Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Management of Cushing disease

Abstract

Cushing disease is caused by a corticotroph tumor of the pituitary gland. Patients with Cushing disease are usually treated with transsphenoidal surgery, as this approach leads to remission in 70–90% of cases and is associated with low morbidity when performed by experienced pituitary gland surgeons. Nonetheless, among patients in postoperative remission, the risk of recurrence of Cushing disease could reach 20–25% at 10 years after surgery. Patients with persistent or recurrent Cushing disease might, therefore, benefit from a second pituitary operation (which leads to remission in 50–70% of cases), radiation therapy to the pituitary gland or bilateral adrenalectomy. Remission after radiation therapy occurs in 85% of patients with Cushing disease after a considerable latency period. Interim medical therapy is generally advisable after patients receive radiation therapy because of the long latency period. Bilateral adrenalectomy might be considered in patients who do not improve following transsphenoidal surgery, particularly patients who are very ill and require rapid control of hypercortisolism, or those wishing to avoid the risk of hypopituitarism associated with radiation therapy. Adrenalectomized patients require lifelong adrenal hormone replacement and are at risk of Nelson syndrome. The development of medical therapies with improved efficacy might influence the management of this challenging condition.

Key Points

  • Transsphenoidal surgery is advisable for most patients with newly diagnosed Cushing disease and often leads to rapid and sustained remission of hypercortisolism with low morbidity in most cases

  • Pituitary reoperation might be considered in patients with persistent or recurrent Cushing disease, but the remission rate is lower in comparison to initial surgery

  • Pituitary gland radiation therapy might lead to remission in many patients with persistent or recurrent Cushing disease, but takes a considerable time and a lifelong risk of hypopituitarism exists

  • Medical therapy can be used in patients who are awaiting the therapeutic effects of pituitary gland radiation therapy or in very ill patients in preparation for surgery

  • Bilateral adrenalectomy could be considered in patients with persistent or recurrent Cushing disease to control hypercortisolism, but will induce adrenal insufficiency and carries the risk of Nelson syndrome

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Causes of endogenous Cushing syndrome.
Figure 2: Management of patients with Cushing disease.

Similar content being viewed by others

References

  1. Cushing, H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull. Johns Hopkins Hosp. 50, 137–195 (1932).

    Google Scholar 

  2. Cushing, H. The basophil adenomas of the pituitary body. Ann. R. Coll. Surg. Engl. 44, 180–181 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Nieman, L. K. & Ilias, I. Evaluation and treatment of Cushing's syndrome. Am. J. Med. 118, 1340–1346 (2005).

    PubMed  Google Scholar 

  4. Raff, H. & Findling, J. W. A physiologic approach to diagnosis of the Cushing syndrome. Ann. Intern. Med. 138, 980–991 (2003).

    PubMed  Google Scholar 

  5. Arnaldi, G. et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 88, 5593–5602 (2003).

    CAS  PubMed  Google Scholar 

  6. Biller, B. M. et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 93, 2454–2462 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nieman, L. K. et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bonneville, J. F., Cattin, F., Bonneville, F., Schillo, F. & Jacquet, G. Pituitary gland imaging in Cushing's disease [French]. Neurochirurgie 48, 173–185 (2002).

    CAS  PubMed  Google Scholar 

  9. Dwyer, A. J. et al. Pituitary adenomas in patients with Cushing disease: initial experience with Gd-DTPA-enhanced MR imaging. Radiology 163, 421–426 (1987).

    CAS  PubMed  Google Scholar 

  10. Hardy, J. Excision of pituitary adenomas by trans-sphenoidal approach [French]. Union Med. Can. 91, 933–945 (1962).

    CAS  PubMed  Google Scholar 

  11. Oldfield, E. H. et al. Preoperative lateralization of ACTH-secreting pituitary microadenomas by bilateral and simultaneous inferior petrosal venous sinus sampling. N. Engl. J. Med. 312, 100–103 (1985).

    CAS  PubMed  Google Scholar 

  12. Oldfield, E. H. et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N. Engl. J. Med. 325, 897–905 (1991).

    CAS  PubMed  Google Scholar 

  13. Barker, F. G. 2nd, Klibanski, A. & Swearingen, B. Transsphenoidal surgery for pituitary tumors in the United States, 1996–2000: mortality, morbidity, and the effects of hospital and surgeon volume. J. Clin. Endocrinol. Metab. 88, 4709–4719 (2003).

    CAS  PubMed  Google Scholar 

  14. Semple, P. L. & Laws, E. R. Jr. Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing's disease. J. Neurosurg. 91, 175–179 (1999).

    CAS  PubMed  Google Scholar 

  15. Swearingen, B. et al. Long-term mortality after transsphenoidal surgery for Cushing disease. Ann. Intern. Med. 130, 821–824 (1999).

    CAS  PubMed  Google Scholar 

  16. Fitzgerald, P. A. et al. Cushing's disease: transient secondary adrenal insufficiency after selective removal of pituitary microadenomas; evidence for a pituitary origin. J. Clin. Endocrinol. Metab. 54, 413–422 (1982).

    CAS  PubMed  Google Scholar 

  17. Ram, Z. et al. Early repeat surgery for persistent Cushing's disease. J. Neurosurg. 80, 37–45 (1994).

    CAS  PubMed  Google Scholar 

  18. Patil, C. G. et al. Late recurrences of Cushing's disease after initial successful transsphenoidal surgery. J. Clin. Endocrinol. Metab. 93, 358–362 (2008).

    CAS  PubMed  Google Scholar 

  19. Sonino, N., Zielezny, M., Fava, G. A., Fallo, F. & Boscaro, M. Risk factors and long-term outcome in pituitary-dependent Cushing's disease. J. Clin. Endocrinol. Metab. 81, 2647–2652 (1996).

    CAS  PubMed  Google Scholar 

  20. Invitti, C. et al. Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. J. Clin. Endocrinol. Metab. 84, 440–448 (1999).

    CAS  PubMed  Google Scholar 

  21. Hammer, G. D. et al. Transsphenoidal microsurgery for Cushing's disease: initial outcome and long-term results. J. Clin. Endocrinol. Metab. 89, 6348–6357 (2004).

    CAS  PubMed  Google Scholar 

  22. Rollin, G. A., Ferreira, N. P., Junges, M., Gross, J. L. & Czepielewski, M. A. Dynamics of serum cortisol levels after transsphenoidal surgery in a cohort of patients with Cushing's disease. J. Clin. Endocrinol. Metab. 89, 1131–1139 (2004).

    CAS  PubMed  Google Scholar 

  23. Shimon, I., Ram, Z., Cohen, Z. R. & Hadani, M. Transsphenoidal surgery for Cushing's disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery 51, 57–62 (2002).

    PubMed  Google Scholar 

  24. Carrasco, C. A. et al. Midnight salivary cortisol determination for assessing the outcome of transsphenoidal surgery in Cushing's disease. J. Clin. Endocrinol. Metab. 93, 4728–4734 (2008).

    CAS  PubMed  Google Scholar 

  25. Bochicchio, D., Losa, M. & Buchfelder, M. Factors influencing the immediate and late outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by the European Cushing's Disease Survey Group. J. Clin. Endocrinol. Metab. 80, 3114–3120 (1995).

    CAS  PubMed  Google Scholar 

  26. Rees, D. A. et al. Long-term follow-up results of transsphenoidal surgery for Cushing's disease in a single centre using strict criteria for remission. Clin. Endocrinol. (Oxf.) 56, 541–551 (2002).

    CAS  Google Scholar 

  27. Chee, G. H., Mathias, D. B., James, R. A. & Kendall-Taylor, P. Transsphenoidal pituitary surgery in Cushing's disease: can we predict outcome? Clin. Endocrinol. (Oxf.) 54, 617–626 (2001).

    CAS  Google Scholar 

  28. Guilhaume, B. et al. Transsphenoidal pituitary surgery for the treatment of Cushing's disease: results in 64 patients and long term follow-up studies. J. Clin. Endocrinol. Metab. 66, 1056–1064 (1988).

    CAS  PubMed  Google Scholar 

  29. Blevins, L. S. Jr, Christy, J. H., Khajavi, M. & Tindall, G. T. Outcomes of therapy for Cushing's disease due to adrenocorticotropin-secreting pituitary macroadenomas. J. Clin. Endocrinol. Metab. 83, 63–67 (1998).

    CAS  PubMed  Google Scholar 

  30. Yap, L. B., Turner, H. E., Adams, C. B. & Wass, J. A. Undetectable postoperative cortisol does not always predict long-term remission in Cushing's disease: a single centre audit. Clin. Endocrinol. (Oxf.) 56, 25–31 (2002).

    CAS  Google Scholar 

  31. Dehdashti, A. R. & Gentili, F. Current state of the art in the diagnosis and surgical treatment of Cushing disease: early experience with a purely endoscopic endonasal technique. Neurosurg. Focus. 23, E9 (2007).

    PubMed  Google Scholar 

  32. Zada, G., Governale, L. S. & Laws, E. R. Jr. Intraoperative conversion from endoscopic to microscopic approach for the management of sellar pathology: incidence and rationale in a contemporary series. World Neurosurg. 73, 334–337 (2010).

    PubMed  Google Scholar 

  33. Trainer, P. J. et al. Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successful treatment. Clin. Endocrinol. (Oxf.) 38, 73–78 (1993).

    CAS  Google Scholar 

  34. Estrada, J. et al. The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing's disease. J. Clin. Endocrinol. Metab. 86, 5695–5699 (2001).

    CAS  PubMed  Google Scholar 

  35. Esposito, F. et al. Clinical review: Early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing's disease. J. Clin. Endocrinol. Metab. 91, 7–13 (2006).

    CAS  PubMed  Google Scholar 

  36. Chen, J. C. et al. Transsphenoidal microsurgical treatment of Cushing disease: postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test. J. Neurosurg. 98, 967–973 (2003).

    PubMed  Google Scholar 

  37. Barbetta, L. et al. Assessment of cure and recurrence after pituitary surgery for Cushing's disease. Acta Neurochir. (Wien.) 143, 477–482 (2001).

    CAS  Google Scholar 

  38. Avgerinos, P. C. et al. The corticotropin-releasing hormone test in the postoperative evaluation of patients with cushing's syndrome. J. Clin. Endocrinol. Metab. 65, 906–913 (1987).

    CAS  PubMed  Google Scholar 

  39. Castinetti, F. et al. A combined dexamethasone desmopressin test as an early marker of postsurgical recurrence in Cushing's disease. J. Clin. Endocrinol. Metab. 94, 1897–1903 (2009).

    CAS  PubMed  Google Scholar 

  40. van Aken, M. O., de Herder, W. W., van der Lely, A. J., de Jong, F. H. & Lamberts, S. W. Postoperative metyrapone test in the early assessment of outcome of pituitary surgery for Cushing's disease. Clin. Endocrinol. (Oxf.) 47, 145–149 (1997).

    CAS  Google Scholar 

  41. Pereira, A. M. et al. Long-term predictive value of postsurgical cortisol concentrations for cure and risk of recurrence in Cushing's disease. J. Clin. Endocrinol. Metab. 88, 5858–5864 (2003).

    CAS  PubMed  Google Scholar 

  42. Nunes, M. L. et al. Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients. J. Clin. Endocrinol. Metab. 94, 456–462 (2009).

    CAS  PubMed  Google Scholar 

  43. Tani, Y. et al. Ectopic ACTH syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing's disease. Endocr. J. 57, 679–686 (2010).

    CAS  PubMed  Google Scholar 

  44. Valassi, E. et al. Delayed remission after transsphenoidal surgery in patients with Cushing's disease. J. Clin. Endocrinol. Metab. 95, 601–610 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Patil, C. G. et al. Outcomes after repeat transsphenoidal surgery for recurrent Cushing's disease. Neurosurgery 63, 266–271 (2008).

    PubMed  Google Scholar 

  46. Estrada, J. et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. N. Engl. J. Med. 336, 172–177 (1997).

    CAS  PubMed  Google Scholar 

  47. Littley, M. D. et al. Long-term follow-up of low-dose external pituitary irradiation for Cushing's disease. Clin. Endocrinol. (Oxf.) 33, 445–455 (1990).

    CAS  Google Scholar 

  48. Laws, E. R. Jr & Vance, M. L. Radiosurgery for pituitary tumors and craniopharyngiomas. Neurosurg. Clin. N. Am. 10, 327–336 (1999).

    PubMed  Google Scholar 

  49. Sheehan, J. M., Vance, M. L., Sheehan, J. P., Ellegala, D. B. & Laws, E. R. Jr. Radiosurgery for Cushing's disease after failed transsphenoidal surgery. J. Neurosurg. 93, 738–742 (2000).

    CAS  PubMed  Google Scholar 

  50. Colin, P. et al. Treatment of pituitary adenomas by fractionated stereotactic radiotherapy: a prospective study of 110 patients. Int. J. Radiat. Oncol. Biol. Phys. 62, 333–341 (2005).

    PubMed  Google Scholar 

  51. Devin, J. K. et al. The efficacy of linear accelerator radiosurgery in the management of patients with Cushing's disease. Stereotact. Funct. Neurosurg. 82, 254–262 (2004).

    PubMed  Google Scholar 

  52. Levy, R. P. et al. Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840 patients. Stereotact. Funct. Neurosurg. 57, 22–35 (1991).

    CAS  PubMed  Google Scholar 

  53. Petit, J. H. et al. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J. Clin. Endocrinol. Metab. 93, 393–399 (2008).

    CAS  PubMed  Google Scholar 

  54. Minniti, G. et al. Long-term follow-up results of postoperative radiation therapy for Cushing's disease. J. Neurooncol. 84, 79–84 (2007).

    PubMed  Google Scholar 

  55. Castinetti, F. et al. Gamma knife radiosurgery is a successful adjunctive treatment in Cushing's disease. Eur. J. Endocrinol. 156, 91–98 (2007).

    CAS  PubMed  Google Scholar 

  56. Landolt, A. M. et al. Octreotide may act as a radioprotective agent in acromegaly. J. Clin. Endocrinol. Metab. 85, 1287–1289 (2000).

    CAS  PubMed  Google Scholar 

  57. Feigl, G. C., Bonelli, C. M., Berghold, A. & Mokry, M. Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function. J. Neurosurg. 97 (Suppl.), 415–421 (2002).

    PubMed  Google Scholar 

  58. Sheehan, J. P. et al. Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J. Neurosurg. 102, 678–691 (2005).

    PubMed  Google Scholar 

  59. Brada, M. et al. The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin. Endocrinol. (Oxf.) 38, 571–578 (1993).

    CAS  Google Scholar 

  60. Minniti, G., Traish, D., Ashley, S., Gonsalves, B. & Brada, M. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J. Clin. Endocrinol. Metab. 90, 800–804 (2005).

    CAS  PubMed  Google Scholar 

  61. Nieman, L. K. Medical therapy of Cushing's disease. Pituitary 5, 77–82 (2002).

    CAS  PubMed  Google Scholar 

  62. Schteingart, D. E. Drugs in the medical treatment of Cushing's syndrome. Expert Opin. Emerg. Drugs. 14, 661–671 (2009).

    CAS  PubMed  Google Scholar 

  63. Sonino, N., Boscaro, M., Paoletta, A., Mantero, F. & Ziliotto, D. Ketoconazole treatment in Cushing's syndrome: experience in 34 patients. Clin. Endocrinol. (Oxf.) 35, 347–352 (1991).

    CAS  Google Scholar 

  64. McCance, D. R., Ritchie, C. M., Sheridan, B. & Atkinson, A. B. Acute hypoadrenalism and hepatotoxicity after treatment with ketoconazole. Lancet 1, 573 (1987).

    CAS  PubMed  Google Scholar 

  65. Tabarin, A. et al. Use of ketoconazole in the treatment of Cushing's disease and ectopic ACTH syndrome. Clin. Endocrinol. (Oxf.) 34, 63–69 (1991).

    CAS  Google Scholar 

  66. Verhelst, J. A. et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome. Clin. Endocrinol. (Oxf.) 35, 169–178 (1991).

    CAS  Google Scholar 

  67. Gormley, M. J. et al. Cushing's syndrome in pregnancy—treatment with metyrapone. Clin. Endocrinol. (Oxf.) 16, 283–293 (1982).

    CAS  Google Scholar 

  68. Lindsay, J. R., Jonklaas, J., Oldfield, E. H. & Nieman, L. K. Cushing's syndrome during pregnancy: personal experience and review of the literature. J. Clin. Endocrinol. Metab. 90, 3077–3083 (2005).

    CAS  PubMed  Google Scholar 

  69. Luton, J. P. et al. Treatment of Cushing's disease by o,p'DDD. Survey of 62 cases. N. Engl. J. Med. 300, 459–464 (1979).

    CAS  PubMed  Google Scholar 

  70. Leiba, S. et al. The protracted effect of o, p'-DDD in Cushing's disease and its impact on adrenal morphogenesis of young human embryo. Ann. Endocrinol. (Paris) 50, 49–53 (1989).

    CAS  Google Scholar 

  71. Allolio, B. et al. Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in Cushing's syndrome. Klin. Wochenschr. 66, 361–364 (1988).

    CAS  PubMed  Google Scholar 

  72. Schulte, H. M., Benker, G., Reinwein, D., Sippell, W. G. & Allolio, P. Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushing's syndrome and dose-response relationship in normal subjects. J. Clin. Endocrinol. Metab. 70, 1426–1430 (1990).

    CAS  PubMed  Google Scholar 

  73. Thorén, M., Adamson, U. & Sjöberg, H. E. Aminoglutethimide and metyrapone in the management of Cushing's syndrome. Acta Endocrinol. (Copenh.) 109, 451–457 (1985).

    Google Scholar 

  74. Dewis, P., Anderson, D. C., Bu'lock, D. E., Earnshaw, R. & Kelly, W. F. Experience with trilostane in the treatment of Cushing's syndrome. Clin. Endocrinol. (Oxf.) 18, 533–540 (1983).

    CAS  Google Scholar 

  75. Klibanski, A. Clinical practice. Prolactinomas. N. Engl. J. Med. 362, 1219–1226 (2010).

    CAS  PubMed  Google Scholar 

  76. de Bruin, C., Feelders, R. A., Lamberts, S. W. & Hofland, L. J. Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome. Rev. Endocr. Metab. Disord. 10, 91–102 (2009).

    CAS  PubMed  Google Scholar 

  77. Pivonello, R. et al. 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. 94, 223–230 (2009).

    CAS  PubMed  Google Scholar 

  78. Godbout, A. et al. Cabergoline monotherapy in the long-term treatment of Cushing's disease. Eur. J. Endocrinol. 163, 709–716 (2010).

    CAS  PubMed  Google Scholar 

  79. Schade, R., Andersohn, F., Suissa, S., Haverkamp, W. & Garbe, E. Dopamine agonists and the risk of cardiac-valve regurgitation. N. Engl. J. Med. 356, 29–38 (2007).

    CAS  PubMed  Google Scholar 

  80. Zanettini, R. et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N. Engl. J. Med. 356, 39–46 (2007).

    CAS  PubMed  Google Scholar 

  81. Valassi, E., Klibanski, A. & Biller, B. M. Clinical Review: Potential cardiac valve effects of dopamine agonists in hyperprolactinemia. J. Clin. Endocrinol. Metab. 95, 1025–1033 (2010).

    CAS  PubMed  Google Scholar 

  82. Ben-Shlomo, A. et al. Differential ligand-mediated pituitary somatostatin receptor subtype signaling: implications for corticotroph tumor therapy. J. Clin. Endocrinol. Metab. 94, 4342–4350 (2009).

    CAS  PubMed  Google Scholar 

  83. Boscaro, M. et al. Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J. Clin. Endocrinol. Metab. 94, 115–122 (2009).

    CAS  PubMed  Google Scholar 

  84. Feelders, R. A. et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. N. Engl. J. Med. 362, 1846–1848 (2010).

    CAS  PubMed  Google Scholar 

  85. Vilar, L. et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing's disease. Pituitary 13, 123–129 (2010).

    CAS  PubMed  Google Scholar 

  86. Kreutzer, J. et al. No effect of the PPAR-gamma agonist rosiglitazone on ACTH or cortisol secretion in Nelson's syndrome and Cushing's disease in vitro and in vivo. Clin. Neuropathol. 28, 430–439 (2009).

    CAS  PubMed  Google Scholar 

  87. Castinetti, F. et al. Merits and pitfalls of mifepristone in Cushing's syndrome. Eur. J. Endocrinol. 160, 1003–1010 (2009).

    CAS  PubMed  Google Scholar 

  88. Porterfield, J. R. et al. Surgery for Cushing's syndrome: an historical review and recent ten-year experience. World J. Surg. 32, 659–677 (2008).

    PubMed  Google Scholar 

  89. Vella, A. et al. Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome. J. Clin. Endocrinol. Metab. 86, 1596–1599 (2001).

    CAS  PubMed  Google Scholar 

  90. Chapuis, Y., Chastanet, S., Dousset, B. & Luton, J. P. Bilateral laparoscopic adrenalectomy for Cushing's disease. Br. J. Surg. 84, 1009 (1997).

    CAS  PubMed  Google Scholar 

  91. Smith, P. W. et al. Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J. Am. Coll. Surg. 208, 1059–1064 (2009).

    PubMed  Google Scholar 

  92. Thompson, S. K. et al. Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing's disease: a 10-year experience. Ann. Surg. 245, 790–794 (2007).

    PubMed  PubMed Central  Google Scholar 

  93. Nagesser, S. K. et al. Long-term results of total adrenalectomy for Cushing's disease. World J. Surg. 24, 108–113 (2000).

    CAS  PubMed  Google Scholar 

  94. Thompson, G. B. et al. Laparoscopic versus open posterior adrenalectomy: a case-control study of 100 patients. Surgery 122, 1132–1136 (1997).

    CAS  PubMed  Google Scholar 

  95. Chow, J. T. et al. Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience. Clin. Endocrinol. (Oxf.) 68, 513–519 (2008).

    Google Scholar 

  96. Assalia, A. & Gagner, M. Laparoscopic adrenalectomy. Br. J. Surg. 91, 1259–1274 (2004).

    CAS  PubMed  Google Scholar 

  97. Nelson, D. H. et al. ACTH-producing tumor of the pituitary gland. N. Engl. J. Med. 259, 161–164 (1958).

    CAS  PubMed  Google Scholar 

  98. Assié, G. et al. Corticotroph tumor progression after adrenalectomy in Cushing's Disease: a reappraisal of Nelson's Syndrome. J. Clin. Endocrinol. Metab. 92, 172–179 (2007).

    PubMed  Google Scholar 

  99. De Tommasi, C., Vance, M. L., Okonkwo, D. O., Diallo, A. & Laws, E. R. Jr. Surgical management of adrenocorticotropic hormone-secreting macroadenomas: outcome and challenges in patients with Cushing's disease or Nelson's syndrome. J. Neurosurg. 103, 825–830 (2005).

    PubMed  Google Scholar 

  100. Vik-Mo, E. O. et al. Gamma knife stereotactic radiosurgery of Nelson syndrome. Eur. J. Endocrinol. 160, 143–148 (2009).

    CAS  PubMed  Google Scholar 

  101. Yanovski, J. A., Cutler, G. B. Jr, Chrousos, G. P. & Nieman, L. K. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA 269, 2232–2238 (1993).

    CAS  PubMed  Google Scholar 

  102. Valassi, E. et al. Concomitant medication use can confound Interpretation of the combined dexamethasone-corticotropin releasing hormone test in Cushing's syndrome. J. Clin. Endocrinol. Metab. 94, 4851–4859 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Doppman, J. L. et al. Gadolinium DTPA enhanced MR imaging of ACTH-secreting microadenomas of the pituitary gland. J. Comput. Assist. Tomogr. 12, 728–735 (1988).

    CAS  PubMed  Google Scholar 

  104. Hall, W. A., Luciano, M. G., Doppman, J. L., Patronas, N. J. & Oldfield, E. H. Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann. Intern. Med. 120, 817–820 (1994).

    CAS  PubMed  Google Scholar 

  105. Nieman, L. K. et al. The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing's syndrome. Ann. Intern. Med. 105, 862–867 (1986).

    CAS  PubMed  Google Scholar 

  106. Bakiri, F. et al. Treatment of Cushing's disease by transsphenoidal, pituitary microsurgery: prognosis factors and long-term follow-up. J. Endocrinol. Invest. 19, 572–580 (1996).

    CAS  PubMed  Google Scholar 

  107. Knappe, U. J. & Lüdecke, D. K. Persistent and recurrent hypercortisolism after transsphenoidal surgery for Cushing's disease. Acta Neurochir. Suppl. 65, 31–34 (1996).

    CAS  PubMed  Google Scholar 

  108. Cavagnini, F. & Pecori Giraldi, F. Epidemiology and follow-up of Cushing's disease. Ann. Endocrinol. (Paris) 62, 168–172 (2001).

    CAS  Google Scholar 

  109. Flitsch, J., Knappe, U. J. & Lüdecke, D. K. The use of postoperative ACTH levels as a marker for successful transsphenoidal microsurgery in Cushing's disease. Zentralbl Neurochir. 64, 6–11 (2003).

    CAS  PubMed  Google Scholar 

  110. Salenave, S. et al. Pituitary magnetic resonance imaging findings do not influence surgical outcome in adrenocorticotropin-secreting microadenomas. J. Clin. Endocrinol. Metab. 89, 3371–3376 (2004).

    CAS  PubMed  Google Scholar 

  111. Atkinson, A. B., Kennedy, A., Wiggam, M. I., McCance, D. R. & Sheridan, B. Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance. Clin. Endocrinol. (Oxf.) 63, 549–559 (2005).

    Google Scholar 

  112. Hofmann, B. M. & Fahlbusch, R. Treatment of Cushing's disease: a retrospective clinical study of the latest 100 cases. Front. Horm. Res. 34, 158–184 (2006).

    PubMed  Google Scholar 

  113. Acebes, J. J., Martino, J., Masuet, C., Montanya, E. & Soler, J. Early post-operative ACTH and cortisol as predictors of remission in Cushing's disease. Acta Neurochir. (Wien.) 149, 471–479 (2007).

    CAS  Google Scholar 

  114. Rollin, G., Ferreira, N. P. & Czepielewski, M. A. Prospective evaluation of transsphenoidal pituitary surgery in 108 patients with Cushing's disease. Arq. Bras. Endocrinol. Metabol. 51, 1355–1361 (2007).

    PubMed  Google Scholar 

  115. Hofmann, B. M. et al. Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J. Neurosurg. 108, 9–18 (2008).

    PubMed  Google Scholar 

  116. Prevedello, D. M. et al. Management of Cushing's disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J. Neurosurg. 109, 751–759 (2008).

    PubMed  Google Scholar 

  117. Fomekong, E., Maiter, D., Grandin, C. & Raftopoulos, C. Outcome of transsphenoidal surgery for Cushing's disease: a high remission rate in ACTH-secreting macroadenomas. Clin. Neurol. Neurosurg. 111, 442–449 (2009).

    PubMed  Google Scholar 

  118. Jagannathan, J. et al. Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease. J. Neurosurg. 111, 531–539 (2009).

    PubMed  PubMed Central  Google Scholar 

  119. Murayama, M. et al. Long term follow-up of Cushing's disease treated with reserpine and pituitary irradiation. J. Clin. Endocrinol. Metab. 75, 935–942 (1992).

    CAS  PubMed  Google Scholar 

  120. Tsang, R. W. et al. Role of radiation therapy in clinical hormonally-active pituitary adenomas. Radiother. Oncol. 41, 45–53 (1996).

    CAS  PubMed  Google Scholar 

  121. Witt, T. C., Kondziolka, D., Flickinger, J. C. & Lunsford, L. D. in Gamma knife radiosurgery for pituitary tumors (eds Lunsford, L. D., Kondziolka, D. & Flickinger, J. C.) 114–127 (Karger, Basel, 1998).

    Google Scholar 

  122. Kobayashi, T., Kida, Y. & Mori, Y. Gamma knife radiosurgery in the treatment of Cushing disease: long-term results. J. Neurosurg. 97, 422–428 (2002).

    PubMed  Google Scholar 

  123. Jagannathan, J. et al. Gamma Knife surgery for Cushing's disease. J. Neurosurg. 106, 980–987 (2007).

    PubMed  Google Scholar 

Download references

Acknowledgements

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to all aspects of this review.

Corresponding author

Correspondence to Nicholas A. Tritos.

Ethics declarations

Competing interests

B. M. K. Biller has been a consultant for Novartis and has received grant/research support from Corcept and Novartis. B. Swearingen has been a consultant for Novartis. N. A. Tritos declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tritos, N., Biller, B. & Swearingen, B. Management of Cushing disease. Nat Rev Endocrinol 7, 279–289 (2011). https://doi.org/10.1038/nrendo.2011.12

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.12

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing