Summary
Since Don Nelson’s first description in 1958 of a pituitary macroadenoma occurring after adrenalectomy in a patient with Cushing’s disease, the “Nelson’s syndrome” has long been feared. However, major medical advances, such as pituitary imaging with MRI, surgery by the transsphenoidal route, and safe radiotherapy, have changed the way corticotroph tumor progression (CTP) can be monitored and treated. Rather than “wait” for the late occurrence of Nelson’s syndrome, as defined originally with the complications of macroadenomas, we can now detect, early and precisely, the possible occurrence of CTP long before the classical features of Nelson’s syndrome have developed.
In a recent study of 53 patients followed by MRI after bilateral adrenalectomy, we showed that 3 years after adrenalectomy, the proportion of patients showing evidence of CTP reached 39%; this number tended to plateau at 47% after 7 years. Thus, ca. 50% of the patients showed no evidence of CTP under this time period. Factors that were found to be significantly associated with a higher risk to develop CTP were duration of Cushing’s disease, baseline ACTH plasma level in the year following adrenalectomy, and the rate of increase in ACTH plasma levels after adrenalectomy.
If necessary, pituitary surgery and/or radiotherapy can control the CTP in a majority of situations. The CTP does not seem accelerated during the pregnancy.
There is no question that pituitary surgery remains the first-line treatment in most patients with Cushing’s disease. Yet, when complete removal of a corticotroph tumor is not achievable, total bilateral adrenalectomy can be considered among the various therapeutic options in Cushing’s disease. The CTP is not constant and is manageable in most cases. There is a definite need for new pharmacologic agent directed against corticotroph tumors.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Nelson DH, Meakin JW, Dealy JB, Jr, Matson DD, Emerson K, Jr, Thorn GW. ACTH-producing tumor of the pituitary gland. N Engl J Med 1958;259(4):161–164.
Salassa RM, Kearns TP, Kernohan JW, Sprague RG, Maccarty CS. Pituitary tumors in patients with Cushing’s syndrome. J Clin Endocrinol Metab 1959;19:1523–1539.
Montgomery DA, Welbourn RB, McCaughey WT, Gleadhill CA. Pituitary tumours manifested after adrenalectomy for Cushing’s syndrome. Lancet 1959;2:707–710.
Glenn F, Karl RC, Horwith M. The surgical treatment of Cushing’s syndrome. Ann Surg 1958;148(3):365–374.
Rees JR, Zilva JF. Diabetes insipidus complicating total adrenalectomy. J Clin Pathol 1959;12:530–534.
Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137–195.
Nelson DH, Meakin JW, Thorn GW. ACTH-producing pituitary tumors following adrenalectomy for Cushing’s syndrome. Ann Intern Med 1960;52:560–569.
Assié G, Bahurel H, Bertherat J, Kujas M, Legmann P, Bertagna X. The Nelson’s syndrome… revisited. Pituitary 2004;7(4):209–215; review.
Assié G, Bahurel H, Coste J, Silvera S, Kujas M, Dugué MA, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X. Corticotroph tumor progression after adrenalectomy in Cushing’s disease: a reappraisal of Nelson’s syndrome. J Clin Endocrinol Metab 2007;92(1):172–179.
Juliani G, Avataneo T, Potenzoni F, Sorrentino T. [CT and MR compared in the study of hypophysis]. Radiol Med (Torino) 1989;77(1–2):51–64.
Johnson MR, Hoare RD, Cox T, et al. The evaluation of patients with a suspected pituitary microadenoma: computer tomography compared to magnetic resonance imaging. Clin Endocrinol (Oxf) 1992;36(4):335–338.
Vest-Courtalon C, Ravel A, Perez N, et al. [Pituitary gland MRI and Cushing disease: report of 14 operated patients]. J Radiol 2000;81(7):781–786.
Bahurel-Barrera H, Assie G, Silvera S, Bertagna X, Coste J, Legmann P. Inter- and intra-observer variability in detection and progression assessment with MRI of microadenoma in Cushing’s disease patients followed up after bilateral adrenalectomy. Pituitary 2008;11(3):263–269.
Jornayvaz FR, Assié G, Bienvenu M, Coste J, Legmann P, Bertherat J, Bertagna X. Pregnancy does not accelerate corticotroph tumor progression in Nelson’s syndrome. Endocrine Society Annual Meeting 2009, P1–P610.
Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, Hofland LJ, Lamberts SW, Colao A. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009;94(1):223–230.
Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M, Snyder P, Tabarin A, Biller BM, Findling J, Melmed S, Darby CH, Hu K, Wang Y, Freda PU, Grossman AB, Frohman LA, Bertherat J. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 2009;94(1):115–122.
Heaney AP, Fernando M, Yong WH, Melmed S. Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med 2002;8(11):1281–1287.
Paez-Pereda M, Kovalovsky D, Hopfner U, Theodoropoulou M, Pagotto U, Uhl E, Losa M, Stalla J, Grubler Y, Missale C, Arzt E, Stalla GK. Retinoic acid prevents experimental Cushing syndrome. J Clin Invest 2001;108(8):1123–1131.
Bertagna X, Raux-Demay MC, Guilhaume B, et al. Cushing’s disease. In: Melmed S, (ed) The Pituitary. 2nd edition. Malden: Blackwell, 2002:496–560.
de Keyzer Y, Bertagna X, Lenne F, et al. Proopiomelanocortin gene expression in ACTH secreting non-pituitary tumors. J Clin Invest 1985;76:1892–1898.
Raffin-Sanson ML, de Keyzer Y, Bertagna X. Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Eur J Endocrinol 2003;149(2):79–90; review
Dahia PL, Grossman AB. The molecular pathogenesis of corticotroph tumors. Endocr Rev 1999;20(2):136–155.
de Keyzer Y, Rene P, Lenne F, Auzan C, Clauser E, Bertagna X. V3 vasopressin receptor and corticotropic phenotype in pituitary and nonpituitary tumors. Horm Res 1997;47(4–6):259–262; review.
Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990;71(6):1427–1433.
Gicquel C, Le Bouc Y, Luton JP, Girard F, Bertagna X. Monoclonality of corticotroph macroadenomas in Cushing’s disease. J Clin Endocrinol Metab 1992;75(2):472–475.
Wolfsen AR, Odell WD. The dose-response relationship of ACTH and cortisol in Cushing’s disease. Clin Endocrinol (Oxf) 1980;12(6):557–568.
Suda T, Tozawa F, Dobashi I, Horiba N, Ohmori N, Yamakado M, Yamada M, Demura H. Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro. J Clin Invest 1993;92(6):2790–2795.
Resetic J, Reiner Z, Ludecke D, Riznar-Resetic V, Sekso M. The effects of cortisol, 11-epicortisol, and lysine vasopressin on DNA and RNA synthesis in isolated human adrenocorticotropic hormone-secreting pituitary tumor cells. Steroids 1990;55(3):98–100.
Dahia PL, Honegger J, Reincke M, et al. Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors. J Clin Endocrinol Metab 1997;82(4):1088–1093.
Nolan LA, Levy A. Temporally sensitive trophic responsiveness of the adrenalectomized rat anterior pituitary to dexamethasone challenge: relationship between mitotic activity and apoptotic sensitivity. Endocrinology 2003;144(1):212–219.
Karl M, Von Wichert G, Kempter E, et al. Nelson’s syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene. J Clin Endocrinol Metab 1996;81(1):124–129.
Huizenga NA, de Lange P, Koper JW, et al. Human adrenocorticotropin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol Metab 1998;83(3):917–921.
Carey RM, Varma SK, Drake CR, Jr, et al. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing’s syndrome. A clinical, morphologic, and biochemical study. N Engl J Med 1984;311(1):13–20.
Gertz BJ, Contreras LN, McComb DJ, Kovacs K, Tyrrell JB, Dallman MF. Chronic administration of corticotropin-releasing factor increases pituitary corticotroph number. Endocrinology 1987;120(1):381–388.
Stenzel-Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W. Development of Cushing’s syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 1992;130(6):3378–3386.
de Keyzer Y, Rene P, Beldjord C, Lenne F, Bertagna X. Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours. Clin Endocrinol (Oxf) 1998;49(4):475–482.
Dieterich KD, Gundelfinger ED, Ludecke DK, Lehnert H. Mutation and expression analysis of corticotropin-releasing factor 1 receptor in adrenocorticotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 1998;83(9):3327–3331.
McNicol AM, Carbajo-Perez E. Aspects of anterior pituitary growth, with special reference to corticotrophs. Pituitary 1999;1(3–4):257–268.
Wynn PC, Harwood JP, Catt KJ, Aguilera G. Regulation of corticotropin-releasing factor (CRF) receptors in the rat pituitary gland: effects of adrenalectomy on CRF receptors and corticotroph responses. Endocrinology 1985;116(4):1653–1659.
Sakai K, Horiba N, Sakai Y, Tozawa F, Demura H, Suda T. Regulation of corticotropin-releasing factor receptor messenger ribonucleic acid in rat anterior pituitary. Endocrinology 1996;137(5):1758–1763.
Hornyak M, Weiss MH, Nelson DH, Couldwell WT. Nelson syndrome: historical perspectives and current concepts. Neurosurg Focus 2007;23(3):E12.
Acknowledgments
The authors are indebted to Stéphane Gaillard (Neurosurgery Department, Hôpital Foch), Hélène Bahurel, Marie Bienvenue, Paul Legmann (Radiology Department, Hôpital Cochin), Bertrand Dousset (Endocrine Surgery, Hôpital Cochin), and Michèle Kujas (Pathology Department, Hôpital La Pitié).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Assie, G., Guignat, L., Bertherat, J., Bertagna, X. (2010). Revisiting the Nelson’s Syndrome: Corticotroph Tumor Progression After Bilateral Adrenalectomy in Cushing’s Disease. In: Bronstein, M. (eds) Cushing's Syndrome. Contemporary Endocrinology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-449-4_15
Download citation
DOI: https://doi.org/10.1007/978-1-60327-449-4_15
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60327-448-7
Online ISBN: 978-1-60327-449-4
eBook Packages: MedicineMedicine (R0)