Skip to main content

Advertisement

SpringerLink
Log in

Medical therapy for Cushing’s disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Morbidity and mortality in Cushing’s disease (CD) patients are increased if patients are not appropriately treated. Surgery remains the first line therapy, however the role of medical therapy has become more prominent in patients when biochemical remission is not achieved/or recurs after surgery, while waiting effects of radiation therapy or when surgery is contraindicated. Furthermore, use of preoperative medical therapy has been also recognized. In addition to centrally acting therapies (reviewed elsewhere in this special issue), adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are frequently used. A PubMed search of all original articles or abstracts detailing medical therapy in CD, published within 12 months (2013–2014), were identified and pertinent data extracted. Although not prospectively studied, ketoconazole and metyrapone have been the most frequently used medical therapies. A large retrospective ketoconazole study showed that almost half of patients who continued on ketoconazole therapy achieved biochemical control and clinical improvement; however almost 20 % discontinued ketoconazole due to poor tolerability. Notably, hepatotoxicity was usually mild and resolved after drug withdrawal. Etomidate remains the only drug available for intravenous use. A new potent inhibitor of both aldosterone synthase and 11β-hydroxylase, following the completion of a phase II study LCI699 is being studied in a large phase III with promising results. Mifepristone, a glucocorticoid receptor antagonist, has been approved for hyperglycemia associated with Cushing’s syndrome based on the results of a prospective study where it produced in the majority of patients’ significant clinical and metabolic improvement. Absence of both a biochemical marker for remission and/or diagnosis of adrenal insufficiency remain, however, a limiting factor. Patient characteristics and preference should guide the choice between different medications in the absence of clinical trials comparing any of these therapies. Despite significant progress, there is still a need for a medical therapy that is more effective and with less adverse effects for patients with CD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Feelders RA, Pulgar SJ, Kempel A, Pereira AM (2012) The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 167(3):311–326

    Article  CAS  PubMed  Google Scholar 

  2. Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A (2008) Cushing’s syndrome. Endocrinol Metab Clin North Am 37(1):135–149 ix

    Article  CAS  PubMed  Google Scholar 

  3. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M (2008) Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 93(7):2454–2462

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Fleseriu M, Petersenn S (2012) Medical management of Cushing’s disease: what is the future? Pituitary 15(3):330–341

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Thorn GW, Renold AE, Goldfien A, Nelson DH, Reddy WJ, Hertz R (1956) Inhibition of corticosteroid secretion by amphenone in a patient with adrenocortical carcinoma. N Engl J Med 254(12):547–551

    Article  CAS  PubMed  Google Scholar 

  6. Nieman LK (2013) Update in the medical therapy of Cushing’s disease. Curr Opin Endocrinol Diabetes Obes 20(4):330–334

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Nieman LK (2002) Medical therapy of Cushing’s disease. Pituitary 5(2):77–82

    Article  CAS  PubMed  Google Scholar 

  8. Petersenn S (2011) Medical management of Cushing’s disease. In: Swearingen B, Biller B (eds) Endocrine updates: Cushing’s disease, vol 31. Springer, New York, pp 167–182

    Google Scholar 

  9. Gadelha MR, Vieira Neto L (2014) Efficacy of medical treatment in Cushing’s disease: a systematic review. Clin Endocrinol (Oxf) 80(1):1–12

    Article  CAS  Google Scholar 

  10. Trainer PJ (2014) Next generation medical therapy for Cushing’s syndrome—can we measure a benefit? J Clin Endocrinol Metab 99(4):1157–1160

    Article  CAS  PubMed  Google Scholar 

  11. Bertagna X, Pivonello R, Fleseriu M, Zhang Y, Robinson P, Taylor A, Watson CE, Maldonado M, Hamrahian AH, Boscaro M, Biller BM (2014) LCI699, a potent 11beta-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):1375–1383

    Article  CAS  PubMed  Google Scholar 

  12. Castinetti F, Morange I, Jaquet P, Conte-Devolx B, Brue T (2008) Ketoconazole revisited: a preoperative or postoperative treatment in Cushing’s disease. Eur J Endocrinol 158(1):91–99

    Article  CAS  PubMed  Google Scholar 

  13. Cuevas-Ramos D, Fleseriu M (2014) Treatment of Cushing’s disease: a mechanistic update. J Endocrinol 223(2):R19–R39

    Article  CAS  PubMed  Google Scholar 

  14. Daniel E, Aylwin S, Mustafa O, Ball S, Munir A, Boelaert K, Chortis V, Cuthbertson DJ, Daousi C, Rajeev S, Davis J, Cheer K, Drake W, Gunganah K, Grossman A, Gurnell M, Powlson A, Karavitaki N, Huquet I, Kearney T, Mohit K, Meeran K, Hill N, Rees A, Trainer PJ, Lansdown AJ, Minder A-EH, Newell-Price J (2014) Effectiveness of metyrapone in 195 patients with Cushing’s syndrome. Paper presented at the Society for Endocrinology BES 2014, Liverpool, UK

  15. Feelders RA, Hofland LJ (2013) Medical treatment of Cushing’s disease. J Clin Endocrinol Metab 98(2):425–438

    Article  CAS  PubMed  Google Scholar 

  16. Pivonello R, Fleseriu M, Young J, Bertagna X, Hamrahian AH, Molitch ME, Shimizu C, Tanaka T, Shimatsu A, White T, Hilliard A, Tian C, Sauter N, Biller BM (2014) LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary free cortisol levels in patients with Cushing’s disease: 22-week, multicenter, open-label study. Paper presented at the 16th International Congress of Endocrinology & the Endocrine Society’s 96th Annual Meeting & Expo, Chicago

  17. 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(2):137–143

    CAS  PubMed  Google Scholar 

  18. Deutschbein T, Broecker-Preuss M, Hartmann MF, Althoff R, Wudy SA, Mann K, Petersenn S (2011) Measurement of urinary free cortisol by current immunoassays: need for sex-dependent reference ranges to define hypercortisolism. Horm Metab Res 43(10):714–719

    Article  CAS  PubMed  Google Scholar 

  19. Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Sen K, Salgado LR, Colao A, Biller BM (2014) High variability in baseline urinary free cortisol values in patients with Cushing’s disease. Clin Endocrinol (Oxf) 80(2):261–269

    Article  CAS  Google Scholar 

  20. Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth JD, Winterer JC, Loriaux DL (1991) Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 72(1):39–45

    Article  CAS  PubMed  Google Scholar 

  21. Fleseriu M, Loriaux DL, Ludlam WH (2007) Second-line treatment for Cushing’s disease when initial pituitary surgery is unsuccessful. Curr Opin Endocrinol Diabetes Obes 14(4):323–328

    Article  PubMed  Google Scholar 

  22. Perogamvros I, Owen LJ, Newell-Price J, Ray DW, Trainer PJ, Keevil BG (2009) Simultaneous measurement of cortisol and cortisone in human saliva using liquid chromatography-tandem mass spectrometry: application in basal and stimulated conditions. J Chromatogr B Anal Technol Biomed Life Sci 877(29):3771–3775

    Article  CAS  Google Scholar 

  23. Feldman D (1986) Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis. Endocr Rev 7(4):409–420

    Article  CAS  PubMed  Google Scholar 

  24. Sonino N (1987) The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 317(13):812–818

    Article  CAS  PubMed  Google Scholar 

  25. Miller JW, Crapo L (1993) The medical treatment of Cushing’s syndrome. Endocr Rev 14(4):443–458

    Article  CAS  PubMed  Google Scholar 

  26. Federal Drug Administration (2013) FDA drug safety communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm

  27. Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, Caron P, Luca F, Donadille B, Vantyghem MC, Bihan H, Delemer B, Raverot G, Motte E, Philippon M, Morange I, Conte-Devolx B, Quinquis L, Martinie M, Vezzosi D, Le Bras M, Baudry C, Christin-Maitre S, Goichot B, Chanson P, Young J, Chabre O, Tabarin A, Bertherat J, Brue T (2014) Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 99(5):1623–1630

    Article  CAS  PubMed  Google Scholar 

  28. The European Medicines Agency (2014) Ketoconazole HRA recommended for approval in Cushing’s syndrome. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2014/09/WC500173638.pdf

  29. Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D (1991) Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients. Clin Endocrinol (Oxf) 35(4):347–352

    Article  CAS  Google Scholar 

  30. Glass AR, Eil C (1988) Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D and total serum calcium in hypercalcemic patients. J Clin Endocrinol Metab 66(5):934–938

    Article  CAS  PubMed  Google Scholar 

  31. Lake-Bakaar G, Scheuer PJ, Sherlock S (1987) Hepatic reactions associated with ketoconazole in the United Kingdom. Br Med J 294(6569):419–422

    Article  CAS  Google Scholar 

  32. Lewis JH, Zimmerman HJ, Benson GD, Ishak KG (1984) Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology 86(3):503–513

    CAS  PubMed  Google Scholar 

  33. van der Pas R, Hofland LJ, Hofland J, Taylor AE, Arlt W, Steenbergen J, van Koetsveld PM, de Herder WW, de Jong FH, Feelders RA (2012) Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol 215(3):403–412

    Article  PubMed  Google Scholar 

  34. Riedl M, Maier C, Zettinig G, Nowotny P, Schima W, Luger A (2006) Long term control of hypercortisolism with fluconazole: case report and in vitro studies. Eur J Endocrinol 154(4):519–524

    Article  CAS  PubMed  Google Scholar 

  35. Gower DB (1974) Modifiers of steroid-hormone metabolism: a review of their chemistry, biochemistry and clinical applications. J Steroid Biochem 5(5):501–523

    Article  CAS  PubMed  Google Scholar 

  36. Verhelst JA, Trainer PJ, Howlett TA, Perry L, Rees LH, Grossman AB, Wass JA, Besser GM (1991) Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 35(2):169–178

    Article  CAS  Google Scholar 

  37. Feelders RA, Hofland LJ, de Herder WW (2010) Medical treatment of Cushing’s syndrome: adrenal-blocking drugs and ketaconazole. Neuroendocrinology 92(Suppl):1111–1115

    Google Scholar 

  38. Jeffcoate WJ, Rees LH, Tomlin S, Jones AE, Edwards CR, Besser GM (1977) Metyrapone in long-term management of Cushing’s disease. Br Med J 2(6081):215–217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouverture M, Simon D, Laudat MH, Touitou Y, Bricaire H (1979) Treatment of Cushing’s disease by O, p’DDD. Survey of 62 cases. N Engl J Med 300(9):459–464

    Article  CAS  PubMed  Google Scholar 

  40. Schteingart DE, Tsao HS, Taylor CI, McKenzie A, Victoria R, Therrien BA (1980) Sustained remission of Cushing’s disease with mitotane and pituitary irradiation. Ann Intern Med 92(5):613–619

    Article  CAS  PubMed  Google Scholar 

  41. Robinson BG, Hales IB, Henniker AJ, Ho K, Luttrell BM, Smee IR, Stiel JN (1987) The effect of o, p’-DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol (Oxf) 27(4):437–444

    Article  CAS  Google Scholar 

  42. Baudry C, Coste J, Bou Khalil R, Silvera S, Guignat L, Guibourdenche J, Abbas H, Legmann P, Bertagna X, Bertherat J (2012) Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol 167(4):473–481

    Article  CAS  PubMed  Google Scholar 

  43. Kerkhofs T, Derijks L, Ettaieb H, Eekhoff EM, Neef K, Gelderblom H, den Hartigh J, Guchelaar HJ, Haak HR (2014) Short-term variation in mitotane plasma levels confirms the importance of trough level monitoring. Eur J Endocrinol pii:EJE-14-0388

  44. Schulte HM, Benker G, Reinwein D, Sippell WG, Allolio B (1990) 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(5):1426–1430

    Article  CAS  PubMed  Google Scholar 

  45. Greening JE, Brain CE, Perry LA, Mushtaq I, Sales Marques J, Grossman AB, Savage MO (2005) Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing’s disease. Horm Res 64(3):140–143

    Article  CAS  PubMed  Google Scholar 

  46. Heyn J, Geiger C, Hinske CL, Briegel J, Weis F (2012) Medical suppression of hypercortisolemia in Cushing’s syndrome with particular consideration of etomidate. Pituitary 15(2):117–125

    Article  CAS  PubMed  Google Scholar 

  47. Zarnecki KG, Kelly N, Peppard W, Herrmann D, Findling JW (2014) Continuous etomidate infusion for the management of severe hypercortisolism in ACTH-dependent Cushing’s syndrome: a case series. Paper presented at the Endocrine Society’s 96th Annual Meeting and Expo, Chicago

  48. Ross RJ, Miell JP, Holly JM, Maheshwari H, Norman M, Abdulla AF, Buchanan CR (1991) Levels of GH binding activity, IGFBP-1, insulin, blood glucose and cortisol in intensive care patients. Clin Endocrinol (Oxf) 35(4):361–367

    Article  CAS  Google Scholar 

  49. Valassi E, Crespo I, Gich I, Rodriguez J, Webb SM (2012) A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing’s syndrome. Clin Endocrinol (Oxf) 77(5):735–742

    Article  CAS  Google Scholar 

  50. Amar L, Azizi M, Menard J, Peyrard S, Watson C, Plouin PF (2010) Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. Hypertension 56(5):831–838

    Article  CAS  PubMed  Google Scholar 

  51. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C (2012) Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 97(6):2039–2049

    Article  CAS  PubMed  Google Scholar 

  52. Fleseriu M, Molitch ME, Gross C, Schteingart DE, Vaughan TB 3rd, Biller BM (2013) A new therapeutic approach in the medical treatment of Cushing’s syndrome: glucocorticoid receptor blockade with mifepristone. Endocr Pract 19(2):313–326

    Article  PubMed  Google Scholar 

  53. Federal Drug Administration (2012) FDA approves Korlym for patients with endogenous Cushing’s syndrome. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm292462.htm

  54. Katznelson L, Loriaux DL, Feldman D, Braunstein GD, Schteingart DE, Gross C (2014) Global clinical response in Cushing’s syndrome patients treated with mifepristone. Clin Endocrinol (Oxf) 80(4):562–569

    Article  CAS  Google Scholar 

  55. Johanssen S, Allolio B (2007) Mifepristone (RU 486) in Cushing’s syndrome. Eur J Endocrinol 157(5):561–569

    Article  CAS  PubMed  Google Scholar 

  56. Fleseriu M, Findling JW, Koch CA, Schlaffer SM, Buchfelder M, Gross C (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):3718–3727

    Article  CAS  PubMed  Google Scholar 

  57. Belanoff JK, Blasey CM, Clark RD, Roe RL (2010) Selective glucocorticoid receptor (type II) antagonist prevents and reverses olanzapine-induced weight gain. Diabetes Obes Metab 12(6):545–547

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The author thanks Andy Rekito, M.S., and Shirley McCartney, Ph.D., for graphic and editorial assistance, respectively. No funding source has been received for this manuscript.

Conflict of interest

Dr. Fleseriu—research grants to Oregon Health & Science University from Cortendo, Ipsen, Novartis Opko, and Pfizer; ad-hoc scientific consultant/advisor Genentech, Novartis, Xoma, Dr. Petersenn— presentation at workshops organized by Novartis and Ipsen, member of advisory boards for Ipsen, Novartis, Pfizer, and Roche.

Author information

Authors and Affiliations

  1. Departments of Medicine (Endocrinology) and Neurological Surgery, Northwest Pituitary Center, Oregon Health & Science University, Mail Code BTE 28, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Maria Fleseriu & Stephan Petersenn

Authors
  1. Maria Fleseriu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephan Petersenn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Fleseriu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fleseriu, M., Petersenn, S. Medical therapy for Cushing’s disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary 18, 245–252 (2015). https://doi.org/10.1007/s11102-014-0627-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-014-0627-0

Keywords

Search

Navigation