Adrenal incidentaloma: management of patients with functionally autonomous cortisol synthesis

Abstract

Over recent decades due to improved visualization (ultrasound, computer tomography and magnetic resonance imaging) prevalence of adrenal incidentaloma has increased. The term «adrenal incidentaloma» is generic and includes a group of tumors of various morphology and over 1 cm in diameter accidentally discovered during radiologic investigation. The found tumor can be hormonally inactive or actively releasing different hormones, malignant or benign, and originating from different adrenal zones or having non-specific organ origin. Based on the frequency of revealing and clinical significance the most noteworthy is functionally autonomous cortisol synthesis. It means changes of hypothalamic pituitary adrenal axis without classic clinically prominent signs of cortisol excess such as proximal myopathy, stretch marks, body fat redistribution and other metabolic changes related to cortisol. Currently a large number of recommendations on the management and tactics of treatment of adrenal incidentaloma can be found in the literature. Based on the analysis of these guidelines the conclusions were made about the diagnostic errors and incorrect approaches to the choice of treatment of such patients. Recently a lot of studies have been directed to the early detection of carbohydrate and lipid metabolism disorders, relation with obesity and type 2 diabetes mellitus, arterial hypertension and osteoporosis for preserved quality of life of such patients. Influence of hypercorticism is considered to worsen the course of these conditions but at the moment no effect of adrenalectomy on mortality and life duration was confirmed.

Keywords

adrenal incidentaloma / functionally autonomous cortisol secretion / Cushing’s syndrome / hypercortisolism

References

[1] Nieman L.K., Biller B.M., Findling J.W. et al. Treatment of Cushing's syndrome: An Endocrine Society Cli­nical Practice Guideline. J. Clin. Endocrinol. Metab. 2015; 100 (8): 2807–2831. DOI: 10.1210/jc.2015-1818.

[2] Nieman L.K., Biller B.M., Findling J.W. et al. Treatment of Cushing's syndrome: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2015; 100 (8): 2807-2831. DOI: 10.1210/jc.2015-1818.

[3] Beltsevich D.G., Melnichenko G.A., Kuznetsov N.S. et al. Russian Association of Endocrino­logists clinical practice guideline for adrenal incidentalomas differential diagnosis. Endokrinnaya khirurgiya. 2016; 10 (4): 31–42. (In Russ.)

[4] Бельцевич Д.Г., Мельниченко Г.А., Кузнецов Н.С. и др. Клинические рекомендации Российской ассоциации эндокринологов по дифференциальной диагностике инциденталом надпочечников. Эндокрин. хир. 2016; 10 (4): 31-42. DOI: 10.14341/serg2016431-42.

[5] Kuznetsov N.S., Tikhonova O.V. Subclinical Cushing's syndrome due to unilateral or bilateral adrenal incidentalomas. Problems of diagnostic and indication to surgical treatment. Review of literature. Endokrinnaya khirurgiya. 2015; 9 (1): 22–34. (In Russ.)

[6] Кузнецов Н.С., Тихонова О.В. Субклинический синдром Кушинга, обусловленный одно- и двусторонними образованиями надпочечников. Проблемы диагностики и показаний к хирургическому лечению. Обзор литературы. Эндокрин. хир. 2015; 9 (1): 22-34. DOI: 10.14341/serg2015122-34.

[7] Di Dalmazi G., Pasquali R., Beuschlein F. et al. Subclinical hypercortisolism: a state, a syndrome, or a disease? Eur. J. Endocrinol. 2015; 173 (4): 61–71. DOI: 10.1530/

[8] Di Dalmazi G., Pasquali R., Beuschlein F. et al. Subclinical hypercortisolism: a state, a syndrome, or a disease? Eur. J. Endocrinol. 2015; 173 (4): 61-71. DOI: 10.1530/ EJE-15-0272.

[9] EJE-15-0272.

[10] Berruti A., Baudin E., Gelderblom H. et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2012; 23 (7): 131-138. DOI: 10.1093/annonc/mds231.

[11] Berruti A., Baudin E., Gelderblom H. et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2012; 23 (7): 131–138. DOI: 10.1093/annonc/mds231.

[12] Fassnacht M., Arlt W., Bancos I. et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 2016; 175 (2): 1-34. DOI: 10.1530/eje-16-0467.

[13] Fassnacht M., Arlt W., Bancos I. et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 2016; 175 (2): 1–34. DOI: 10.1530/eje-16-0467.

[14] Lacroix A., Feelders R.A., Stratakis C.E. et al. Cushing’s syndrome. Lancet. 2015; 386 (9996): 913-927. DOI: 10.1016/S0140-6736(14)61375-1.

[15] Lacroix A., Feelders R.A., Stratakis C.E. et al. Cu­shing’s syndrome. Lancet. 2015; 386 (9996): 913–927. DOI: 10.1016/S0140-6736(14)61375-1.

[16] Lacroix A., Ndiaye N., Tremblay J. et al. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocrine Rev. 2001; 22 (1): 75-110. DOI: 10.1210/edrv.22.1.0420.

[17] Lacroix A., Ndiaye N., Tremblay J. et al. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocrine Rev. 2001; 22 (1): 75–110. DOI: 10.1210/edrv.22.1.0420.

[18] 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.

[19] 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.

[20] Goh G., Scholl U.I., Healy J.M. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nature Genet. 2014; 46 (6): 613-617. DOI: 10.1038/ng.2956.

[21] Goh G., Scholl U.I., Healy J.M. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nature Genet. 2014; 46 (6): 613–617. DOI: 10.1038/ng.2956.

[22] Light K., Jenkins P.J., Weber A. et al. Are activating mutations of the adrenocorticotropin receptor involved in adrenal cortical neoplasia? Life Sci. 1995; 56 (18): 1523-1527. DOI: 10.1016/0024-3205(95)00114-L.

[23] Light K., Jenkins P.J., Weber A. et al. Are activa­ting mutations of the adrenocorticotropin receptor involved in adrenal cortical neoplasia? Life Sci. 1995; 56 (18): 1523–1527. DOI: 10.1016/0024-3205(95)00114-L.

[24] Swords F.M., Noon L.A., King P.J., Clark A.J. Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene. Mol. Cell. Endocrinol. 2004; 213 (2): 149-154. DOI: 10.1016/j.mce.2003.10.052.

[25] Swords F.M., Noon L.A., King P.J., Clark A.J. Constitutive activation of the human ACTH receptor resul­ting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene. Mol. Cell. Endocrinol. 2004; 213 (2): 149–154. DOI: 10.1016/j.mce.2003.10.052.

[26] Alencar G.A., Lerario A.M., Nishi M.Y. et al. ARMC5 mutations are a frequent cause of primary macronodular adrenal hyperplasia. J. Clin. Endocrinol. Metabol. 2014; 99 (8): 1501-1509. DOI: 10.1210/jc.2013-4237.

[27] Alencar G.A., Lerario A.M., Nishi M.Y. et al. ARMC5 mutations are a frequent cause of primary macronodular adrenal hyperplasia. J. Clin. Endocrinol. Metabol. 2014; 99 (8): 1501–1509. DOI: 10.1210/jc.2013-4237.

[28] Assie G., Libe R., Espiard S. et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. New Engl. J. Med. 2013; 369: 2105-2114. DOI: 10.1056/NEJMoa1304603.

[29] Assie G., Libe R., Espiard S. et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. New Engl. J. Med. 2013; 369: 2105–2114. DOI: 10.1056/NEJMoa1304603.

[30] Elbelt U., Trovato A., Kloth M. et al. Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma. J. Clin. Endocrinol. Metabol. 2015; 100 (1): 119-128. DOI: 10.1210/jc.2014-2648.

[31] Elbelt U., Trovato A., Kloth M. et al. Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma. J. Clin. Endocrinol. Metabol. 2015; 100 (1): 119–128. DOI: 10.1210/jc.2014-2648.

[32] Schorr I., Ney R.L. Abnormal hormone responses of an adrenocortical cancer adenyl cyclase. J. Clin. Invest. 1971; 50 (6): 1295-1300. DOI: 10.1172/JCI106608.

[33] Schorr I., Ney R.L. Abnormal hormone responses of an adrenocortical cancer adenyl cyclase. J. Clin. Invest. 1971; 50 (6): 1295–1300. DOI: 10.1172/JCI106608.

[34] Hamet P., Larochelle P., Franks D.J. et al. Cushing syndrome with food-dependent periodic hormonogenesis. Clin. Invest. Med. 1987; 10 (6): 530-533. PMID: 2831001.

[35] Hamet P., Larochelle P., Franks D.J. et al. Cushing syndrome with food-dependent periodic hormonogenesis. Clin. Invest. Med. 1987; 10 (6): 530–533. PMID: 2831001.

[36] Lacroix A., Bolte E., Tremblay J. et al. Gastric inhibitory polypeptide dependent cortisol hypersecretion - a new cause of Cushing’s syndrome. New Engl. J. Med. 1992; 327: 974-980. DOI: 10.1056/NEJM199210013271402.

[37] Lacroix A., Bolte E., Tremblay J. et al. Gastric inhibitory polypeptide dependent cortisol hypersecretion — a new cause of Cushing’s syndrome. New Engl. J. Med. 1992; 327: 974–980. DOI: 10.1056/NEJM199210013271402.

[38] Reznik Y., Allali-Zerah V., Chayvialle J.A. et al. Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. New Engl. J. Med. 1992; 327 (14): 981-986. DOI: 10.1056/NEJM199210013271403.

[39] Reznik Y., Allali-Zerah V., Chayvialle J.A. et al. Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. New Engl. J. Med. 1992; 327 (14): 981–986. DOI: 10.1056/NEJM199210013271403.

[40] Lacroix A., Baldacchino V., Bourdeau I. et al. Cushing’s syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol. Metabol. 2004; 15 (8): 375-382. DOI: 10.1016/S1043-2760(04)00188-2.

[41] Lacroix A., Baldacchino V., Bourdeau I. et al. Cu­shing’s syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol. Metabol. 2004; 15 (8): ­375–382. DOI: 10.1016/S1043-2760(04)00188-2.

[42] Lacroix A., Bourdeau I., Lampron A. et al. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin. Endocrinol. 2010; 73 (1): 1-15. DOI: 10.1111/j.1365-2265.2009.03689.x.

[43] Lacroix A., Bourdeau I., Lampron A. et al. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin. Endocrinol. 2010; 73 (1): 1–15. DOI: 10.1111/j.1365-2265.2009.03689.x.

[44] Mermejo L.M., Mazzuco T.L., Grunenwald S. et al. ACTH-independent macronodular adrenal hyperplasia. Endocrinol. Metabol. 2011; 26 (1): 1-11. DOI: 10.3803/EnM.2011.26.1.1.

[45] Mermejo L.M., Mazzuco T.L., Grunenwald S. et al. ACTH-independent macronodular adrenal hyperplasia. Endocrinol. Metabol. 2011; 26 (1): 1–11. DOI: 10.3803/EnM.2011.26.1.1.

[46] Mircescu H., Jilwan J., N’Diaye N. et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome? J. Clin. Endocrinol. Metabol. 2000; 85 (10): 3531-3536. DOI: 10.1210/jcem.85.10.6865.

[47] Mircescu H., Jilwan J., N’Diaye N. et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome? J. Clin. Endocrinol. Metabol. 2000; 85 (10): 3531–3536. DOI: 10.1210/jcem.85.10.6865.

[48] Reznik Y., Lefebvre H., Rohmer V. et al. Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study. Clin. Endocrinol. 2004; 61 (3): 311-319. DOI: 10.1111/j.1365-2265.2004.02048.x.

[49] Reznik Y., Lefebvre H., Rohmer V. et al. Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study. Clin. Endocrinol. 2004; 61 (3): 311–319. DOI: 10.1111/j.1365-2265.2004.02048.x.

[50] Libe R., Coste J., Guignat L. et al. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing’s syndrome. Eur. J. Endocrinol. 2010; 163 (1): 129-138. DOI: 10.1530/EJE-10-0195.

[51] Libe R., Coste J., Guignat L. et al. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing’s syndrome. Eur. J. Endocrinol. 2010; 163 (1): 129–138. DOI: 10.1530/EJE-10-0195.

[52] Hofland J., Hofland L.J., van Koetsveld P.M. et al. ACTH-independent macronodularadrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of argininevasopressin type 1a receptor to 11b-hydroxylase. Orphanet J. Rare Dis. 2013; 8: 142. DOI: 10.1186/1750-1172-8-142.

[53] Hofland J., Hofland L.J., van Koetsveld P.M. et al. ACTH-independent macronodularadrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro respon­ses to hormonal stimuli and coupling of argininevasopressin type 1a receptor to 11b-hydroxylase. Orphanet J. Rare Dis. 2013; 8: 142. DOI: 10.1186/1750-1172-8-142.

[54] Hsiao H.P., Kirschner L.S., Bourdeau I. et al. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropinin dependent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J. Clin. Endocrinol. Metab. 2009; 94 (8): 2930-2937. DOI: 10.1210/jc.2009-0516.

[55] Hsiao H.P., Kirschner L.S., Bourdeau I. et al. Cli­nical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropinin dependent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J. Clin. Endocrinol. Metab. 2009; 94 (8): 2930–2937. DOI: 10.1210/jc.2009-0516.

[56] Joubert M., Louiset E., Rego J.L. et al. Aberrant adrenal sensitivity to vasopressin in adrenal tumours associated with subclinical or overt autonomous hypercortisolism: is this explained by an overexpression of vasopressin receptors? Clin. Endocrinol. 2008; 68 (5): 692-699. DOI: 10.1111/j.1365-2265.2007.03106.x.

[57] Joubert M., Louiset E., Rego J.L. et al. Aberrant adrenal sensitivity to vasopressin in adrenal tumours ­associated with subclinical or overt autonomous hypercortisolism: is this explained by an overexpression of vasopressin receptors? Clin. Endocrinol. 2008; 68 (5): 692–699. DOI: 10.1111/j.1365-2265.2007.03106.x.

[58] Albiger N.M., Occhi G., Mariniello B. et al. Food-dependent Cushing’s syndrome: from molecular characterization to therapeutical results. Eur. J. Endocrinol. 2007; 157 (6): 771-778. DOI: 10.1530/EJE-07-0253.

[59] Albiger N.M., Occhi G., Mariniello B. et al. Food-dependent Cushing’s syndrome: from molecular cha­racterization to therapeutical results. Eur. J. Endocrinol. 2007; 157 (6): 771–778. DOI: 10.1530/EJE-07-0253.

[60] Bertherat J., Contesse V., Louiset E. et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing’s syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J. Clin. Endocrinol. Metab. 2005; 90 (3): 1302-1310. DOI: 10.1210/jc.2004-1256.

[61] Bertherat J., Contesse V., Louiset E. et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing’s syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J. Clin. Endocrinol. Metab. 2005; 90 (3): 1302–1310. DOI: 10.1210/jc.2004-1256.

[62] Lampron A., Bourdeau I., Hamet P. et al. Whole genome expression profiling of glucose-dependent insulinotropic peptide (GIP) - and adrenocorticotropin-dependent adrenal hyperplasias reveals novel targets for the study of GIP-dependent Cushing’s syndrome. J. Clin. Endocrinol. Metab. 2006; 91 (9): 3611-3618. DOI: 10.1210/jc.2006-0221.

[63] Lampron A., Bourdeau I., Hamet P. et al. Whole genome expression profiling of glucose-dependent insulinotropic peptide (GIP) — and adrenocorticotropin-dependent adrenal hyperplasias reveals novel targets for the study of GIP-dependent Cushing’s syndrome. J. Clin. Endocrinol. Metab. 2006; 91 (9): 3611–3618. DOI: 10.1210/jc.2006-0221.

[64] N’Diaye N., Hamet P., Tremblay J. et al. Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent Cushing’s syndrome. J. Clin. Endocrinol. Metab. 1999; 84 (8): 2616-2622. DOI: 10.1210/jcem.84.8.5930.

[65] N’Diaye N., Hamet P., Tremblay J. et al. Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent Cu­shing’s syndrome. J. Clin. Endocrinol. Metab. 1999; 84 (8): 2616–2622. DOI: 10.1210/jcem.84.8.5930.

[66] Chabre O., Liakos P., Vivier J. et al. Gastric inhibitory polypeptide (GIP) stimulates cortisol secretion, cAMP production and DNA synthesis in an adrenal adenoma responsible for food-dependent Cushing’s syndrome. Endocrine Res. 1998; 24 (3-4): 851-856. DOI: 10.3109/07435809809032696.

[67] Chabre O., Liakos P., Vivier J. et al. Gastric inhibitory polypeptide (GIP) stimulates cortisol secretion, cAMP production and DNA synthesis in an adrenal ade­noma responsible for food-dependent Cushing’s syndrome. Endocrine Res. 1998; 24 (3–4): 851–856. DOI: 10.3109/07435809809032696.

[68] Swords F.M., Aylwin S., Perry L. et al. The aberrant expression of the gastric inhibitory polypeptide (GIP) receptor in adrenal hyperplasia: does chronic adrenocorticotropin exposure stimulate up-regulation of GIP receptors in Cushing’s disease? J. Clin. Endocrinol. Metab. 2005; 90 (5): 3009-3016. DOI: 10.1210/jc.2004-0946.

[69] Swords F.M., Aylwin S., Perry L. et al. The aberrant expression of the gastric inhibitory polypeptide (GIP) receptor in adrenal hyperplasia: does chronic adrenocorticotropin exposure stimulate up-regulation of GIP receptors in Cushing’s disease? J. Clin. Endocrinol. Metab. 2005; 90 (5): 3009–3016. DOI: 10.1210/jc.2004-0946.

[70] Antonini S.R., Baldacchino V., Tremblay J. et al. Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing’s syndrome. Clin. Endocrinol. 2006; 64 (1): 29-36. DOI: 10.1111/j.1365-2265.2005.02411.x.

[71] Antonini S.R., Baldacchino V., Tremblay J. et al. Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing’s syndrome. Clin. Endocrinol. 2006; 64 (1): 29–36. DOI: 10.1111/j.1365-2265.2005.02411.x.

[72] Mazzuco T.L., Chabre O., Sturm N. et al. Ectopic expression of the gastric inhibitory polypeptide receptor gene is a sufficient genetic event to induce benign adrenocortical tumor in a xenotransplantation model. Endocrinology. 2006; 147 (2): 782-790. DOI: 10.1210/en.2005-0921.

[73] Mazzuco T.L., Chabre O., Sturm N. et al. Ectopic expression of the gastric inhibitory polypeptide receptor gene is a sufficient genetic event to induce benign adrenocortical tumor in a xenotransplantation model. Endocrino­logy. 2006; 147 (2): 782–790. DOI: 10.1210/en.2005-0921.

[74] Chui M.H., Ozbey N.C., Ezzat S. et al. Case report: adrenal LH/hCG receptor overexpression and gene amplification causing pregnancy-induced Cushing’s syndrome. Endocrin. Pathol. 2009; 20 (4): 256-261. DOI: 10.1007/s12022-009-9090-2.

[75] Chui M.H., Ozbey N.C., Ezzat S. et al. Case report: adrenal LH/hCG receptor overexpression and gene amplification causing pregnancy-induced Cushing’s syndrome. Endocrin. Pathol. 2009; 20 (4): 256–261. DOI: 10.1007/s12022-009-9090-2.

[76] Blake M.A., Cronin C.G., Boland G.W. Adrenal imaging. AJR Am. J. Roentgenol. 2010; 194 (6): 1450-1460. DOI: 10.2214/AJR.10.4547.

[77] Blake M.A., Cronin C.G., Boland G.W. Adrenal ima­ging. AJR Am. J. Roentgenol. 2010; 194 (6): 1450–1460. DOI: 10.2214/AJR.10.4547.

[78] Olsen H., Nordenström E., Bergenfelz A. et al. Subclinical hypercortisolism and CT appearance in adrenal incidentalomas: a multicenter study from Southern Sweden. Endocrine. 2012; 42 (1): 164-173. DOI: 10.1007/s12020-012-9622-2.

[79] Olsen H., Nordenström E., Bergenfelz A. et al. Subclinical hypercortisolism and CT appearance in adrenal incidentalomas: a multicenter study from Southern Sweden. Endocrine. 2012; 42 (1): 164–173. DOI: 10.1007/s12020-012-9622-2.

[80] Kohara K. Sarcopenic obesity in aging population: current status and future directions for research. Endocrine. 2014; 45 (1): 15-25. DOI: 10.1007/s12020-013-9992-0.

[81] Kohara K. Sarcopenic obesity in aging population: current status and future directions for research. Endocrine. 2014; 45 (1): 15–25. DOI: 10.1007/s12020-013-9992-0.

[82] Schneider H.J., Dimopoulou C., Stalla G.K. et al. Discriminatory value of signs and symptoms in Cushing’s syndrome revisited: what has changed in 30 years? Clin. Endocrinol. 2013; 78 (1): 153-154. DOI: 10.1111/j.1365-2265.2012.04488.x.

[83] Schneider H.J., Dimopoulou C., Stalla G.K. et al. Discriminatory value of signs and symptoms in Cu­shing’s syndrome revisited: what has changed in 30 years? Clin. ­Endocrinol. 2013; 78 (1): 153–154. DOI: 10.1111/j.1365-2265.2012.04488.x.

[84] NIH state-of-the-science statement on management of the clinically inapparent adrenal mass («incidentaloma»). NIH Consensus and State-of-the-Science Statements. 2002; 19 (2): 1-25. PMID: 14768652.

[85] NIH state-of-the-science statement on management of the clinically inapparent adrenal mass («incidentaloma»). NIH Consensus and State-of-the-Science Statements. 2002; 19 (2): 1–25. PMID: 14768652.

[86] Nieman L.K., Biller B.M., Findling J.W. et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2008; 93 (5): 1526-1540. DOI: 10.1210/jc.2008-0125.

[87] Nieman L.K., Biller B.M., Findling J.W. et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2008; 93 (5): 1526–1540. DOI: 10.1210/jc.2008-0125.

[88] Tabarin A., Bardet S., Bertherat J. et al. French Society of Endocrinology Consensus. Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus. Annales d’Endocrinologie. 2008; 69 (6): 487-500. DOI: 10.1016/j.ando.2008.09.003.

[89] Tabarin A., Bardet S., Bertherat J. et al. French Society of Endocrinology Consensus. Exploration and ma­nagement of adrenal incidentalomas. French Society of Endocrinology Consensus. Annales d’Endocrinologie. 2008; 69 (6): 487–500. DOI: 10.1016/j.ando.2008.09.003.

[90] Zeiger M.A., Thompson G.B., Duh Q.Y. et al. American Association of Clinical Endocrinologists; American Association of Endocrine Surgeons. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocrin. Pract. 2009; 15 (1): 1-20. DOI: 10.4158/EP.15.S1.1.

[91] Zeiger M.A., Thompson G.B., Duh Q.Y. et al. Ame­rican Association of Clinical Endocrinologists; American Association of Endocrine Surgeons. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the ma­nagement of adrenal incidentalomas. Endocrin. Pract. 2009; 15 (1): 1–20. DOI: 10.4158/EP.15.S1.1.

[92] Terzolo M., Stigliano A., Chiodini I. et al. Italian Association of Clinical Endocrinologists. AME position statement on adrenal incidentaloma. Eur. J. Endocrinol. 2011; 164 (6): 851-870. DOI: 10.1530/EJE-10-1147.

[93] Terzolo M., Stigliano A., Chiodini I. et al. Italian Association of Clinical Endocrinologists. AME position statement on adrenal incidentaloma. Eur. J. Endocrinol. 2011; 164 (6): 851–870. DOI: 10.1530/EJE-10-1147.

[94] Shen J., Sun M., Zhou B., Yan J. Nonconformity in the clinical practice guidelines for subclinical Cushing’s syndrome: which guidelines are trustworthy? Eur. J. Endocrinol. 2014; 171 (4): 421-431. DOI: 10.1530/EJE-14-0345.

[95] Shen J., Sun M., Zhou B., Yan J. Nonconformity in the clinical practice guidelines for subclinical Cushing’s syndrome: which guidelines are trustworthy? Eur. J. Endocrinol. 2014; 171 (4): 421–431. DOI: 10.1530/EJE-14-0345.

[96] 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.

[97] 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.

[98] Кузнецов Н.С., Бельцевич Д.Г., Ванушко В.Э. и др. Дифференциальная диагностика инциденталом надпочечников. Эндокрин. хир. 2011; (1): 5-16. DOI: 10.14341/2306-3513-2011-1-5-16.

[99] Kuznetsov N.S., Beltsevich D.G., Vanushko V.E. et al. Differential diagnosis of adrenal incidentalomas. Endokrinnaya khirurgiya. 2011; (1): 5–16. (In Russ.)

[100] Молашенко Н.В., Платонова Н.М., Бельцевич Д.Г и др. Дифференциальная диагностика инциденталом надпочечников. Ожирение и метаболизм. 2016; 13 (4): 39-44. DOI: 10.14341/OMET2016439-44.

[101] Molashenko N.V., Platonova N.M., Beltsevich D.G. et al. Diagnosis and differential diagnosis of adrenal incidentalomas. Ozhirenie i metabolizm. 2016; 13 (4): 39–44. (In Russ.)

[102] De Leo M., Pivonello R., Auriemma R.S. et al. Cardiovascular disease in Cushing’s syndrome: heart versus vasculature. Neuroendocrinology. 2010; 92 (1): 50-54. DOI: 10.1159/000318566.

[103] De Leo M., Pivonello R., Auriemma R.S. et al. Cardiovascular disease in Cushing’s syndrome: heart versus vasculature. Neuroendocrinology. 2010; 92 (1): 50–54. DOI: 10.1159/000318566.

[104] Anagnostis P., Athyros V.G., Tziomalos K. et al. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J. Clin. Endocrinol. Metabol. 2009; 94 (8): 2692-2701. DOI: 10.1210/jc.2009-0370.

[105] Anagnostis P., Athyros V.G., Tziomalos K. et al. Clinical review: the pathogenetic role of cortisol in the me­tabolic syndrome: a hypothesis. J. Clin. Endocrinol. Metabol. 2009; 94 (8): 2692–2701. DOI: 10.1210/jc.2009-0370.

[106] Iacobone M., Citton M., Scarpa M. et al. Systematic review of surgical treatment of subclinical Cushing’s syndrome. Brit. J. Surg. 2015; 102 (4): 318-330. DOI: 10.1002/bjs.9742.

[107] Iacobone M., Citton M., Scarpa M. et al. Systematic review of surgical treatment of subclinical Cushing’s syndrome. Brit. J. Surg. 2015; 102 (4): 318–330. DOI: 10.1002/bjs.9742.

[108] Ivović M., Marina L.V., Vujović S. et al. Nondiabetic patients with either subclinical Cushing’s or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: clinical implications. Metabolism. 2013; 62 (6): 786-792. DOI: 10.1016/j.metabol.2012.12.006.

[109] Ivović M., Marina L.V., Vujović S. et al. Nondiabe­tic patients with either subclinical Cushing’s or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: clinical implications. Metabolism. 2013; 62 (6): 786–792. DOI: 10.1016/j.metabol.2012.12.006.

[110] Androulakis I.I., Kaltsas G.A., Kollias G.E. et al. Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion. J. Clin. Endocrinol. Metabol. 2014; 99 (8): 2754-2762. DOI: 10.1210/jc.2013-4064.

[111] Androulakis I.I., Kaltsas G.A., Kollias G.E. et al. Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to ­excessive cortisol secretion. J. Clin. Endocrinol. Metabol. 2014; 99 (8): 2754–2762. DOI: 10.1210/jc.2013-4064.

[112] Debono M., Prema A., Hughes T.J. et al. Visceral fat accumulation and postdexamethasone serum cortisol levels in patients with adrenal incidentaloma. J. Clin. Endocrinol. Metabol. 2013; 98 (6): 2383-2391. DOI: 10.1210/jc.2012-4276.

[113] Debono M., Prema A., Hughes T.J. et al. Visceral fat accumulation and postdexamethasone serum cortisol levels in patients with adrenal incidentaloma. J. Clin. Endocrinol. Metabol. 2013; 98 (6): 2383–2391. DOI: 10.1210/jc.2012-4276.

[114] Papanastasiou L., Pappa T., Samara C. et al. Nonalcoholic fatty liver disease in subjects with adrenal incidentaloma. Eur. J. Clin. Invest. 2012; 42 (11): 1165-1172. DOI: 10.1111/j.1365-2362.2012.02707.x.

[115] Papanastasiou L., Pappa T., Samara C. et al. Nonalcoholic fatty liver disease in subjects with adrenal incidentaloma. Eur. J. Clin. Invest. 2012; 42 (11): 1165–1172. DOI: 10.1111/j.1365-2362.2012.02707.x.

[116] Tо́th M., Grossman A. Glucocorticoid-induced osteoporosis: lessons from Cushing’s syndrome. Clin. Endocrinol. 2013; 79 (1): 1-11. DOI: 10.1111/cen.12189.

[117] Tо́th M., Grossman A. Glucocorticoid-induced osteo­porosis: lessons from Cushing’s syndrome. Clin. Endocrinol. 2013; 79 (1): 1–11. DOI: 10.1111/cen.12189.

[118] Tauchmanova` L., Pivonello R., De Martino M.C. et al. Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism. Eur. J. Endocrinol. 2007; 157 (3): 359-366. DOI: 10.1530/EJE-07-0137.

[119] Tauchmanova` L., Pivonello R., De Martino M.C. et al. Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism. Eur. J. Endocrinol. 2007; 157 (3): 359–366. DOI: 10.1530/EJE-07-0137.

[120] 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. Endocrin. Metabol. 2009; 94 (9): 3207-3214. DOI: 10.1210/jc.2009-0468.

[121] 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. Endocrin. Metabol. 2009; 94 (9): 3207–3214. DOI: 10.1210/jc.2009-0468.

[122] Morelli V., Eller-Vainicher C., Salcuni A.S. 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.

[123] Morelli V., Eller-Vainicher C., Salcuni A.S. 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.

[124] Miller W.L., Auchus R.J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Rev. 2011; 32 (1): 81-151. DOI: 10.1210/er.2010-0013.

[125] Miller W.L., Auchus R.J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Rev. 2011; 32 (1): 81–151. DOI: 10.1210/er.2010-0013.

[126] Baulieu E.E., Thomas G., Legrain S. et al. Dehydroepiandrosterone (DHEA) DHEA sulfate, and aging: contribution of the DHEA ge Study to a sociobiomedical issue. PNAS. 2000; 97 (8): 4279-4284. DOI: 10.1073/pnas.97.8.4279.

[127] Baulieu E.E., Thomas G., Legrain S. et al. Dehydro­epiandrosterone (DHEA) DHEA sulfate, and aging: contribution of the DHEA ge Study to a sociobiomedical issue. PNAS. 2000; 97 (8): 4279–4284. DOI: 10.1073/pnas.97.8.4279.

[128] Nair K.S., Rizza R.A., O’Brien P. et al. DHEA in elderly women and DHEA or testosterone in elderly men. New Engl. J. Med. 2006; 355 (16): 1647-1659. DOI: 10.1056/NEJMoa054629.

[129] Nair K.S., Rizza R.A., O’Brien P. et al. DHEA in elderly women and DHEA or testosterone in elderly men. New Engl. J. Med. 2006; 355 (16): 1647–1659. DOI: 10.1056/NEJMoa054629.

[130] 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. Metabol. 2002; 87 (11): 4872-4878. DOI: 10.1210/jc.2001-011766.

[131] 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. Metabol. 2002; 87 (11): 4872–4878. DOI: 10.1210/jc.2001-011766.

[132] 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.

[133] 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.

[134] 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. Lancet. Diabetes Endocrinol. 2014; 2 (5): 396-405. DOI: 10.1016/S2213-8587(13)70211-0.

[135] 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. Lancet. Diabetes Endocrinol. 2014; 2 (5): 396–405. DOI: 10.1016/S2213-8587(13)70211-0.

[136] Morelli V, Reimondo G., Giordano R. et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J. Clin. Endocrinol. Metabol. 2014; 99 (3): 827-834. DOI: 10.1210/jc.2013-3527.

[137] Morelli V, Reimondo G., Giordano R. et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J. Clin. Endocrinol. Metabol. 2014; 99 (3): 827–834. DOI: 10.1210/jc.2013-3527.

[138] Debono M., Bradburn M., Bull M. et al. Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J. Clin. Endocrinol. Metabol. 2014; 99 (12): 4462-4470. DOI: 10.1210/jc.2014-3007.

[139] Debono M., Bradburn M., Bull M. et al. Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J. Clin. Endocrinol. Metabol. 2014; 99 (12): 4462–4470. DOI: 10.1210/jc.2014-3007.

[140] Barry M.K., van Heerden J.A., Farely D.R. et al. Can adrenal incidentalomas be safely observed? World J. Surg. 1998; 22 (6): 599-604. DOI: 10.1007/s002689900441.

[141] Barry M.K., van Heerden J.A., Farely D.R. et al. Can adrenal incidentalomas be safely observed? World J. Surg. 1998; 22 (6): 599–604. DOI: 10.1007/s002689900441.

[142] Sirе́n J., Tervahartiala P., Sivula A. et al. Natural course of adrenal incidentalomas: seven-year follow-up study. World J. Surg. 2000; 24 (5): 579-582. DOI: 10.1007/s002689910095.

[143] Sirе́n J., Tervahartiala P., Sivula A. et al. Natural course of adrenal incidentalomas: seven-year follow-up study. World J. Surg. 2000; 24 (5): 579–582. DOI: 10.1007/s002689910095.

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