Advertisement

Endocrine

, Volume 64, Issue 1, pp 1–13 | Cite as

Autonomous cortisol secretion in adrenal incidentalomas

  • Marta Araujo-CastroEmail author
  • Miguel Antonio Sampedro NúñezEmail author
  • Mónica MarazuelaEmail author
Review
  • 180 Downloads

Abstract

Adrenal incidentalomas (AI) are one of the most frequent reasons for consultation in Endocrinology, as they are present in 3–10% of the general population. Up to 20% of them may have autonomous cortisol secretion (ACS), a term that refers to AI carriers with biochemical evidence of excess cortisol, but without the “specific” clinical signs of Cushing’s syndrome. As ACS is associated with an increased risk of diabetes, obesity, high blood pressure (HBP), osteoporosis, cardiovascular events, and global mortality; its correct identification is of great importance. There are different laboratory assays to detect ACS, but all of them have some limitations. The dexamethasone suppression test is the most accepted for screening. However, there is no consensus on the cutoff point that should be used. Low levels of ACTH and DHEA-S and high urinary free cortisol are also associated with ACS, but in isolation they are of little value to establish the diagnosis. Considering its clinical implications and the lack of consensus in the diagnosis and in which is the most appropriate management of these patients, this review offers a quick reference guide of ACS, presenting an exhaustive review of the topic: its definition, epidemiology, diagnosis, clinical implications, treatment, and follow-up.

Keywords

Adrenal incidentalomas Hypercortisolism Autonomous cortisol secretion Cushing's syndrome 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    J. Wagner, D.C. Aron, Incidentalomas—A ‘disease’ of modern imaging technology. Best Pract. Res. Clin. Endocrinol. Metab. 26(1), 3–8 (2012).  https://doi.org/10.1016/j.beem.2011.08.006 CrossRefPubMedGoogle Scholar
  2. 2.
    G. Favia, F. Lumachi, S. Basso, D.F. D’Amico, Management of incidentally discovered adrenal masses and risk of malignancy. Surgery 128(6), 918–924 (2000).  https://doi.org/10.1067/msy.2000.109965 CrossRefPubMedGoogle Scholar
  3. 3.
    L. Barzon, N. Sonino, F. Fallo, G. Palu, M. Boscaro, Prevalence and natural history of adrenal incidentalomas. Eur. J. Endocrinol. 149(4), 273–285 (2003)CrossRefPubMedGoogle Scholar
  4. 4.
    M.M. Grumbach, B.M. Biller, G.D. Braunstein, K.K. Campbell, J.A. Carney, P.A. Godley et al. Management of the clinically inapparent adrenal mass (‘incidentaloma’). Ann. Intern. Med. 138(5), 424–429 (2003)CrossRefPubMedGoogle Scholar
  5. 5.
    P. Anagnostis, A. Karagiannis, K. Tziomalos, A.I. Kakafika, V.G. Athyros, D.P. Mikhailidis, Adrenal incidentaloma: a diagnostic challenge. HormONES 8(3), 163–184 (2009)CrossRefPubMedGoogle Scholar
  6. 6.
    M. Fassnacht, W. Arlt, I. Bancos, H. Dralle, J. Newell-Price, A.M. 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).  https://doi.org/10.1530/EJE-16-0467 CrossRefPubMedGoogle Scholar
  7. 7.
    I. Chiodini, Diagnosis and treatment of subclinical hypercortisolism. J. Clin. Endocrinol. Metab. 96(5), 1223–1236 (2011).  https://doi.org/10.1210/jc.2010-2722. Epub 2011 Mar 2CrossRefPubMedGoogle Scholar
  8. 8.
    G. Di Dalmazi, V. Vicennati, E. Rinaldi, A.M. Morselli-Labate, E. Giampalma, C.G. 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).  https://doi.org/10.1530/EJE-11-1039. Epub 2012 Jan 20CrossRefPubMedGoogle Scholar
  9. 9.
    A.A. Gheorghisan-Galateanu, M. Carsote, A. Valea, Incidentaloma: from general practice to specific endocrine frame. J. Pak. Med Assoc. 67(6), 917–922 (2017)PubMedGoogle Scholar
  10. 10.
    F. Mantero, M. Terzolo, G. Arnaldi, G. Osella, A.M. Masini, A.F. Alì et al. A survey on adrenal incidentaloma in Italy. J. Clin. Endocrinol. Metab. 85(2), 637–644 (2000)PubMedGoogle Scholar
  11. 11.
    S. Bovio, A. Cataldi, G. Reimondo, P. Sperone, S. Novello, A. Berruti et al. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J. Endocrinol. Invest. 29(4), 298–302 (2006)CrossRefPubMedGoogle Scholar
  12. 12.
    R.T. Kloos, M. Korobkin, N.W. Thompson, I.R. Francis, B. Shapiro, M.D. Gross, Incidentally discovered adrenal masses. Cancer Treat. Res. 89, 263–292 (1997)CrossRefPubMedGoogle Scholar
  13. 13.
    S.K. Mayer, L.L. Oligny, C. Deal, S. Yazbeck, N. Gagné, H. Blanchard, Childhood adrenocortical tumors: case series and reevaluation of prognosis--a 24-year experience. J. Pediatr. Surg. 32(6), 911–915 (1997)CrossRefPubMedGoogle Scholar
  14. 14.
    M. Terzolo, A. Stigliano, I. Chiodini, P. Loli, L. Furlani, G.,M. Arnaldi et al. AME position statement on adrenal incidentaloma. Eur. J. Endocrinol. 164(6), 851–870 (2011).  https://doi.org/10.1530/EJE-10-1147. Epub 2011 Apr 6CrossRefPubMedGoogle Scholar
  15. 15.
    L.K. Nieman, B.M. 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).  https://doi.org/10.1210/jc.2008-0125. Epub 2008 Mar 11CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    B. Bülow, S. Jansson, C. Juhlin, L. Steen, M. Thorén, H. Wahrenberg et al. Adrenal incidentaloma—follow-up results from a Swedish prospective study. Eur. J. Endocrinol. 154(3), 419–423 (2006)CrossRefPubMedGoogle Scholar
  17. 17.
    R. Libè, C. Dall’Asta, L. Barbetta, A. Baccarelli, P.R. Beck-Peccoz et al. Long-term follow-up study of patients with adrenal incidentalomas. Eur. J. Endocrinol. 147(4), 489–494 (2002)CrossRefPubMedGoogle Scholar
  18. 18.
    M. Terzolo, A. Pia, G.M. Reimondo, Subclinical Cushing’s syndrome: definition and management. Clin. Endocrinol. 76(1), 12–18 (2012).  https://doi.org/10.1111/j.1365-2265.2011.04253.x CrossRefGoogle Scholar
  19. 19.
    I. Chiodini, C.E. Vainicher, V. Morelli, S. Palmieri, E. Cairoli, A.S. Salcuni et al. Endogenous subclinical hypercortisolism and bone: a clinical review. Eur. J. Endocrinol. 175(6), R265–R282 (2016)CrossRefPubMedGoogle Scholar
  20. 20.
    M. Boronat, A. Moreno, S. Ramón y Cajal, E. Pineda, T. Lucas, J. Estrada, Subclinical Cushing’s syndrome due to adrenal myelolipoma. Arch. Pathol. Lab Med. 121(7), 735–737 (1997)PubMedGoogle Scholar
  21. 21.
    K. Duan, K.G. Hernandez, O. Mete, Clinicopathological correlates of adrenal cushing’s syndrome. Postgrad. Med J. 91(1076), 331–342 (2015).  https://doi.org/10.1136/postgradmedj-2014-202612rep CrossRefPubMedGoogle Scholar
  22. 22.
    G.M. Goddard, A. Ravikumar, A.C. Levine, Adrenal mild hypercortisolism. Endocrinol. Metab. Clin. North Am. 44(2), 371–379 (2015).  https://doi.org/10.1016/j.ecl.2015.02.009 CrossRefPubMedGoogle Scholar
  23. 23.
    N.S. Ross, Epidemiology of Cushing’s syndrome and subclinical disease. Endocrinol. Metab. Clin. North Am. 23(3), 539–546 (1994)CrossRefPubMedGoogle Scholar
  24. 24.
    M. Reincke, J. Nieke, G.P. Krestin, W. Saeger, B. Allolio, W. Winkelmann, Preclinical Cushing's syndrome in adrenal incidentalomas—comparison with adrenal Cushing's syndrome. J. Clin. Endocrinol. Metab. 75(3), 826–832 (1992)PubMedGoogle Scholar
  25. 25.
    M.A. Zeiger, G.B. Thompson, Q.Y. Duh, A.H. Hamrahian, P. Angelos, D. Elaraj 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. 15(5), 450–453 (2009)CrossRefPubMedGoogle Scholar
  26. 26.
    W.F. Young Jr., Clinical practice. The incidentally discovered adrenal mass. N. Engl. J. Med. 356(6), 601–610 (2007)CrossRefPubMedGoogle Scholar
  27. 27.
    T.J. Cawood, P.J. Hunt, D. O’Shea, D. Cole, S.T. Soule, Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink? Eur. J. Endocrinol. 161(4), 513–527 (2009).  https://doi.org/10.1530/EJE-09-0234. Epub 2009 May 13CrossRefPubMedGoogle Scholar
  28. 28.
    A. Tabarin, S. Bardet, J. Bertherat, B. Dupas, O. Chabre, E. Hamoir et al. Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus. Ann. Endocrinol. 69(6), 487–500 (2008).  https://doi.org/10.1016/j.ando.2008.09.003. Epub 2008 Nov 20CrossRefGoogle Scholar
  29. 29.
    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).  https://doi.org/10.1210/jc.2014-3007 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    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).  https://doi.org/10.1016/S2213-8587(13)70211-0. Epub 2014 Jan 29CrossRefPubMedGoogle Scholar
  31. 31.
    T. Katabami, R. Obi, N. Shirai, S. Naito, N. Saito, Discrepancies in results of low-and high-dose dexamethasone suppression tests for diagnosing preclinical Cushing’s syndrome. Endocr. J. 52(4), 463–469 (2005)CrossRefPubMedGoogle Scholar
  32. 32.
    S. Tsagarakis, P. Kokkoris, C. Roboti, C. Malagari, J. Kaskarelis, V. Vlassopoulou et al. The low-dose dexamethasone suppression test in patients with adrenal incidentalomas: comparisons with clinically euadrenal subjects and patients with Cushing’s syndrome. Clin. Endocrinol. 48(5), 627–633 (1998)CrossRefGoogle Scholar
  33. 33.
    L.K. Nieman, B.M. 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).  https://doi.org/10.1210/jc.2008-0125. Epub 2008 Mar 11CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    A.W. Meikle, Dexamethasone suppression tests: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin. Endocrinol. 16(4), 401–408 (1982)CrossRefGoogle Scholar
  35. 35.
    C. Hempen, S. Elfering, A.H. Mulder, F.A. van den Bergh, R.G. Maatman, Dexamethasone suppression test: Development of a method for simultaneous determination of cortisol and dexamethasone in human plasma by liquid chromatography/tandem mass spectrometry. Ann. Clin. Biochem. 49(Pt 2), 170–176 (2012).  https://doi.org/10.1258/acb.2011.011004. Epub 2012 Jan 12CrossRefPubMedGoogle Scholar
  36. 36.
    G. Arnaldi, A. Angeli, A.B. Atkinson, X. Bertagna, F. Cavagnini, G.P. Chrousos et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 88(12), 5593–5602 (2003)CrossRefPubMedGoogle Scholar
  37. 37.
    J. Newell-Price, Diagnosis/differential diagnosis of Cushing’s syndrome: a review of best practice. Best. Pract. Res Clin. Endocrinol. Metab. 23, S5–S14 (2009)CrossRefPubMedGoogle Scholar
  38. 38.
    S. Santos, E. Santos, S. Gaztambide, J. Salvador, Diagnóstico y diagnóstico diferencial del síndrome de Cushing. Endocrinol. Nutr. 56(2), 71–84 (2009).  https://doi.org/10.1016/S1575-0922(09)70555-8. Epub 2009 May 1CrossRefPubMedGoogle Scholar
  39. 39.
    F. Ceccato, G. Antonelli, M. Barbot, M. Zilio, L. Mazzai, R. Gatti et al. The diagnostic performance of urinary free cortisol is better than the cortisol: cortisone ratio in detecting de novo Cushing’s syndrome: the use of a LC–MS/MS method in routine clinical practice. Eur. J. Endocrinol. 171(1), 1–7 (2014).  https://doi.org/10.1530/EJE-14-0061. Epub 2014 Apr 17CrossRefPubMedGoogle Scholar
  40. 40.
    F. Ceccato, M. Boscaro, Cushing’s syndrome: screening and diagnosis. High Blood Press Cardiovasc Prev. 23(3), 209–215 (2016).  https://doi.org/10.1007/s40292-016-0153-4 CrossRefPubMedGoogle Scholar
  41. 41.
    A. Kotłowska, T. Puzyn, K. Sworczak, P. Stepnowski, P. Szefer, Metabolomic biomarkers in urine of cushing’s syndrome patients. Int J. Mol. Sci. 18(2), pii: E294 (2017).  https://doi.org/10.3390/ijms18020294 CrossRefGoogle Scholar
  42. 42.
    J. Newell-Price, X. Bertagna, A.B. Grossman, L.K. Nieman, Cushing’s syndrome. Lancet 367(9522), 1605–1617 (2006)CrossRefPubMedGoogle Scholar
  43. 43.
    F. Pecori Giraldi, A. Saccani, F. Cavagnini, Assessment of ACTH assay variability: a multicenter study. Eur. J. Endocrinol. 164(4), 505–512 (2011).  https://doi.org/10.1530/EJE-10-0962. Epub 2011 Jan 20CrossRefPubMedGoogle Scholar
  44. 44.
    M. Terzolo, S. Bovio, A. Pia, P.A. Conton, G. Reimondo, C.T. Dall’Asta et al. Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma. Eur. J. Endocrinol. 153(2), 307–315 (2005)CrossRefPubMedGoogle Scholar
  45. 45.
    D.A. Papanicolaou, N. Mullen, I. Kyrou, L.K. Nieman, Nighttime salivary cortisol: A useful test for the diagnosis of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 87(10), 4515–4521 (2002)CrossRefPubMedGoogle Scholar
  46. 46.
    M. Doi, N. Sekizawa, Y. Tani, K. Tsuchiya, R. Kouyama, T. Tateno et al. Late-night salivary cortisol as a screening test for the diagnosis of Cushing’s syndrome in Japan. Endocr. J. 55(1), 121–126 (2008). Epub 2008 Jan 17CrossRefPubMedGoogle Scholar
  47. 47.
    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).  https://doi.org/10.1530/EJE-08-0485. Epub 2008 Oct 3CrossRefPubMedGoogle Scholar
  48. 48.
    F. Ceccato, M. Barbot, N. Albiger, G. Antonelli, M. Zilio, M. Todeschini et al. Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma. Endocrine 59(3), 510–519 (2018).  https://doi.org/10.1007/s12020-017-1421-3. Epub 2017 Sep 27CrossRefPubMedGoogle Scholar
  49. 49.
    I. Perogamvros, B.G. Keevil, D.W. Ray, P.J. Trainer, Salivary cortisone is a potential biomarker for serum free cortisol. J. Clin. Endocrinol. Metab. 95(11), 4951–4958 (2010).  https://doi.org/10.1210/jc.2010-1215. Epub2010 Aug 4CrossRefPubMedGoogle Scholar
  50. 50.
    M. Castro, P.C. Elias, A.R. Quidute, F.P. Halah, A.C. Moreira, Out-patient screening for Cushing’s syndrome: the sensitivity of the combination of circadian rhythm and overnight dexamethasone suppression salivary cortisol tests. J. Clin. Endocrinol. Metab. 84(3), 878–882 (1999)PubMedGoogle Scholar
  51. 51.
    K. Mészáros, G. Karvaly, Z. Márta, B. Magda, J. Tőke, N. Szücs et al. Diagnostic performance of a newly developed salivary cortisol and cortisone measurement using an LC–MS/MS method with simple and rapid sample preparation. J. Endocrinol. Invest 41(3), 315–323 (2018).  https://doi.org/10.1007/s40618-017-0743-6. Epub 2017 Aug 16CrossRefPubMedGoogle Scholar
  52. 52.
    S.K. Baid, N. Sinaii, M. Wade, D. Rubino, L.K. Nieman, Radioimmunoassay and tandem mass spectrometry measurement of bedtime salivary cortisol levels: a comparison of assays to establish hypercortisolism. J. Clin. Endocrinol. Metab. 92(8), 3102–3107 (2007). Epub 2007 Jun 5CrossRefPubMedGoogle Scholar
  53. 53.
    E. Badrick, C. Kirschbaum, M. Kumari, The relationship between smoking status and cortisol secretion. J. Clin. Endocrinol. Metab. 92(3), 819–824 (2007). Epub 2006 Dec 19CrossRefPubMedGoogle Scholar
  54. 54.
    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)CrossRefPubMedGoogle Scholar
  55. 55.
    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
  56. 56.
    J.M. Lee, M.K. Kim, S.H. Ko, J.M. Koh, B.Y. Kim, S.W. Kim et al. Clinical Guidelines for the management of adrenal incidentaloma. Endocrinol. Metab. 32(2), 200–218 (2017).  https://doi.org/10.3803/EnM.2017.32.2.200 CrossRefGoogle Scholar
  57. 57.
    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).  https://doi.org/10.1007/s12020-014-0387-7. Epub 2014 Aug 22CrossRefPubMedGoogle Scholar
  58. 58.
    G. Di Dalmazi, F. Fanelli, M. Mezzullo, E. Casadio, E. Rinaldi, S. Garelli et al. Steroid profiling by LC-MS/MS in nonsecreting and subclinical cortisol-secreting adrenocortical adenomas. J. Clin. Endocrinol. Metab. 100(9), 3529–3538 (2015).  https://doi.org/10.1210/JC.2015-1992. Epub2015 Jul 10CrossRefPubMedGoogle Scholar
  59. 59.
    A.S. Salcuni, V. Morelli, C. Eller 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).  https://doi.org/10.1530/EJE-15-0977. Epub 2015 Dec 2CrossRefPubMedGoogle Scholar
  60. 60.
    M. Terzolo, A. Pia, A. Alì, 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)CrossRefPubMedGoogle Scholar
  61. 61.
    B. Masserini, V. Morelli, S. Palmieri, C. Eller-Vainicher, V. Zhukouskaya, E. Cairoli et al. Lipid abnormalities in patients with adrenal incidentalomas: Role of subclinical hypercortisolism and impaired glucose metabolism. J. Endocrinol. Invest. 38(6), 623–628 (2015).  https://doi.org/10.1007/s40618-014-0232-0. Epub 2015 Jan 23CrossRefPubMedGoogle Scholar
  62. 62.
    C. Scaroni, M. Zilio, M. Foti, M. Boscaro, Glucose metabolism abnormalities in cushing syndrome: from molecular basis to clinical management. Endocr. Rev. 38(3), 189–219 (2017).  https://doi.org/10.1210/er.2016-1105 CrossRefPubMedGoogle Scholar
  63. 63.
    E. Ellis, P.K. Chin, P.J. Hunt, H. Lunt, J.G. Lewis, S.G. Soule, Is late-night salivary cortisol a better screening test for possible cortisol excess than standard screening tests in obese patients with Type 2. Diabetes? N. Z. Med J. 125(1353), 47–58 (2012)PubMedGoogle Scholar
  64. 64.
    K. Mullan, N. Black, A. Thiraviaraj, P.M. Bell, C. Burgess, S.J. Hunter et al. Is there value in routine screening for Cushing’s syndrome in patients with diabetes? J. Clin. Endocrinol. Metab. 95(5), 2262–2265 (2010).  https://doi.org/10.1210/jc.2009-2453. Epub 2010 Mar 17CrossRefPubMedGoogle Scholar
  65. 65.
    L. Gagliardi, I.M. Chapman, P. O’Loughlin, D.J. Torpy, Screening for subclinical Cushing’s syndrome in type 2 diabetes mellitus: low false-positive rates with nocturnal salivary cortisol. Horm. Metab. Res. 42(4), 280–284 (2010).  https://doi.org/10.1055/s-0029-1246191. Epub 2010 Jan 29CrossRefPubMedGoogle Scholar
  66. 66.
    G.B. Cansu, S. Atılgan, M.K. Balcı, R. Sarı, S. Özdem, H.A. Altunbaş, Which type 2 diabetes mellitus patients should be screened for subclinical Cushing’s syndrome? Hormone. 16(1), 22–32 (2017).  https://doi.org/10.14310/horm.2002.1716 CrossRefGoogle Scholar
  67. 67.
    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).  https://doi.org/10.1097/HJH.0000000000000415 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    T. Mancini, B. Kola, F. Mantero, M. Boscaro, G. Arnaldi, High cardiovascular risk in patients with Cushing’s syndrome according to 1999WHO/ISH guidelines. Clin. Endocrinol. 61(6), 768–777 (2004)CrossRefGoogle Scholar
  69. 69.
    Bancos I., Alahdab F., Crowley R.K., Chortis V., Delivanis D.A., Erickson D6 et al. Therapy of endocrine disease: improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and subclinical Cushing’s syndrome: a systematic review and meta-analysis. Eur. J. Endocrinol. 2016;175(6):R283–R295. Epub 2016 Jul 22.Google Scholar
  70. 70.
    M. Grasso, M. Boscaro, C. Scaroni, F. Ceccato, Secondary Arterial Hypertension: From Routine Clinical Practice to Evidence in Patients with Adrenal Tumor. High. Blood Press Cardiovasc Prev. 25(4), 345–354 (2018).  https://doi.org/10.1007/s40292-018-0288-6. Epub 2018 Nov 10CrossRefPubMedGoogle Scholar
  71. 71.
    I. Chiodini, M. Torlontano, V. Carnevale, G. Guglielmi, M. Cammisa, V. Trischitta et al. Bone loss rate in adrenal incidentalomas: a longitudinal study. J. Clin. Endocrinol. Metab. 86(11), 5337–5341 (2001)CrossRefPubMedGoogle Scholar
  72. 72.
    V. Morelli, C. Eller-Vainicher, A.S. Salcuni, F. Coletti, L. Iorio, G. Muscogiuri 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. 26(8), 1816–1821 (2011).  https://doi.org/10.1002/jbmr.398 CrossRefPubMedGoogle Scholar
  73. 73.
    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).  https://doi.org/10.1210/jc.2009-0468. Epub 2009 Jun 23CrossRefPubMedGoogle Scholar
  74. 74.
    C. Eller-Vainicher, V. Morelli, F.M. Ulivieri, S. Palmieri, V.V. Zhukouskaya, E. Cairoli et al. Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism. J. Bone Miner. Res. 27(10), 2223–2230 (2012).  https://doi.org/10.1002/jbmr.1648 CrossRefPubMedGoogle Scholar
  75. 75.
    R.S. Hardy, H. Zhou, M.J. Seibel, M.S. Cooper, Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy. Endocr. Rev. 39(5), 519–548 (2018).  https://doi.org/10.1210/er.2018-00097 CrossRefPubMedGoogle Scholar
  76. 76.
    V. Morelli, F. Donadio, C. Eller-Vainicher, V. Cirello, L. Olgiati, C. Savoca et al. Role of glucocorticoid receptor polymorphism in adrenal incidentalomas. Eur. J. Clin. Invest 40(9), 803–811 (2010).  https://doi.org/10.1111/j.1365-2362.2010.02330.x. Epub 2010 Jun 23CrossRefPubMedGoogle Scholar
  77. 77.
    V.V. Zhukouskaya, C. Eller-Vainicher, A. Gaudio, E. Cairoli, F.M. Ulivieri, S.,V. Palmieri et al. In postmenopausal female subjects with type 2 diabetes mellitus vertebral fractures are independently associated with cortisol secretion and sensitivity. J. Clin. Endocrinol. Metab. 100(4), 1417–1425 (2015).  https://doi.org/10.1210/jc.2014-4177. Epub 2015 Jan 15CrossRefPubMedGoogle Scholar
  78. 78.
    L. Buckley, G. Guyatt, H.A. Fink, M. Cannon, J. Grossman, K.E. Hansen et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Care Res. 69(8), 1095–1110 (2017).  https://doi.org/10.1002/acr.23279. Epub 2017 Jun 6CrossRefGoogle Scholar
  79. 79.
    S. Lekamwasam, J.D. Adachi, D. Agnusdei, J. Bilezikian, S. Boonen, F. Borgström et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos. Int. 23(9), 2257–2276 (2012).  https://doi.org/10.1007/s00198-012-1958-1. Epub 2012 Mar 21CrossRefPubMedGoogle Scholar
  80. 80.
    G.P. Bernini, A. Moretti, C. Oriandini, M. Bardini, C. Taurino, A. Salvetti, Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas. Br. J. Cancer 92(6), 1104–1109 (2005)CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    S. Yener, M. Baris, A. Peker, O. Demir, B. Ozgen, M. Secil, Autonomous cortisol secretion in adrenal incidentalomas and increased visceral fat accumulation during follow-up. Clin. Endocrinol. 87(5), 425–432 (2017).  https://doi.org/10.1111/cen.13408. Epub2017 Aug 2CrossRefGoogle Scholar
  82. 82.
    M. Debono, J. Newell-Price, Subclinical hypercortisolism in adrenal incidentaloma. Curr. Opin. Endocrinol. Diabetes Obes. 22(3), 185–192 (2015).  https://doi.org/10.1097/MED.0000000000000151 CrossRefPubMedGoogle Scholar
  83. 83.
    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
  84. 84.
    R. Świątkowska-stodulska, A. Skibowska-bielińska, P. Wiśniewski, K. Sworczak, Activity of selected coagulation factors in overt and subclinical hypercortisolism. Endocr. J. 62(8), 687–694 (2015).  https://doi.org/10.1507/endocrj.EJ14-0539. Epub 2015 May 13CrossRefPubMedGoogle Scholar
  85. 85.
    M. Karakose, B. Karbek, M. Sahin, M.S. Arslan, O. Topaloglu, G. Erden et al. The association of autoimmune thyroiditis and non-functional adrenal incidentalomas with insulin resistance. Arch. Endocrinol. Metab. 59(1), 42–46 (2015).  https://doi.org/10.1590/2359-3997000000008 CrossRefPubMedGoogle Scholar
  86. 86.
    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
  87. 87.
    V. Morelli, A. Scillitani, M. Arosio, I. Chiodini, Follow-up of patients with adrenal incidentaloma, in accordance with the European society of endocrinology guidelines: could we be safe? J. Endocrinol. Invest. 40(3), 331–333 (2017).  https://doi.org/10.1007/s40618-016-0558-x. Epub 2016 Oct 15CrossRefPubMedGoogle Scholar
  88. 88.
    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)CrossRefPubMedGoogle Scholar
  89. 89.
    I.C. Mitchell, R.J. Auchus, K. Juneja, A.Y. Chang, S.A. Holt, W.H. Snyder et al. Subclinical Cushing’s syndrome is not subclinical: improvement after adrenalectomy in 9 patients. Surgery 142(6), 900–905 (2007)CrossRefPubMedGoogle Scholar
  90. 90.
    A. Toniato, I. Merante-Boschin, G. Opocher, M.R. Pelizzo, F. Schiavi, E. Ballotta, Surgical versus conservative management for subclinical cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann. Surg. 249(3), 388–391 (2009).  https://doi.org/10.1097/SLA.0b013e31819a47d2 CrossRefPubMedGoogle Scholar
  91. 91.
    S. Midorikawa, H. Sanada, S. Hashimoto, T. Suzuki, T. Watanabe, The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin. Endocrinol. 54(6), 797–804 (2001)CrossRefGoogle Scholar
  92. 92.
    R. Emral, A.R. Uysal, M. Asik, S. Gullu, D. Corapcioglu, V. Tonyukuk et al. Prevalence of subclinical Cushing’s syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes. Endocr. J. 50(4), 399–408 (2003)CrossRefPubMedGoogle Scholar
  93. 93.
    M. Tsuiki, A. Tanabe, S. Takagi, M. Naruse, K. Takano, Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing’s syndrome. Endocr. J. 55(4), 737–745 (2008). Epub 2008 May 28CrossRefPubMedGoogle Scholar
  94. 94.
    J. Patrova, I. Jarocka, H. Wahrenberg, H. Falhammar, Clinical outcomes in adrenal incidentaloma: experience from one center. Endocr. Pract. 21(8), 870–877 (2015).  https://doi.org/10.4158/EP15618.OR. Epub 2015 Jun 29CrossRefPubMedGoogle Scholar
  95. 95.
    I. Bourdeau, N. El Ghorayeb, N. Gagnon, A. Lacroix, Management of endocrine disease: Differential diagnosis, investigation and therapy of bilateral adrenal incidentalomas. Eur. J. Endocrinol. 179(2), R57–R67 (2018).  https://doi.org/10.1530/EJE-18-0296. Epub 2018 May 10CrossRefPubMedGoogle Scholar
  96. 96.
    N. El Ghorayeb, I. Bourdeau, A. Lacroix, Multiple aberrant hormone receptors in Cushing’s syndrome. Eur. J. Endocrinol. 173(4), M45–M60 (2015).  https://doi.org/10.1530/EJE-15-0200. Epub 2015 May 13CrossRefPubMedGoogle Scholar
  97. 97.
    R. Libé, J. Coste, L. Guignat, F. Tissier, H. Lefebvre, G. Barrande 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. 163(1), 129–138 (2010).  https://doi.org/10.1530/EJE-10-0195. Epub 2010 Apr 8CrossRefPubMedGoogle Scholar
  98. 98.
    D.A. Vassiliadi, G. Ntali, T. Stratigou, M. Adali, S. Tsagarakis, Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas. Endocrine 40(3), 437–444 (2011).  https://doi.org/10.1007/s12020-011-9490-1. Epub 2011 May 20CrossRefPubMedGoogle Scholar
  99. 99.
    E. Vassilatou, A. Vryonidou, D. Ioannidis, S.A. Paschou, M. Panagou, I. Tzavara, Bilateral adrenal incidentalomas differ from unilateral adrenal incidentalomas in subclinical cortisol hypersecretion but not in potential clinical implications. Eur. J. Endocrinol. 171(1), 37–45 (2014).  https://doi.org/10.1530/EJE-13-0848. Epub 2014 Apr 17CrossRefPubMedGoogle Scholar
  100. 100.
    J.D. Pasternak, C.D. Seib, N. Seiser, J.B. Tyrell, C. Liu, R.M. Cisco et al. Differences between bilateral adrenal incidentalomas and unilateral lesions. JAMA Surg. 150(10), 974–978 (2015).  https://doi.org/10.1001/jamasurg.2015.1683 CrossRefPubMedGoogle Scholar
  101. 101.
    E. Debillon, F.L. Velayoudom-Cephise, S. Salenave, P. Caron, P. Chaffanjon, T. Wagner et al. Unilateral adrenalectomy as a first-line treatment of cushing’s syndrome in patients with primary bilateral macronodular adrenal hyperplasia. J. Clin. Endocrinol. Metab. 100(12), 4417–4424 (2015).  https://doi.org/10.1210/jc.2015-2662. Epub 2015 Oct 9CrossRefPubMedGoogle Scholar
  102. 102.
    Y. Xu, W. Rui, Y. Qi, C. Zhang, J. Zhao, X. Wang et al. The role of unilateral adrenalectomy in corticotropin-independent bilateral adrenocortical hyperplasias. World J. Surg. 37(7), 1626–1632 (2013).  https://doi.org/10.1007/s00268-013-2059-9 CrossRefPubMedGoogle Scholar
  103. 103.
    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).  https://doi.org/10.1210/jc.2013-3527. Epub 2014 Jan 1CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Endocrinology, Hospital Universitario La PrincesaInstituto de Investigación PrincesaMadridSpain

Personalised recommendations