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Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease

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Abstract

The expression of dopamine receptor subtypes has been reported in corticotroph adenomas, and this finding support the possibility for medical treatment of Cushing’s disease (CD) with dopamine agonists when conventional treatment has failed. The aim of this study was to evaluate the effectiveness of cabergoline (at doses of up 3 mg/week), alone or combined with relatively low doses of ketoconazole (up to 400 mg/day), in 12 patients with CD unsuccessfully treated by transsphenoidal surgery. After 6 months of cabergoline therapy, normalization of 24 h urinary free cortisol (UFC) levels occurred in three patients (25%) at doses ranging from 2–3 mg/week, whereas reductions ranging from 15.0 to 48.4% were found in the remaining. The addition of ketonocazole to the nine patients without an adequate response to cabergoline was able to normalize UFC excretion in six patients (66.7%) at doses of 200 mg/day (three patients), 300 mg/day (two patients) and 400 mg/day (one patient). In the remaining patients UFC levels did not normalize but a significant reduction ranging from to 44.4 to 51.7% was achieved. In two of the six responsive patients to combination therapy, the weekly dose of cabergoline could be later reduced from 3 to 2 mg. Our findings demonstrated that cabergoline monotherapy was able to reverse hypercortisolism in 25% of patients with CD unsuccessfully treated by surgery. Moreover, the addition of relatively low doses of ketoconazole led to normalization of UFC in about two-thirds of patients not achieving a full response to cabergoline.

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References

  1. Pivonello R, De Martino MC, De Leo M et al (2008) Cushing’s syndrome. Endocrinol Metab Clin North Am 37:135–149

    Article  CAS  PubMed  Google Scholar 

  2. Nieman LK, Biller BM, Findling JW et al (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540

    Article  CAS  PubMed  Google Scholar 

  3. Vilar L, Freitas MC, Faria M et al (2007) Pitfalls in the diagnosis of Cushing’s syndrome. Arq Brasil Endocrinol Metab 51:1207–1216

    Google Scholar 

  4. Biller BM, Grossman AB, Stewart PM et al (2008) Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 93:2454–2462

    Article  CAS  PubMed  Google Scholar 

  5. Newell-Price J, Bertagna X, Grossman AB et al (2006) Cushing’s syndrome. Lancet 367:1605–1617

    Article  CAS  PubMed  Google Scholar 

  6. Vance ML (2009) Cushing’s disease: radiation therapy. Pituitary 12:11–14

    Article  PubMed  Google Scholar 

  7. Smith PW, Turza KC, Carter CO et al (2009) Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J Am Coll Surg 208:1059–1064

    Article  PubMed  Google Scholar 

  8. Dang CN, Trainer P (2007) Pharmacological management of Cushing’s syndrome: an update. Arq Bras Endocrinol Metabol 51:1339–1348

    PubMed  Google Scholar 

  9. Moncet D, Morando DJ, Pitoia F et al (2007) Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushing’s syndrome. Medicina (B Aires) 67:26–31

    CAS  Google Scholar 

  10. Sonino N, Boscaro M (1999) Medical therapy for Cushing’s disease. Endocrinol Metab Clin North Am 28:211–222

    Article  CAS  PubMed  Google Scholar 

  11. Lamberts SW, Klijn JG, De Quijada M et al (1980) The mechanism of the suppressive action of bromocriptine on adrenocorticotropin secretion in patients with Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 51:307–311

    Article  CAS  PubMed  Google Scholar 

  12. Krieger DT, Amorosa L, Linick F (1975) Cyproheptadine-induced remission of Cushing’s disease. N Engl J Med 293:893–896

    Article  CAS  PubMed  Google Scholar 

  13. Colao A, Pivonello R, Tripodi FS et al (1997) Failure of long-term therapy with sodium valproate in Cushing’s disease. J Endocrinol Invest 20:387–392

    CAS  PubMed  Google Scholar 

  14. 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 94:223–230

    Article  CAS  PubMed  Google Scholar 

  15. Pivonello R, Faggiano A, Di Salle F et al (1999) Complete remission of Nelson’s syndrome after 1-year treatment with cabergoline. J Endocrinol Invest 22:860–886

    CAS  PubMed  Google Scholar 

  16. Casulari LA, Naves LA, Mello PA et al (2004) Nelson’s syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res 62:300–305

    Article  CAS  PubMed  Google Scholar 

  17. Boscaro M, Ludlam WH, Atkinson B et al (2009) 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

    Article  CAS  PubMed  Google Scholar 

  18. Vilar L, Freitas MC, Naves LA et al (2008) The role of non-invasive dynamic tests in the diagnosis of Cushing’s syndrome. J Endocrinol Invest 31:1008–1013

    CAS  PubMed  Google Scholar 

  19. Miller JW, Crapo L (1993) The medical treatment of Cushing’s syndrome. Endocr Rev 14:443–458

    CAS  PubMed  Google Scholar 

  20. Lamberts SW, Birkenhager JC (1976) Bromocriptine in Nelson’s syndrome and Cushing’s disease. Lancet 2:811

    Article  CAS  PubMed  Google Scholar 

  21. Lamberts SW, Timmermans HA, De Jong FH, Birkenhager JC (1977) The role of dopaminergic depletion in the pathogenesis of Cushing’s disease and the possible consequences for medical therapy. Clin Endocrinol (Oxf) 7:185–193

    Article  CAS  Google Scholar 

  22. Mercado-Asis LB, Yasuda K, Murayama M et al (1992) Beneficial effects of high daily dose bromocriptine treatment in Cushing’s disease. Endocrinol Jpn 39:385–395

    CAS  PubMed  Google Scholar 

  23. Bevan JS, Webster J, Burke CW, Scanlon MF (1992) Dopamine agonists and pituitary tumor shrinkage. Endocr Rev 13:220–240

    CAS  PubMed  Google Scholar 

  24. Petrossians P, Ronci N, Valdes-Socin H et al (2001) ACTH silent adenoma shrinking under cabergoline. Eur J Endocrinol 144:51–57

    Article  CAS  PubMed  Google Scholar 

  25. Miyoshi T, Otsuka F, Takeda M et al (2004) Effect of cabergoline treatment on Cushing’s disease caused by aberrant adrenocorticotropin-secreting macroadenoma. J Endocrinol Invest 27:1055–1059

    CAS  PubMed  Google Scholar 

  26. Tsjoen G, Defeyter I, Van De Saffele J, Rubens R, Vandeweghe M (2002) Macroprolactinoma associated with Cushing’s disease, successfully treated with cabergoline. J Endocrinol Invest 25:172–175

    CAS  Google Scholar 

  27. Pivonello R, Ferone D, de Herder WW et al (2004) Dopamine receptor expression and function in corticotroph pituitary tumors. J Clin Endocrinol Metab 89:2452–2462

    Article  CAS  PubMed  Google Scholar 

  28. de Bruin C, Pereira AM, Feelders RA et al (2009) Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J Clin Endocrinol Metab 94:1118–1124

    Article  PubMed  CAS  Google Scholar 

  29. Godbout A, Manavela M, Danilowicz K et al. (2008) Long-term therapy with cabergoline in Cushing’s disease. Program of the 90th annual meeting of the endocrine society, San Francisco, CA, 2008 (p 2–130)

  30. Colao A, Lombardi G, Annunziato L (2000) Cabergoline. Expert Opin Pharmacother 1:555–574

    Article  CAS  PubMed  Google Scholar 

  31. Lamberts SW, de Lange SA, Stefanko SZ (1982) Adrenocorticotropin-secreting pituitary adenomas originate from the anterior or the intermediate lobe in Cushing’s disease: differences in the regulation of hormone secretion. J Clin Endocrinol Metab 54:286–291

    Article  CAS  PubMed  Google Scholar 

  32. Croughs RJM, Koppeschaar HPF, Van’t Verlaat JW, McNicol AM (1989) Bromocriptine-responsive Cushing’s disease associated with anterior pituitary corticotroph hyperplasia or normal pituitary gland. J Clin Endocrinol Metab 68:495–498

    Article  CAS  PubMed  Google Scholar 

  33. Bricaire L, Brue T (2007) New medical treatments in Cushing’s disease. Ann Endocrinol (Paris) 68(Suppl 1):18–20

    Google Scholar 

  34. Colao A, Galderisi M, Di Sarno A et al (2008) Increased prevalence of tricuspid regurgitation in patients with prolactinomas chronically treated with cabergoline. J Clin Endocr Metab 93:3777–3784

    Article  CAS  PubMed  Google Scholar 

  35. Czepielewski MA, Rollin GAFS, Bruno OD, Vilar L (2009) Treatment of Cushing’s syndrome. In: Vilar L (ed) Clinical Endocrinology, 4th edn. Guanabara Koogan, Rio, pp 459–475

    Google Scholar 

  36. Colao A, Di Sarno A, Marzullo P et al (2000) New medical approaches in pituitary adenomas. Horm Res 53(Suppl 3):76–87

    Article  CAS  PubMed  Google Scholar 

  37. Pivonello R, De Leo M, De Martino MC et al. (2009) Effeectiveness and safety of combined therapy with low dose ketoconazole and cabergoline in patients with Cushing’s disease partially responsive to monotherapy with cabergoline. Program of the 11th international pituitary congress, Washington, DC, pp 36–40

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Authors and Affiliations

  1. Division of Endocrinology, Hospital das Clínicas, Federal University of Pernambuco, Recife, Brazil

    Lucio Vilar, Maria Juliana Arruda, Carla M. Arahata, Lidiane Moura e Silva, Rodrigo Agra, Lisete Pontes, Larissa Montenegro, José Luciano Albuquerque & Viviane Canadas

  2. Pernambuco Center for Diabetes and Endocrinology, Federal University of Pernambuco, Recife, Brazil

    Lucio Vilar

  3. Division of Endocrinology, Hospital Universitário de Brasilia, Brasilia, Brazil

    Luciana A. Naves & Monalisa F. Azevedo

  4. Rua Clovis Silveira Barros, 84/1202, Boa Vista, Recife, CEP 50.050-270, Brazil

    Lucio Vilar

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  1. Lucio Vilar
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Correspondence to Lucio Vilar.

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Vilar, L., Naves, L.A., Azevedo, M.F. et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary 13, 123–129 (2010). https://doi.org/10.1007/s11102-009-0209-8

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