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Review

Current strategies for the treatment of severe Cushing’s syndrome

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References

• Cushing’s syndrome treatment should target on excision of the primary source of hypercortisolemia.

  • Sarlis NJ, Chanock SJ, Nieman LK. Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J Clin Endocrinol Metab. 2000;85:42–47.
  • Van Zaane B, Nur E, Squizzato A, et al. Hypercoagulable state in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab. 2009;94:2743–2750.
  • Kamenický P, Droumaguet C, Salenave S, 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;96:2796–2804.
  • Alexandraki KI, Grossman AB. Emergency treatment of florid Cushing’s syndrome in endocrine and metabolic medical emergencies: a clinician’s guide. Endocrine Press; 2014. DOI:10.1210/EME.9781936704811.
  • Hall JJ, Hughes CA, Foisy MM, et al. Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir. Int J STD AIDS. 2013;24:748–752.
  • Steffensen C, Bak AM, Rubeck KZ, et al. Epidemiology of Cushing’s syndrome. Neuroendocrinology. 2010;92(Suppl 1):1–5.
  • Lindholm J, Juul S, Jørgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86:117–123.
  • Alexandraki KI, Grossman AB. The ectopic ACTH syndrome. Rev Endocr Metab Disord. 2010;11:117–126.
  • Kaltsas GA, Nomikos P, Kontogeorgos G, et al. Clinical review: Diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab. 2005;90:3089–3099.
  • Corcuff JB, Young J, Masquefa-Giraud P, et al. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. Eur J Endocrinol. 2015;172:473–478.
  • Alexandraki KI, Grossman AB. Cushing’s syndrome. In: Bandeira F, Gharib H, Golbert A, et al., editors. Endocrinology and diabetes: a problem oriented approach. New York (NY): Springer Science+Business Media; 2014. p. 99–111.
  • Christ-Crain M, Jutla S, Widmer I, et al. Measurement of serum free cortisol shows discordant responsivity to stress and dynamic evaluation. J Clin Endocrinol Metab. 2007;92:1729–1735.
  • Boonen E, Bornstein SR, Van den Berghe G. New insights into the controversy of adrenal function during critical illness. Lancet Diabetes Endocrinol. 2015;3:805–815.
  • Arlt A, Harbeck B, Anlauf M, et al. Fatal pneumocystis jirovecii pneumonia in a case of ectopic Cushing’s syndrome due to neuroendocrine carcinoma of the kidney. Exp Clin Endocrinol Diabetes. 2008;116:515–519.
  • van Haalen FM, Broersen LH1, Jorgensen JO, et al. Management of endocrine disease: mortality remains increased in Cushing’s disease despite biochemical remission: a systematic review and meta-analysis. Eur J Endocrinol. 2015;172:R143–9.
  • Yaneva M, Kalinov K, Zacharieva S. Mortality in Cushing’s syndrome: data from 386 patients from a single tertiary referral center. Eur J Endocrinol. 2013;169:621–627.
  • Alexandraki KI, Grossman AB. Novel insights in the diagnosis of Cushing’s syndrome. Neuroendocrinology. 2010;92(Suppl 1):35–43.
  • Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:1526–1540.
  • Carroll T, Raff H, Findling JW. Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis. Endocr Pract. 2009;15:335–342.
  • Reincke M, Ritzel K, Osswald A, et al. A critical re-appraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur J Endocrinol. 2015;173:M23–M32.

• Bilateral adrenalectomy is a relatively safe and highly effective treatment and provides adequate control of long-term comorbidities associated with hypercortisolism.

  • Stuijver DJ, van Zaane B, Feelders RA, et al. Incidence of venous thromboembolism in patients with Cushing’s syndrome: a multicenter cohort study. J Clin Endocrinol Metab. 2011;96:3525–3532.
  • van der Pas R, de Herder WW, Hofland LJ, et al. New developments in the medical treatment of Cushing’s syndrome. Endocr Relat Cancer. 2012;19:R205–23.
  • Pai M, Douketis JD, Section Editors Lawrence LK Leung, Jess Mandel, Deputy Editor Geraldine Finlay. Prevention of venous thromboembolic disease in medical patients. Topic 1346 version 40.0. Literature review current through Mar 2013, This topic last updated Feb 12, 2013.
  • Oosterhuis JK, van den Berg G, Monteban-Kooistra WE, et al. Life-threatening Pneumocystis jiroveci pneumonia following treatment of severe Cushing’s syndrome. Neth J Med. 2007;65(6):215–217.
  • Drake WM, Perry LA, Hinds CJ, et al. Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing’s syndrome and peritonitis. J Clin Endocrinol Metab. 1998;83:3542–3544.
  • Nagy-Mignotte H, Shestaeva O, Vignoud L, et al. Prognostic impact of paraneoplastic Cushing’s syndrome in small-cell lung cancer. J Thorac Oncol. 2014;9:497–505.
  • Alexandraki KI, Grossman AB. Medical therapy for Cushing’s disease: past and future modes of treatment. Eur Endocrinol. 2009;4:74–80.
  • Cuevas-Ramos D, Fleseriu M. Treatment of Cushing’s disease: a mechanistic update. J Endocrinol. 2014;223:R19–39.
  • Jeffcoate WJ, Rees LH, Tomlin S, et al Metyrapone in long-term management of Cushing’s disease. Br J Med. 1977;2:215–217.
  • Donckier J, Burrin JM, Ramsay ID, et al. Successful control of Cushing’s disease in the elderly with long term metyrapone. Postgrad Med J. 1986;62:727–730.
  • Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in the treatment of Cushing’s syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab. 2015;100:4146–4154.
  • 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. 1991;35:169–178.
  • Connell JM, Cordiner J, Davies DL, et al. Pregnancy complicated by Cushing’s syndrome: potential hazard of metyrapone therapy. Case report. Br J Obstet Gynaecol. 1985;92:1192–1195.
  • Monaghan PJ, Owen LJ, Trainer PJ, et al. Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone. Ann Clin Biochem. 2011;48:441–446.
  • 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.
  • Jimenez Reina L, Leal-Cerro A, Garcia J, et al. In vitro effects of ketoconazole on corticotrope cell morphology and ACTH secretion of two pituitary adenomas removed from patients with Nelson’s syndrome. Acta Endocrinol (Copenh). 1989;121:185–190.
  • Loose DS, Stover EP, Feldman D. Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells. J Clin Invest. 1983;72:404–408.
  • Castinetti F, Morange I, Jaquet P, et al. Ketoconazole revisited: a preoperative or postoperative treatment in Cushing’s disease. Eur J Endocrinol. 2008;158:91–99.
  • Duarte PA, Chow CC, Simmons F, et al. Fatal hepatitis associated with ketoconazole therapy. Arch Intern Med. 1984;144:1069–1070.
  • 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.
  • Lamberts SW, Bons EG, Bruining HA, et al. 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. 1987;240:259–264.
  • Klausen NO, Moelgaard J, Ferguson AH, et al. Negative synacthen test during etomidate infusion. Lancet. 1983;2:848.
  • Krakoff J, Koch CA, Calis KA, et al. Use of a parenteral propylene glycol-containing etomidate preparation for the long-term management of ectopic Cushing’s syndrome. J Clin Endocrinol Metab. 2001;86:4104–4108.
  • Johnson TN, Canada TW. Etomidate use for Cushing’s syndrome caused by an ectopic adrenocorticotropic hormone-producing tumor. Ann Pharmacother. 2007;41:350–353.
  • Greening JE, Brain CE, Perry LA, et al. Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing’s disease. Horm Res. 2005;64:140–143.
  • Preda VA, Sen J, Karavitaki N, et al., et al. Etomidate in the management or hypercortisolaemia in Cushing’s syndrome: a review. Eur J Endocrinol. 2012;167:137–143.
  • Schulte HM, Benker G, Reinwein D, et al. Infusion of low dose etomidate: correction of hypercortislemia in patients with Cushing’s syndrome and dose–response relationship in normal subjects. J Clin Endocrinol Metab. 1990;70:1426–1430.
  • Bertagna X, Bertagna C, Laudat MH, et al. Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing’s syndrome. J Clin Endocrinol Metab. 1986;63:639–643.
  • 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.
  • de Bruin C, Hofland LJ, Nieman LK, et al. Mifepristone effects on tumor somatostatin receptor expression in two patients with Cushing’s syndrome due to ectopic adrenocorticotropin secretion. J Clin Endocrinol Metab. 2012;97:455–462.
  • Castinetti F, Fassnacht M, Johanssen S, et al Merits and pitfalls of mifepristone in Cushing’s syndrome. Eur J Endocrinol. 2009;160:1003–1010.
  • Chu JW, Matthias DF, Belanoff J, et al. Successful long-term treatment of refractory Cushing’s disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab. 2001;86:3568–3573.
  • Fleseriu M, Findling JW, Koch CA, et al. 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. 2014;99:3718–3727.

• Long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with Cushing’s disease and remained stable over time without evidence of tumor growth.

  • Cueto C, Brown JHU. Biological studies on an adrenocorticolytic agent and the isolation of the active components. Endocrinology. 1958;62:326–333.
  • Fassnacht M, Libe R, Kroiss M, et al. Adrenocortical carcinoma: a clinician’s update. Nat Rev Endocrinol. 2011;7:323–335.
  • Chortis V, Taylor AE, Schneider P, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5_-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab. 2013;98:161–171.
  • Tripto-Shkolnik L, Blumenfeld Z, Bronshtein M, et al. Pregnancy in a patient with adrenal carcinoma treated with mitotane: a case report and review of literature. J Clin Endocrinol Metab. 2013;98:443–447.
  • Alexandraki KI, Kaltsas GA, le Roux CW, et al. Assessment of serum-free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study. Clin Endocrinol (Oxf). 2010;72:305–311.
  • Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. 1999;20:157–198.
  • Miller GM, Alexander JM, Bikkal HA, et al. Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab. 1995;80:1386–1392.
  • Schonbrunn A. Glucocorticoids down-regulate somatostatin receptors on pituitary cells in culture. Endocrinology. 1982;110:1147–1154.
  • Stalla GK, Brockmeier SJ, Renner U, et al. Octreotide exerts different effects in vivo and in vitro in Cushing’s disease. Eur J Endocrinol. 1994;130:125–131.
  • van der Pas R, Feelders RA, Gatto F, et al Preoperative normalization of cortisol levels in Cushing’s disease after medical treatment: consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamine agonists. J Clin Endocrinol Metab. 2013;98:E1880–90.
  • Park S, Kamegai J, Kineman RD. Role of glucocorticoids in the regulation of pituitary somatostatin receptor subtype (sst1-sst5) mRNA levels: evidence for direct and somatostatin-mediated effects. Neuroendocrinology. 2003;78:163–175.
  • Batista DL, Zhang X, Gejman R, et al. The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pitutiary adenomas. J Clin Endocrinol Metab. 2006;91:4482–4488.
  • Lamberts SW, Uitterlinden P, Klijn JM. The effect of the long-acting somatostatin analogue SMS 201-995 on ACTH secretion in Nelson’s syndrome and Cushing’s disease. Acta Endocrinol (Copenh). 1989;120:760–766.
  • Invitti C, De Martin M, Brunani A, et al. Treatment of Cushing’s syndrome with the long-acting somatostatin analogue SMS 201-995 (sandostatin). Clin Endocrinol (Oxf). 1990;32:275–281.
  • Ambrosi B, Bochicchio D, Fadin C, et al. Failure of somatostatin and octreotide to acutely affect the hypothalamic-pituitary-adrenal function in patients with corticotropin hypersecretion. J Endocrinol Invest. 1990;13:257–261.
  • van der Hoek J, Waaijers M, van Koetsveld PM, et al Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. Am J Physiol Endocrinol Metab. 2005;289:E278–87.
  • 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.
  • 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.
  • Simeoli C, Auriemma RS, Tortora F, et al. The treatment with pasireotide in Cushing’s disease: effects of long-term treatment on tumor mass in the experience of a single center. Endocrine. 2015;50:725–740.

• Pasireotide cause marked tumor shrinkage after 1 year of treatment, while it may drive in tumor mass disappearance.

  • de Bruin C, Feelders RA, Lamberts SW, et al. Somatostatin and dopamine receptors as targets for medical treatment of Cushing’s syndrome. Rev Endocr Metab Disord. 2009;10:91–102.
  • Colao A, De Block C, Gaztambide MS, et al. Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary. 201;17:180–186.
  • 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.
  • Plöckinger U, Hoffmann U, Geese M, et al. DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours. Eur J Endocrinol. 2012;166:223–234.
  • Caron MG, Beaulieu M, Raymond V, et al. Dopaminergic receptors in the anterior pituitary gland. Correlation of [3H]dihydroergocryptine binding with the dopaminergic control of prolactin release. J Biol Chem. 1978;253:2244–2253.
  • Stefaneanu L, Kovacs K, Horvath E, et al. Dopamine D2 receptor gene expression in human adenohypophysial adenomas. Endocrine. 2001;14:329–336.
  • 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.
  • Cronin MJ, Cheung CY, Wilson CB, et al. [3H]Spiperone binding to human anterior pituitaries and pituitary adenomas secreting prolactin, growth hormone, and adrenocorticotropic hormone. J Clin Endocrinol Metab. 1980;50:387–391.
  • Pirker W, Riedl M, Luger A, et al. Dopamine D2 receptor imaging in pituitary adenomas using iodine-123-epidepride and SPECT. J Nucl Med. 1996;37:1931–1937.
  • Kawamura M, Nakano T, Miki H, et al. Bromocriptine-responsive Cushing’s disease; clinical and biochemical remission accompanied by amelioration of impaired ocular movement. Intern Med. 2007;46:1117–1122.
  • Boscaro M, Benato M, Mantero F. Effect of bromocriptine in pituitary-dependent Cushing’s syndrome. Clin Endocrinol (Oxf). 1983;19:485–491.
  • Illouz F, Dubois-Ginouves S, Laboureau S, et al. Use of cabergoline in persisting Cushing’s disease. Ann Endocrinol (Paris). 2006;67:353–356.
  • 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.
  • 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.
  • 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.
  • Delgado V, Biermasz NR, van Thiel SW, et al. Changes in heart valve structure and function in patients treated with dopamine agonists for prolactinomas, a 2-year follow-up study. Clin Endocrinol (Oxf). 2012;77:99–105.
  • Pivonello R, Ferone D, de Herder WW, et al. Dopamine receptor expression and function in corticotroph ectopic tumors. J Clin Endocrinol Metab. 2007;92:65–69.
  • 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.

• Cabergoline and ketoconazole combination treatment is more effective than either treatment alone with no difference whether initial treatment is the one or the other.

  • Diakatou E, Alexandraki KI, Tsolakis AV, et al. Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores. Clin Endocrinol (Oxf). 2015;83:420–428.
  • Riedl M, Maier C, Zettinig G, et al. Long term control of hypercortisolism with fluconazole: case report and in vitro studies. Eur J Endocrinol. 2006;154:519–524.
  • Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation. 2011;124:1945–1955.
  • Bertagna X, Pivonello R, Fleseriu M, et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014;99:1375–1383.

• LCI699 given in 12 patients achieved UFC normalization in 92% of patients.

  • Li L, Vashisht K, Boisclair J, et al. Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats. Toxicol Appl Pharmacol. 2015;286:224–233.
  • Syro LV, Ortiz LD, Scheithauer BW, et al. Treatment of pituitary neoplasms with temozolomide: a review. Cancer. 2011;117:454–462.
  • McCormack AI, Wass JA, Grossman AB. Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status. Eur J Clin Invest. 2011;41:1133–1148.
  • Dillard TH, Gultekin SH, Delashaw JB Jr, et al. Temozolomide for corticotroph pituitary adenomas refractory to standard therapy. Pituitary. 2011;14:80–91.
  • Curtò L, Torre ML, Ferraù F, et al. Temozolomide-induced shrinkage of a pituitary carcinoma causing Cushing’s disease – report of a case and literature review. Sci World J. 2010;10:2132–2138.
  • Alexandraki K, Boutzios G, Nikolopoulos G, et al. Optic neuropathy following radiotherapy for Cushing’s disease followed by the diagnosis of pituitary carcinoma. Endocr Abstr. 2015;37:EP754.
  • Alexandraki KI, Kaltsas G. Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy. Endocrine. 2012;41:40–52.
  • Fernando MA, Heaney AP. a1-Adrenergic receptor antagonists: novel therapy for pituitary adenomas. Mol Endocrinol. 2005;19:3085–3096.
  • Ortiz LD, Syro LV, Scheithauer BW, et al. Anti-VEGF therapy in pitutiary carcinoma. Pituitary. 2012;15:445–449.
  • Ferone D, Pivonello C, Vitale G, et al. Molecular basis of pharmacological therapy in Cushing’s disease. Endocrine. 2013;46:181–198.
  • Liu NA, Jiang H, Ben-Shlomo A, et al. Targeting zebrafish and murin pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Pnas. 2011;108:8414–8419.
  • Fukuoka H, Cooper O, Ben-Shlomo A, et al. EGFR as therapeutic target for human, canine, and mouse ACTH-secreting pitutiary adenomas. J Clin Invest. 2011;121:4712–4721.
  • Baudry C, Paepegaey AC, Groussin L. Reversal of Cushing’s syndrome syndrome by vandetanib in medullary thyroid carcinoma. N Engl J Med. 2013;369:584–586.
  • Nella AA, Lodish MB, Fox E, et al. Vandetanib successfully controls medullary thyroid cancer-related Cushing syndrome in an adolescent patient. J Clin Endocrinol Metab. 2014;99:3055–3059.
  • Barroso-Sousa R, Lerario AM, Evangelista J, et al. Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH (adrenocorticotropic hormone) syndrome. Thyroid. 2014;24:1062–1066.
  • Fassnacht M, Terzolo M, Allolio B, et al Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366:2189–2197.
  • Dworakowska D, Dudka D, Weistman G, et al. The anti-proliferative effect of anti-EGFR tyrosine kinase inhibitor in combination with mitotane on H295R adrenocortical cancer cells. Endocr Abstr. 2014;35:P586.
  • Ntali G, Asimakopoulou A, Siamatras T, et al. Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up. Eur J Endocrinol. 2013;169:715–723.
  • Morris LF, Harris RS, Milton DR, et al. Impact and timing of bilateral adrenalectomy for refractory adrenocorticotropic hormone-dependent Cushing’s syndrome. Surgery. 2013;154:1174–1183.
  • Farage M, Costa MA, Godoy-Matos AF. A rare case of Cushing syndrome by cyclic ectopic-ACTH. Arq Bras Endocrinol Metabol. 2012;56:324–330.
  • Corsello SM, Senes P, Iezzi R, et al., et al. Cushing’s syndrome due to a bronchial ACTH-secreting carcinoid successfully treated with radiofrequency ablation (RFA). J Clin Endocrinol Metab. 2014;99:E862–5.

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