Abstract
Adrenalectomy is a radical therapeutic approach to control hypercortisolism in some patients with Cushing's disease. However it may be complicated by the Nelson's syndrome, defined by the association of a pituitary macroadenoma and high ACTH secretion after adrenalectomy. This definition has not changed since the end of the fifties. Today the Nelson's syndrome must be revisited with new to criteria using more sensitive diagnostic tools, especially the pituitary magnetic resonance imaging.
In this paper we will review the pathophysiological aspects of corticotroph tumor growth, with reference to the impact of adrenalectomy. The main epidemiological data on the Nelson's syndrome will be presented.
More importantly, we will propose a new pathophysiological and practical approach to this question which attempts to evaluate the Corticotroph Tumor Progression after adrenalectomy, rather than to diagnose the Nelson's syndrome. We will discuss the consequences for the management of Cushing's disease patients after adrenalectomy, and will also draw some perspectives.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
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 John Hopkins Hosp 1932;50:137–195.
Bertagna X, Raux-Demay MC, Guilhaume B et al. Cushing's Disease. In The Pituitary, S. Melmed, ed, 2nd ed. Blackwell 2002: pp 496–560.
de Keyzer, 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(34):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.
van Wijk PA, van Neck JW, Rijnberk A, Croughs RJ, Mol JA. Proliferation of the murine corticotropic tumour cell line AtT20 is affected by hypophysiotrophic hormones, growth factors and glucocorticoids. Mol Cell Endocrinol 1995;111(1):13–19.
Nagesser SK, van Seters AP, Kievit J, Hermans J, Krans HM, van de Velde CJ. Long-term results of total adrenalectomy for Cushing's disease. World J Surg 2000;24(1):108–113.
Barnett AH, Livesey JH, Friday K, Donald RA, Espiner EA. Comparison of preoperative and postoperative ACTH concentrations after bilateral adrenalectomy in Cushing's disease. Clin Endocrinol (Oxf) 1983;18(3):301–305.
Kelly WF, MacFarlane IA, Longson D, Davies D, Sutcliffe H. Cushing's disease treated by total adrenalectomy: Long-term observations of 43 patients. Q J Med 1983;52(206):224–231.
Streeten DH, Anderson GHJ. Endocrine Society Meeting 1994:abstract 44c.
Chapuis Y, Pitre J, Conti F, Abboud B, Pras-Jude N, Luton JP. Role and operative risk of bilateral adrenalectomy in hypercortisolism. World J Surg 1996;20(7):775–779; discussion 779–780.
Kasperlik-Zaluska AA, Nielubowicz J, Wislawski J, et al. Nelson's syndrome: Incidence and prognosis. Clin Endocrinol (Oxf) 1983;19(6):693–698.
Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg P. Patient's age is a simple predictive factor for the development of Nelson's syndrome after total adrenalectomy for Cushing's disease. J Clin Endocrinol Metab 1994;79(3):887–889.
Manolas KJ, Farmer HM, Wilson HK, et al. The pituitary before and after adrenalectomy for Cushing's syndrome. World J Surg 1984;8(3):374–387.
Moore TJ, Dluhy RG, Williams GH, Cain JP. Nelson's syndrome: Frequency, prognosis, and effect of prior pituitary irradiation. Ann Intern Med 1976;85(6):731–734.
Watson RG, van Heerden JA, Northcutt RC, Grant CS, Ilstrup DM. Results of adrenal surgery for Cushing's syndrome: 10 years' experience. World J Surg 1986;10(4):531–538.
Sonino N, Zielezny M, Fava GA, Fallo F, Boscaro M. Risk factors and long-term outcome in pituitary-dependent Cushing's disease. J Clin Endocrinol Metab 1996;81(7):2647–2652.
Welbourn RB, Montgomery DA, Kennedy TL. The natural history of treated Cushing's syndrome. Br J Surg 1971;58(1):1–16.
Grabner P, Hauer-Jensen M, Jervell J, Flatmark A. Long-term results of treatment of Cushing's disease by adrenalectomy. Eur J Surg 1991;157(8):461–464.
Bennett AH, Cain JP, Dluhy RG, Tynes WV, Harrison JH, Thorn GW. Surgical treatment of adrenocortical hyperplasia: 20-year experience. J Urol 1973;109(3):321–324.
Moreira AC, Castro M, Machado HR. Longitudinal evaluation of adrenocorticotrophin and beta-lipotrophin plasma levels following bilateral adrenalectomy in patients with Cushing's disease. Clin Endocrinol (Oxf) 1993;39(1):91–96.
Jenkins PJ, Trainer PJ, Plowman PN, et al. The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 1995;80(1):165–171.
Pereira MA, Halpern A, Salgado LR, et al. A study of patients with Nelson's syndrome. Clin Endocrinol (Oxf) 1998;49(4):533–539.
Thomas CG, Jr., Smith AT, Benson M, Griffith J. Nelson's syndrome after Cushing's disease in childhood: A continuing problem. Surgery 1984;96(6):1067–1077.
Imai T, Funahashi H, Tanaka Y, et al. Adrenalectomy for treatment of Cushing syndrome: Results in 122 patients and long-term follow-up studies. World J Surg 1996;20(7):781–786; discussion 786–787.
McCance DR, Russell CF, Kennedy TL, Hadden DR, Kennedy L, Atkinson AB. Bilateral adrenalectomy: Low mortality and morbidity in Cushing's disease. Clin Endocrinol (Oxf) 1993;39(3):315–321.
Cohen KL, Noth RH, Pechinski T. Incidence of pituitary tumors following adrenalectomy. A long-term follow-up study of patients treated for Cushing's disease. Arch Intern Med 1978;138(4):575–579.
Ernest I, Ekman H. Adrenalectomy in Cushing's disease. A long-term follow-up. Acta Endocrinol Suppl (Copenh) 1972;160:3–41.
Hopwood NJ, Kenny FM. Incidence of Nelson's syndrome after adrenalectomy for Cushing's disease in children: Results of a nationwide survey. Am J Dis Child 1977;131(12):1353–1356.
Krieger DT, Samojlik E, Bardin CW. Cortisol and androgen secretion in a case of Nelson's syndrome with paratesticular tumors: Response to cyproheptadine therapy. J Clin Endocrinol Metab 1978;47(4):837–844.
Baranetsky NG, Zipser RD, Goebelsmann U, et al. Adrenocorticotropin-dependent virilizing paraovarian tumors in Nelson's syndrome. J Clin Endocrinol Metab 1979;49(3):381–386.
Ntalles K, Kostoglou-Athanassiou I, Georgiou E, Ikkos D. Paratesticular tumours in a patient with Nelson's syndrome. Horm Res 1996;45(6):291–294.
Shekarriz M, Schneider C, Sabanegh E, Kempter F, Waldherr R. Excessive testosterone production in a patient with Nelson syndrome and bilateral testicular tumors. Urol Int 1996;56(3):200–203.
Johnson RE, Scheithauer B. Massive hyperplasia of testicular adrenal rests in a patient with Nelson's syndrome. Am J Clin Pathol 1982;77(4):501–507.
Mahmoud-Ahmed AS, Suh JH. Radiation therapy for Cushing's disease: A review. Pituitary 2002;5(3):175–180.
Vella A, Thompson GB, Grant CS, van Heerden JA, Farley DR, Young WF Jr. Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 2001;86(4):1596–1599.
van der Hoek J, Waaijers M, van Koetsveld PM, Sprij-Mooij D, Feelders RA, Schmid HA, Schoeffter P, Hoyer D, Cervia D, Taylor JE, Culler MD, Lamberts SW, Hofland LJ. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. Am J Physiol Endocrinol Metab 2005 March 15
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.
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. Epub 2002 Oct 15.
Schacke H, Schottelius A, Docke WD, Strehlke P, Jaroch S, Schmees N, Rehwinkel H, Hennekes H, Asadullah K. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc Natl Acad Sci USA 2004; 101(1):227–232. Epub 2003 Dec 23.
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.
Melmed S. Mechanisms for pituitary tumorigenesis: The plastic pituitary. J Clin Invest 2003;112(11):1603–1618. Review.
Heaney AP, Melmed SR. Molecular targets in pituitary tumours. Nat Rev Cancer 2004;4(4):285–295. Review.
Evans CO, Young AN, Brown MR, Brat DJ, Parks JS, Neish AS, Oyesiku NM. Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction. J Clin Endocrinol Metab 2001;86(7):3097–3107.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Assié, G., Bahurel, H., Bertherat, J. et al. The Nelson's syndrome... revisited. Pituitary 7, 209–215 (2004). https://doi.org/10.1007/s11102-005-1403-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11102-005-1403-y