochemical and ultrastructural study of four cases with a review of the literature. Am J Clin Pathol. 96:334–340. 1991.

34. Doppman JL, Nieman LK, Travis WD, Miller DL, Cutler GB Jr, Chrousos GP, Norton JA. CT and MR imaging of massive macronodular adrenocortical disease: a rare cause of autonomous primary adrenal hypercortisolism. J Comput Assist Tomogr. 15:773–779. 1991.

35. Rockall AG, Babar SA, Sohaib SA, Isidori AM, Diaz-Cano S, Monson JP, Grossman AB, Reznek RH. CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome. Radiographics. 24:435–452. 2004.

36. N'Diaye N, Hamet P, Tremblay J, Boutin JM, Gaboury L, Lacroix A. Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent cushing's syndrome. J Clin Endocrinol Metab. 84:2616–2622. 1999.

37. Kirk JM, Brain CE, Carson DJ, Hyde JC, Grant DB. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome. J Pediatr. 134:789–792. 1999.

38. Latronico AC, Reincke M, Mendonca BB, Arai K, Mora P, Allolio B, Wajchenberg BL, Chrousos GP, Tsigos C. No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms. J Clin Endocrinol Metab. 80:875–877. 1995.

39. Swords FM, Noon LA, King PJ, Clark AJ. Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene. Mol Cell Endocrinol. 213:149–154. 2004.

40. Aarskog D, Tveteraas E. McCune-Albright's syndrome following adrenalectomy for Cushing's syndrome in infancy. J Pediatr. 73:89–96. 1968.

41. Benjamin DR, McRoberts JW. Polyostotic fibrous dysplasia associated with Cushing syndrome. Arch Pathol. 96:175–178. 1973.

42. MacMahon HE. Albright's syndrome–thirty years later. (Polyostotic fibrous dysplasia). Pathol Annu. 6:81–146. 1971.

43. Danon M, Robboy SJ, Kim S, Scully R, Crawford JD. Cushing syndrome, sexual precocity, and polyostotic fibrous dysplasia (Albright syndrome) in infancy. J Pediatr. 87:917–921. 1975.

44. Mauras N, Blizzard RM. The McCune-Albright syndrome. Acta Endocrinol Suppl (Copenh). 279:207–217. 1986.

45. Fragoso MC, Domenice S, Latronico AC, Martin RM, Pereira MA, Zerbini MC, Lucon AM, Mendonca BB. Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J Clin Endocrinol Metab. 88:21472151. 2003.

46. Mircescu H, Jilwan J, N'Diaye N, Bourdeau I, Tremblay J, Hamet P, Lacroix A. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome? J Clin Endocrinol Metab. 85:35313536. 2000.

47. Lacroix A, Baldacchino V, Bourdeau I, Hamet P, Tremblay J. Cushing's syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol Metab. 15:375–382. 2004.

48. Bertagna X, Groussin L, Luton JP, Bertherat J. Aberrant receptor-mediated Cushing's syndrome. Horm Res 59 Suppl. 1:99–103. 2003.

49. Libe R, Coste J, Guignat L, Tissier F, Lefebvre H, Barrande G, Ajzenberg C, Tauveron I, Clauser E, Dousset B, Bertagna X, Bertherat J, Groussin L. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome. Eur J Endocrinol. 163:129–138. 2010.

50. Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J, Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf). 73:1–15. 2010.

51. Reznik Y, Lefebvre H, Rohmer V, Charbonnel B, Tabarin A, Rodien P, Lecomte P, Bardet S, Coffin C, Mahoudeau J. Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study. Clin Endocrinol (Oxf). 61:311–319. 2004.

52. Lacroix A, Mircescu H, Hamet P. Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing's syndrome. Endocrinologist. 9:9–15. 1999.

53. Perraudin V, Delarue C, De Keyzer Y, Bertagna X, Kuhn JM, Contesse V, Clauser E, Vaudry H. Vasopressin-responsive adrenocortical tumor in a mild Cushing's syndrome: in vivo and in vitro studies. J Clin Endocrinol Metab. 80:2661–2667. 1995.

54. Horiba N, Suda T, Aiba M, Naruse M, Nomura K, Imamura M, Demura H. Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 80:2336–2341. 1995.

55. Iida K, Kaji H, Matsumoto H, Okimura Y, Abe H, Fujisawa M, Kamidono S, Chihara K. Adrenocorticotrophin-independent macronodular adrenal hyperplasia in a patient with lysine vasopressin responsiveness but insensitivity to gastric inhibitory polypeptide. Clin Endocrinol (Oxf). 47:739745. 1997.

56. Lacroix A, Tremblay J, Touyz RM, Deng LY, Lariviere R, Cusson JR, Schiffrin EL, Hamet P. Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing's syndrome, and orthostatic hypotension. J Clin Endocrinol Metab. 82:24142422. 1997.

57. Daidoh H, Morita H, Hanafusa J, Mune T, Murase H, Sato M, Shibata T, Suwa T, Ishizuka T, Yasuda K. In vivo and in vitro effects of AVP and V1a receptor antagonist on Cushing's syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia. Clin Endocrinol (Oxf). 49:403–409. 1998.

58. Arnaldi G, Gasc JM, de Keyzer Y, Raffin-Sanson ML, Perraudin V, Kuhn JM, Raux-Demay MC, Luton JP, Clauser E, Bertagna X. Variable expression of the V1 vasopressin receptor modulates the phenotypic response of steroid-secreting adrenocortical tumors. J Clin Endocrinol Metab. 83:20292035. 1998.

59. Mune T, Murase H, Yamakita N, Fukuda T, Murayama M, Miura A, Suwa T, Hanafusa J, Daido H, Morita H, Yasuda K. Eutopic overexpression of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 87:5706–5713. 2002.

60. Louiset E, Contesse V, Groussin L, Cartier D, Duparc C, Perraudin V, Bertherat J, Lefebvre H. Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing's syndrome: molecular, immunohistochemical and pharmacological correlates. J Endocrinol. 196:1–9. 2008.

61. Cartier D, Lihrmann I, Parmentier F, Bastard C, Bertherat J, Caron P, Kuhn JM, Lacroix A, Tabarin A, Young J, Vaudry H, Lefebvre H. Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome. J Clin Endocrinol Metab. 88:248–254. 2003.

62. Mannelli M, Ferruzzi P, Luciani P, Crescioli C, Buci L, Corona G, Serio M, Peri A. Cushing's syndrome in a patient with bilateral macronodular adrenal hyperplasia responding to cisapride: an in vivo and in vitro study. J Clin Endocrinol Metab. 88:4616–4622. 2003.

63. Louiset E, Contesse V, Groussin L, Cartier D, Duparc C, Barrande G, Bertherat J, Vaudry H, Lefebvre H. Expression of serotonin7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome. J Clin Endocrinol Metab. 91:4578–4586. 2006.

64. Lebrethon MC, Avallet O, Reznik Y, Archambeaud F, Combes J, Usdin TB, Narboni G, Mahoudeau J, Saez JM. Food-dependent Cushing's syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients. J Clin Endocrinol Metab. 83:4514–4519. 1998.

65. Groussin L, Perlemoine K, Contesse V, Lefebvre H, Tabarin A, Thieblot P, Schlienger JL, Luton JP, Bertagna X, Bertherat J. The ectopic expression of the gastric inhibitory polypeptide receptor is frequent in adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia, but rare in unilateral tumors. J Clin Endocrinol Metab. 87:1980–1985. 2002.

66. Croughs RJ, Zelissen PM, van Vroonhoven TJ, Hofland LJ, N'Diaye N, Lacroix A, de Herder WW. GIP-dependent adrenal Cushing's syndrome with incomplete suppression of ACTH. Clin Endocrinol (Oxf). 52:235240. 2000.

67. de Herder WW, Hofland LJ, Usdin TB, de Jong FH, Uitterlinden P, van Koetsveld P, Mezey E, Bonner TI, Bonjer HJ, Lamberts SW. Food-dependent Cushing's syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells. J Clin Endocrinol Metab. 81:3168–3172. 1996.

68. Chabre O, Liakos P, Vivier J, Chaffanjon P, Labat-Moleur F, Martinie M, Bottari SP, Bachelot I, Chambaz EM, Defaye G, Feige JJ. Cushing's syndrome due to a gastric inhibitory polypeptide-dependent adrenal adenoma: insights into hormonal control of adrenocortical tumorigenesis. J Clin Endocrinol Metab. 83:3134–3143. 1998.

69. N'Diaye N, Tremblay J, Hamet P, De Herder WW, Lacroix A. Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing's syndrome. J Clin Endocrinol Metab. 83:27812785. 1998.

70. Hamet P, Larochelle P, Franks DJ, Cartier P, Bolte E. Cushing syndrome with food-dependent periodic hormonogenesis. Clin Invest Med. 10:530533. 1987.

71. Mazzuco TL, Chabre O, Sturm N, Feige JJ, Thomas M. Ectopic expression of the gastric inhibitory polypeptide receptor gene is a sufficient genetic event to induce benign adrenocortical tumor in a xenotransplantation model. Endocrinology. 147:782–790. 2006.

72. Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P. Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing's syndrome. N Engl J Med. 337:1429–1434. 1997.

73. Miyamura N, Tsutsumi A, Senokuchi H, Nakamaru K, Kawashima J, Sakai K, Taguchi T, Tokunaga H, Nishida K, Uehara M, Sakakida M, Araki E. A case of ACTH-independent macronodular adrenal hyperplasia: simultaneous expression of several aberrant hormone receptors in the adrenal gland. Endocr J. 50:333–340. 2003.

74. Mazzuco TL, Thomas M, Martinie M, Cherradi N, Sturm N, Feige JJ, Chabre O. Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome. Arq Bras Endocrinol Metabol. 51:1452–1462. 2007.

75. Mazzuco TL, Chaffanjon P, Martinie M, Sturm N, Chabre O. Adrenal Cushing's syndrome due to bilateral macronodular adrenal hyperplasia: prediction of the efficacy of beta-blockade therapy and interest of unilateral adrenalectomy. Endocr J. 56:867–877. 2009.

76. Assie G, Louiset E, Sturm N, Rene-Corail F, Groussin L, Bertherat J, Thomas M, Lefebvre H, Feige JJ, Clauser E, Chabre O, Cherradi N. Systematic analysis of G protein-coupled receptor gene expression in adrenocorticotropin-independent macronodular adrenocortical hyperplasia identifies novel targets for pharmacological control of adrenal Cushing's syndrome. J Clin Endocrinol Metab. 95:E253–262. 2010.

77. Dall'Asta C, Ballare E, Mantovani G, Ambrosi B, Spada A, Barbetta L, Colombo P, Travaglini P, Loli P, Beck-Peccoz P. Assessing the presence of abnormal regulation of cortisol secretion by membrane hormone receptors: in vivo and in vitro studies in patients with functioning and nonfunctioning adrenal adenoma. Horm Metab Res. 36:578–583. 2004.

78. Bugalho MJ, Li X, Rao CV, Soares J, Sobrinho LG. Presence of a Gs alpha mutation in an adrenal tumor expressing LH/hCG receptors and clinically associated with Cushing's syndrome. Gynecol Endocrinol. 14:50–54. 2000.

79. Bertherat J, Contesse V, Louiset E, Barrande G, Duparc C, Groussin L, Emy P, Bertagna X, Kuhn JM, Vaudry H, Lefebvre H. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab. 90:1302–1310. 2005.

80. Feelders RA, Lamberts SW, Hofland LJ, van Koetsveld PM, Verhoef-Post M, Themmen AP, de Jong FH, Bonjer HJ, Clark AJ, van der Lely AJ, de Herder WW. Luteinizing hormone (LH)-responsive Cushing's syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro. J Clin Endocrinol Metab. 88:230–237. 2003.

81. Nakamura Y, Son Y, Kohno Y, Shimono D, Kuwamura N, Koshiyama H, Sasano H, Matsuda T. Case of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II. Endocrine. 15:57–61. 2001.

82. Pralong FP, Gomez F, Guillou L, Mosimann F, Franscella S, Gaillard RC. Food-dependent Cushing's syndrome: possible involvement of leptin in cortisol hypersecretion. J Clin Endocrinol Metab. 84:3817–3822. 1999.

83. Louiset E, Duparc C, Groussin L, Laquerriere A, Kuhn JM, Reznik Y, Bertherat J, Lefebvre H. Abnormal sensitivity of cortisol secretion to glucagon in primary adrenal Cushing's syndrome. In: Schimmer BP, Dufau M, Brownie AC. Adrenal Cortex Conference, Proceedings of the 13 th Adrenal Cortex Conference, pp52, 2008 June 11–14, San Francisco. 2008. (Abstract 33).

84. Mazzuco TL, Chabre O, Feige JJ, Thomas M. Aberrant expression of human luteinizing hormone receptor by adrenocortical cells is sufficient to provoke both hyperplasia and Cushing's syndrome features. J Clin Endocrinol Metab. 91:196–203. 2006.

85. Contesse V, Reznik Y, Louiset E, Duparc C, Cartier D, Sicard F, Laquerriere A, Parmentier F, Kuhn JM, Vaudry H, Lefebvre H. Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin: in vivo and in vitro studies. J Clin Endocrinol Metab. 90:2843–2850. 2005.

86. Joubert M, Louiset E, Rego JL, Contesse V, Kong LC, Benhaim A, Mittre H, Lefebvre H, Reznik Y. Aberrant adrenal sensitivity to vasopressin in adrenal tumours associated with subclinical or overt autonomous hypercortisolism: is this explained by an overexpression of vasopressin receptors? Clin Endocrinol (Oxf). 68:692–699. 2008.

87. Louiset E, Cartier D, Contesse V, Duparc C, Lihrmann I, Young J, Bertherat J, Reznik Y, Kuhn JM, Laquerriere A, Vaudry H, Lefebvre H. Paradoxical inhibitory effect of serotonin on cortisol production from adrenocortical lesions causing Cushing's syndrome. Endocr Res. 30:951–954. 2004.

88. Louiset E, Duparc C, Young J, Bram L, Boutelet I, Groussin L. Cortisol secretion is dependent on intraadrenal production of ACTH in macronodular adrenal hyperplasia causing Cushing's syndrome. In: Brownie AC, Dufau M, Schimmer BP, Auchus R. Adrenal Cortex Conference. Proceedings of the 14th Adrenal Cortex Conference. 2010 June 16–18, San Diego. 2010.

89. Imöhl M, Köditz R, Stachon A, Müller KM, Nicolas V, Pfeilschifter J, Krieg M. [Catecholamine-dependent hereditary Cushing's syndrome – follow-up after unilateral adrenalectomy]. Med Klin (Munich). 97:747–753. 2002.

90. Boronat M, Lucas T, Barcelo B, Alameda C, Hotait H, Estrada J. Cushing's syndrome due to autonomous macronodular adrenal hyperplasia: longterm follow-up after unilateral adrenalectomy. Postgrad Med J. 72:614–616. 1996.

91. Lamas C, Alfaro JJ, Lucas T, Lecumberri B, Barcelo B, Estrada J. Is unilateral adrenalectomy an alternative treatment for ACTH-independent macronodular adrenal hyperplasia?: longterm follow-up of four cases. Eur J Endocrinol. 146:237–240. 2002.

92. Reznik Y, Allali-Zerah V, Chayvialle JA, Leroyer R, Leymarie P, Travert G, Lebrethon MC, Budi I, Balliere AM, Mahoudeau J. Food-dependent Cushing's syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med. 327:981–986. 1992.

93. Preumont V, Mermejo LM, Damoiseaux P, Lacroix A, Maiter D. Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome. Horm Metab Res. 2011. [Epub ahead of print].

Fig. 1.

CT scan from 3 patients with AIMAH and Cushing's syndrome. The left and right upper panels are from the same patient and illustrate the variable nature of nodular hyperplasia of both adrenals on sequential slices of CT scan. The white arrows are pointed towards the adrenal glands.

Fig. 2.

Regulation of steroidogenesis by aberrant hormone receptors in adrenal cortex. In this model, the ectopic or eutopic receptors regulate steroidogenesis by mimicking the cellular events triggered by ACTH receptors activation. Reproduced with permission from Lacroix et al. Trends Endocrinol Metab 15:375–382, 2004 [47].

Fig. 3.

Further in vivo characterization of aberrant adrenal hormone receptors following the initial screening protocol. Adapted from Lacroix et al. The Endocrinologist 9:9–15, 1999 [52].

Fig. 4.

Hypothesis of sequential genetic events leading to AIMAH. The initial event is the aberrant expression of the LH/hCG receptor in the adrenal cortex during early embryonic life. Upon stimulation of this receptor, as during pregnancy (activation by hCG), diffuse adrenal hyperplasia (polyclonal) and transient CS occurs, but this is still reversible when hCG and LH levels are reduced following delivery. After menopause, the constant elevation of LH causes diffuse hyperplasia and CS. Other (second, third) somatic events occur progressively with time in a small number of cells; the monoclonal proliferation of these cells leads to appearance of several nodules which have maintained the expression of aberrant LH/hCGR. The inhibition of LH levels is able to control the excess production of steroids; this may be able to induce regression of adrenal growth at the stage of hyperplasia, but it may become insufficient to cause tumor regression when other oncogenic events have provided additional growth advantage to these cells. Reproduced with permission from Lacroix et al. Trends Endocrinol Metab 15:375–382, 2004 [47].

Table 1.

In vivo screening protocol to detect the presence of aberrant hormone receptors in adrenal Cushing's syndrome

Time (min)	Day 1	Day 2	Day 3
–60	Fasting-supine	Fasting-supine	Fasting-supine
–15	*	*	*
0	Upright *	GnRH 100 µg i.v. *	Glucagon 1 mg i.v. *
+30	Upright *	*	*
+60	Upright *	*	*
+90	Upright *	*	*
+120	Upright *	*	*
+150	Supine *	(meal)
+180	Mixed meal *		Vasopressin 10 IU i.m. *
+210	*		*
+240	*		*
+270	*	*	*
+300	*	TRH 200 µ g i.v. *	*
+330		*
+360	ACTH 1–24 250 µ g iv*	*	Metoclopramide 10 mg orally*
+390	*	*	*
+420	*	*	*
+450	*		*
+480	*		*

^* Blood samples for determination of cortisol. ACTH, other hormones, and vital signs. Modified with permission from Lacroix et al. The Endocrinologist 9:9–15, 1999 [52].

Table 2.

Medical treatment options for identified aberrant adrenal hormone receptors using an in vivo screening protocol in AIMAH

Aberrant receptor	In vivo screening protocol	Medical treatment options
GIP receptor	Mixed meal, oral glucose	Octreotide, GIPR antagonist
Vasopressin receptor (V1, V2, V3)	Upright posture administration of arginine-vasopressin or desmopressin	VP receptor antagonist
β-adrenergic receptor	Upright posture, isoproterenol infusion	β-blockers
LH/hCG receptor	GnRH administration; hCG, recombinant LH	Long-acting GnRH agonist
5-HT4 receptor	Administration of 5-HT4 receptor agonists	5-HT4 receptor antagonist
AT-1 receptor	Upright posture, angiotensin infusion	AT-1 receptor antagonist

GIP, gastric inhibitory polypeptide; LH/hCG, luteinizing hormone/human chorionic gonadotropin.

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