Skip to main content
SpringerLink
Log in

Subclinical Cushing's Syndrome

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Clinically inapparent adrenal masses, or adrenal incidentalomas, are discovered inadvertently in the course of workup or treatment of unrelated disorders. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner, that is not fully restrained by pituitary feed-back, in 5 to 20% of cases depending on study protocols and diagnostic criteria. A number of different alterations in the endocrine tests aimed to assess the function of the hypothalamic-pituitary-adrenal axis has been demonstrated in such patients. This heterogeneous condition has been termed as subclinical Cushing's syndrome, a definition that is more accurate than preclinical Cushing's syndrome since the evolution towards clinically overt hypercortisolism does occur rarely, if ever. The criteria for qualifying subclinical cortisol excess are controversial and we presently do not have sufficient evidence to define a gold standard for the diagnosis of subclinical Cushing's syndrome. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipoproteinemia has been described in patients with subclinical Cushing's syndrome; however, there is not evidence-based demonstration of its long-term complications and, consequently, the management of this condition is largely empirical. Either adrenalectomy or careful observation associated with treatment of metabolic syndrome has been suggested as treatment options because data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered adrenal masses. End Rev 1995;16:460–484.

    CAS  Google Scholar 

  2. Grumbach MM, Biller BMK, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JKT, Oertel YC, Posner MC, Schlechte JA, Wieand HS. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 2003;138:424–429.

    PubMed  Google Scholar 

  3. Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: Update in diagnosis and management. End Rev 2004;25(2):309–340.

    Google Scholar 

  4. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Alì A, Giovanetti M, Opocher G, Angeli A. A survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab 2000;85:637–644.

    Article  CAS  PubMed  Google Scholar 

  5. Aron DC. The adrenal incidentaloma: Disease of modern technology and public health problem. Rev End Metab Disord 2001;2:335–342.

    CAS  Google Scholar 

  6. Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winkelman W. Preclinical Cushing's syndrome in adrenal “incidentalomas”: Comparison with adrenal Cushing's syndrome. J Clin Endocrinol Metab 1992;75:826–832.

    Article  CAS  PubMed  Google Scholar 

  7. Ambrosi B, Peverelli S, Passini E, Re T, Ferrario R, Colombo P, Sartorio A, Faglia G. Abnormalities of endocrine function in patients with clinically “silent” adrenal masses. Eur J Endocrinol 1995;132:422–428.

    CAS  PubMed  Google Scholar 

  8. Terzolo M, Alì A, Osella G, Cesario F, Paccotti P, Angeli A. Subclinical Cushing's syndrome in adrenal incidentaloma. Clin Endocrinol (Oxf) 1998;48:89–97.

    Article  CAS  Google Scholar 

  9. Mc Leod M, Thompson N, Gross M, Bondeson A, Bondeson L. Sub-clinical Cushing's syndrome in patients with adrenal gland incidentalomas. Pitfalls in diagnosis and management. Am Surgeon 1990;56:398–403.

    CAS  Google Scholar 

  10. Caplan RH, Strutt PJ, Wickus GG. Subclinical hormone secretion by incidentally discovered adrenal masses. Arch Surg 1994;129:291–296.

    CAS  PubMed  Google Scholar 

  11. Fernandez-Real JM, Ricart-Engel W, Simò R. Pre-clinical Cushing's syndrome: Report of three cases and literature review. Horm Res 1994;41:230–235.

    CAS  PubMed  Google Scholar 

  12. Barzon L, Sonino N, Fallo F, Palu `G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003;149:273–285.

    Article  CAS  PubMed  Google Scholar 

  13. Ross NS. Epidemiology of Cushing's syndrome and subclinical disease. Endocrinol Metab Clin North Am 1994;23:539–546.

    CAS  PubMed  Google Scholar 

  14. Young WF. Management approaches to adrenal incidentalomas: A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;29:159–185.

    PubMed  Google Scholar 

  15. Terzolo M, Osella G, Alì A, Angeli A. Adrenal incidentalomas. In De Herder WW, ed. Functional and Morphological Imaging of the Endocrine System. Endocrine Updates, vol. 7. Boston: Kluwer Academic Publishers, 2000:191–211.

    Google Scholar 

  16. Barzon L, Scaroni C, Sonino N, Fallo F, Paoletta A, Boscaro M. Risk factors and long-term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab 1999;84:520–526.

    CAS  PubMed  Google Scholar 

  17. Reincke M. Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am 2000;29:42–56.

    Article  Google Scholar 

  18. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M. Diagnosis and complications of Cushing's syndrome: A consensus statement. J Clin Endocrinol Metab 2003;88:5593–5602.

    CAS  PubMed  Google Scholar 

  19. C. Invitti, F. Pecori Giraldi, M. De Martin, F. Cavagnini. Diagnosis and management of Cushing's syndrome: Results of an Italian multicentre study. J Clin Endocrinol Metab 1999;84:440–448.

    CAS  PubMed  Google Scholar 

  20. Barzon L, Scaroni C, Sonino N, Fallo F, Gregianin M, Macrì C, Boscaro M. Incidentally discovered adrenal tumors: Endocrine and scintigraphic correlates. J Clin Endocrinol Metab 1988;83:55–62.

    Google Scholar 

  21. Bardet S, Rohmer V, Murat A, Guillemot C, Marèchaud R, Chupin M, Lecomte P, Simon D, Delemer B, Schneebelli S, Beutter D, Jacquin V, Peltier P, Charbonnel B West France Study Group on Incidentalomas. 131I-6-β-iodomethylnorcholesterol scintigraphy: An assessment of its role in the investigation of adrenocortical incidentalomas. Clin Endocrinol (Oxf) 1996;44:587–596.

    Article  CAS  Google Scholar 

  22. Francis IR, Korobkin M, Quint L, Gross MD, Shapiro B. Integrated imaging of adrenal disease. Radiology 1992;184:1–13.

    CAS  PubMed  Google Scholar 

  23. Osella G, Terzolo M, Borretta G, Magro G, Alì A, Piovesan A, Paccotti P, Angeli A. Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas). J Clin Endocrinol Metab 1994;79:1532–1539.

    Article  CAS  PubMed  Google Scholar 

  24. Rizza RA, Wahner HW, Spelsberg TC, Northcutt RC, Moses HL. Visualization of nonfunctioning adrenal adenomas with iodocholesterol: Possible relationship to subcellular distrubution of tracer. J Nucl Med 1978;19:458–463.

    CAS  PubMed  Google Scholar 

  25. Flecchia D, Mazza E, Carlini M, Blatto A, Olivieri F, Serra G, Camanni F, Messina M. Reduced serum levels of dehydroepiandrosterone sulphate in adrenal incidentalomas: A marker of adrenocortical tumour. Clin Endocrinol (Oxf) 1995;42:129–134.

    CAS  Google Scholar 

  26. Bencsik Z, Szabolcs I, Kovacs Z, Ferencz A, Voros A, Kaszas I, Bor K, Gonczi J, Goth M, Kovacs L, Dohan O, Szilagyi G. 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 1996;81:1726–1729.

    Article  CAS  PubMed  Google Scholar 

  27. Tsagarakis S, Roboti C, Kokkoris P, Vasiliou V, Alevizaki C, Thalassinon N. Elevated post-dexamethasone suppression cortisol concentrations correlate with hormonal alterations of the hypothalamo-pituitary-adrenal axis in patients with adrenal incidentalomas. Clin Endocrinol (Oxf) 1998;49:165–171.

    Article  CAS  Google Scholar 

  28. Lavoie H, Lacroix A. Partially autonomous cortisol secretion by incidentally discovered adrenal adenomas. Trends Endocrinol Metab 1995;6:191–197.

    CAS  Google Scholar 

  29. Huizenga NATM, Koper JW, De Lange P, Pols HAP, Stolk RP, Burger H, Grobbee DE, Brinkmann AO, De Jong FH, Lamberts SWJ. A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo. J Clin Endocrirnol Metab 1988;83:144–151.

    Google Scholar 

  30. Kievit J, Haak HR. Diagnosis and treatment of adrenal incidentaloma: A cost-effectiveness analysis. Endocrinol Metab Clin North Am 2000;29:69–88.

    Article  CAS  PubMed  Google Scholar 

  31. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001;86:713–718.

    Article  CAS  PubMed  Google Scholar 

  32. Angeli A, Terzolo M. Editorial: Adrenal incidentaloma — a modern disease with old complications. [Editorial comment] J Clin Endocrinol Metab 2002;87:4869–4871.

    Article  CAS  PubMed  Google Scholar 

  33. Terzolo M, Pia A, Alì A, Osella G, Reimondo G, Bovio S, Daffara F, Procopio M, Paccotti P, Borretta G, Angeli A. Adrenal incidentaloma: A new cause of the metabolic syndrome? J Clin Endocrinol Metab 2002;87:998–1003.

    Article  CAS  PubMed  Google Scholar 

  34. Fernandez-Real JM, Ricart EW, Simò R, Salinas I, Webb SM. Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours. Clin Endocrinol (Oxf) 1998;49:53–61.

    CAS  Google Scholar 

  35. Garrapa GGM, Pantanetti P, Arnaldi G, Mantero F, Faloia E. Body composition and metabolic features in women with adrenal incidentaloma or Cushing's syndrome. J Clin Endocrinol Metab 2001;86:5301–5306.

    Article  CAS  PubMed  Google Scholar 

  36. Tauchmanova L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri E-A, Fazio S, Lombardi G. Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 2002;87:4872–4878.

    CAS  PubMed  Google Scholar 

  37. Reincke M, Fassnacht M, Vath S, Mora P, Allolio B. Adrenal incidentalomas: A manifestation of the metabolic syndrome? Endocr Res 1996;22:757–761.

    CAS  PubMed  Google Scholar 

  38. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:1210–1214.pdf terzolo

    CAS  PubMed  Google Scholar 

  39. Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR, Williams GR. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110:1245–1250.

    Article  PubMed  Google Scholar 

  40. Barry MK, van Heerden JA, Farley DR, Grant CS, Thompson GB, Ilstrup DM. Can adrenal incidentalomas be safely observed? World J Surg 1998;22:599–603.

    Article  CAS  PubMed  Google Scholar 

  41. Siren J, Tervahartiala P, Sivula A, Haapiainen R. Natural course of adrenal incidentalomas: Seven-year follow-up study. World J Surg 2000;24:579–582.

    CAS  PubMed  Google Scholar 

  42. Torlontano M, Chiodini I, Pileri M, Guglielmi G, Cammisa M, Modoni S, Carnevale V, Trischitta V, Scillitani A. Altered bone mass and turnover in female patients with adrenal incidentaloma: The effect of subclinical hypercortisolism. J Clin Endocrinol Metab 1999;84:2381–2385.

    Article  CAS  PubMed  Google Scholar 

  43. Chiodini I, Torlontano M, Carnevale V, Guglielmi G, Cammisa M, Trischitta V, Scillitani A. Bone loss rate in adrenal incidentalomas: A longitudinal study. J Clin Endocrinol Metab 2001;86:5337–5341.

    Article  CAS  PubMed  Google Scholar 

  44. Chiodini I, Tauchmanova L, Torlontano M, Battista C, Guglielmi G, Cammisa M, Colao A, Carnevale V, Rossi R, Di Lembo S, Trischitta V, Scillitani A. Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism. J Clin Endocrinol Metab 2002;87:5491–5494.

    Article  CAS  PubMed  Google Scholar 

  45. Rossi R, Tauchmanova L, Luciano A, Di Martino M, Battista C, Del Viscovo L, Nuzzo V, Lombardi G. Subclinical Cushing's syndrome in patients with adrenal incidentaloma: Clinical and biochemical features. J Clin Endocrinol Metab 2000;85:1440–1448.

    Article  CAS  PubMed  Google Scholar 

  46. Tauchmanova L, Rossi R, Nuzzo V, del Puente A, Esposito-del Puente A, Pizzi C, Fonderico F, Lupoli G, Lombardi G. Bone loss determined by quantitative ultrasonometry correlates inversely with disease activity in patients with endogenous glucocorticoid excess due to adrenal mass. Eur J Endocrinol 2001;145:241–247.

    Article  CAS  PubMed  Google Scholar 

  47. Osella G, Reimondo G, Peretti P, Alì A, Paccotti P, Angeli A, Terzolo M. The patients with incidentally discovered adrenal adenoma (incidentaloma) are not at increased risk of osteoporosis. J Clin Endocrinol Metab 2001;86:604–607.

    Article  CAS  PubMed  Google Scholar 

  48. Chiodini I, Guglielmi G, Battista C, Carnevale V, Torlontano M, Cammisa M, Trischitta V, Scillitani A. Spinal volumetric bone mineral density and vertebral fractures in female patients with adrenal incidentalomas: The effects of subclinical hypercortisolism and gonadal status. J Clin Endocrinol Metab 2004;89:2237–2241.

    Article  CAS  PubMed  Google Scholar 

  49. Virkkala A, Valimaki M, Pelkonen R, Huikuri K, Kahri A, Kivisaari L, Korhonen T, Salmi J, Seppala P. Endocrine abnormalities in patients with adrenal tumours incidentally discovered on computed tomography. Acta Endocrinol 1989;121:67–72.

    CAS  PubMed  Google Scholar 

  50. Jockenhövel F, Kuck W, Hauffa B, Reinhardt W, Benker G, Lederbogen S, Olbricht Th, Reinwein D. Conservative and surgical management of incidentally discovered adrenal tumors (incidentalomas). J Endocrinol Invest 1992;15:331–337.

    PubMed  Google Scholar 

  51. Bastounis EA, Karayiannakis AJ, Anapliotou MLG, Nakopoulou L, Makri GG, Papalambros EL. Incidentalomas of the adrenal gland: Diagnostic and therapeutic implications. Am Surg 1997;63:356–360.

    CAS  PubMed  Google Scholar 

  52. Grossrubatscher E, Vignati F, Possa M, Loli P. The natural history of incidentally discovered adrenocortical adenomas: A retrospective evaluation. J Endocrinol Invest 2001;24:846–855.

    CAS  PubMed  Google Scholar 

  53. Libè R, Dall’Asta C, Barbetta L, Baccarelli A, Beck-Peccoz P, Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas. Eur J Endocrinol 2002;147:489–494.

    PubMed  Google Scholar 

  54. Terzolo M, Bovio S, Pia A, Libè R, Dall’Asta C, Cicala V, Conton P, Bemporad D, Parenti G, Borretta G, Angeli A, Mannelli M, Ambrosi B, Mantero F. Proceedings of the 12th International Congress of Endocrinology. August 31–September 4, 2004, Lisbon.

  55. Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:1881–1893.

    Article  CAS  PubMed  Google Scholar 

  56. Midorikawa S, Sanada H, Hashimoto S, Suzuki T, Watanabe T. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol (Oxf) 2001;49:311–316.

    Google Scholar 

  57. Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M, Lombardi G. Persistence of increased cardiovascular risk in patients with Cushing's disease after five years of successful cure. J Clin Endocrinol Metab 1999;84:2664–2672.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medicina Interna I, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, ASO San Luigi, Regione Gonzole, 10, Orbassano, Italy

    Massimo Terzolo, Giuseppe Reimondo, Silvia Bovio & Alberto Angeli

  2. Medicina Interna I, ASO San Luigi, Regione Gonzole, 10, 10043, Orbassano, Italy

    Massimo Terzolo

Authors
  1. Massimo Terzolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuseppe Reimondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Bovio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alberto Angeli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Terzolo.

Additional information

This work was partially supported by grants of the University of Turin (ex-60% funds).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Terzolo, M., Reimondo, G., Bovio, S. et al. Subclinical Cushing's Syndrome. Pituitary 7, 217–223 (2004). https://doi.org/10.1007/s11102-005-4024-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-005-4024-6

Key Words

Search

Navigation