, Volume 47, Issue 1, pp 9–20 | Cite as

Managing Cushing’s disease: the state of the art

  • Annamaria Colao
  • Marco Boscaro
  • Diego Ferone
  • Felipe F. Casanueva


Cushing’s disease is a rare chronic disease caused by a pituitary adenoma, which leads to excess secretion of adrenocorticotropic hormone (ACTH). The over-production of ACTH leads to hyperstimulation of the adrenal glands and a chronic excess of cortisol, resulting in the signs and symptoms of a severe clinical state (Cushing’s syndrome) that leads to significant morbidity, negative impacts on the patient’s quality of life, and, if untreated, increased mortality. The management of patients with Cushing’s disease is complicated by the heterogeneity of the condition, with signs and symptoms that overlap with those of other diseases, and high subclinical incidence rates. Controversies surrounding the tests used for screening and identifying patients with Cushing’s disease add to the challenge of patient management. Surgical intervention to remove the adenoma is the first-line treatment for patients with Cushing’s disease, but medical therapies are useful in patients who relapse or are unsuitable for surgery. The recent introduction of pasireotide, the first pituitary-directed medical therapy, expands the number of treatment options available for patients with Cushing’s disease. This state-of-the-art review aims to provide an overview of the most recent scientific research and clinical information regarding Cushing’s disease. Continuing research into improving the diagnosis and treatment of Cushing’s disease will help to optimize patient management.


Cushing’s disease ACTH Cortisol Pituitary Management 


  1. 1.
    S.S. Praw, A.P. Heaney, Medical treatment of Cushing’s disease: overview and recent findings. Int. J. Gen. Med. 29, 209–217 (2009)Google Scholar
  2. 2.
    J. Newell-Price, X. Bertagna, A.B. Grossman et al., Cushing’s syndrome. Lancet 367, 1605–1617 (2006)PubMedGoogle Scholar
  3. 3.
    J. Lindholm, S. Juul, J.O. Jørgensen et al., Incidence and late prognosis of Cushing’s syndrome: a population-based study. J. Clin. Endocrinol. Metab. 86, 117–123 (2001)PubMedGoogle Scholar
  4. 4.
    J. Etxabe, J.A. Vazquez, Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin. Endocrinol. (Oxf) 40, 479–484 (1994)Google Scholar
  5. 5.
    R. Pivonello, M.C. De Martino, M. De Leo et al., Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 37, 135–149 (2008)PubMedGoogle Scholar
  6. 6.
    M. Boscaro, G. Arnaldi, Approach to the patient with possible Cushing’s syndrome. J. Clin. Endocrinol. Metab. 94, 3121–3131 (2009)PubMedGoogle Scholar
  7. 7.
    C. Steffensen, A.M. Bak, K.Z. Rubeck et al., Epidemiology of Cushing’s syndrome. Neuroendocrinology 92, 1–5 (2010)PubMedGoogle Scholar
  8. 8.
    L. Guignat, J. Bertherat, The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. Eur. J. Endocrinol. 163, 9–13 (2010)PubMedGoogle Scholar
  9. 9.
    J. Kreutzer, R. Fahlbusch, Diagnosis and treatment of pituitary tumors. Curr. Opin. Neurol. 17, 693–703 (2004)PubMedGoogle Scholar
  10. 10.
    A.S. Kanter, A.O. Diallo, J.A. Jane Jr et al., Single-center experience with pediatric Cushing’s disease. J. Neurosurg. 103, 413–420 (2005)PubMedGoogle Scholar
  11. 11.
    D.F. Kelly, Transsphenoidal surgery for Cushing’s disease: a review of success rates, remission predictors, management of failed surgery, and Nelson’s Syndrome. Neurosurg. Focus 23, E5 (2007)PubMedGoogle Scholar
  12. 12.
    J. Newell-Price, A.B. Grossman, Differential diagnosis of Cushing’s syndrome. Arq. Bras. Endocrinol. Metabol. 51, 1199–1206 (2007)PubMedGoogle Scholar
  13. 13.
    B.M. Biller, A.B. Grossman, P.M. Stewart et al., Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 93, 2454–2462 (2008)PubMedCentralPubMedGoogle Scholar
  14. 14.
    D.M. Prevedello, N. Pouratian, J. Sherman et al., Management of Cushing’s disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J. Neurosurg. 109, 751–759 (2008)PubMedGoogle Scholar
  15. 15.
    G. Arnaldi, M. Boscaro, New treatment guidelines on Cushing’s disease. F1000 Med. Rep. 1, 64 (2009)Google Scholar
  16. 16.
    L.S. Blevins Jr, N. Sanai, S. Kunwar et al., An approach to the management of patients with residual Cushing’s disease. J. Neurooncol. 94, 313–319 (2009)PubMedCentralPubMedGoogle Scholar
  17. 17.
    B.M. Biller, A. Colao, S. Petersenn et al., Prolactinomas, Cushing’s disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas. BMC Endocr. Disord. 10, 10 (2010)PubMedCentralPubMedGoogle Scholar
  18. 18.
    N. Sonino, F. Fallo, G.A. Fava, Psychosomatic aspects of Cushing’s syndrome. Rev. Endocr. Metab. Disord. 11, 95–104 (2010)PubMedGoogle Scholar
  19. 19.
    A. Rizk, J. Honegger, M. Milian et al., Treatment options in Cushing’s disease. Clin. Med. Insights. Oncol. 6, 75–84 (2012)PubMedCentralPubMedGoogle Scholar
  20. 20.
    F. Castinetti, M. Nagai, H. Dufour et al., Gamma knife radiosurgery is a successful adjunctive treatment in Cushing’s disease. Eur. J. Endocrinol. 156, 91–98 (2007)PubMedGoogle Scholar
  21. 21.
    J.K. Devin, G.S. Allen, A.J. Cmelak et al., The efficacy of linear accelerator radiosurgery in the management of patients with Cushing’s disease. Stereotact. Funct. Neurosurg. 82, 254–262 (2004)PubMedGoogle Scholar
  22. 22.
    M. Boschetti, M. De Lucchi, M. Giusti et al., Partial visual recovery from radiation-induced optic neuropathy after hyperbaric oxygen therapy in a patient with Cushing disease. Eur. J. Endocrinol. 154, 813–818 (2006)PubMedGoogle Scholar
  23. 23.
    C.N. Dang, P. Trainer, Pharmacological management of Cushing’s syndrome: an update. Arq. Bras. Endocrinol. Metabol. 51, 1339–1348 (2007)PubMedGoogle Scholar
  24. 24.
    A. Colao, S. Petersenn, J. Newell-Price et al., A 12-month phase 3 study of pasireotide in Cushing’s disease. N. Engl. J. Med. 366, 914–924 (2012)PubMedGoogle Scholar
  25. 25.
    J. Bertherat, W. Ludlam, R. Pivonello et al., Long-term use of pasireotide in Cushing’s disease: 24-month safety results from a randomized Phase III study. Endocr. Abstr. 27, P1405 (2012)Google Scholar
  26. 26.
    M. Yaneva, S. Vandeva, S. Zacharieva et al., Genetics of Cushing’s syndrome. Neuroendocrinology 92, 6–10 (2010)PubMedGoogle Scholar
  27. 27.
    Genetics Home Reference. http://ghr.nlm.nih.gov/ (2013). Accessed 5 July 2013
  28. 28.
    A. Lacroix, ACTH-independent macronodular adrenal hiperplasia. Best practice and research. Clin. Endocrinol. Metab. 23, 245–259 (2009)Google Scholar
  29. 29.
    S.M. Webb, X. Badia, M.J. Barahona et al., Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. Eur. J. Endocrinol. 158, 623–630 (2008)PubMedGoogle Scholar
  30. 30.
    A. Santos, E. Resmini, M.A. Martínez et al., Quality of life in patients with pituitary tumors. Curr. Opin. Endocrinol. Diabetes Obes. 16, 299–303 (2009)PubMedGoogle Scholar
  31. 31.
    A. Colao, A. Cozzolino, R. Pivonello, Quality of life in patients with Cushing’s disease: a modern approach. Clin. Endocrinol. 76, 776–777 (2012)Google Scholar
  32. 32.
    L.K. Nieman, B.M. Biller, J.W. Findling et al., The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008)PubMedCentralPubMedGoogle Scholar
  33. 33.
    L. Katznelson, J.S. Bogan, J.R. Trob et al., Biochemical assessment of Cushing’s disease in patients with corticotroph macroadenomas. J. Clin. Endocrinol. Metab. 83, 1619–1623 (1998)PubMedGoogle Scholar
  34. 34.
    R.C. Bakker, P.R. Gallas, J.A. Romijn et al., Cushing’s syndrome complicated by multiple opportunistic infections. J. Endocrinol. Invest. 21, 329–333 (1998)PubMedGoogle Scholar
  35. 35.
    A. Faggiano, R. Pivonello, D. Melis et al., Nephrolithiasis in Cushing’s disease: prevalence, etiopathogenesis, and modification after disease cure. J. Clin. Endocrinol. Metab. 88, 2076–2080 (2003)PubMedGoogle Scholar
  36. 36.
    L. Tauchmanovà, R. Pivonello, M.C. De Martino et al., Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism. Eur. J. Endocrinol. 157, 359–366 (2007)PubMedGoogle Scholar
  37. 37.
    S.G. Kosseifi, D.N. Nassour, M.A. Shaikh et al., Nodular pulmonary histoplasmosis in Cushing’s disease: a case report and literature review. Tenn. Med. 100, 44–46 (2007)PubMedGoogle Scholar
  38. 38.
    A.W. van der Eerden, M. den Heijer, W.J. Oyen et al., Cushing’s syndrome and bone mineral density: lowest Z scores in young patients. Neth. J. Med. 65, 137–141 (2007)PubMedGoogle Scholar
  39. 39.
    G. Kaltsas, P. Makras, Skeletal diseases in Cushing’s syndrome: osteoporosis versus arthropathy. Neuroendocrinology 92, 60–64 (2010)PubMedGoogle Scholar
  40. 40.
    R.A. Feelders, S.J. Pulgar, A. Kempel, A.M. Pereira, The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur. J. Endocrinol. 167, 311–2620 (2012)PubMedGoogle Scholar
  41. 41.
    M.D. Bronstein, L.R. Salgado, N.R. de Castro Musolino, Medical management of pituitary adenomas: the special case of management of the pregnant woman. Pituitary 5, 99–107 (2002)PubMedGoogle Scholar
  42. 42.
    L. Tauchmanovà, R. Rossi, B. Biondi et al., Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J. Clin. Endocrinol. Metab. 87, 4872–4878 (2002)PubMedGoogle Scholar
  43. 43.
    R. Pivonello, A. Faggiano, G. Lombardi et al., The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 34, 327–339 (2005)PubMedGoogle Scholar
  44. 44.
    M. De Leo, R. Pivonello, R.S. Auriemma et al., Cardiovascular disease in Cushing’s syndrome: heart versus vasculature. Neuroendocrinology 92, 50–54 (2010)PubMedGoogle Scholar
  45. 45.
    F. Fallo, G. Famoso, D. Capizzi et al., Coronary microvascular function in patients with Cushing’s syndrome. Endocrine 43, 206–213 (2013)PubMedGoogle Scholar
  46. 46.
    S. Savastano, R. Pivonello, A. Colao, Bariatric surgery for obesity and hidden Cushing syndrome. Surg. Obes. Relat. Dis. 5, 121–122 (2009)PubMedGoogle Scholar
  47. 47.
    P. Chanson, S. Salenave, Metabolic syndrome in Cushing’s syndrome. Neuroendocrinology 92, 96–101 (2010)PubMedGoogle Scholar
  48. 48.
    E.B. Geer, W. Shen, D. Gallagher et al., MRI assessment of lean and adipose tissue distribution in female patients with Cushing’s disease. Clin. Endocrinol. 73, 469–475 (2010)Google Scholar
  49. 49.
    O.M. Dekkers, E. Horváth-Puhó, J.O. Jørgensen et al., Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J. Clin. Endocrinol. Metab. 98, 2277–2284 (2013)PubMedGoogle Scholar
  50. 50.
    G. Arnaldi, A. Angeli, A.B. Atkinson et al., Diagnosis and complications of Cushing’s syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 88, 5593–5602 (2003)PubMedGoogle Scholar
  51. 51.
    D. Graversen, P. Vestergaard, K. Stochholm et al., Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur. J. Intern. Med. 23, 278–282 (2012)PubMedGoogle Scholar
  52. 52.
    R.N. Clayton, D. Raskauskiene, R.C. Reulen et al., Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J. Clin. Endocrinol. Metab. 96, 632–642 (2011)PubMedGoogle Scholar
  53. 53.
    O.M. Dekkers, N.R. Biermasz, A.M. Pereira et al., Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J. Clin. Endocrinol. Metab. 92, 976–981 (2007)PubMedGoogle Scholar
  54. 54.
    E. Valassi, I. Crespo, A. Santos, S.M. Webb, Clinical consequences of Cushing’s syndrome. Pituitary 15, 319–329 (2012)PubMedGoogle Scholar
  55. 55.
    R. Pivonello, M.C. De Martino, M. De Leo et al., Cushing’s syndrome: aftermath of the cure. Arq. Bras. Endocrinol. Metabol. 51, 1381–1391 (2007)PubMedGoogle Scholar
  56. 56.
    A. Faggiano, R. Pivonello, S. Spiezia et al., Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J. Clin. Endocrinol. Metab. 88, 2527–2533 (2003)PubMedGoogle Scholar
  57. 57.
    A. Colao, R. Pivonello, S. Spiezia et al., Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J. Clin. Endocrinol. Metab. 84, 2664–2672 (1999)PubMedGoogle Scholar
  58. 58.
    C. Di Somma, R. Pivonello, S. Loche et al., Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing’s disease: a prospective study. Clin Endocrinol (Oxf). 58, 302–308 (2003)PubMedGoogle Scholar
  59. 59.
    A. Faggiano, R. Pivonello, M. Filippella et al., Spine abnormalities and damage in patients cured from Cushing’s disease. Pituitary 4, 153–161 (2001)PubMedGoogle Scholar
  60. 60.
    O. Ragnarsson, G. Johannsson, Management of endocrine disease: Cushing’s syndrome: a structured short- and long-term management plan for patients in remission. Eur. J. Endocrinol. 169, R139–R152 (2013)PubMedGoogle Scholar
  61. 61.
    C. Garcia, B.M. Biller, A. Klibanski, The role of the clinical laboratory in the diagnosis of Cushing syndrome. Am. J. Clin. Pathol. 120, S38–S45 (2003)PubMedGoogle Scholar
  62. 62.
    J. Newell-Price, P. Trainer, M. Besser et al., The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr. Rev. 19, 647–672 (1998)PubMedGoogle Scholar
  63. 63.
    L.F. Chan, H.L. Storr, A.B. Grossman et al., Pediatric Cushing’s syndrome: clinical features, diagnosis, and treatment. Arq. Bras. Endocrinol. Metabol. 51, 1261–1271 (2007)PubMedGoogle Scholar
  64. 64.
    F. Lumachi, P. Marchesi, D. Miotto et al., CT and MR imaging of the adrenal glands in cortisol-secreting tumors. Anticancer Res. 31, 2923–2926 (2011)PubMedGoogle Scholar
  65. 65.
    D.C. Aron, Cushing’s syndrome: why is diagnosis so difficult? Rev. Endocr. Metab. Disord. 11, 105–116 (2010)PubMedGoogle Scholar
  66. 66.
    S. Hasinski, Assessment of adrenal glucocorticoid function. Which tests are appropriate for screening? Postgrad. Med. 104(61–64), 69–72 (1998)Google Scholar
  67. 67.
    D. Vassiliadi, S. Tsagarakis, Unusual causes of Cushing’s syndrome. Arq. Bras. Endocrinol. Metabol. 51, 1245–1252 (2007)PubMedGoogle Scholar
  68. 68.
    T.B. Carroll, J.W. Findling, Cushing’s syndrome of nonpituitary causes. Curr. Opin. Endocrinol. Diabetes Obes. 16, 308–315 (2009)PubMedGoogle Scholar
  69. 69.
    M.M. Foisy, E.M. Yakiwchuk, I. Chiu et al., Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med. 9, 389–396 (2008)PubMedGoogle Scholar
  70. 70.
    J. Lo, S.K. Grinspoon, Adrenal function in HIV infection. Curr. Opin. Endocrinol. Diabetes Obes. 17, 205–209 (2010)PubMedGoogle Scholar
  71. 71.
    C. Bernecker, T.B. West, G. Mansmann et al., Hypercortisolism caused by ritonavir associated inhibition of CYP 3A4 under inhalative glucocorticoid therapy. 2 case reports and a review of the literature. Exp. Clin. Endocrinol. Diabetes 120, 125–127 (2012)PubMedGoogle Scholar
  72. 72.
    C. Levin, H.I. Maibach, Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. Am. J. Clin. Dermatol. 3, 141–147 (2002)PubMedGoogle Scholar
  73. 73.
    B. Coureau, J.F. Bussières, S. Tremblay, Cushing’s syndrome induced by misuse of moderate- to high-potency topical corticosteroids. Ann. Pharmacother. 42, 1903–1907 (2008)PubMedGoogle Scholar
  74. 74.
    T. Tempark, V. Phatarakijnirund, S. Chatproedprai et al., Exogenous Cushing’s syndrome due to topical corticosteroid application: case report and review literature. Endocrine 38, 328–334 (2010)PubMedGoogle Scholar
  75. 75.
    E. Castela, E. Archier, S. Devaux et al., Topical corticosteroids in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy. J. Eur. Acad. Dermatol. Venereol. 26, 47–51 (2012)PubMedGoogle Scholar
  76. 76.
    L. Vilar, Mda C. Freitas, M. Faria et al., Pitfalls in the diagnosis of Cushing’s syndrome. Arq. Bras. Endocrinol. Metabol. 51, 1207–1216 (2007) Google Scholar
  77. 77.
    F. Pecori Giraldi, Recent challenges in the diagnosis of Cushing’s syndrome. Horm. Res. 71, 123–127 (2009)Google Scholar
  78. 78.
    D.G. Morris, A.B. Grossman, Dynamic tests in the diagnosis and differential diagnosis of Cushing’s syndrome. J. Endocrinol. Invest. 26, 64–73 (2003)PubMedGoogle Scholar
  79. 79.
    M.B. Elamin, M.H. Murad, R. Mullan et al., Accuracy of diagnostic tests for Cushing’s syndrome: a systematic review and metaanalyses. J. Clin. Endocrinol. Metab. 93, 1553–1562 (2008)PubMedGoogle Scholar
  80. 80.
    H. Raff, Update on late-night salivary cortisol for the diagnosis of Cushing’s syndrome: methodological considerations. Endocrine. Epub ahead of print (2013)Google Scholar
  81. 81.
    A. Viardot, P. Huber, J.J. Puder et al., Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test. J. Clin. Endocrinol. Metab. 90, 5730–5736 (2005)PubMedGoogle Scholar
  82. 82.
    S.A. Doi, J. Clark, A.W. Russell, Concordance of the late night salivary cortisol in patients with Cushing’s syndrome and elevated urine-free cortisol. Endocrine 43, 327–333 (2013)PubMedGoogle Scholar
  83. 83.
    C.A. Carrasco, M. García, M. Goycoolea et al., Reproducibility and performance of one or two samples of salivary cortisol in the diagnosis of Cushing’s syndrome using an automated immunoassay system. Endocrine 41, 487–493 (2012)PubMedGoogle Scholar
  84. 84.
    T. Psaras, M. Milian, V. Hattermann et al., Demographic factors and the presence of comorbidities do not promote early detection of Cushing’s disease and acromegaly. Exp. Clin. Endocrinol. Diabetes 119, 21–25 (2011)PubMedGoogle Scholar
  85. 85.
    A. Meyer, M. Behrend, Cushing’s syndrome: adrenalectomy and long-term results. Dig. Surg. 21, 363–370 (2004)PubMedGoogle Scholar
  86. 86.
    L. Manenschijn, J.W. Koper, E.L. van den Akker et al., A novel tool in the diagnosis and follow-up of (cyclic) Cushing’s syndrome: measurement of long-term cortisol in scalp hair. J. Clin. Endocrinol. Metab. 97, E1836–E1843 (2012)PubMedGoogle Scholar
  87. 87.
    P. Leach, A.H. Abou-Zeid, T. Kearney et al., Endoscopic transsphenoidal pituitary surgery: evidence of an operative learning curve. Neurosurgery. 67, 1205–1212 (2010)PubMedGoogle Scholar
  88. 88.
    X. Bertagna, L. Guignat, Approach to the Cushing’s disease patient with persistent/recurrent hypercortisolism after pituitary surgery. J. Clin. Endocrinol. Metab. 98, 1307–1318 (2013)PubMedGoogle Scholar
  89. 89.
    D.A. Rees, F.W. Hanna, J.S. Davies 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)Google Scholar
  90. 90.
    I. Shimon, Z. Ram, Z.R. Cohen et al., Transsphenoidal surgery for Cushing’s disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery. 51, 57–61 (2002)PubMedGoogle Scholar
  91. 91.
    G.D. Hammer, J.B. Tyrrell, K.R. Lamborn et al., Transsphenoidal microsurgery for Cushing’s disease: initial outcome and long-term results. J. Clin. Endocrinol. Metab. 89, 6348–6357 (2004)PubMedGoogle Scholar
  92. 92.
    A.B. Atkinson, A. Kennedy, M.I. Wiggam et al., 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
  93. 93.
    G. Rollin, N.P. Ferreira, M.A. Czepielewski, Prospective evaluation of transsphenoidal pituitary surgery in 108 patients with Cushing’s disease. Arq. Bras. Endocrinol. Metabol. 51, 1355–1361 (2007)PubMedGoogle Scholar
  94. 94.
    B.M. Hofmann, M. Hlavac, R. Martinez et al., Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J. Neurosurg. 108, 9–18 (2008)PubMedGoogle Scholar
  95. 95.
    A.S. Mahmoud-Ahmed, J.H. Suh, Radiation therapy for Cushing’s disease: a review. Pituitary. 5, 175–180 (2002)PubMedGoogle Scholar
  96. 96.
    R.B. Friedman, E.H. Oldfield, L.K. Nieman et al., Repeat transsphenoidal surgery for Cushing’s disease. J. Neurosurg. 71, 520–527 (1989)PubMedGoogle Scholar
  97. 97.
    R.J. Benveniste, W.A. King, J. Walsh et al., Repeated transsphenoidal surgery to treat recurrent or residual pituitary adenoma. J. Neurosurg. 102, 1004–1012 (2005)PubMedGoogle Scholar
  98. 98.
    L.S. Blevins Jr, J.H. Christy, M. Khajavi et al., Outcomes of therapy for Cushing’s disease due to adrenocorticotropin-secreting pituitary macroadenomas. J. Clin. Endocrinol. Metab. 83, 63–67 (1998)PubMedGoogle Scholar
  99. 99.
    N. Sonino, M. Zielezny, G.A. Fava et al., Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J. Clin. Endocrinol. Metab. 81, 2647–2652 (1996)PubMedGoogle Scholar
  100. 100.
    G. Assié, H. Bahurel, J. Coste 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)PubMedGoogle Scholar
  101. 101.
    M. Boscaro, L. Barzon, F. Fallo et al., Cushing’s syndrome. Lancet 357, 783–791 (2001)PubMedGoogle Scholar
  102. 102.
    R.A. Feelders, L.J. Hofland, Medical treatment of Cushing’s disease. J. Clin. Endocrinol. Metab. 98, 425–438 (2013)PubMedGoogle Scholar
  103. 103.
    Pasireotide Summary of Product Characteristics: http://www.medicines.org.uk/emc/medicine/26746/SPC#INDICATIONS (2013). Accessed in 5 July 2013
  104. 104.
    H.A. Schmid, Pasireotide (SOM230): development, mechanism of action and potential applications. Mol. Cell. Endocrinol. 286, 69–74 (2008)PubMedGoogle Scholar
  105. 105.
    N.K. Djedovic, S.J. Rainbow, Detection of synthetic glucocorticoids by liquid chromatography–tandem mass spectrometry in patients being investigated for Cushing’s syndrome. Ann. Clin. Biochem. 48, 542–549 (2011)PubMedGoogle Scholar
  106. 106.
    A.E. Kulle, M. Welzel, P.M. Holterhus, F.G. Riepe, Principles and clinical applications of liquid chromatography–tandem mass spectrometry for the determination of adrenal and gonadal steroid hormones. J. Endocrinol. Invest. 34, 702–708 (2011)PubMedGoogle Scholar
  107. 107.
    B.M. Fong, S. Tam, K.S. Leung, Improved liquid chromatography-tandem mass spectrometry method in clinical utility for the diagnosis of Cushing’s syndrome. Anal. Bioanal. Chem. 396, 783–790 (2010)PubMedGoogle Scholar
  108. 108.
    T. Deutschbein, M. Broecker-Preuss, J. Flitsch et al., Salivary cortisol as a diagnostic tool for Cushing’s syndrome and adrenal insufficiency: improved screening by an automatic immunoassay. Eur. J. Endocrinol. 166, 613–618 (2012)PubMedGoogle Scholar
  109. 109.
    H. Raff, Cushing’s syndrome: diagnosis and surveillance using salivary cortisol. Pituitary. 15, 64–70 (2012)PubMedGoogle Scholar
  110. 110.
    R. Pivonello, D. Ferone, W.W. de Herder et al., Dopamine receptor expression and function in corticotroph pituitary tumors. J. Clin. Endocrinol. Metab. 89, 2452–2462 (2004)PubMedGoogle Scholar
  111. 111.
    C. de Bruin, R.A. Feelders, A.M. Waaijers et al., Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro. J. Mol. Endocrinol. 42, 47–56 (2009)PubMedGoogle Scholar
  112. 112.
    R. Pivonello, M.C. De Martino, P. Cappabianca 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)PubMedGoogle Scholar
  113. 113.
    E.F. Adams, M.J. Ashby, S.M. Brown et al., Bromocriptine suppresses ACTH secretion from human pituitary tumour cells in culture by a dopaminergic mechanism. Clin. Endocrinol. (Oxf) 15, 479–484 (1981)Google Scholar
  114. 114.
    C. Invitti, M. De Martin, L. Danesi et al., Effect of injectable bromocriptine in patients with Cushing’s disease. Exp. Clin. Endocrinol. Diabetes 103, 266–271 (1995)PubMedGoogle Scholar
  115. 115.
    C. de Bruin, R.A. Feelders, S.W. Lamberts et al., Somatostatin and dopamine receptors as targets for medical treatment of Cushing’s Syndrome. Rev. Endocr. Metab. Disord. 10, 91–102 (2009)PubMedGoogle Scholar
  116. 116.
    M. Rocheville, D.C. Lange, U. Kumar et al., Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288, 154–157 (2000)PubMedGoogle Scholar
  117. 117.
    A.P. Heaney, M. Fernando, W.H. Yong et al., Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat. Med. 8, 1281–1287 (2002)PubMedGoogle Scholar
  118. 118.
    X. Bertagna, R. Pivonello, M. Fleseriu, et al., Normal urinary cortisol with LCI699 in patients with Cushing’s disease: preliminary results from a proof-of-concept study. 15th Congress of the European NeuroEndocrine Association (ENEA 2012), Vienna, Austria; Klinische Endokrinologie und Stoffwechsel, 5, 22: abstract OC04 (2012)Google Scholar
  119. 119.
    A. Godbout, M. Manavela, K. Danilowicz et al., Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur. J. Endocrinol. 163, 709–716 (2010)PubMedGoogle Scholar
  120. 120.
    M. Boschetti, F. Gatto, M. Arvigo et al., Role of dopamine receptors in normal and tumoral pituitary corticotropic cells and adrenal cells. Neuroendocrinology 92, 17–22 (2010)PubMedGoogle Scholar
  121. 121.
    M.D. Culler, Somatostatin-dopamine chimeras: a novel approach to treatment of neuroendocrine tumors. Horm. Metab. Res. 43, 854–857 (2011)PubMedGoogle Scholar
  122. 122.
    F. Pecori Giraldi, A.G. Ambrogio, M. Andrioli et al., Potential role for retinoic acid in patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 97, 3577–3583 (2012)PubMedGoogle Scholar
  123. 123.
    M. Fleseriu, B.M. Biller, J.W. Findling et al., Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J. Clin. Endocrinol. Metab. 97, 2039–2049 (2012)PubMedGoogle Scholar
  124. 124.
    F. Castinetti, B. Conte-Devolx, T. Brue, Medical treatment of Cushing’s syndrome: glucocorticoid receptor antagonists and mifepristone. Neuroendocrinology 92, 125–130 (2010)PubMedGoogle Scholar
  125. 125.
    F. Castinetti, T. Brue, B. Conte-Devolx, The use of the glucocorticoid receptor antagonist mifepristone in Cushing’s syndrome. Curr. Opin. Endocrinol. Diabetes. Obesity. 19, 295–299 (2012)Google Scholar
  126. 126.
    J.D. Carmichael, M. Fleseriu, Mifepristone: is there a place in the treatment of Cushing’s disease? Endocrine 44, 20–32 (2013)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Annamaria Colao
    • 1
  • Marco Boscaro
    • 2
  • Diego Ferone
    • 3
  • Felipe F. Casanueva
    • 4
    • 5
  1. 1.Dipartimento di Medicina Clinica e ChirurgiaUniversità Federico II di NapoliNaplesItaly
  2. 2.Division of Endocrinology and MetabolismUniversity Politecnica delle MarcheAnconaItaly
  3. 3.Endocrinology, Department of Internal Medicine and Medical Specialties and Center of Excellence for Biomedical Research, IRCCS-AOU San Martino-ISTUniversity of GenoaGenoaItaly
  4. 4.Department of MedicineSantiago de Compostela UniversitySantiago de CompostelaSpain
  5. 5.CIBER Obesity and NutritionInstitute of Health Carlos IIIMadridSpain

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