, Volume 18, Issue 2, pp 253–262 | Cite as

Medical combination therapies in Cushing’s disease

  • Lucio VilarEmail author
  • Luciana A. Naves
  • Márcio C. Machado
  • Marcello D. Bronstein



There has been growing interest on medical therapy for the management of Cushing’s disease (CD), particularly in cases of persistent or recurrent hypercortisolism. Ketoconazole, an inhibitor of adrenal steroidogenesis, is the most widely used drug, whereas cabergoline and pasireotide are the most promising centrally acting agents. The main purpose of this review article is to highlight the options of medical treatment for CD, with a special emphasis on combination therapies, a topic that has only been addressed by a limited number of studies.


According to the results of these studies, combination therapies involving medications with additive or synergistic effects on ACTH and cortisol secretion seem quite attractive as they yield higher probability of longterm control of the hypercortisolism at lower doses, a lower incidence of side-effects, and possibly a lower rate of treatment escapes. Currently, ketoconazole, cabergoline, and pasireotide are the best drugs to be prescribed in combination.


Cushing’s disease Medical combination therapies 


Conflict of interest

Marcello Bronstein is a principal investigator of the clinical trial CSOM230G2304 (Pasireotide LAR for Cushing´s disease). The other authors have no conflicts of interest to disclose.


  1. 1.
    Colao A, Boscaro M, Ferone D, Casanueva FF (2014) Managing Cushing’s disease: the state of the art. Endocrine 47(1):9–20CrossRefPubMedGoogle Scholar
  2. 2.
    Tritos NA, Biller BM (2014) Cushing’s disease. Handb Clin Neurol 124:221–234CrossRefPubMedGoogle Scholar
  3. 3.
    Biller BM, Grossman AB, Stewart PM et al (2008) Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 93(7):2454–2462CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Sheth SA, Bourne SK, Tritos NA, Swearingen B (2012) Neurosurgical treatment of Cushing disease. Neurosurg Clin N Am 23(4):639–651CrossRefPubMedGoogle Scholar
  5. 5.
    Atkinson AB, Kennedy A, Wiggam MI, McCance DR, Sheridan B (2005) Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance. Clin Endocrinol (Oxf) 63(5):549–559CrossRefGoogle Scholar
  6. 6.
    Patil CG, Prevedello DM, Lad SP et al (2008) Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab 93(2):358–362CrossRefPubMedGoogle Scholar
  7. 7.
    Fleseriu M (2012) Medical management of persistent and recurrent Cushing’s disease. Neurosurg Clin N Am 23(4):653–668CrossRefPubMedGoogle Scholar
  8. 8.
    Pashtan I, Oh KS, Loeffler JS (2014) Radiation therapy in the management of pituitary adenomas. Handb Clin Neurol 124:317–324CrossRefPubMedGoogle Scholar
  9. 9.
    Oßwald A, Plomer E, Dimopoulou C et al (2014) Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. Eur J Endocrinol 171(2):209–215CrossRefPubMedGoogle Scholar
  10. 10.
    Vilar L, Naves LA, Azevedo MF et al (2010) Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary 13(2):123–129CrossRefPubMedGoogle Scholar
  11. 11.
    Feelders RA, Hofland LJ (2013) Medical treatment of Cushing’s disease. J Clin Endocrinol Metab 98(2):425–438CrossRefPubMedGoogle Scholar
  12. 12.
    Feelders RA, de Bruin C, Pereira AM et al (2010) Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med 362(2):1846–1848CrossRefPubMedGoogle Scholar
  13. 13.
    Fleseriu M, Petersenn S (2013) New avenues in the medical treatment of Cushing’s disease: corticotroph tumor targeted therapy. J Neurooncol 114(1):1–11CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Fleseriu M (2014) Recent advances in the medical treatment of Cushing’s disease. F1000prime Rep 6:18CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Tritos NA, Biller BM (2012) Advances in medical therapies for Cushing’s syndrome. Discov Med 13(69):171–179PubMedGoogle Scholar
  16. 16.
    Tritos NA, Biller BM (2014) Medical management of Cushing’s disease. J Neurooncol 117(3):407–414CrossRefPubMedGoogle Scholar
  17. 17.
    Trainer PJ (2013) New options for the medical treatment of Cushing’s syndrome. Indian J Endocrinol Metab 17(2):245–248CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Cuevas-Ramos D, Fleseriu M (2014) Treatment of Cushing’s disease: a mechanistic update. J Endocrinol 223(2):R19–R39CrossRefPubMedGoogle Scholar
  19. 19.
    Castinetti F, Laurence G, Pauline G et al (2014) Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 99(5):1623–1630CrossRefPubMedGoogle Scholar
  20. 20.
    Juszczak A, Ertorer ME, Grossman A (2013) The therapy of Cushing’s disease in adults and children: an update. Horm Metab Res 45(2):109–117PubMedGoogle Scholar
  21. 21.
    Lewis JH, Zimmerman HJ, Benson GD, Ishak KG (1984) Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology 86(3):503–513PubMedGoogle Scholar
  22. 22.
    Verhelst JA, Trainer PJ, Howlett TA et al (1991) Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 35(2):169–178CrossRefGoogle Scholar
  23. 23.
    Baudry C, Coste J, Bou Khalil R et al (2012) Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol 167(4):473–481CrossRefPubMedGoogle Scholar
  24. 24.
    Preda VA, Sen J, Karavitaki N, Grossman AB (2012) Etomidate in the management of hypercortisolaemia in Cushing’s syndrome: a review. Eur J Endocrinol 167(4):137–143PubMedGoogle Scholar
  25. 25.
    Fleseriu M, Petersenn S (2012) Medical management of Cushing’s disease: what is the future? Pituitary 15(3):330–341CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Bertagna X, Pivonello R, Fleseriu M et al (2014) LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab 99(4):1375–1383CrossRefPubMedGoogle Scholar
  27. 27.
    Fleseriu M, Biller BM, Findling JW, SEISMIC Study Investigators et al (2012) Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 97(6):2039–2049CrossRefPubMedGoogle Scholar
  28. 28.
    Carmichael JD, Fleseriu M (2013) Mifepristone: is there a place in the treatment of Cushing’s disease? Endocrine 44(1):20–32CrossRefPubMedGoogle Scholar
  29. 29.
    Fleseriu M, Findling JW, Koch CA et al (2014) Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing’s disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J Clin Endocrinol Metab 99(10):3718–3727CrossRefPubMedGoogle Scholar
  30. 30.
    Gadelha MR, Vieira Neto L (2014) Efficacy of medical treatment in Cushing’s disease: a systematic review. Clin Endocrinol (Oxf) 80(1):1–12CrossRefGoogle Scholar
  31. 31.
    Pecori Giraldi F, Ambrogio AG, Andrioli M et al (2012) Potential role for retinoic acid in patients with Cushing’s disease. J Clin Endocrinol Metab 97(10):3577–3583CrossRefPubMedGoogle Scholar
  32. 32.
    Vilar L, Freitas MC, Naves LA et al (2008) Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1,234 patients. J Endocrinol Investig 31(5):436–444CrossRefGoogle Scholar
  33. 33.
    Vilar L, Azevedo MF, Naves LA et al (2011) Role of the addition of cabergoline to the management of acromegalic patients resistant to longterm treatment with octreotide LAR. Pituitary 14(2):148–156CrossRefPubMedGoogle Scholar
  34. 34.
    Vilar L, Czepielewski MA, Naves LA, Rollin GA, Casulari LA, Coelho CE (2007) Substantial shrinkage of adenomas cosecreting growth hormone and prolactin with use of cabergoline therapy. Endocr Pract 13(4):396–402CrossRefPubMedGoogle Scholar
  35. 35.
    Chanson P, Salenave S, Kamenicky P (2014) Acromegaly. Handb Clin Neurol 124:197–219CrossRefPubMedGoogle Scholar
  36. 36.
    Pivonello R, De Martino MC, Cappabianca P et al (2009) 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(1):223–230CrossRefPubMedGoogle Scholar
  37. 37.
    Godbout A, Manavela MP, Danilowicz K et al (2010) Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol 163(5):709–716CrossRefPubMedGoogle Scholar
  38. 38.
    Lila AR, Gopal RA, Acharya SV et al (2010) Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy. Endocr Pract 16(6):968–976CrossRefPubMedGoogle Scholar
  39. 39.
    Güven A, Baltacıoğlu F, Dursun F, Cebeci AN, Kırmızıbekmez H (2013) Remission with cabergoline in adolescent boys with Cushing’s disease. J Clin Res Pediatr Endocrinol 5(3):194–198CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Manavela MP, Danilowicz K, Bruno OD (2012) Macrocorticotropinoma shrinkage and control of hypercortisolism under long-term cabergoline therapy: case report. Pituitary 15(Suppl 1):33–36CrossRefPubMedGoogle Scholar
  41. 41.
    Casulari LA, Naves LA, Mello PA, Pereira Neto A, Papadia C (2004) Nelson’s syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res 62(6):300–305CrossRefPubMedGoogle Scholar
  42. 42.
    Barber TM, Adams E, Wass JA (2014) Nelson syndrome: definition and management. Handb Clin Neurol 124:327–337CrossRefPubMedGoogle Scholar
  43. 43.
    Cuevas-Ramos D, Fleseriu M (2014) Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 52(3):R223–R240CrossRefPubMedGoogle Scholar
  44. 44.
    Ben-Shlomo A, Schimd H, Wawrowsky K (2010) Differential ligand mediated pituitary somatostatin receptor subtype signaling: implications for corticotroph tumor therapy. J Clin Endocrinol Metab 94(11):4342–4350CrossRefGoogle Scholar
  45. 45.
    Neggers SJ, van der Lely AJ (2014) Medical approach to pituitary tumors. Handb Clin Neurol 124:303–316CrossRefPubMedGoogle Scholar
  46. 46.
    Murray RD, Kim K, Ren SG et al (2004) The novel somatostatin ligand (SOM230) regulates human and rat anterior pituitary hormone secretion. J Clin Endocrinol Metab 89(6):3027–3032CrossRefPubMedGoogle Scholar
  47. 47.
    Colao A, Petersenn S, Newell-Price J, Pasireotide B2305 Study Group et al (2012) A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 366(10):914–924CrossRefPubMedGoogle Scholar
  48. 48.
    Boscaro M, Bertherat J, Findling J et al (2014) Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, phase II study. Pituitary 17(4):320–326CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Colao A, De Block C, Gaztambide MS et al (2014) Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary 17(2):180–186CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Kamenicky P, Droumaguet C, Salenave S et al (2011) Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab 96(9):2796–2804CrossRefPubMedGoogle Scholar
  51. 51.
    Child DF, Burke CW, Burley DM, Rees LH, Fraser TR (1976) Drug controlled of Cushing’s syndrome. Combined aminoglutethimide and metyrapone therapy. Acta Endocrinol (Cph) 82(2):330–341Google Scholar
  52. 52.
    Trainer PJ, Besser M (1994) Cushing’s syndrome. Therapy directed at the adrenal glands. Endocrinol Metab Clin N Am 23(3):571–584Google Scholar
  53. 53.
    Pivonello R, De Leo M, De Martino MC et al (2009) Effectiveness and safety of combined therapy with low dose ketoconazole and cabergoline in patients with Cushing’s disease partially responsive to monotherapy with cabergoline. In: Program of the 11th international pituitary congress, Washington, pp 36–40Google Scholar
  54. 54.
    Barbot M, Albiger N, Ceccato F et al (2014) Combination therapy for Cushing’s disease: effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole? Pituitary 17(2):109–117CrossRefPubMedGoogle Scholar
  55. 55.
    Vignati F, Loli P (1996) Additive effect of ketoconazole and octreotide in the treatment of severe adrenocorticotropin dependent hypercortisolism. J Clin Endocrinol Metab 81(8):2885–2890PubMedGoogle Scholar
  56. 56.
    Van Schaeybroeck S, Van Imschoot S, Cochez P (2002) Ectopic ACTH-syndrome due to a thymic carcinoid tumor. Acta Clin Belg 57(1):23–25CrossRefPubMedGoogle Scholar
  57. 57.
    European Medicines Agency (EMA) (2012) European public assessment report. verified 10/10/2014
  58. 58.
    Nieman LK (2013) Update in the medical therapy of Cushing’s disease. Curr Opin Endocrinol Diabetes Obes 20(4):330–334PubMedCentralPubMedGoogle Scholar
  59. 59.
    Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC (2000) Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288(5463):154–157CrossRefPubMedGoogle Scholar
  60. 60.
    Di Ieva A, Rotondo F, Syro LV, Cusimano MD, Kovacs K (2014) Aggressive pituitary adenomas–diagnosis and emerging treatments. Nat Rev Endocrinol 10(7):423–435CrossRefPubMedGoogle Scholar
  61. 61.
    Dillard TH, Gultekin SH, Delashaw JB et al (2011) Temozolomide for corticotroph pituitary adenomas refractory to standard therapy. Pituitary 14(1):80–91CrossRefPubMedGoogle Scholar
  62. 62.
    Bode H, Seiz M, Lammert A et al (2010) SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp Clin Endocrinol Diabetes 118(10):760–763CrossRefPubMedGoogle Scholar
  63. 63.
    Zacharia BE, Gulati AP, Bruce JN et al (2014) High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM): a case series. Neurosurgery 74(4):E447–E455CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lucio Vilar
    • 1
    Email author
  • Luciana A. Naves
    • 2
  • Márcio C. Machado
    • 3
  • Marcello D. Bronstein
    • 3
  1. 1.Division of Endocrinology, Hospital das ClínicasFederal University of PernambucoRecifeBrazil
  2. 2.Division of EndocrinologyBrasilia University HospitalBrasíliaBrazil
  3. 3.Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das ClinicasUniversity of São PauloSão PauloBrazil

Personalised recommendations