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Medical suppression of hypercortisolemia in Cushing’s syndrome with particular consideration of etomidate

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Abstract

Cushing’s syndrome is associated with excessive cortisol secretion by the adrenal gland or ectopic tumours and may result in diabetes, hypertension, and life-threatening infections with high mortality rates especially in the case of surgical resection. Although surgical resection is the treatment of choice, patients may benefit from preceding medical therapy. This may especially be useful as an adjunctive approach in emergency settings, if patients cannot undergo surgery, if surgery or radiotherapy fails, or if the tumour recurs. Medical therapy can be categorized in three different groups—inhibition of steroidogenesis, suppression of adrenocorticotropic hormone, and antagonism of the glucocorticoid receptor. However, the majority of common drugs are not available for parenteral administration, which may evoke a management problem in emergency settings or in patients unable to tolerate oral medication. The carboxylated imidazole etomidate is a well known parenteral induction agent for general anaesthesia. Besides its hypnotic properties, etomidate also has α-adrenergic characteristics and inhibits the enzyme 11-deoxycortisol ß-hydroxylase, which catalyzes the final step of the conversion of cholesterol to cortisol. Adverse outcomes have been reported when used for sedation in septic or trauma patients probably by its interference with steroid homeostasis. However, its capability of inhibition of the 11-deoxycortisol ß-hydroxylase leads to suppression of cortisol secretion which has been demonstrated to be a useful tool in severe and complicated hypercortisolemia. Within this article, we review the data concerning different pharmacological approaches with particular consideration of etomidate in order to suppress steroidogenesis in patients with Cushing’s syndrome.

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References

  1. Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C et al (2001) Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 86:117–123

    Article  PubMed  CAS  Google Scholar 

  2. Schteingart DE (2009) Drugs in the medical treatment of cushing’s syndrome. Expert Opin Emerg Drugs 14:661–671

    Article  PubMed  CAS  Google Scholar 

  3. Lutgers HL, Vergragt J, Dong PV, de Vries J, Dullaart RP, van den Berg G et al (2010) Severe hypercortisolism: a medical emergency requiring urgent intervention. Crit Care Med 38:1598–1601

    Article  PubMed  Google Scholar 

  4. Ross EJ, Linch DC (1982) Cushing’s syndrome–killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet 320:646–649

    Article  Google Scholar 

  5. Sarlis NJ, Chanock SJ, Nieman LK (2000) Cortisolemic indices predict severe infections in cushing syndrome due to ectopic production of adrenocorticotropin. J Clin Endocrinol Metab 85:42–47

    Article  PubMed  CAS  Google Scholar 

  6. Watson RG, van Heerden JA, Northcutt RC, Grant CS, Ilstrup DM (1986) Results of adrenal surgery for cushing’s syndrome: 10 years′ experience. World J Surg 10:531–538

    Article  PubMed  CAS  Google Scholar 

  7. Takagi S, Tanabe A, Tsuiki M, Naruse M, Takano K (2009) Hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal cushing’s syndrome. Endocr J 56:1009–1018

    Article  PubMed  CAS  Google Scholar 

  8. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM et al (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540

    Article  PubMed  CAS  Google Scholar 

  9. Newell-Price J (2009) Diagnosis/differential diagnosis of cushing’s syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab 23(Suppl 1):S5–S14

    Article  PubMed  Google Scholar 

  10. Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. Lancet 367:1605–1617

    Article  PubMed  CAS  Google Scholar 

  11. Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, Feldman D (2001) Successful long-term treatment of refractory cushing’s disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab 86:3568–3573

    Article  PubMed  CAS  Google Scholar 

  12. Mettauer N, Brierley J (2009) A novel use of etomidate for intentional adrenal suppression to control severe hypercortisolemia in childhood. Pediatr Crit Care Med 10:e37–e40

    Article  PubMed  Google Scholar 

  13. Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH (2007) Medical management of cushing disease. Neurosurg Focus 23:E10

    PubMed  Google Scholar 

  14. Porterfield JR, Thompson GB, Young WF Jr et al (2008) Surgery for cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 32:659–677

    Article  PubMed  Google Scholar 

  15. Thompson SK, Hayman AV, Ludlam WH, Deveney CW, Loriaux DL, Sheppard BC (2007) Improved quality of life after bilateral laparoscopic adrenalectomy for cushing’s disease: a 10-year experience. Ann Surg 245:790–794

    Article  PubMed  Google Scholar 

  16. Malley D, Boris R, Kaul S et al (2008) Synchronous bilateral adrenalectomy for adrenocorticotropic-dependent cushing’s syndrome. J Soc Laparoendosc Surg 12:198–201

    Google Scholar 

  17. Assié G, Antoni G, Tissier F et al (2007) Prognostic parameters of metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 92:148–154

    Article  PubMed  Google Scholar 

  18. Markoe AM, Serber W, Micaily B et al (1991) Radiation therapy for adjunctive treatment of adrenal cortical carcinoma. Am J Clin Oncol 14:170–174

    Article  PubMed  CAS  Google Scholar 

  19. Fassnacht M, Hahner S, Polat B et al (2006) Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab 91:4501–4504

    Article  PubMed  CAS  Google Scholar 

  20. Abraham J, Bakke S, Rutt A et al (2002) A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist. Cancer 94:2333–2343

    Article  PubMed  CAS  Google Scholar 

  21. Williamson SK, Lew D, Miller GJ et al (2000) PhaseII evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a southwest oncology group study. Cancer 88:1159–1165

    Article  PubMed  CAS  Google Scholar 

  22. Feelders RA, Hofland LJ, de Herder WW (2010) Medical treatment of cushing’s syndrome: adrenal-blocking drugs and ketaconazole. Neuroendocrinology 92:111–115

    Article  PubMed  CAS  Google Scholar 

  23. Engelhardt D, Weber MM (1994) Therapy of cushing’s syndrome with steroid biosynthesis inhibitors. J Steroid Biochem Mol Biol 49:261–267

    Article  PubMed  CAS  Google Scholar 

  24. Nieman LK (2002) Medical therapy of cushing’s disease. Pituitary 5:77–82

    Article  PubMed  CAS  Google Scholar 

  25. Colao A, Pivonello R, Tripodi FS, Orio F Jr, Ferone D, Cerbone G et al (1997) Failure of long-term therapy with sodium valproate in cushing’s disease. J Endocrinol Invest 20:387–392

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Suri D, Weiss RE (2005) Effect of pioglitazone on adrenocorticotropic hormone and cortisol secretion in cushing’s disease. J Clin Endocrinol Metab 90:1340–1346

    Article  PubMed  CAS  Google Scholar 

  28. Mercado-Asis LB, Yanovski JA, Tracer HL, Chik CL, Cutler GB Jr (1997) Acute effects of bromocriptine, cyproheptadine, and valproic acid on plasma adrenocorticotropin secretion in Nelson’s syndrome. J Clin Endocrinol Metab 82:514–517

    Article  PubMed  CAS  Google Scholar 

  29. de Bruin C, Pereira AM, Feelders RA, Romijn JA, Roelfsema F, Sprij-Mooij DM et al (2009) Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J Clin Endocrinol Metab 94:1118–1124

    Article  PubMed  Google Scholar 

  30. Kraus J, Woltje M, Schonwetter N, Hollt V (1998) Alternative promoter usage and tissue specific expression of the mouse somatostatin receptor 2 gene. FEBS Lett 428:165–170

    Article  PubMed  CAS  Google Scholar 

  31. Bertagna X, Favrod-Coune C, Escourolle H, Beuzeboc P, Christoforov B, Girard F et al (1989) Suppression of ectopic adrenocorticotropin secretion by the long-acting somatostatin analog octreotide. J Clin Endocrinol Metab 68:988–991

    Article  PubMed  CAS  Google Scholar 

  32. Boerlin V, van der Hoek J, Beglinger C, Poon KW, Hartmann S, Dutreix C et al (2003) New insights on SOM230, a universal somatostatin receptor ligand. J Endocrinol Invest 26:14–16

    PubMed  CAS  Google Scholar 

  33. Hofland LJ, van der Hoek J, Feelders R, van Aken MO, van Koetsveld PM, Waaijers M et al (2005) The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol 152:645–654

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  35. Santen RJ, Misbin RI (1981) Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy 1:95–120

    PubMed  CAS  Google Scholar 

  36. Misbin RI, Canary J, Willard D (1976) Aminoglutethimide in the treatment of cushing’s syndrome. J Clin Pharmacol 16:645–651

    PubMed  CAS  Google Scholar 

  37. Schteingart DE, Conn JW (1967) Effects of aminoglutethimide upon adrenal function and cortisol metabolism in Cushing’s syndrome. J Clin Endocrinol Metab 27:1657–1666

    Article  PubMed  CAS  Google Scholar 

  38. Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D (1983) Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 71:1495–1499

    Article  PubMed  CAS  Google Scholar 

  39. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouverture M, Simon D et al (1979) Treatment of Cushing’s disease by O, p′DDD. Survey of 62 cases. N Engl J Med 300:459–464

    Article  PubMed  CAS  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 92:613–619

    PubMed  CAS  Google Scholar 

  41. Leiba S, Weinstein R, Shindel B, Lapidot M, Stern E, Levavi H et al (1989) 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

    CAS  Google Scholar 

  42. Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P (1997) Propranolol therapy for ectopic beta-adrenergic receptors in adrenal cushing’s syndrome. N Engl J Med 337:1429–1434

    Article  PubMed  CAS  Google Scholar 

  43. Lacroix A, Hamet P, Boutin JM (1999) Leuprolide acetate therapy in luteinizing hormone–dependent cushing’s syndrome. N Engl J Med 341:1577–1581

    Article  PubMed  CAS  Google Scholar 

  44. Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P et al (2009) Merits and pitfalls of mifepristone in cushing’s syndrome. Eur J Endocrinol 160:1003–1010

    Article  PubMed  CAS  Google Scholar 

  45. Dabbagh A, Sa’adat N, Heidari Z (2009) Etomidate infusion in the critical care setting for suppressing the acute phase of cushing’s syndrome. Anesth Analg 108:238–239

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM (1998) Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with cushing’s syndrome and peritonitis. J Clin Endocrinol Metab 83:3542–3544

    Article  PubMed  CAS  Google Scholar 

  48. Krakoff J, Koch CA, Calis KA, Alexander RH, Nieman LK (2001) Use of a parenteral propylene glycol-containing etomidate preparation for the long-term management of ectopic cushing’s syndrome. J Clin Endocrinol Metab 86:4104–4108

    Article  PubMed  CAS  Google Scholar 

  49. Johnson TN, Canada TW (2007) Etomidate use for cushing’s syndrome caused by an ectopic adrenocorticotropic hormone-producing tumor. Ann Pharmacother 41:350–353

    Article  PubMed  CAS  Google Scholar 

  50. Hadzija BW, Lubarsky DA (1995) Compatibility of etomidate, thiopental sodium, and propofol injections with drugs commonly administered during induction of anesthesia. Am J Health Syst Pharm 52:997–999

    PubMed  CAS  Google Scholar 

  51. Van Hamme MJ, Ghoneim MM, Ambre JJ (1978) Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology 49:274–277

    Article  PubMed  Google Scholar 

  52. Meuldermans WE, Heykants JJ (1976) The plasma protein binding and distribution of etomidate in dog, rat and human blood. Arch Int Pharmacodyn Ther 221:150–162

    PubMed  CAS  Google Scholar 

  53. de Ruiter G, Popescu DT, de Boer AG, Smeekens JB, Breimer DD (1981) Pharmacokinetics of etomidate in surgical patients. Arch Int Pharmacodyn Ther 249:180–188

    PubMed  Google Scholar 

  54. Paris A, Philipp M, Tonner PH, Steinfath M, Lohse M, Scholz J et al (2003) Activation of alpha 2B-adrenoceptors mediates the cardiovascular effects of etomidate. Anesthesiology 99:889–895

    Article  PubMed  CAS  Google Scholar 

  55. Fry DE, Griffiths H (1984) The inhibition by etomidate of the 11 beta-hydroxylation of cortisol. Clin Endocrinol (Oxf) 20:625–629

    Article  CAS  Google Scholar 

  56. Reddy RV, Moorthy SS, Dierdorf SF, Deitch RD Jr, Link L (1993) Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg 77:1008–1011

    Article  PubMed  CAS  Google Scholar 

  57. Wells JK (1985) Comparison of ICI 35868, etomidate and methohexitone for day-case anaesthesia. Br J Anaesth 57:732–735

    Article  PubMed  CAS  Google Scholar 

  58. McCollum JS, Dundee JW (1986) Comparison of induction characteristics of four intravenous anaesthetic agents. Anaesthesia 41:995–1000

    Article  PubMed  CAS  Google Scholar 

  59. Scheffer GJ, Ten Voorde BJ, Karemaker JM, Ros HH, de Lange JJ (1993) Effects of thiopentone, etomidate and propofol on beat-to-beat cardiovascular signals in man. Anaesthesia 48:849–855

    Article  PubMed  CAS  Google Scholar 

  60. Lundy JB, Slane ML, Frizzi JD (2007) Acute adrenal insufficiency after a single dose of etomidate. J Intensive Care Med 22:111–117

    Article  PubMed  Google Scholar 

  61. 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 70:1426–1430

    Article  PubMed  CAS  Google Scholar 

  62. Allolio B, Stuttmann R, Fischer H, Leonhard W, Winkelmann W (1983) Long-term etomidate and adrenocortical suppression. Lancet 322:626

    Article  Google Scholar 

  63. Gärtner R, Albrecht M, Müller OA (1986) Effect of etomidate on hypercortisolism due to ectopic ACTH production. Lancet 1:275

    Article  PubMed  Google Scholar 

  64. Allolio B, Schulte HM, Kaulen D, Reincke M, Jaursch-Hancke C, Winkelmann W (1988) Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in cushing’s syndrome. Klin Wochenschr 66:361–364

    Article  PubMed  CAS  Google Scholar 

  65. Herrmann BL, Mitchell A, Saller B (2001) Transsphenoidal hypophysectomy of a patient with an ACTH-producing pituitary adenoma and an “empty sella” after pretreatment with etomidate. Dtsch Med Wochenschr 126:232–234

    Article  PubMed  CAS  Google Scholar 

  66. Bilgin YM, van der Wiel HE, Fischer HR, De Herder WW (2007) Treatment of severe psychosis due to ectopic cushing’s syndrome. J Endocrinol Invest 30:776–779

    PubMed  CAS  Google Scholar 

  67. Lamberts SW, Bons EG, Bruining HA, de Jong FH (1987) Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells. J Pharmacol Exp Ther 240:259–264

    PubMed  CAS  Google Scholar 

  68. Varga I, Rácz K, Kiss R et al (1993) Direct inhibitory effect of etomidate on corticosteroid secretion in human pathologic adrenocortical cells. Steroids 58:64–68

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology–Grosshadern, University of Munich (LMU), Marchioninistrasse 15, 81377, Munich, Germany

    Jens Heyn, Christian L. Hinske, Josef Briegel & Florian Weis

  2. Department of Cardiology and Intensive Care Medicine, Bogenhausen Hospital, Englschalkinger Straße 77, 81925, Munich, Germany

    Carolin Geiger

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  1. Jens Heyn
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Correspondence to Jens Heyn.

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Heyn, J., Geiger, C., Hinske, C.L. et al. Medical suppression of hypercortisolemia in Cushing’s syndrome with particular consideration of etomidate. Pituitary 15, 117–125 (2012). https://doi.org/10.1007/s11102-011-0314-3

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