endosergЭндокринная хирургияEndocrine Surgery2306-35132310-3965Типография «Печатных дел Мастер»10.14341/serg2016113-22endoserg-7874Research ArticleОбзоры литературыReview of literatureАктуальность и перспективные направления изучения проблемы субклинического синдрома Кушинга.Relevance and perspective concept of investigation of subclinical Cushing syndrome.КузнецовНиколай СергеевичKuznetsovNikolay S.

д.м.н., заведующий отделом хирургии, Институт клинической эндокринологии

MD, PhD

kuznetcov-enc@yandex.ruЛаткинаНонна ВадимовнаLatkinaNonna V.

к.м.н., старший научный сотрудник, отдел хирургии, Институт клинической эндокринологии

MD, PhD

latkina_enc@mail.ruКаминарскаяЮлия АндреевнаKaminarskayaYulya A.

врач-эндокринолог

MD

osipovaulia@gmail.comФГБУ “Эндокринологический научный центр” Минздрава РоссииРоссияEndocrinology Research CentreRussian FederationГАУЗ МО “Химкинская центральная клиническая больница”, Московская областьРоссияKhimki Central Clinical HospitalRussian Federation2016250220161011322Copyright © Кузнецов Н.С., Латкина Н.В., Каминарская Ю.А., 20162016Кузнецов Н.С., Латкина Н.В., Каминарская Ю.А.Kuznetsov N.S., Latkina N.V., Kaminarskaya Y.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.surg-endojournals.ru/jour/article/view/7874

Субклинический синдром Кушинга наиболее часто выявляется (от 5 до 25% случаев) среди инциденталом надпочечников. Клиническая значимость данного состояния была подтверждена многочисленными исследованиями, показавшими “метаболические последствия” хронической автономной гиперсекреции кортизола. Этим больным в большей степени, в сравнении с общей популяцией, свойственны такие проявления метаболического синдрома как ожирение, нарушение углеводного обмена, гипертония, что определяет их в группу высокого кардиоваскулярного риска. Все это требует от практикующих врачей тщательного обследования пациентов с инциденталомами надпочечников на предмет гормональной активности образования, а также определения показаний к проведению оперативного вмешательства. Однако единого мнения о тактике ведения этой группы пациентов не существует. Патогенез субклинического синдрома Кушинга остается неясным. Понимание механизмов развития кортизол-продуцирующих опухолей позволило бы выявить клинико-генетическую неоднородность данной когорты, определить прогноз заболевания и показания к проведению хирургической операции, разработать медикаментозные методы лечения. Целью этой обзорной статьи является рассмотрение современных взглядов на диагностику, патогенез и лечение субклинического синдрома Кушинга, определение перспективных направлений работы.

Subclinical Cushing’s syndrome is the most widespread variant of hormonal activity among adrenal incidentalomas. The clinical significance of this condition has been confirmed by numerous studies showing “metabolic consequences” of chronic autonomous cortisol hypersecretion. Some clinical symptomatology of metabolic syndrome, such as obesity, impaired carbohydrate metabolism and hypertension, are peculiar to subclinical hypercorticism more than to population. This requires a thorough examination of patients with adrenal incidentalomas for hormonal activity, as well as determining the indications for surgical intervention. In the current era of evidence-based medicine, the overall management of these tumors remains empirical. The pathogenesis of subclinical Cushing’s syndrome remains unclear. Understanding of the mechanisms of chronic autonomous cortisol hypersecretion would enable to identify clinical and genetic heterogeneity of this condition, to determine prognosis and indications for surgery and to develop pharmacological methods of treatment. The purpose of this article is to review the current views on the diagnosis, pathogenesis and treatment of subclinical Cushing’s syndrome, identifying perspective directions of work.

субклинический синдром Кушингаинциденталомаавтономная гиперсекреция кортизоламетаболический синдромгенетикаэпигенетикаsubclinical Cushing`s syndromeautonomous cortisol hypersecretionincidentalomasmetabolic syndromeepigeneticsgeneticsReferencesTerzolo M, Stigliano A, Chiodini I, et al. AME Position Statement on adrenal incidentaloma. Eur J Endocrinol. 2011;164(6):851-870. doi: 10.1530/eje-10-1147.Terzolo M, Stigliano A, Chiodini I, et al. AME Position Statement on adrenal incidentaloma. Eur J Endocrinol. 2011;164(6):851-870. doi: 10.1530/eje-10-1147.Young WF. The Incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601-610. doi: 10.1056/NEJMcp065470.Young WF. The Incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601-610. doi: 10.1056/NEJMcp065470.Mantero F, Arnaldi G. Management approaches to adrenal incidentalomas. Endocrinol Metab Clin North Am. 2000;29(1):107-125. doi: 10.1016/s0889-8529(05)70119-5.Mantero F, Arnaldi G. Management approaches to adrenal incidentalomas. Endocrinol Metab Clin North Am. 2000;29(1):107-125. doi: 10.1016/s0889-8529(05)70119-5.Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: An Endocrine Society Clinical Practice Guideline. J Clin Endocr Metab. 2008;93(9):3266-3281. doi: 10.1210/jc.2008-0104.Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: An Endocrine Society Clinical Practice Guideline. J Clin Endocr Metab. 2008;93(9):3266-3281. doi: 10.1210/jc.2008-0104.Terzolo M, Bovio S, Pia A, et al. Subclinical Cushing's syndrome. Arq Bras Endocrinol Metabol. 2007;51(8):1272-1279.Terzolo M, Bovio S, Pia A, et al. Subclinical Cushing's syndrome. Arq Bras Endocrinol Metabol. 2007;51(8):1272-1279.Reincke M. Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am. 2000;29(1):43-56. doi: 10.1016/s0889-8529(05)70115-8.Reincke M. Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am. 2000;29(1):43-56. doi: 10.1016/s0889-8529(05)70115-8.Beierwaltes WH, Sturman MF, Ryo U, Ice RD. Imaging functional nodules of the adrenal glands with 131-I-19-iodocholesterol. J Nucl Med. 1974;15(4):246-251.Beierwaltes WH, Sturman MF, Ryo U, Ice RD. Imaging functional nodules of the adrenal glands with 131-I-19-iodocholesterol. J Nucl Med. 1974;15(4):246-251.Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab. 2010;95(9):4106-4113. doi: 10.1210/jc.2010-0457.Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab. 2010;95(9):4106-4113. doi: 10.1210/jc.2010-0457.Terzolo M. Adrenal incidentaloma: A new cause of the metabolic syndrome? J Clin Endocrinol Metab. 2002;87(3): 998-1003. doi: 10.1210/jcem.87.3.8277.Terzolo M. Adrenal incidentaloma: A new cause of the metabolic syndrome? J Clin Endocrinol Metab. 2002;87(3): 998-1003. doi: 10.1210/jcem.87.3.8277.Chiodini I, Morelli V, Salcuni AS, et al. Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J Clin Endocr Metab. 2010;95(6):2736-2745. doi: 10.1210/jc.2009-2387.Chiodini I, Morelli V, Salcuni AS, et al. Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J Clin Endocr Metab. 2010;95(6):2736-2745. doi: 10.1210/jc.2009-2387.Chiodini I, Morelli V, Masserini B, et al. Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: An Italian Multicenter Study. J Clin Endocrinol Metab. 2009;94(9):3207-3214. doi: 10.1210/jc.2009-0468.Chiodini I, Morelli V, Masserini B, et al. Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: An Italian Multicenter Study. J Clin Endocrinol Metab. 2009;94(9):3207-3214. doi: 10.1210/jc.2009-0468.Toniato A, Merante-Boschin I, Opocher G, et al. Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg. 2009;249(3):388-391. doi: 10.1097/SLA.0b013e31819a47d2.Toniato A, Merante-Boschin I, Opocher G, et al. Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg. 2009;249(3):388-391. doi: 10.1097/SLA.0b013e31819a47d2.Emral R, Uysal AR, Asik M, et al. Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentaloma: Clinical, biochemical and surgical outcomes. Endocr J. 2003;50(4):399-408. doi: 10.1507/endocrj.50.399.Emral R, Uysal AR, Asik M, et al. Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentaloma: Clinical, biochemical and surgical outcomes. Endocr J. 2003;50(4):399-408. doi: 10.1507/endocrj.50.399.Mansmann G, Lau J, Balk E, et al. The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr Rev. 2004;25(2):309-340. doi: 10.1210/er.2002-0031.Mansmann G, Lau J, Balk E, et al. The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr Rev. 2004;25(2):309-340. doi: 10.1210/er.2002-0031.Starker LF, Kunstman JW, Carling T. Subclinical Cushing syndrome. Surg Clin North Am. 2014;94(3):657-668. doi: 10.1016/j.suc.2014.02.008.Starker LF, Kunstman JW, Carling T. Subclinical Cushing syndrome. Surg Clin North Am. 2014;94(3):657-668. doi: 10.1016/j.suc.2014.02.008.Reimondo G, Allasino B, Bovio S, et al. Pros and cons of dexamethasone suppression test for screening of subclinical Cushing's syndrome in patients with adrenal incidentalomas. J Endocrinol Invest. 2011;34(1):e1-5. doi: 10.3275/7167.Reimondo G, Allasino B, Bovio S, et al. Pros and cons of dexamethasone suppression test for screening of subclinical Cushing's syndrome in patients with adrenal incidentalomas. J Endocrinol Invest. 2011;34(1):e1-5. doi: 10.3275/7167.Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (“incidentaloma“). Ann Intern Med. 2003;138(5):424-429.Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (“incidentaloma“). Ann Intern Med. 2003;138(5):424-429.Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executive summary of recommendations. Endocr Pract. 2009;15(5):450-453. doi: 10.4158/EP.15.5.450.Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executive summary of recommendations. Endocr Pract. 2009;15(5):450-453. doi: 10.4158/EP.15.5.450.Read GF, Walker RF, Wilson DW, Griffiths K. Steroid analysis in saliva for the assessment of endocrine function. Ann N Y Acad Sci. 1990;595(1 Steroid Forma):260-274.Read GF, Walker RF, Wilson DW, Griffiths K. Steroid analysis in saliva for the assessment of endocrine function. Ann N Y Acad Sci. 1990;595(1 Steroid Forma):260-274.doi: 10.1111/j.1749-6632.1990.tb34300.x.doi: 10.1111/j.1749-6632.1990.tb34300.x.Garde AH, Hansen ÅM. Longterm stability of salivary cortisol. Scand J Clin Lab Invest. 2009;65(5):433-436. doi: 10.1080/00365510510025773.Garde AH, Hansen ÅM. Longterm stability of salivary cortisol. Scand J Clin Lab Invest. 2009;65(5):433-436. doi: 10.1080/00365510510025773.Nunes M-L, Vattaut S, Corcuff J-B, et al. Late-night salivary cortisol for diagnosis of overt and subclinical Cushing’s syndrome in hospitalized and ambulatory patients. J Clin Endocr Metab. 2009;94(2):456-462. doi: 10.1210/jc.2008-1542.Nunes M-L, Vattaut S, Corcuff J-B, et al. Late-night salivary cortisol for diagnosis of overt and subclinical Cushing’s syndrome in hospitalized and ambulatory patients. J Clin Endocr Metab. 2009;94(2):456-462. doi: 10.1210/jc.2008-1542.Mengden T, Hubmann P, Muller J, et al. Urinary free cortisol versus 17-hydroxycorticosteroids a comparative study of their diagnostic value in Cushing's syndrome. The Clinical Investigator. 1992;70(7). doi: 10.1007/bf00184788.Mengden T, Hubmann P, Muller J, et al. Urinary free cortisol versus 17-hydroxycorticosteroids a comparative study of their diagnostic value in Cushing's syndrome. The Clinical Investigator. 1992;70(7). doi: 10.1007/bf00184788.Carroll BJ, Curtis GC, Davies BM, et al. Urinary free cortisol excretion in depression. Psychol Med. 1976;6(1):43-50.Carroll BJ, Curtis GC, Davies BM, et al. Urinary free cortisol excretion in depression. Psychol Med. 1976;6(1):43-50.Duclos M, Corcuff JB, Etcheverry N, et al. Abdominal obesity increases overnight cortisol excretion. J Endocrinol Invest. 1999;22(6):465-471. doi: 10.1007/BF03343591.Duclos M, Corcuff JB, Etcheverry N, et al. Abdominal obesity increases overnight cortisol excretion. J Endocrinol Invest. 1999;22(6):465-471. doi: 10.1007/BF03343591.Mericq MV. High fluid intake increases urine free cortisol excretion in normal subjects. J Clin Endocrinol Metab. 1998;83(2):682-684. doi: 10.1210/jcem.83.2.4555.Mericq MV. High fluid intake increases urine free cortisol excretion in normal subjects. J Clin Endocrinol Metab. 1998;83(2):682-684. doi: 10.1210/jcem.83.2.4555.Kidambi S, Raff H, Findling JW. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome. Eur J Endocrinol. 2007;157(6): 725-731. doi: 10.1530/eje-07-0424.Kidambi S, Raff H, Findling JW. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome. Eur J Endocrinol. 2007;157(6): 725-731. doi: 10.1530/eje-07-0424.Eller-Vainicher C, Morelli V, Salcuni AS, et al. Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma. Eur J Endocrinol. 2010;163(6):925-935. doi: 10.1530/eje-10-0602.Eller-Vainicher C, Morelli V, Salcuni AS, et al. Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma. Eur J Endocrinol. 2010;163(6):925-935. doi: 10.1530/eje-10-0602.Valli N, Catargi B, Ronci N, et al. Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas. Eur J Endocrinol. 2001;144(4):401-408.Valli N, Catargi B, Ronci N, et al. Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas. Eur J Endocrinol. 2001;144(4):401-408.Tanabe A, Naruse M, Nishikawa T, et al. Autonomy of cortisol secretion in clinically silent adrenal incidentaloma. Horm Metab Res. 2001;33(7):444-450. doi: 10.1055/s-2001-16234.Tanabe A, Naruse M, Nishikawa T, et al. Autonomy of cortisol secretion in clinically silent adrenal incidentaloma. Horm Metab Res. 2001;33(7):444-450. doi: 10.1055/s-2001-16234.Shiwa T, Oki K, Yamane K, et al. Significantly high level of late-night free cortisol to creatinine ratio in urine specimen in patients with subclinical Cushing's syndrome. Clin Endocrinol (Oxf). 2013;79(5):617-622. doi: 10.1111/cen.12197.Shiwa T, Oki K, Yamane K, et al. Significantly high level of late-night free cortisol to creatinine ratio in urine specimen in patients with subclinical Cushing's syndrome. Clin Endocrinol (Oxf). 2013;79(5):617-622. doi: 10.1111/cen.12197.Terzolo M, Bovio S, Reimondo G, et al. Subclinical Cushing's syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am. 2005;34(2):423-439, x. doi: 10.1016/j.ecl.2005.01.008.Terzolo M, Bovio S, Reimondo G, et al. Subclinical Cushing's syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am. 2005;34(2):423-439, x. doi: 10.1016/j.ecl.2005.01.008.Masserini B, Morelli V, Bergamaschi S, et al. The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma. Eur J Endocrinol. 2009;160(1):87-92. doi: 10.1530/EJE-08-0485.Masserini B, Morelli V, Bergamaschi S, et al. The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma. Eur J Endocrinol. 2009;160(1):87-92. doi: 10.1530/EJE-08-0485.Chiodini I. Clinical review: Diagnosis and treatment of subclinical hypercortisolism. J Clin Endocrinol Metab. 2011;96(5):1223-1236. doi: 10.1210/jc.2010-2722.Chiodini I. Clinical review: Diagnosis and treatment of subclinical hypercortisolism. J Clin Endocrinol Metab. 2011;96(5):1223-1236. doi: 10.1210/jc.2010-2722.Tsagarakis S, Vassiliadi D, Thalassinos N. Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications. J Endocrinol Invest. 2006;29(5):471-482. doi: 10.1007/BF03344133.Tsagarakis S, Vassiliadi D, Thalassinos N. Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications. J Endocrinol Invest. 2006;29(5):471-482. doi: 10.1007/BF03344133.Osella G, Terzolo M, Borretta G, et al. Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas). J Clin Endocrinol Metab. 1994;79(6):1532-1539. doi: 10.1210/jcem.79.6.7989452.Osella G, Terzolo M, Borretta G, et al. Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas). J Clin Endocrinol Metab. 1994;79(6):1532-1539. doi: 10.1210/jcem.79.6.7989452.Di Dalmazi G, Kisker C, Calebiro D, et al. Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing's syndrome: a European multicentric study. J Clin Endocrinol Metab.2014;99(10):E2093-2100. doi: 10.1210/jc.2014-2152.Di Dalmazi G, Kisker C, Calebiro D, et al. Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing's syndrome: a European multicentric study. J Clin Endocrinol Metab.2014;99(10):E2093-2100. doi: 10.1210/jc.2014-2152.Beuschlein F, Fassnacht M, Assie G, et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med. 2014;370(11):1019-1028.Beuschlein F, Fassnacht M, Assie G, et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med. 2014;370(11):1019-1028.doi: 10.1056/NEJMoa1310359.doi: 10.1056/NEJMoa1310359.Cao Y, He M, Gao Z, et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome. Science. 2014;344(6186):913-917. doi: 10.1126/science.1249480.Cao Y, He M, Gao Z, et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome. Science. 2014;344(6186):913-917. doi: 10.1126/science.1249480.Thiel A, Reis AC, Haase M, et al. PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases. Eur J Endocrinol. 2015;172(6): 677-685. doi: 10.1530/EJE-14-1113.Thiel A, Reis AC, Haase M, et al. PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases. Eur J Endocrinol. 2015;172(6): 677-685. doi: 10.1530/EJE-14-1113.Sato Y, Maekawa S, Ishii R, et al. Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. Science. 2014;344(6186):917-920. doi: 10.1126/science.1252328.Sato Y, Maekawa S, Ishii R, et al. Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. Science. 2014;344(6186):917-920. doi: 10.1126/science.1252328.Goh G, Scholl UI, Healy JM, et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet. 2014;46(6):613-617. doi: 10.1038/ng.2956.Goh G, Scholl UI, Healy JM, et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet. 2014;46(6):613-617. doi: 10.1038/ng.2956.Cao C, Yang X, Li L, et al. Increased expression of CYP17 and CYP11B1 in subclinical Cushing's syndrome due to adrenal adenomas. Int J Urol. 2011;18(10):691-696. doi: 10.1111/j.1442-2042.2011.02836.x.Cao C, Yang X, Li L, et al. Increased expression of CYP17 and CYP11B1 in subclinical Cushing's syndrome due to adrenal adenomas. Int J Urol. 2011;18(10):691-696. doi: 10.1111/j.1442-2042.2011.02836.x.Mitsuhiro K, Masashi D, Takashi Y. Epigenetic controls of CYP11B2 and CYP11B1 gene in subclinical Cushing syndrome associated with overproduction of aldosterone. Endocr. Soc. 96th Annu. Meet. Expo, 2014.Mitsuhiro K, Masashi D, Takashi Y. Epigenetic controls of CYP11B2 and CYP11B1 gene in subclinical Cushing syndrome associated with overproduction of aldosterone. Endocr. Soc. 96th Annu. Meet. Expo, 2014.Streuli C. Extracellular matrix remodelling and cellular differentiation. Curr Opin Cell Biol. 1999;11(5):634-640. doi: 10.1016/S0955-0674(99)00026-5.Streuli C. Extracellular matrix remodelling and cellular differentiation. Curr Opin Cell Biol. 1999;11(5):634-640. doi: 10.1016/S0955-0674(99)00026-5.Crickard K, Ill CR, Jaffe RB. Control of proliferation of human fetal adrenal cells in vitro. J Clin Endocrinol Metab. 1981;53(4):790-796. doi: 10.1210/jcem-53-4-790.Crickard K, Ill CR, Jaffe RB. Control of proliferation of human fetal adrenal cells in vitro. J Clin Endocrinol Metab. 1981;53(4):790-796. doi: 10.1210/jcem-53-4-790.Chamoux E, Narcy A, Lehoux JG, Gallo-Payet N. Fibronectin, laminin, and collagen IV interact with ACTH and angiotensin II to dictate specific cell behavior and secretion in human fetal adrenal cells in culture. Endocr Res.2002;28(4):637-640. doi: 10.1081/ERC-120016978.Chamoux E, Narcy A, Lehoux JG, Gallo-Payet N. Fibronectin, laminin, and collagen IV interact with ACTH and angiotensin II to dictate specific cell behavior and secretion in human fetal adrenal cells in culture. Endocr Res.2002;28(4):637-640. doi: 10.1081/ERC-120016978.Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond). 1999;96(5):513-523. doi: 10.1042/CS19980388.Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond). 1999;96(5):513-523. doi: 10.1042/CS19980388.van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest. 2009;39(2):81-93. doi: 10.1111/j.1365-2362.2008.02067.x.van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest. 2009;39(2):81-93. doi: 10.1111/j.1365-2362.2008.02067.x.Rossi R, Tauchmanova L, Luciano A, et al. Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features. J Clin Endocrinol Metab. 2000;85(4):1440-1448. doi: 10.1210/jcem.85.4.6515.Rossi R, Tauchmanova L, Luciano A, et al. Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features. J Clin Endocrinol Metab. 2000;85(4):1440-1448. doi: 10.1210/jcem.85.4.6515.Tauchmanova L, Rossi R, Biondi B, et al. Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab. 2002;87(11):4872-4878. doi: 10.1210/jc.2001-011766.Tauchmanova L, Rossi R, Biondi B, et al. Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab. 2002;87(11):4872-4878. doi: 10.1210/jc.2001-011766.Morelli V, Masserini B, Salcuni AS, et al. Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Clin Endocrinol (Oxf). 2010;73(2): 161-166. doi: 10.1111/j.1365-2265.2010.03794.x.Morelli V, Masserini B, Salcuni AS, et al. Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Clin Endocrinol (Oxf). 2010;73(2): 161-166. doi: 10.1111/j.1365-2265.2010.03794.x.Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000;85(2):637-644. doi: 10.1210/jcem.85.2.6372.Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000;85(2):637-644. doi: 10.1210/jcem.85.2.6372.Bernini GP, Moretti A, Oriandini C, et al. Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas. Br J Cancer. 2005;92(6): 1104-1109. doi: 10.1038/sj.bjc.6602459.Bernini GP, Moretti A, Oriandini C, et al. Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas. Br J Cancer. 2005;92(6): 1104-1109. doi: 10.1038/sj.bjc.6602459.Terzolo M, Bovio S, Pia A, et al. Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma. Eur J Endocrinol. 2005;153(2):307-315. doi: 10.1530/eje.1.01959.Terzolo M, Bovio S, Pia A, et al. Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma. Eur J Endocrinol. 2005;153(2):307-315. doi: 10.1530/eje.1.01959.Sereg M, Szappanos A, Toke J, et al. Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study. Eur J Endocrinol. 2009; 160(4):647-655. doi: 10.1530/EJE-08-0707.Sereg M, Szappanos A, Toke J, et al. Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study. Eur J Endocrinol. 2009; 160(4):647-655. doi: 10.1530/EJE-08-0707.Vassilatou E, Vryonidou A, Michalopoulou S, et al. Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin Endocrinol (Oxf). 2009;70(5):674-679. doi: 10.1111/j.1365-2265.2008.03492.x.Vassilatou E, Vryonidou A, Michalopoulou S, et al. Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin Endocrinol (Oxf). 2009;70(5):674-679. doi: 10.1111/j.1365-2265.2008.03492.x.Giordano R, Marinazzo E, Berardelli R, et al. Long-term morphological, hormonal, and clinical follow-up in a single unit on 118 patients with adrenal incidentalomas. Eur J Endocrinol. 2010;162(4):779-785. doi: 10.1530/EJE-09-0957.Giordano R, Marinazzo E, Berardelli R, et al. Long-term morphological, hormonal, and clinical follow-up in a single unit on 118 patients with adrenal incidentalomas. Eur J Endocrinol. 2010;162(4):779-785. doi: 10.1530/EJE-09-0957.Comlekci A, Yener S, Ertilav S, et al. Adrenal incidentaloma, clinical, metabolic, follow-up aspects: single centre experience. Endocrine. 2010;37(1):40-46. doi: 10.1007/s12020-009-9260-5.Comlekci A, Yener S, Ertilav S, et al. Adrenal incidentaloma, clinical, metabolic, follow-up aspects: single centre experience. Endocrine. 2010;37(1):40-46. doi: 10.1007/s12020-009-9260-5.Giordano R, Guaraldi F, Berardelli R, et al. Glucose metabolism in patients with subclinical Cushing's syndrome. Endocrine. 2012;41(3):415-423. doi: 10.1007/s12020-012-9628-9.Giordano R, Guaraldi F, Berardelli R, et al. Glucose metabolism in patients with subclinical Cushing's syndrome. Endocrine. 2012;41(3):415-423. doi: 10.1007/s12020-012-9628-9.Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study. The Lancet Diabetes & Endocrinology. 2014;2(5):396-405. doi: 10.1016/s2213-8587(13)70211-0.Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study. The Lancet Diabetes & Endocrinology. 2014;2(5):396-405. doi: 10.1016/s2213-8587(13)70211-0.Di Dalmazi G, Vicennati V, Rinaldi E, et al. Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: a large cross-sectional study.Eur J Endocrinol. 2012;166(4):669-677. doi: 10.1530/eje-11-1039.Di Dalmazi G, Vicennati V, Rinaldi E, et al. Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: a large cross-sectional study.Eur J Endocrinol. 2012;166(4):669-677. doi: 10.1530/eje-11-1039.Morelli V, Eller-Vainicher C, Salcuni AS, et al. Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: A multicenter longitudinal study. J Bone Miner Res. 2011;26(8):1816-1821. doi: 10.1002/jbmr.398.Morelli V, Eller-Vainicher C, Salcuni AS, et al. Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: A multicenter longitudinal study. J Bone Miner Res. 2011;26(8):1816-1821. doi: 10.1002/jbmr.398.Chiodini I. Bone loss rate in adrenal incidentalomas: A longitudinal study. J Clin Endocrinol Metab. 2001;86(11): 5337-5341. doi: 10.1210/jcem.86.11.8022.Chiodini I. Bone loss rate in adrenal incidentalomas: A longitudinal study. J Clin Endocrinol Metab. 2001;86(11): 5337-5341. doi: 10.1210/jcem.86.11.8022.Eller-Vainicher C, Morelli V, Ulivieri FM, et al. Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism. J Bone Miner Res. 2012;27(10):2223-2230.doi: 10.1002/jbmr.1648.Eller-Vainicher C, Morelli V, Ulivieri FM, et al. Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism. J Bone Miner Res. 2012;27(10):2223-2230.doi: 10.1002/jbmr.1648.Lane NE, Yao W. Glucocorticoid-induced bone fragility. Ann N Y Acad Sci. 2010;1192(1):81-83. doi: 10.1111/j.1749-6632.2009.05228.x.Lane NE, Yao W. Glucocorticoid-induced bone fragility. Ann N Y Acad Sci. 2010;1192(1):81-83. doi: 10.1111/j.1749-6632.2009.05228.x.Midorikawa S, Sanada H, Hashimoto S, et al. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol (Oxf). 2001;54(6):797-804. doi: 10.1046/j.1365-2265.2001.01274.x.Midorikawa S, Sanada H, Hashimoto S, et al. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol (Oxf). 2001;54(6):797-804. doi: 10.1046/j.1365-2265.2001.01274.x.Mitchell IC, Auchus RJ, Juneja K, et al. “Subclinical Cushing’s syndrome” is not subclinical: improvement after adrenalectomy in 9 patients. Surgery. 2007;142(6):900-905.e901. doi: 10.1016/j.surg.2007.10.001.Mitchell IC, Auchus RJ, Juneja K, et al. “Subclinical Cushing’s syndrome” is not subclinical: improvement after adrenalectomy in 9 patients. Surgery. 2007;142(6):900-905.e901. doi: 10.1016/j.surg.2007.10.001.Bernini G, Moretti A, Iacconi P, et al. Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery. Eur J Endocrinol. 2003;148(2):213-219. doi: 10.1530/eje.0.1480213.Bernini G, Moretti A, Iacconi P, et al. Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery. Eur J Endocrinol. 2003;148(2):213-219. doi: 10.1530/eje.0.1480213.Calebiro D, Di Dalmazi G, Bathon K, et al. cAMP signaling in cortisol-producing adrenal adenoma. Eur J Endocrinol. 2015;173(4):M99-M106. doi: 10.1530/eje-15-0353.Calebiro D, Di Dalmazi G, Bathon K, et al. cAMP signaling in cortisol-producing adrenal adenoma. Eur J Endocrinol. 2015;173(4):M99-M106. doi: 10.1530/eje-15-0353.

The authors declare that there are no conflicts of interest present.