, Volume 66, Issue 3, pp 650–659 | Cite as

Cardiometabolic profile of non-functioning and autonomous cortisol-secreting adrenal incidentalomas. Is the cardiometabolic risk similar or are there differences?

  • Marta Araujo-CastroEmail author
  • Cristina Robles Lázaro
  • Paola Parra Ramírez
  • Martín Cuesta Hernández
  • Miguel Antonio Sampedro Núñez
  • Mónica Marazuela
Original Article



To study the differences in the cardiometabolic profile between patients with non-functioning adrenal incidentalomas (NFAI) and incidentalomas with autonomous cortisol secretion (ACS).


A total of 149 patients with adrenal incidentalomas were retrospectively evaluated and followed-up for a mean time of 34.6 months at Departments of Endocrinology and Metabolic Diseases Units of four tertiary Spanish hospitals. Patients were grouped as NFAI or ACS adenomas based on two cutoffs in the dexamethasone suppression test (DST): 3.0 µg/dl (NFAIDST3 or ACSDST3) and 1.8 µg/dl (ACSDST1.8 and NFAIDST1.8).


The mean age of both groups was 62.0 (10.31) and was similar in ACS and NFAI. The prevalence of diabetes, high blood pressure, cardiovascular, and cerebrovascular disease was higher in ACS than in NFAI, but differences only reached statistical significance for cerebrovascular disease using the 3.0 µg/dl cutoff (15.8% vs 2.3%, p = 0.01) and for diabetes using the 1.8 µg/dl cutoff (38.0% vs 22.0%, p = 0.04). No differences were found in the prevalence of dyslipidemia. The prevalence of obesity was lower in patients with ACS than in NFAI 26.3% vs 39.2%, p = 0.18 (NFAIDST3 vs ACSDST3) and 32.1% vs 40.6%, p = 0.56 (ACSDST1.8 vs NFAIDST1.8), but the differences did not reach statistical significance. Maximum adenoma diameter (R-squared = 0.15, p < 0.001) and cerebrovascular disease (OR = 1.59, p = 0.04) were the only parameters that could be predicted by the DST. The DST was an inadequate predictor of clinical (systolic and diastolic blood pressure, body mass index), hormonal (DHEAS, ACTH, UFC, and basal serum cortisol), biochemical (glucose, cholesterol, LDL, HDL, and triglycerides), and other radiological (laterality, lipid content) parameters. Throughout the follow-up, patients did not develop overt Cushing’s Syndrome; three NFAIDST3 developed ACSDST3, eight NFAIDST1.8 developed ACSDST1.8, and one NFAIDST1.8 progressed to ACSDST3. In both groups (NFAI and ACS) the metabolic profile remained stable.


Our data suggest higher prevalence of diabetes and cerebrovascular disease in ACS patients compared with NFAI. However, probably because of the small sample size, the differences only reached statistical significance using the cutoffs of 1.8 µg/dl for diabetes and 3.0 µg/dl for cerebrovascular disease. Patients with ACS and NFAI rarely progress to more aggressive forms of hypercortisolism, and the metabolic profile usually remains stable during the follow-up.


Autonomous cortisol secretion (ACS) Non-functioning adrenal incidentaloma (NFAI) Adrenal incidentaloma (AI) Dexamethasone suppression test (DST) 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    M. Fassnacht, W. Arlt, I. Bancos, H. Dralle, J. Newell-Price, A. Sahdev 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. 175(2), G1–G34 (2016). CrossRefPubMedGoogle Scholar
  2. 2.
    M. Terzolo, A. Stigliano, I. Chiodini, P. Loli, L. Furlani, G. Arnaldi et al. AME position statement on adrenal incidentaloma. Eur. J. Endocrinol. 164(6), 851–870 (2011). Epub 2011 Apr 6CrossRefPubMedGoogle Scholar
  3. 3.
    L.K. Nieman, B.M.K. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93(5), 1526–1540 (2008). Epub 2008 Mar 11CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    M. Araujo-Castro, M.A. Sampedro Núñez, M. Marazuela, Autonomous cortisol secretion in adrenal incidentalomas. Endocrine 64(1), 1–13 (2019). Epub 2019 Mar 7CrossRefPubMedGoogle Scholar
  5. 5.
    A. Ruiz, T. Michalopoulou, A. Megia, S. Näf, I. Simón-Muela, E. Solano et al. Accuracy of new recommendations for adrenal incidentalomas in the evaluation of excessive cortisol secretion and follow-up. Eur. J. Clin. Investig. 49(2), e13048 (2019). Epub 2018 Dec 7CrossRefGoogle Scholar
  6. 6.
    M. Terzolo, A. Pia, G. Reimondo, Subclinical Cushing’s syndrome: definition and management. Clin. Endocrinol. 76(1), 12–18 (2012). CrossRefGoogle Scholar
  7. 7.
    R. Rossi, L. Tauchmanova, A. Luciano, M. Di Martino, C. Battista, L. Del Viscovo et al. Subclinical Cushing’s syndrome in patients with adrenal incidentaloma: clinical and biochemical features. J. Clin. Endocrinol. Metab. 85(4), 1440–1448 (2000)PubMedGoogle Scholar
  8. 8.
    M. Terzolo, A. Pia, A. Ali, G. Osella, G. Reimondo, S. Bovio et al. Adrenal incidentaloma: a new cause of the metabolic syndrome? J. Clin. Endocrinol. Metab. 87(3), 998–1003 (2002)CrossRefGoogle Scholar
  9. 9.
    G. Di Dalmazi, V. Vicennati, E. Rinaldi, A.M. Morselli-Labate, E. Giampalma, C. Mosconi 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. 166(4), 669–677 (2012). Epub 2012 Jan 20CrossRefPubMedGoogle Scholar
  10. 10.
    M. Debono, M. Bradburn, M. Bull, B. Harrison, R.J. Ross, J. Newell-Price, Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J. Clin. Endocrinol. Metab. 99(12), 4462–4470 (2014). CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    I.I. Androulakis, G.A. Kaltsas, G.E. Kollias, A.C. Markou, A.K. Gouli, D.A. Thomas et al. Patients with apparently non-functioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion. J. Clin. Endocrinol. Metab. 99(8), 2754–2762 (2014). Epub 2014 Apr 8CrossRefPubMedGoogle Scholar
  12. 12.
    I. Chiodini, Clinical review: diagnosis and treatment of subclinical hypercortisolism. J. Clin. Endocrinol. Metab. 96(5), 1223–1236 (2011). Epub 2011 Mar 2CrossRefPubMedGoogle Scholar
  13. 13.
    I. Chiodini, V. Morelli, B. Masserini, A.S. Salcuni, C. Eller-Vainicher, R. Viti 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. 94(9), 3207–3214 (2009). Epub 2009 Jun 23CrossRefPubMedGoogle Scholar
  14. 14.
    M. Peppa, E. Boutati, C. Koliaki, N. Papaefstathiou, E. Garoflos, T. Economopoulos et al. Insulin resistance and metabolic syndrome in patients with non-functioning adrenal incidentalomas: A cause-effect relationship? Metabolism 59(10), 1435–1441 (2010). Epub 2010 Feb 13CrossRefPubMedGoogle Scholar
  15. 15.
    H. Yilmaz, N.B. Tütüncü, M. Şahin, Two-year follow-up of thirty-two non-functional benign adrenal incidentalomas. J. Endocrinol. Investig. 32(11), 913–916 (2009). Epub2009 Jul 14CrossRefGoogle Scholar
  16. 16.
    B. Masserini, V. Morelli, S. Bergamaschi, F. Ermetici, C. Eller-Vainicher, A.M. Barbieri et al. The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma. Eur. J. Endocrinol. 160(1), 87–92 (2009). Epub 2008 Oct 3CrossRefPubMedGoogle Scholar
  17. 17.
    A. Tanabe, M. Naruse, T. Nishikawa, T. Yoshimoto, T. Shimizu, T. Seki et al. Autonomy of cortisol secretion in clinically silent adrenal incidentaloma. Horm. Metab. Res. 33(7), 444–450 (2001)CrossRefGoogle Scholar
  18. 18.
    A.S. Salcuni, V. Morelli, C.E. Vainicher, S. Palmieri, E. Cairoli, A. Spada et al. Adrenalectomy reduces the risk of vertebral fractures in patients with monolateral adrenal incidentalomas and subclinical hypercortisolism. Eur. J. Endocrinol. 174(3), 261–269 (2016). Epub 2015 Dec 2CrossRefPubMedGoogle Scholar
  19. 19.
    V. Morelli, B. Masserini, A.S. Salcuni, C. Eller-Vainicher, C. Savoca, R. Viti et al. Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Clin. Endocrinol. 73(2), 161–166 (2010). Epub 2010 Feb 23CrossRefGoogle Scholar
  20. 20.
    Association American Diabetes., Updates to the standards of medical care in diabetes-2018. Diabetes Care. 41(9), 2045–2047 (2018). CrossRefGoogle Scholar
  21. 21.
    National Cholesterol Education Program (NCEP), Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 106(25), 3143–3421 (2002).Google Scholar
  22. 22.
    B. Bulow, S. Jansson, C. Juhlin, L. Steen, M. Thoren, H. Wahrenberg et al. Adrenal incidentaloma - follow-up results from a Swedish prospective study. Eur. J. Endocrinol. 154(3), 419–423 (2006)CrossRefGoogle Scholar
  23. 23.
    R. Libe, C. Dall’Asta, L. Barbetta, A. Baccarelli, P. Beck-Peccoz, B. Ambrosi, Long-term follow-up study of patients with adrenal incidentalomas. Eur. J. Endocrinol. 147(4), 489–494 (2002)CrossRefGoogle Scholar
  24. 24.
    L. Barzon, N. Sonino, F. Fallo, G. Palù, M. Boscaro, Prevalence and natural history of adrenal incidentalomas. Eur. J. Endocrinol. 149(4), 273–285 (2003)CrossRefGoogle Scholar
  25. 25.
    J.W. Dobbie, Adrenocortical nodular hyperplasia: the ageing adrenal. J. Pathol. 99(1), 1–18 (1969)CrossRefGoogle Scholar
  26. 26.
    L. Papanastasiou, K. Alexandraki, I.I. Androulakis, S. Fountoulakis, T. Kounadi, A. Markou et al. Concomitant alterations of metabolic parameters, cardiovascular risk factors and altered cortisol secretion in patients with adrenal incidentalomas during prolonged follow-up. Clin. Endocrinol. 86(4), 488–498 (2017). Epub 2017 Jan 25CrossRefGoogle Scholar
  27. 27.
    J.M. Baena Díez, J.L. del Val García, J.T. Pelegrina, J.L. Martínez Martínez, R.M. Peñacoba, I.G. Tejón et al. Epidemiología de las enfermedades cardiovasculares y factores de riesgo en atención primaria. Rev. Esp. Cardiol. 58, 367–373 (2005). Vol. 58 Núm.04CrossRefPubMedGoogle Scholar
  28. 28.
    J.A. Whitworth, G.J. Mangos, J.J. Kelly, Cushing, cortisol, and cardiovascular disease. Hypertension 36(5), 912–916 (2000)CrossRefGoogle Scholar
  29. 29.
    A.M. Isidori, C. Graziadio, R.M. Paragliola, A. Cozzolino, A.G. Ambrogio, A. Colao et al. The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on cardiovascular complications. J. Hypertens. 33(1), 44–60 (2015). CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    D. Lopez, M.A. Luque-Fernandez, A. Steele, G.K. Adler, A. Turchin, A. Vaidya, “Nonfunctional” adrenal Tumors and the risk for incident diabetes and cardiovascular outcomes: a cohort study. Ann. Intern Med. 165(8), 533–542 (2016). Epub 2016 Aug 2CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    G. Mazziotti, C. Gazzaruso, A. Giustina, Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol. Metab. 22(12), 499–506 (2011). Epub 2011 Oct 11CrossRefPubMedGoogle Scholar
  32. 32.
    G.I. Sydney, K.J. Ioakim, S.A. Paschou, Insulin resistance and adrenal incidentalomas: a bidirectional relationship. Maturitas 121, 1–6 (2019). Epub 2018 Dec 5CrossRefPubMedGoogle Scholar
  33. 33.
    A. Belfiore, F. Frasca, G. Pandini, L. Sciacca, R. Vigneri, Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr. Rev. 30(6), 586–623 (2009). Epub 2009 Sep 14CrossRefPubMedGoogle Scholar
  34. 34.
    F. Peruzzi, M. Prisco, M. Dews, P. Salomoni, E. Grassilli, G. Romano et al. Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol. Cell Biol. 19(10), 7203–7215 (1999)CrossRefGoogle Scholar
  35. 35.
    E. Nyman, G. Cedersund, P. Strålfors, Insulin signaling—mathematical modeling comes of age. Trends Endocrinol. Metab. 23(3), 107–115 (2012). Epub 2012 Jan 28CrossRefPubMedGoogle Scholar
  36. 36.
    D. Ish-Shalom, G. Tzivion, C.T. Christoffersen, B. Ursø, P. De Meyts, D. Naor, Mitogenic potential of insulin on lymphoma cells lacking IGF‐1 receptor. Ann. N Y Acad. Sci. 766, 409–415 (1995)CrossRefGoogle Scholar
  37. 37.
    G. Di Dalmazi, V. Vicennati, S. Garelli, E. Casadio, E. Rinaldi, E. Giampalma 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. 2(5), 396–405 (2014). Epub 2014 Jan 29CrossRefPubMedGoogle Scholar
  38. 38.
    L.F. Starker, J.W. Kunstman, T. Carling, Subclinical Cushing syndrome: a review. Surg. Clin. N. Am. 94(3), 657–668 (2014). Epub 2014 Apr 24CrossRefPubMedGoogle Scholar
  39. 39.
    S. Tsagarakis, D. Vassiliadi, N. Thalassinos, Endogenous subclinical hypercortisolism: diagnostic uncertainties and clinical implications. J. Endocrinol. Investig. 29(5), 471–482 (2006)CrossRefGoogle Scholar
  40. 40.
    S. Kidambi, H. Raff, J.W. Findling, Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur. J. Endocrinol. 157(6), 725–731 (2007)CrossRefGoogle Scholar
  41. 41.
    S. Yener, H. Yilmaz, T. Demir, M. Secil, A. Comlekci, DHEAS for the prediction of subclinical Cushing’s syndrome: perplexing or advantageous? Endocrine 48(2), 669–676 (2015). Epub 2014 Aug 22CrossRefPubMedGoogle Scholar
  42. 42.
    G. Osella, M. Terzolo, G. Borretta, G. Magro, A. Ali, A. Piovesan et al. Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas). J. Clin. Endocrinol. Metab. 79(6), 1532–1539 (1994)CrossRefGoogle Scholar
  43. 43.
    Z. Bencsik, I. Szabolcs, Z. Kovács, A. Ferencz, A. Vörös, I. Kaszás et al. Low dehydroepiandrosterone sulfate (DHEA-S) level is not a good predictor of hormonal activity in nonselected patients with incidentally detected adrenal tumors. J. Clin. Endocrinol. Metab. 81(5), 1726–1729 (1996)PubMedGoogle Scholar
  44. 44.
    I. Ilias, A. Sahdev, R.H. Reznek, A.B. Grossman, K. Pacak, The optimal imaging of adrenal tumours: a comparison of different methods. Endocr. Relat. Cancer 14(3), 587–599 (2007)CrossRefGoogle Scholar
  45. 45.
    S. Yener, S. Ertilav, M. Secil, B. Akinci, T. Demir, L. Kebapcilar et al. Increased risk of unfavorable metabolic outcome during short-term follow-up in subjects with non-functioning adrenal adenomas. Med. Princ. Pract. 21(5), 429–434 (2012). Epub 2012 Mar 2CrossRefPubMedGoogle Scholar
  46. 46.
    V. Morelli, G. Reimondo, R. Giordano, S. Della Casa, C. Policola, S. Palmieri et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J. Clin. Endocrinol. Metab. 99(3), 827–834 (2014). Epub 2014 Jan 1CrossRefPubMedGoogle Scholar
  47. 47.
    L. Barzon, C. Scaroni, N. Sonino, F. Fallo, A. Paoletta, M. Boscaro, Risk factors and long-term follow-up of adrenal incidentalomas. J. Clin. Endocrinol. Metab. 84(2), 520–526 (1999)PubMedGoogle Scholar
  48. 48.
    L. Barzon, F. Fallo, N. Sonino, M. Boscaro, Development of overt Cushing’s syndrome in patients with adrenal incidentaloma. Eur. J. Endocrinol. 146(1), 61–66 (2002)CrossRefGoogle Scholar
  49. 49.
    V. Morelli et al. Role of glucocorticoid receptor polymorphism in adrenal incidentalomas. Eur. J. Clin. Investig. 40(9), 803–811 (2010). CrossRefGoogle Scholar
  50. 50.
    V. Morelli et al. Cardiovascular events in patients with mild autonomous cortisol secretion: analysis with artificial neural networks. Eur. J. Endocrinol. 177(1), 73–83 (2017). CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Endocrinology DepartmentRamón y Cajal University HospitalMadridSpain
  2. 2.Endocrinology DepartmentSalamanca Clinical University HospitalSalamancaSpain
  3. 3.Endocrinology DepartmentLa Paz University HospitalMadridSpain
  4. 4.Endocrinology DepartmentSan Carlos Clinical University HospitalMadridSpain
  5. 5.Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)MadridSpain
  6. 6.Endocrinology DepartmentPrincesa University HospitalMadridSpain

Personalised recommendations