Bilateral Adrenalectomy Versus Medical Management for Cushing’s Syndrome with Bilateral Adrenal Hyperplasia

  • Colleen Majewski
Part of the Difficult Decisions in Surgery: An Evidence-Based Approach book series (DDSURGERY)


Cushing’s syndrome due to bilateral adrenal hyperplasia is a rare disease with a high morbidity and mortality rate. The hypercortisolism found in Cushing’s syndrome leads to obesity and its associated diseases, higher risk of infections, and conditions associated with collagen breakdown. Surgical resection of the source of cortisol is curative but results in a patient with permanent adrenal insufficiency and the need for life-long medications. Bilateral adrenalectomy has been the standard treatment, but a unilateral adrenalectomy has provided good outcomes and reduces the chance of life-long hypoadrenalism. Laparscopic and synchronous removal of the adrenal glands has offered a cure with less complications and morbidity. Medical therapies decrease cortisol production by inhibiting ACTH, inhibiting cortisol, or blocking the action of cortisol at the level of the glucocorticoid receptor. Combination medical therapy can offer faster improvement in cortisol levels. The following chapter reviews the benefits and risks of surgical versus medical therapy in patients with Cushing’s syndrome due to bilateral adrenal hyperplasia.


Cushing’s syndrome Hypercortisolism Adrenalectomy Bilateral adrenal hyperplasia Medical therapy 


  1. 1.
    Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001;86(9):4041–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocr Rev. 2001;22(1):75–110.PubMedGoogle Scholar
  3. 3.
    Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J, Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol. 2010;73(1):1–15.Google Scholar
  4. 4.
    Ravikumar A, Levine AC. Genetic basis of bilateral macronodular hyperplasia. Endocr Pract. 2015;21(4):390–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Beuschlein F, Schulze E, Mora P, Gensheimer HP, Maser-Gluth C, Allolio B, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors. J Clin Endocrinol Metab. 1998;83(7):2585–8.PubMedGoogle Scholar
  6. 6.
    Arlt W, Biehl M, Taylor AE, Hahner S, Libe R, Hughes BA, et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocrinol Metab. 2011;96(12):3775–84.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Howlett TA, Rees LH, Besser GM. Cushing’s syndrome. Clin Endocrinol Metab. 1985;14(4):911–45.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lumachi F, Marchesi P, Miotto D, Motta R. CT and MR imaging of the adrenal glands in cortisol-secreting tumors. Anticancer Res. 2011;31(9):2923–6.PubMedGoogle Scholar
  9. 9.
    Rockall AG, Babar SA, Sohaib SA, Isidori AM, Diaz-Cano S, Monson JP, et al. CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome. Radiographics. 2004;24(2):435–52.CrossRefPubMedGoogle Scholar
  10. 10.
    Lumachi F, Zucchetta P, Marzola MC, Bui F, Casarrubea G, Angelini F, et al. Usefulness of CT scan, MRI and radiocholesterol scintigraphy for adrenal imaging in Cushing’s syndrome. Nucl Med Commun. 2002;23(5):469–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Yu KC, Fraker DL, Ziessman HA. Atlas of iodocholesterol scintigraphy (NP-59) in Cushing’s syndrome with CT and MR correlation. Clin Nucl Med. 1996;21(2):136–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Sarkar SD, Cohen EL, Beierwaltes WH, Ice RD, Cooper R, Gold EN. A new and superior adrenal imaging agent, 131I-6beta-iodomethyl-19-nor-cholesterol (NP-59): evaluation in humans. J Clin Endocrinol Metab. 1977;45(2):353–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004;136(6):1227–35.CrossRefPubMedGoogle Scholar
  14. 14.
    Young WF Jr, du Plessis H, Thompson GB, Grant CS, Farley DR, Richards ML, et al. The clinical conundrum of corticotropin-independent autonomous cortisol secretion in patients with bilateral adrenal masses. World J Surg. 2008;32(5):856–62.CrossRefPubMedGoogle Scholar
  15. 15.
    Domino JP, Chionh SB, Lomanto D, Katara AN, Rauff A, Cheah WK. Laparoscopic partial adrenalectomy for bilateral cortisol-secreting adenomas. Asian J Surg. 2007;30(2):154–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Raffaelli M, Brunaud L, De Crea C, Hoche G, Oragano L, Bresler L, et al. Synchronous bilateral adrenalectomy for Cushing’s syndrome: laparoscopic versus posterior retroperitoneoscopic versus robotic approach. World J Surg. 2014;38(3):709–15.CrossRefPubMedGoogle Scholar
  17. 17.
    Aggarwal S, Yadav K, Sharma AP, Sethi V. Laparoscopic bilateral transperitoneal adrenalectomy for Cushing syndrome: surgical challenges and lessons learnt. Surg Laparosc Endosc Percutan Tech. 2013;23(3):324–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Sommerey S, Foroghi Y, Chiapponi C, Baumbach SF, Hallfeldt KK, Ladurner R, et al. Laparoscopic adrenalectomy--10-year experience at a teaching hospital. Langenbecks Arch Surg. 2015;400(3):341–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Osswald A, Plomer E, Dimopoulou C, Milian M, Blaser R, Ritzel K, et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. Eur J Endocrinol. 2014;171(2):209–15.CrossRefPubMedGoogle Scholar
  20. 20.
    Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J, et al. Clinical review: outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab. 2013;98(10):3939–48.CrossRefPubMedGoogle Scholar
  21. 21.
    Xu Y, Rui W, Qi Y, Zhang C, Zhao J, Wang X, et al. The role of unilateral adrenalectomy in corticotropin-independent bilateral adrenocortical hyperplasias. World J Surg. 2013;37(7):1626–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Albiger NM, Ceccato F, Zilio M, Barbot M, Occhi G, Rizzati S, et al. An analysis of different therapeutic options in patients with Cushing’s syndrome due to bilateral macronodular adrenal hyperplasia: a single-centre experience. Clin Endocrinol. 2015;82(6):808–15.CrossRefGoogle Scholar
  23. 23.
    Li J, Yang CH. Diagnosis and treatment of adrenocorticotrophic hormone-independent macronodular adrenocortical hyperplasia: a report of 23 cases in a single center. Exp Ther Med. 2015;9(2):507–12.CrossRefPubMedGoogle Scholar
  24. 24.
    Berr CM, Di Dalmazi G, Osswald A, Ritzel K, Bidlingmaier M, Geyer LL, et al. Time to recovery of adrenal function after curative surgery for Cushing’s syndrome depends on etiology. J Clin Endocrinol Metab. 2015;100(4):1300–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Neychev V, Steinberg SM, Yang L, Mehta A, Nilubol N, Keil MF, et al. Long-term outcome of bilateral laparoscopic adrenalectomy measured by disease-specific questionnaire in a unique group of patients with Cushing’s syndrome. Ann Surg Oncol. 2015;22(Suppl 3):S699–706.CrossRefPubMedGoogle Scholar
  26. 26.
    Krieger DT, Amorosa L, Linick F. Cyproheptadine-induced remission of Cushing’s disease. N Engl J Med. 1975;293(18):893–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Baudry C, Coste J, Bou Khalil R, Silvera S, Guignat L, Guibourdenche J, et al. Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol. 2012;167(4):473–81.CrossRefPubMedGoogle Scholar
  28. 28.
    van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol. 2011;164(4):621–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Valassi E, Crespo I, Gich I, Rodriguez J, Webb SM. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing’s syndrome. Clin Endocrinol. 2012;77(5):735–42.CrossRefGoogle Scholar
  30. 30.
    Verhelst JA, Trainer PJ, Howlett TA, Perry L, Rees LH, Grossman AB, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clin Endocrinol. 1991;35(2):169–78.CrossRefGoogle Scholar
  31. 31.
    Monaghan PJ, Owen LJ, Trainer PJ, Brabant G, Keevil BG, Darby D. Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11beta-hydroxylase inhibitor metyrapone. Ann Clin Biochem. 2011;48(Pt 5):441–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab. 2014;99(5):1623–30.CrossRefPubMedGoogle Scholar
  33. 33.
    Dandona P, Mohiuddin J, Prentice HG. Ketoconazole and adrenocortical secretion. Lancet. 1985;1(8422):227.CrossRefPubMedGoogle Scholar
  34. 34.
    Feelders RA, Hofland LJ. Medical treatment of Cushing’s disease. J Clin Endocrinol Metab. 2013;98(2):425–38.CrossRefPubMedGoogle Scholar
  35. 35.
    Molitch ME. Current approaches to the pharmacological management of Cushing’s disease. Mol Cell Endocrinol. 2015;408:185–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Preda VA, Sen J, Karavitaki N, Grossman AB. Etomidate in the management of hypercortisolaemia in Cushing’s syndrome: a review. Eur J Endocrinol. 2012;167(2):137–43.CrossRefPubMedGoogle Scholar
  37. 37.
    Obata Y, Yamada Y, Baden MY, Hosokawa Y, Saisho K, Tamba S, et al. Long-term efficacy of trilostane for Cushing’s syndrome due to adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia. Intern Med. 2011;50(21):2621–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Bertagna X, Pivonello R, Fleseriu M, Zhang Y, Robinson P, Taylor A, et al. 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. 2014;99(4):1375–83.CrossRefPubMedGoogle Scholar
  39. 39.
    Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012;97(6):2039–49.CrossRefPubMedGoogle Scholar
  40. 40.
    Fleseriu M, Molitch ME, Gross C, Schteingart DE, Vaughan TB 3rd, Biller BM. A new therapeutic approach in the medical treatment of Cushing’s syndrome: glucocorticoid receptor blockade with mifepristone. Endocr Pract. 2013;19(2):313–26.CrossRefPubMedGoogle Scholar
  41. 41.
    Fleseriu M. Medical treatment of Cushing disease: new targets, new hope. Endocrinol Metab Clin N Am. 2015;44(1):51–70.CrossRefGoogle Scholar
  42. 42.
    Katznelson L, Loriaux DL, Feldman D, Braunstein GD, Schteingart DE, Gross C. Global clinical response in Cushing’s syndrome patients treated with mifepristone. Clin Endocrinol. 2014;80(4):562–9.CrossRefGoogle Scholar
  43. 43.
    Pivonello R, Ferone D, de Herder WW, Kros JM, De Caro ML, Arvigo M, et al. Dopamine receptor expression and function in corticotroph pituitary tumors. J Clin Endocrinol Metab. 2004;89(5):2452–62.CrossRefPubMedGoogle Scholar
  44. 44.
    Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev. 2003;24(1):28–47.CrossRefPubMedGoogle Scholar
  45. 45.
    Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914–24.CrossRefPubMedGoogle Scholar
  46. 46.
    Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98(8):3446–53.CrossRefPubMedGoogle Scholar
  47. 47.
    Breitschaft A, Hu K, Hermosillo Resendiz K, Darstein C, Golor G. Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. Diabetes Res Clin Pract. 2014;103(3):458–65.CrossRefPubMedGoogle Scholar
  48. 48.
    Kamenicky P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier JF, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 2011;96(9):2796–804.CrossRefPubMedGoogle Scholar
  49. 49.
    Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605–17.CrossRefPubMedGoogle Scholar
  50. 50.
    Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593–602.CrossRefPubMedGoogle Scholar
  51. 51.
    Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med. 2003;138(12):980–91.CrossRefPubMedGoogle Scholar
  52. 52.
    Lacroix A, Bourdeau I. Bilateral adrenal Cushing’s syndrome: macronodular adrenal hyperplasia and primary pigmented nodular adrenocortical disease. Endocrinol Metab Clin N Am. 2005;34(2):441–58. x.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Endocrinology, Department of MedicineNorthwestern UniversityChicagoUSA

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