Adrenal Cushing Sendromunda Aitipik Hormon Reseptörlerinin Değerlendirilmesi ve Tanı Testlerinin İncelenmesi

Öz

Son zamanlarda yapılan çalışmalarla atipik hormon reseptörlerinin uyarılmasıyla oluşan adrenal Cushing sendromunun patofizyolojisi yeni anlaşılmaya başlansa da hala net değildir. Bu durum sıklıkla ACTH’dan bağımsız makronodüler adrenal hiperplazide ve daha nadir olarak tek taraflı adrenal adenomlarda karşılaşılan bir patolojidir. Zona fasikülatadaki hücrelerin membranında olan ektopik ve anormal hormon reseptörlerinin uyarılması sonucu oluşan aşırı kortizol salgısı adrenal Cushing sendromuna yol açar. Bu atipik reseptörler gastrik inhibitör peptid (GIP), β-adrenerjik agonistler, LH/hCG, vazopressin, serotonin (5HT4) reseptörlerini içermektedir. Ancak, bu reseptörlerin varlığının gösterilmesi oldukça karmaşık ve zahmetlidir. Bu hastalığın tedavisinde cerrahi dışında seçenekler de mevcuttur. Bu yüzden bu reseptörlerin varlığının tespit edilmesi özellikle bilateral adrenallerinde lezyonları olan hastalarda oldukça büyük önem arz etmektedir. Bu derlemede adrenal Cushing sendromuna yol açan bu reseptörlerin ve ayırıcı tanı testlerinin değerlendirilmesi amaçlanmıştır.

Anahtar Kelimeler

• Adrenal cushing sendromu, atipik hormonal reseptörler

Evaluation And Diagnosis Of Aberrant Hormone Receptors İn Adrenal Cushing’s Syndrome

Abstract

The pathophysiology of adrenal Cushing's syndrome generated by the stimulation of atypical hormone receptors is still unclear though it was started to be understood by the recent studies. This is a case of pathology encountered frequently in macronodular adrenal hyperplasia independent of ACTH and rarely in unilateral macronodular adenomas. The excessive secretion of cortisol, which is generated by the stimulation of ectopic and abnormal hormone receptors in membrane of Zona fasciculata cells, leads to adrenal Cushing's syndrome. These atypical receptors include the receptor of gastric inhibitory peptide (GIP), β-adrenergic agonists, LH / hCG, vasopressin, serotonin (5HT4). However, it is quite complex and cumbersome to indicate the presence of these receptors. There are non-surgical options in the treatment of this disease. Therefore, detecting the presence of these receptors is of very great importance particularly for the patients with bilateral lesions in his/her bilateral adrenal. This study aims to examine these receptors leading to adrenal Cushing's syndrome and differential diagnosis tests.

Keywords

• Adrenal Cushing's syndrome, aberrant hormone receptors

References

1. Latronico AC, Chrousos GP. Extensive personal experience: Adrenocortical tumors. J Clin Endocrinol Metab 1997; 82:1317–1324.
2. Nieman LK. Cushing’s syndrome. In: De Groot LJ, Jameson JLe, Burger HG, et al., eds. Endocrinology, 4th ed. Philadephia: W. B. Saunders Co, 2000: 1691–1720.
3. Schorr I, Ney RL. Abnormal hormone responses of an adrenocortical cancer adenyl cyclase. J Clin Invest 1971; 50:1295–1300.
4. Hamet P, Larochelle P, Franks DJ, Cartier P, Bolte E. Cushing syndrome with food-dependent periodic hormonogenesis. Clin Invest Med 1987; 10:530– 533.
5. Tsagarakis S, Tsigos C, Vassiliou V, et al. Fooddependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing’s syndrome: In vivo and in vitro studies. J Clin Endocrinol Metab 2001; 86:583–589.
6. N’Diaye N, Hamet P, Tremblay J, Boutin JM, Gaboury L, Lacroix A. Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptidedependent Cushing’s syndrome. J Clin Endocrinol Metab 1999; 84:2616– 2622 . 7. 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 1999;84:3817–3822.
7. Albiger N.M, Occhi G, Mariniello B, et al. Food dependent Cushing’s syndrome: from molecular characterization to therapeutical results. Eur J Endocrinol 2007; 157:771–778.
8. Bertherat J, Contesse V, Louiset E, et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropinindependent macronodular adrenal hyperplasia causing Cushing’s syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab 2005; 90:1302–1310.

9. 0. Dall’Asta C, Ballare E, Mantovani G, et al. Assessing the presence of abnormal regulation of cortisol secretion by membrane hormone receptors: in vivo and in vitro studies in patients with functioning and non-functioning adrenal adenoma. Horm Metab Res 2004; 36: 578–583. 11. Chabre O, Liakos P, Vivier J, et al. Cushing’s syndrome due to a gastric inhibitory polypeptidedependent adrenal adenoma: Insights into hormonal control of adrenocortical tumorigenesis. J Clin Endocrinol Metab 1998; 83:3134–3143. 12. Lacroix A, Tremblay J, Touyz RM, et al. 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 1997;82:2414–2422.
10. 3. Horiba N, Suda T, Aiba M, et al. Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 1995; 80:2336–2341.
11. 4. Iida K, Kaji H, Matsumoto H, et al. Adrenocorticotrophin-independent macronodular adrenal hyperplasia in a patient with lysine vasopressin responsiveness but insensitivity to gastric inhibitory polypeptide. Clin Endocrinol 1997; 47:739–745.
12. 5. Demura R, Demura H, Nunokawa T, Baba H, Miura K. Responses of plasma ACTH, GH, LH and 11hydroxycorticosteroids to various stimuli in patients with Cushing’s syndrome. J Clin Endocrinol Metab 1972; 34:852–859.
13. 6. Perraudin V, Delarue C, de Keyzer Y, et al. Vasopressin-responsive adrenocortical tumor in a mild Cushing’s syndrome: In vivo and in vitro studies. J Clin Endocrinol Metab 1995; 80:2661– 2667.
14. 7. Makino S, Hashimoto K, Sugiyama M, et al. Cushing’s syndrome due to huge nodular adrenocortical hyperplasia with fluctuation of urinary 17-OHCS excretion. Endocrinol Jpn 1989; 36:655– 663.
15. 8. Bourdeau I, D’Amour P, Hamet P, et al. Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing’s syndrome. J Clin Endocrinol Metab 2001; 86:5534–5540.
16. 9. Mircescu H, Jilwan J, N’Diaye N, et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome? J Clin Endocrinol Metab 2000; 85:3531–3536.
17. 0. Mune T, Murase H, Yamakita N, et al. Eutopic overexpression of vasopressin V1a receptor inadrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2002; 87:5706–5713.
18. 1. Lee S, Hwang R, Lee J, et al. Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia. Clin Endocrinol 2005; 63:62530.
19. 2. Arnaldi G, Gasc JM, de Keyzer Y, et al. Variable expression of the V1 vasopressin receptor modulates the phenotypic response of steroidsecreting adrenocortical tumors. J Clin Endocrinol Metab 1998;83:2029–2035.
20. 3. Mune T, Murase H, Yamakita N, et al. Eutopic overexpression of vasopressin V1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2002; 87:5706–5713.
21. 4. Matsukura S, Kakita T, Sueoka S, et al. Multiple hormone receptors in the adenylate cyclase of human adrenocortical tumors. Cancer Res 1980; 40:3768–3771.
22. 5. Hirata Y, Uchihashi M, Sueoka S, Matsukura S, Fujita T. Presence of ectopic beta-adrenergic receptors on human adrenocortical cortisolproducing adenomas. J Clin Endocrinol Metab 1981; 53:953–957.
23. 6. Katz MS, Kelly TM, Dax EM, Pineyro MA, Partilla JS, Gregerman RI. Ectopic beta-adrenergic receptors coupled to adenylate cyclase in human adrenocortical carcinomas. J Clin Endocrinol Metab 1985;60:900–909.
24. 7. 27-Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P. Propranolol therapy for ectopic betaadrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med 1997;337:1429–1434.
25. 8. Mircescu H, Jilwan J, N’Diaye N, et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome? J Clin Endocrinol Metab 2000; 85:3531–3536.
26. 9. Miyamura N, Tsutsumi A, Senokuchi H, et al. A case of ACTH-independent macronodular adrenal hyperplasia: Simultaneous expression of several aberrant hormone receptors in the adrenal gland. Endocr J 2003; 50:333–340.
27. 0. Imohl M, Koditz R, Stachon A, et al. Catecholaminedependent hereditary Cushing’s syndrome-Followup after unilateral adrenalectomy. Med Klin 2002; 97: 747–753.
28. 1. Miyamura, N, Taguchi T, Murata Y, et al. Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines: detection of the aberrant hormone receptors on adrenal gland. Endocr 2002; 19: 319–326.
29. 2. Lacroix A, Tremblay J, Rousseau G, et al. Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome. N Eng J Med 1997; 337:1429–1434.
30. 3. Mazzuco T.L, Thomas M, Martinie M, et al. Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing’s syndrome. Arq Bras Endocrinol Metabol 2007; 51:1452–1462.
31. 4. Rao CV. The Beginning of a New Era in Reproductive Biology and Medicine: Expression of low levels of functional luteinizing hormone/human chorionic gonadotropin receptors in nongondal tissues. J Physiol Pharmacol 1996; 47:41–53.
32. 5. Pabon JE, Li X, Lei ZM, Sanfilippo JS, Yussman MA, Rao CV. Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J Clin Endocrinol Metab 1996; 81:2397–2400.
33. 6. Seron-Ferre M, Lawrence CC, Jaffe RB. Role of hCG in regulation of the fetal zone of the human fetal adrenal gland. J Clin Endocrinol Metab 1978; 46:834–837.
34. 7. Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone–dependent Cushing’s syndrome. N Engl J Med 1999; 341:1577–1581.
35. 8. Feelders RA, Lamberts SW, Hofland LJ, et al. 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 2003; 88:230–237.
36. 9. Goodarzi MO, Dawson DW, Li X, et al. Virilization in bilateral macronodular adrenal hyperplasia controlled by luteinizing hormone. J Clin Endocrinol Metab 2003;88:73–77.
37. 0. Lefebvre H, Contesse V, Delarue C, et al. Serotonergic regulation of adrenocortical function. Horm Metab Res1998;30:398–403.
38. 1. Cartier D, Lihrmann I, Parmentier F, et al. Overexpression of serotonin4 receptors in cisaprideresponsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing’s syndrome. J Clin Endocrinol Metab 2003; 88:248–254.
39. 2. Yared Z, Antonini S, Lacroix A. Macronodular adrenal hyperplasia with long-term primary hyperaldosteronism and recent cyclical Cushing’s syndrome with aberrant response of cortisol to serotonin agonist 5-HT4 R. The Endocrine Society 85th Meeting Philadelphia, PA 2003; P2-568, 445.
40. 3. Schubert B, Fassnacht M, Beuschlein F, et al. Angiotensin II type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms. Clin Endocrinol 2001; 54:627–632.
41. 4. Nakamura Y, Son Y, Kohno Y, et al. Case of adrenocorticotropic hormoneindependent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II. Endocr 2001; 15:57–61.
42. 5. Lacroix A, Baldacchino V, Bourdeau I, et al. Cushing’s syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol Metab 2004; 15: 375–382.
43. 6. Lacroix A, Ndiaye N, Tremblay J, et al. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocr Rev 2001; 22: 75–110.
44. 7. Lacroix A, Mircescu H, Hamet P. Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing’s syndrome. The Endocrinologist 1999; 9:9–15.
45. 8. Reznik Y, Lefebvre H, Rohmer V, et al. Aberrant sensitivity to multiple ligands in unilateral adrenal incidentaloma: A prospective study. Clin Endocrinol 2004; 61:311–319.
46. 9. Lacroix A, Bourdeau I, Lampron A, Mazzuco TM. Johanne Tremblay, Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol 2010; 73:1–15
47. 0. Swords FM, Aylwin S, Perry L, et al. The aberrant expression of the gastric inhibitory polypeptide (GIP) receptor in adrenal hyperplasia: does chronic adrenocorticotropin exposure stimulate up-regulation of GIP receptors in Cushing's disease? J Clin Endocrinol Metab. 2005; 90: 3009-3016.
48. 1. Mircescu H, Jilwan J, N'Diaye N, et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome? J Clin Endocrinol Metab. 2000; 85:3531-6
49. 2. Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone-dependent Cushing's syndrome. N Engl J Med. 1999; 341:1577-1581.
50. 3. Lacroix A, Bolté E, Tremblay J, et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion-a new cause of Cushing's syndrome. N Engl J Med. 1992 327:974-80.
51. 4. Reznik Y, Allali-Zerah V, Chayvialle JA, et al. Fooddependent Cushing's syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med. 1992; 327:981-986. 55. Tsagarakis S, Tsigos C, Vassiliou V, et al. Fooddependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing's syndrome: in vivo and in vitro studies. J Clin Endocrinol Metab 2001 86:583-589.
52. 6. Reznik Y, Allali-Zerah V, Chayvialle JA, et al. Fooddependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med 1992; 327:981–986.
53. 7. Croughs RJ, Zelissen PM, Van Vroonhoven ThJ,. et al. GIP-dependent adrenal Cushing’s syndrome with incomplete suppression of ACTH. Clin Endocrinol 2000; 52:235–240.
54. 8. de Herder WW, Hofland LJ, Usdin TB, et al. Fooddependent Cushing’s syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells. J Clin Endocrinol Metab 1996; 81:3168–3172.
55. 9. 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 2001; 86:5534–5540.
56. 0. Yared Z, Bourdeau I, Lacroix A. Failure to control Cushing’s syndrome with leuprolide acetate in a case of ACTHindependent bilateral macronodular adrenal hyperplasia with partial regulation of cortisol secretion by LH and hCG. The Endocrine Society 84th Meeting. San Francisco, CA 2002;649.
57. 1. Daidoh H, Morita H, Hanafusa J, et al. 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 1998; 49:403–409.
58. 2. Contesse V, Reznik Y, Louiset E, et al. Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin: in vivo and in vitro studies. J Clin Endocrinol Metab 2005; 90:2843–2850.
59. 3. Lacroix A, Bourdeau I. Bilateral adrenal Cushing’s syndrome: macronodular adrenal hyperplasia and primary pigmented nodular adrenocortical disease. Endocrinol Metab Clin North Am 2005; 34:441–458.