Persistent Cushing’s Disease after Transsphenoidal Surgery: Challenges and Solutions

Abstract

Transsphenoidal surgery remains the primary treatment for Cushing’s disease (CD). However, despite the vast improvements in pituitary surgery, successful treatment of CD remains a great challenge. Although selective transsphenoidal removal of the pituitary tumor is a safe and effective procedure, the disease persists in around 22% of CD patients due to incomplete tumor resection. The persistence of hypercortisolism after pituitary surgery may also be the consequence of a misdiagnosis, as can occur in case of ectopic ACTH secretion or pseudo-Cushing. Considering the elevated mortality and morbidity characterizing the disease, a multidisciplinary approach is needed to minimize potential pitfalls occurring during the diagnosis, avoid surgical failure and provide the best care in those patients who have undergone unsuccessful surgery. In this review, we analyze the factors that could predict remission or persistence of CD after pituitary surgery and revise the therapeutic options in case of surgical failure.

Key words

Cushing’s disease - corticotroph tumor - persistence - remission - steroidogenesis inhibitors - pasireotide

Publication History

Received: 02 March 2020
Received: 08 July 2020

Accepted: 15 July 2020

Article published online:
24 August 2020

• References

• 1 Newell-Price J, Bertagna X, Grossman AB. et al. Cushing’s syndrome. Lancet 2006; 367: 1605-1617
• 2 Valassi E, Santos A, Yaneva M. et al. The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol 2011; 165: 383-392
• 3 Lacroix A, Feelders RA, Stratakis CA. et al. Cushing’s syndrome. Lancet 2015; 386: 913-927
• 4 Clayton RN, Raskauskiene D, Reulen RC. et al. Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: Audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96: 632-642
• 5 Nieman LK, Biller BM, Findling JW. et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100: 2807-2831
• 6 Lindholm J, Juul S, Jorgensen JO. et al. Incidence and late prognosis of cushing’s syndrome: A population-based study. J Clin Endocrinol Metab 2001; 86: 117-123
• 7 Hammer GD, Tyrrell JB, Lamborn KR. et al. Transsphenoidal microsurgery for Cushing’s disease: Initial outcome and long-term results. J Clin Endocrinol Metab 2004; 89: 6348-6357
• 8 Hassan-Smith ZK, Sherlock M, Reulen RC. et al. Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab 2012; 97: 1194-1201
• 9 Hardy J. Transphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg 1969; 16: 185-217
• 10 Cappabianca P, Cavallo LM, Colao A. et al. Endoscopic endonasal transsphenoidal approach: Outcome analysis of 100 consecutive procedures. Minim Invasive Neurosurg 2002; 45: 193-200
• 11 Wagenmakers MA, Boogaarts HD, Roerink SH. et al. Endoscopic transsphenoidal pituitary surgery: A good and safe primary treatment option for Cushing’s disease, even in case of macroadenomas or invasive adenomas. Eur J Endocrinol 2013; 169: 329-337
• 12 Biller BM, Grossman AB, Stewart PM. et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: A consensus statement. J Clin Endocrinol Metab 2008; 93: 2454-2462
• 13 Esposito F, Dusick JR, Cohan P. et al. Clinical review: Early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing’s disease. J Clin Endocrinol Metab 2006; 91: 7-13
• 14 Lambert JK, Goldberg L, Fayngold S. et al. Predictors of mortality and long-term outcomes in treated Cushing’s disease: A study of 346 patients. J Clin Endocrinol Metab 2013; 98: 1022-1030
• 15 Dimopoulou C, Schopohl J, Rachinger W. et al. Long-term remission and recurrence rates after first and second transsphenoidal surgery for Cushing’s disease: Care reality in the Munich Metropolitan Region. Eur J Endocrinol 2014; 170: 283-292
• 16 Rees DA, Hanna FW, Davies JS. et al. Long-term follow-up results of transsphenoidal surgery for Cushing’s disease in a single centre using strict criteria for remission. Clin Endocrinol (Oxf) 2002; 56: 541-551
• 17 Trainer PJ, Lawrie HS, Verhelst J. et al. Transsphenoidal resection in Cushing’s disease: Undetectable serum cortisol as the definition of successful treatment. Clin Endocrinol (Oxf) 1993; 38: 73-78
• 18 Alexandraki KI, Kaltsas GA, Isidori AM. et al. Long-term remission and recurrence rates in Cushing’s disease: Predictive factors in a single-centre study. Eur J Endocrinol 2013; 168: 639-648
• 19 Pereira AM, van Aken MO, van Dulken H. et al. Long-term predictive value of postsurgical cortisol concentrations for cure and risk of recurrence in Cushing’s disease. J Clin Endocrinol Metab 2003; 88: 5858-5864
• 20 Carrasco CA, Coste J, Guignat L. et al. Midnight salivary cortisol determination for assessing the outcome of transsphenoidal surgery in Cushing’s disease. J Clin Endocrinol Metab 2008; 93: 4728-4734
• 21 Amlashi FG, Swearingen B, Faje AT. et al. Accuracy of late-night salivary cortisol in evaluating postoperative remission and recurrence in Cushing’s Disease. J Clin Endocrinol Metab 2015; 100: 3770-3777
• 22 Petersenn S, Beckers A, Ferone D. et al. Therapy of endocrine disease: Outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: Systematic review assessing criteria used to define remission and recurrence. Eur J Endocrinol 2015; 172: R227-R239
• 23 Abu Dabrh AM, Singh Ospina NM, Al Nofal A. et al. Predictors of biochemical remission and recurrence after surgical and radiation treatments of cushing disease: A systematic review and meta-analysis. Endocr Pract 2016; 22: 466-475
• 24 Bertagna X, Guignat L. Approach to the Cushing’s disease patient with persistent/recurrent hypercortisolism after pituitary surgery. J Clin Endocrinol Metab 2013; 98: 1307-1318
• 25 Dickerman RD, Oldfield EH. Basis of persistent and recurrent Cushing disease: An analysis of findings at repeated pituitary surgery. J Neurosurg 2002; 97: 1343-1349
• 26 Rollin G, Ferreira NP, Czepielewski MA. Prospective evaluation of transsphenoidal pituitary surgery in 108 patients with Cushing’s disease. Arq Bras Endocrinol Metabol 2007; 51: 1355-1361
• 27 Hofmann BM, Hlavac M, Martinez R. et al. Long-term results after microsurgery for Cushing disease: Experience with 426 primary operations over 35 years. J Neurosurg 2008; 108: 9-18
• 28 Johnston PC, Kennedy L, Hamrahian AH. et al. Surgical outcomes in patients with Cushing’s disease: The Cleveland clinic experience. Pituitary 2017; 20: 430-440
• 29 Chee GH, Mathias DB, James RA. et al. Transsphenoidal pituitary surgery in Cushing’s disease: Can we predict outcome?. Clin Endocrinol (Oxf) 2001; 54: 617-626
• 30 Prevedello DM, Pouratian N, Sherman J. et al. Management of Cushing’s disease: Outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J Neurosurg 2008; 109: 751-759
• 31 Sonino N, Zielezny M, Fava GA. et al. Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J Clin Endocrinol Metab 1996; 81: 2647-2652
• 32 Vilar L, Freitas Mda C, Faria M. et al. Pitfalls in the diagnosis of Cushing’s syndrome. Arq Bras Endocrinol Metabol 2007; 51: 1207-1216
• 33 Meinardi JR, Wolffenbuttel BH, Dullaart RP. Cyclic Cushing’s syndrome: a clinical challenge. Eur J Endocrinol 2007; 157: 245-254
• 34 Albani A, Berr CM, Beuschlein F. et al. A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome. BMC Endocr Disord 2019; 19: 105
• 35 Newell-Price J, Trainer P, Besser M. et al. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 1998; 19: 647-672
• 36 Valassi E, Swearingen B, Lee H. et al. Concomitant medication use can confound interpretation of the combined dexamethasone-corticotropin releasing hormone test in Cushing’s syndrome. J Clin Endocrinol Metab 2009; 94: 4851-4859
• 37 Berlinska A, Swiatkowska-Stodulska R, Sworczak K Factors affecting dexamethasone suppression test results. Exp Clin Endocrinol Diabetes 2019 Oct 25. doi: 10.1055/a-1017-3217
• 38 Casanueva FF, Barkan AL, Buchfelder M. et al. Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement. Pituitary 2017; 20: 489-498
• 39 Buchfelder M, Schlaffer S. Pituitary surgery for Cushing’s disease. Neuroendocrinology 2010; 92 Suppl 1: 102-106
• 40 Perez-Rivas LG, Theodoropoulou M, Ferrau F. et al. The Gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing’s Disease. J Clin Endocrinol Metab 2015; 100: E997-E1004
• 41 Perez-Rivas LG, Theodoropoulou M, Puar TH. et al. Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor. Eur J Endocrinol 2018; 178: 59-65
• 42 Faucz FR, Tirosh A, Tatsi C. et al. Somatic USP8 gene mutations are a common cause of pediatric cushing disease. J Clin Endocrinol Metab 2017; 102: 2836-2843
• 43 Albani A, Perez-Rivas LG, Dimopoulou C, et al. The USP8 mutational status may predict long-term remission in patients with Cushing’s disease. Clin Endocrinol (Oxf) 2018
• 44 Rubinstein G, Osswald A, Zopp S. et al. Therapeutic options after surgical failure in Cushing’s disease: A critical review. Best Pract Res Clin Endocrinol Metab 2019; 33: 101270
• 45 Liu JK, Fleseriu M, Delashaw JB. et al. Treatment options for Cushing disease after unsuccessful transsphenoidal surgery. Neurosurg Focus 2007; 23: E8
• 46 McLaughlin N, Kassam AB, Prevedello DM. et al. Management of Cushing’s disease after failed surgery−a review. Can J Neurol Sci 2011; 38: 12-21
• 47 Ram Z, Nieman LK, Cutler GB. et al. Early repeat surgery for persistent Cushing’s disease. J Neurosurg 1994; 80: 37-45
• 48 Friedman RB, Oldfield EH, Nieman LK. et al. Repeat transsphenoidal surgery for Cushing’s disease. J Neurosurg 1989; 71: 520-527
• 49 Pivonello R, De Leo M, Cozzolino A. et al. The Treatment of Cushing’s Disease. Endocr Rev 2015; 36: 385-486
• 50 Knappe UJ, Ludecke DK. Persistent and recurrent hypercortisolism after transsphenoidal surgery for Cushing’s disease. Acta Neurochir Suppl 1996; 65: 31-34
• 51 Locatelli M, Vance ML, Laws ER. Clinical review: The strategy of immediate reoperation for transsphenoidal surgery for Cushing’s disease. J Clin Endocrinol Metab 2005; 90: 5478-5482
• 52 Benveniste RJ, King WA, Walsh J. et al. Repeated transsphenoidal surgery to treat recurrent or residual pituitary adenoma. J Neurosurg 2005; 102: 1004-1012
• 53 Wagenmakers MA, Netea-Maier RT, van Lindert EJ. et al. Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: A good therapeutic option for recurrent or persistent Cushing’s disease (CD). Clin Endocrinol (Oxf) 2009; 70: 274-280
• 54 Valderrabano P, Aller J, Garcia-Valdecasas L. et al. Results of repeated transsphenoidal surgery in Cushing’s disease. Long-term follow-up. Endocrinol Nutr 2014; 61: 176-183
• 55 Mahmoud-Ahmed AS, Suh JH. Radiation therapy for Cushing’s disease: A review. Pituitary 2002; 5: 175-180
• 56 Vance ML. Cushing’s disease: Radiation therapy. Pituitary 2009; 12: 11-14
• 57 Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 2011; 96: 1992-2003
• 58 Hentschel SJ, McCutcheon IE. Stereotactic radiosurgery for Cushing disease. Neurosurg Focus 2004; 16: E5
• 59 Starke RM, Williams BJ, Vance ML. et al. Radiation therapy and stereotactic radiosurgery for the treatment of Cushing’s disease: An evidence-based review. Curr Opin Endocrinol Diabetes Obes 2010; 17: 356-364
• 60 Oyesiku NM. Stereotactic radiosurgery for Cushing disease: A review. Neurosurg Focus 2007; 23: E14
• 61 Ironside N, Chen CJ, Lee CC. et al. Outcomes of Pituitary Radiation for Cushing’s Disease. Endocrinol Metab Clin North Am 2018; 47: 349-365
• 62 Castinetti F, Nagai M, Dufour H. et al. Gamma knife radiosurgery is a successful adjunctive treatment in Cushing’s disease. Eur J Endocrinol 2007; 156: 91-98
• 63 Mehta GU, Ding D, Patibandla MR. et al. Stereotactic Radiosurgery for Cushing Disease: Results of an International, Multicenter Study. J Clin Endocrinol Metab 2017; 102: 4284-4291
• 64 Moore JM, Sala E, Amorin A. et al. CyberKnife Radiosurgery in the Multimodal Management of Patients with Cushing Disease. World Neurosurg 2018; 112: e425-e430
• 65 Raffa G, Cotta OA, Ferrau F. et al. Cyberknife stereotactic treatment of pituitary adenomas: A single center experience using different irradiation schemes and modalities. Interdisciplinary Neurosurgery 2019; 16 (June) 31-41
• 66 Shepard MJ, Mehta GU, Xu Z. et al. Technique of Whole-Sellar Stereotactic Radiosurgery for Cushing Disease: Results from a Multicenter, International Cohort Study. World Neurosurg 2018; 116: e670-e679
• 67 Murayama M, Yasuda K, Minamori Y. et al. Long term follow-up of Cushing’s disease treated with reserpine and pituitary irradiation. J Clin Endocrinol Metab 1992; 75: 935-942
• 68 Estrada J, Boronat M, Mielgo M. et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med 1997; 336: 172-177
• 69 Thakkar K, Lila A, Sarathi V. et al. Cabergoline may act as a radioprotective agent in Cushing’s disease. Clin Endocrinol (Oxf) 2020; 92: 55-62
• 70 Sheehan JP, Xu Z, Salvetti DJ. et al. Results of gamma knife surgery for Cushing’s disease. J Neurosurg 2013; 119: 1486-1492
• 71 Castinetti F, Nagai M, Morange I. et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 2009; 94: 3400-3407
• 72 Pont A, Williams PL, Loose DS. et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982; 97: 370-372
• 73 Loose DS, Kan PB, Hirst MA. et al. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 1983; 71: 1495-1499
• 74 Castinetti F, Guignat L, Giraud P. et al. Ketoconazole in Cushing’s disease: Is it worth a try?. J Clin Endocrinol Metab 2014; 99: 1623-1630
• 75 Young J, Bertherat J, Vantyghem MC. et al. Hepatic safety of ketoconazole in Cushing’s syndrome: Results of a Compassionate Use Programme in France. Eur J Endocrinol 2018; 178: 447-458
• 76 Liddle GW, Island D, Lance EM. et al. Alterations of adrenal steroid patterns in man resulting from treatment with a chemical inhibitor of 11 beta-hydroxylation. J Clin Endocrinol Metab 1958; 18: 906-912
• 77 Verhelst JA, Trainer PJ, Howlett TA. et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 1991; 35: 169-178
• 78 Daniel E, Aylwin S, Mustafa O. et al. Effectiveness of Metyrapone in Treating Cushing’s Syndrome: A Retrospective Multicenter Study in 195 Patients. J Clin Endocrinol Metab 2015; 100: 4146-4154
• 79 Preda VA, Sen J, Karavitaki N. et al. Etomidate in the management of hypercortisolaemia in Cushing’s syndrome: A review. Eur J Endocrinol 2012; 167: 137-143
• 80 Hahner S, Fassnacht M. Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs 2005; 6: 386-394
• 81 Fukushima DK, Bradlow HL, Hellman L. Effects of o,p’-DDD on cortisol and 6-beta-hydroxycortisol secretion and metabolism in man. J Clin Endocrinol Metab 1971; 32: 192-200
• 82 Southren AL, Tochimoto S, Strom L. et al. Remission in Cushing’s syndrome with o,p’-DDD. J Clin Endocrinol Metab 1966; 26: 268-278
• 83 Orth DN, Liddle GW. Results of treatment in 108 patients with Cushing’s syndrome. N Engl J Med 1971; 29: 243-247
• 84 Baudry C, Coste J, Bou Khalil R. et al. Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol 2012; 167: 473-481
• 85 Bertagna X, Bertagna C, Luton JP. et al. The new steroid analog RU 486 inhibits glucocorticoid action in man. J Clin Endocrinol Metab 1984; 59: 25-28
• 86 Cadepond F, Ulmann A, Baulieu EE. RU486 (mifepristone): Mechanisms of action and clinical uses. Annu Rev Med 1997; 48: 129-156
• 87 Fleseriu M, Biller BM, Findling JW. et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2012; 97: 2039-2049
• 88 Castinetti F, Brue T, Conte-Devolx B. The use of the glucocorticoid receptor antagonist mifepristone in Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes 2012; 19: 295-299
• 89 Carmichael JD, Fleseriu M. Mifepristone: is there a place in the treatment of Cushing’s disease?. Endocrine 2013; 44: 20-32
• 90 Theodoropoulou M, Reincke M. Tumor-Directed Therapeutic Targets in Cushing Disease. J Clin Endocrinol Metab 2019; 104: 925-933
• 91 Pivonello R, Ferone D, de Herder WW. et al. Dopamine receptor expression and function in corticotroph pituitary tumors. J Clin Endocrinol Metab 2004; 89: 2452-2462
• 92 Pivonello R, De Martino MC, Cappabianca P. et al. 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 2009; 94: 223-230
• 93 Godbout A, Manavela M, Danilowicz K. et al. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol 2010; 163: 709-716
• 94 Barbot M, Albiger N, Ceccato F. et al. Combination therapy for Cushing’s disease: Effectiveness of two schedules of treatment: Should we start with cabergoline or ketoconazole?. Pituitary 2014; 17: 109-117
• 95 Hofland LJ, van der Hoek J, Feelders R. et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol 2005; 152: 645-654
• 96 Bruns C, Lewis I, Briner U. et al. SOM230: A novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol 2002; 146: 707-716
• 97 Schmid HA, Schoeffter P. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors. Neuroendocrinology. 2004; 80 Suppl 1 47-50
• 98 Batista DL, Zhang X, Gejman R. et al. The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab 2006; 91: 4482-4488
• 99 Castillo V, Theodoropoulou M, Stalla J. et al. Effect of SOM230 (pasireotide) on corticotropic cells: Action in dogs with Cushing’s disease. Neuroendocrinology. 2011; 94: 124-136
• 100 Boscaro M, Ludlam WH, Atkinson B. et al. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): A multicenter, phase II trial. J Clin Endocrinol Metab 2009; 94: 115-122
• 101 Feelders RA, de Bruin C, Pereira AM. et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med 2010; 362: 1846-1848
• 102 Colao A, Petersenn S, Newell-Price J. et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012; 366: 914-924
• 103 Boscaro M, Bertherat J, Findling J. et al. Extended treatment of Cushing’s disease with pasireotide: Results from a 2-year, Phase II study. Pituitary 2014; 17: 320-326
• 104 Schopohl J, Gu F, Rubens R. et al. Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial. Pituitary 2015; 18: 604-612
• 105 Pivonello R, Arnaldi G, Scaroni C. et al. The medical treatment with pasireotide in Cushing’s disease: An Italian multicentre experience based on “real-world evidence”. Endocrine 2019; 64: 657-672
• 106 Albani A, Ferrau F, Ciresi A. et al. Pasireotide treatment reduces cardiometabolic risk in Cushing’s disease patients: An Italian, multicenter study. Endocrine 2018; 61: 118-124
• 107 Lacroix A, Gu F, Gallardo W. et al. Efficacy and safety of once-monthly pasireotide in Cushing’s disease: A 12 month clinical trial. Lancet Diabetes Endocrinol 2018; 6: 17-26
• 108 Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly. Pituitary 2016; 19: 536-543
• 109 Petersenn S, Salgado LR, Schopohl J. et al. Long-term treatment of Cushing’s disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial. Endocrine 2017; 57: 156-165
• 110 Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing’s syndrome and pheochromocytoma. N Engl J Med 1992; 327: 1033
• 111 Ritzel K, Beuschlein F, Mickisch A. et al. Clinical review: Outcome of bilateral adrenalectomy in Cushing’s syndrome: A systematic review. J Clin Endocrinol Metab 2013; 98: 3939-3948
• 112 Osswald A, Plomer E, Dimopoulou C. et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. Eur J Endocrinol 2014; 171: 209-215
• 113 Hahner S, Spinnler C, Fassnacht M. et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: A prospective study. J Clin Endocrinol Metab 2015; 100: 407-416
• 114 Nelson DH, Meakin JW, Dealy JB. et al. ACTH-producing tumor of the pituitary gland. N Engl J Med 1958; 259: 161-164
• 115 Assie G, Bahurel H, Coste J. et al. Corticotroph tumor progression after adrenalectomy in Cushing’s Disease: A reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 2007; 92: 172-179
• 116 Vilar L, Naves LA, Azevedo MF. et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary 2010; 13: 123-129
• 117 Lila AR, Gopal RA, Acharya SV. et al. Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy. Endocr Pract 2010; 16: 968-976