Skip to main content

Advertisement

Springer Nature Link
Log in

The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Cushing syndrome (CS) is characterized by increased morbidity and mortality compared to the general population. However, there are patients who have more clinical aggressive forms than others. Aim of the study is to evaluate whether the degree of hypercortisolism, defined by the number of times urinary free cortisol (UFC) levels exceed the upper limit of the normal range (ULN), is related to the worsening of phenotypic features, as well as metabolic and cardiovascular parameters, in a cohort of CS patients. A cross-sectional study was conducted on 192 patients with active CS, consecutively presenting at the outpatients’ clinic of the University Hospitals of Ancona, Naples, and Palermo. Patients were grouped into mild (UFC not exceeding twice the ULN), moderate (2–5 times the ULN), and severe (more than 5 times the ULN) hypercortisolism. Thirty-seven patients (19.3 %) had mild, 115 (59.8 %) moderate, and 40 (20.9 %) severe hypercortisolism. A significant trend of increase among the three groups was demonstrated for 8-, 16-, and 24-h serum cortisol levels (p < 0.001) and serum cortisol after low dose of dexamethasone suppression test (p = 0.001). No significant trend of increase was found regarding phenotype and comorbidities. The degree of hypercortisolism by itself does not appear to be a sufficient parameter to express the severity of CS. Therefore, estimating the severity of CS according to biochemical parameters remains a challenge, while the clinical phenotype and the associated comorbidities might be more useful to assessing the severity of the CS.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. X. Bertagna, L. Guignat, L. Groussin, J. Bertherat, Cushing’s disease. Best Pract. Res. Clin. Endocrinol. Metab. 23(5), 607–623 (2009)

    Article  CAS  PubMed  Google Scholar 

  2. J. Newell-Price, X. Bertagna, A.B. Grossman et al., Cushing’s syndrome. Lancet 367(9522), 1605–1617 (2006)

    Article  CAS  PubMed  Google Scholar 

  3. R. Pivonello, M.C. De Martino, M. De Leo, G. Lombardi, A. Colao, Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 37(1), 135–149 (2008)

    Article  CAS  PubMed  Google Scholar 

  4. R. Pivonello, M. De Leo, A. Cozzolino, A. Colao, The treatment of Cushing’s disease. Endocr. Rev. 36(4), 385–486 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. J. Etxabe, J.A. Vazquez, Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin. Endocrinol. (Oxf) 40(4), 479–484 (1994)

    Article  CAS  Google Scholar 

  6. J. Lindholm, S. Juul, J.O. Jørgensen, J. Astrup, P. Bjerre, Rasmussen U. Feldt et al., Incidence and late prognosis of Cushing’s syndrome: a population-based study. J. Clin. Endocrinol. Metab. 86(1), 117–123 (2001)

    CAS  PubMed  Google Scholar 

  7. G. Arnaldi, T. Mancini, G. Tirabassi, L. Trementino, M. Boscaro, Advances in the epidemiology, pathogenesis, and management of Cushing’s syndrome complications. J. Endocrinol. Invest. 35(4), 434–448 (2012)

    Article  CAS  PubMed  Google Scholar 

  8. R. Pivonello, A. Faggiano, G. Lombardi, A. Colao, The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 34(2), 327–329 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. A. Faggiano, R. Pivonello, S. Spiezia, M.C. De Martino, M. Filippella, C. Di Somma et al., Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J. Clin. Endocrinol. Metab. 88(6), 2527–2533 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. M.C. Amato, V. Guarnotta, C. Giordano, Body composition assessment for the definition of cardiometabolic risk. J. Endocrinol. Invest. 36(7), 537–543 (2013)

    CAS  PubMed  Google Scholar 

  11. G. Arnaldi, T. Mancini, G. Tirabassi, L. Trementino, M. Boscaro, Advances in the epidemiology, pathogenesis, and management of Cushing’s syndrome complications. J. Endocrinol. Invest. 35(4), 434–448 (2012)

    Article  CAS  PubMed  Google Scholar 

  12. M.S. Lionakis, D.P. Kontoyiannis, Glucocorticoids and invasive fungal infections. Lancet 362(9398), 1828–1838 (2003)

    Article  CAS  PubMed  Google Scholar 

  13. D. Graversen, P. Vestergaard, K. Stochholm, C.H. Gravholt, J.O. Jørgensen, Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur. J. Intern. Med. 23(3), 278–282 (2012)

    Article  CAS  PubMed  Google Scholar 

  14. R.N. Clayton, D. Raskauskiene, R.C. Reulen, P.W. Jones, Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J. Clin. Endocrinol. Metab. 96(3), 632–642 (2011)

    Article  CAS  PubMed  Google Scholar 

  15. Z.K. Hassan-Smith, M. Sherlock, R.C. Reulen, W. Arlt, J. Ayuk, A.A. Toogood, M.S. Cooper, A.P. Johnson, P.M. Stewart, Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years. J. Clin. Endocrinol. Metab. 97(4), 1194–1201 (2012)

    Article  CAS  PubMed  Google Scholar 

  16. G. Ntali, A. Asimakopoulou, T. Siamatras, J. Komninos, D. Vassiliadi, M. Tzanela, S. Tsagarakis, A.B. Grossman, J.A. Wass, N. Karavitaki, Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up. Eur. J. Endocrinol. 169(5), 715–723 (2013)

    Article  CAS  PubMed  Google Scholar 

  17. J.R. Lindsay, T. Nansel, S. Baid, J. Gumowski, L.K. Nieman, Longterm impaired quality of life in Cushing’s syndrome despite initial improvement after surgical remission. J. Clin. Endocrinol. Metab. 91(2), 447–453 (2006)

    Article  CAS  PubMed  Google Scholar 

  18. L. Trementino, G. Apolloni, C. Concettoni, M. Cardinaletti, M. Boscaro, G. Arnaldi, Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing’s syndrome. Eur. J. Endocrinol. 166(1), 35–42 (2012)

    Article  CAS  PubMed  Google Scholar 

  19. L.K. Nieman, B.M. Biller, J.W. Findling, M.H. Murad, J. Newell-Price, M.O. Savage, A. Tabarin, Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 100(8), 2807–2831 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. L.K. Nieman, B.M. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart, V.M. Montori, The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 93(5), 1526–1540 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. A. Colao, S. Petersenn, J. Newell-Price, J.W. Findling, F. Gu, M. Maldonado, U. Schoenherr, D. Mills, L.R. Salgado, B.M. Biller, Pasireotide B2305 Study Group, A 12-month phase 3 study of pasireotide in Cushing’s disease. N. Engl. J. Med. 366(10), 914–924 (2012)

    Article  CAS  PubMed  Google Scholar 

  22. S. Petersenn, J. Newell-Price, J.W. Findling, F. Gu, M. Maldonado, K. Sen, L.R. Salgado, A. Colao, B.M. Biller, High variability in baseline urinary free cortisol values in patients with Cushing’s disease. Clin. Endocrinol. (Oxf). 80(2), 261–269 (2014)

    Article  CAS  PubMed  Google Scholar 

  23. J.A. Withworth, World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J. Hypertens. 21(11), 1983–1992 (2003)

    Article  Google Scholar 

  24. D. Matthews, J. Hosker, A. Rudenski, B.A. Naylor, D.F. Treacher, R.C. Turner, Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 28(7), 412–419 (1985)

    Article  CAS  PubMed  Google Scholar 

  25. M. Matsuda, R. DeFronzo, Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22(9), 1462–1470 (1999)

    Article  CAS  PubMed  Google Scholar 

  26. K.M. Utzschneider, R.L. Prigeon, M.V. Faulenbach, J. Tong, D.B. Carr, E.J. Boyko, D.L. Leonetti, M.J. McNeely, W.Y. Fujimoto, S.E. Kahn, Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care 32(2), 335–341 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. M.C. Amato, C. Giordano, M. Galia, A. Criscimanna, S. Vitabile, M. Midiri, A. Galluzzo, AlkaMesy Study Group, Visceral adiposity index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care 33(4), 920–922 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  28. Expert Panel on Detection, Executive summary of the 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). JAMA 285(19), 2486–2497 (2001)

    Article  Google Scholar 

  29. M.N. Starkman, B. Giordani, S. Berent, M.A. Schork, DE Schteingart, Elevated cortisol levels in Cushing’s disease are associated with cognitive decrements. Psychosomat. Med. 63(6), 985 (2001)

    Article  CAS  Google Scholar 

  30. N. Sonino, G.A. Fava, A.R. Raffi, M. Boscaro, F. Fallo, Clinical correlates of major depression in Cushing’s disease. Psychopathology 31(6), 302–306 (1998)

    Article  CAS  PubMed  Google Scholar 

  31. R.C. Bakker, P.R. Gallas, J.A. Romijn, W.M. Wiersinga, Cushing’s syndrome complicated by multiple opportunistic infections. J. Endocrinol. Invest. 21(5), 329–333 (1998)

    Article  CAS  PubMed  Google Scholar 

  32. T. Reinehr, A. Kulle, B. Wolters, C. Knop, N. Lass, M. Welzel, P.M. Holterhus, Relationships between 24-hour urinary free cortisol concentrations and metabolic syndrome in obese children. J. Clin. Endocrinol. Metab. 99(7), 2391–2399 (2014)

    Article  CAS  PubMed  Google Scholar 

  33. N. Sonino, M. Boscaro, F. Fallo, G.A. Fava, A clinical index for rating severity in Cushing’s syndrome. Psychother. Psychosom. 69(4), 216–220 (2000)

    Article  CAS  PubMed  Google Scholar 

  34. J.G. Rosmalen, I.P. Kema, S. Wüst, C. van der Ley, S.T. Visser, H. Snieder, S.J. Bakker, 24 h urinary free cortisol in large-scale epidemiological studies: short-term and long-term stability and sources of variability. Psychoneuroendocrinology 47, 10–16 (2014)

    Article  CAS  PubMed  Google Scholar 

  35. T. Remer, C. Maser-Gluth, S.A. Wudy, Glucocorticoid measurements in health and disease metabolic implications and the potential of 24-h urine analyses. Mini Rev. Med. Chem. 8(2), 153–170 (2008)

    Article  CAS  PubMed  Google Scholar 

  36. M.M. Kushnir, A.L. Rockwood, G.J. Nelson, A.H. Terry, A.W. Meikle, Liquid chromatography tandem mass spectrometry analysis of urinary free cortisol. Clin. Chem. 49(6), 965–967 (2003)

    Article  CAS  PubMed  Google Scholar 

  37. M. Fenske, Urinary free cortisol and cortisone excretion in healthy individuals: influence of water loading. Steroids 71(11–12), 1014–1018 (2006)

    Article  CAS  PubMed  Google Scholar 

  38. K.C.A. Chan, L.C.W. Lit, E.L.K. Law, M.H.L. Tai, C.U. Yung, M.H.M. Chan, C.W.K. Lam, Diminished urinary free cortisol excretion in patients with moderate and severe renal impairment. Clin. Chem. 50(4), 757–759 (2004)

    Article  CAS  PubMed  Google Scholar 

  39. P.C. Elias, E.Z. Martinez, B.F. Barone, L.M. Mermejo, M. Castro, A.C. Moreira, Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 99(6), 2045–2051 (2014)

    Article  CAS  PubMed  Google Scholar 

  40. P. Putignano, P. Toja, A. Dubini, F.P. Giraldi, S.M. Corsello, F. Cavagnini, Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J. Clin. Endocrinol. Metab. 88(9), 4153–4157 (2003)

    Article  CAS  PubMed  Google Scholar 

  41. C. Giordano, V. Guarnotta, R. Pivonello, M.C. Amato, C. Simeoli, A. Ciresi, A. Cozzolino, A. Colao, Is diabetes in Cushing’s syndrome only a consequence of hypercortisolism? Eur. J. Endocrinol. 170(2), 311–319 (2013)

    Article  PubMed  Google Scholar 

  42. A. Colao, R. Pivonello, S. Spiezia, A. Faggiano, D. Ferone, M. Filippella et al., Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J. Clin. Endocrinol. Metab. 84(8), 2664–2672 (1999)

    CAS  PubMed  Google Scholar 

  43. M. Zilio, L. Mazzai, M.T. Sartori, M. Barbot, F. Ceccato, V. Daidone, A. Casonato, G. Saggiorato, F. Noventa, L. Trementino, P. Prandoni, M. Boscaro, G. Arnaldi, C. Scaroni. A venous thromboembolism risk assessment model for patients with Cushing’s syndrome. Endocrine 26, 1–11 (2015)

    Google Scholar 

  44. N.J. Sarlis, S.J. Chanock, L.K. Nieman, Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J. Clin. Endocrinol. Metab. 85(1), 42–47 (2000)

    CAS  PubMed  Google Scholar 

  45. S. Takagi, A. Tanabe, M. Tsuiki, M. Naruse, K. Takano, Hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal Cushing’s syndrome. Endocr. J. 56(8), 1009–1018 (2009)

    Article  CAS  PubMed  Google Scholar 

  46. I. Akaza, T. Yoshimoto, K. Tsuchiya, Y. Hirata, Endothelial dysfunction associated with hypercortisolism is reversible in Cushing’s syndrome. Endocr. J. 57(3), 245–252 (2010)

    Article  PubMed  Google Scholar 

  47. F. Fallo, G. Famoso, D. Capizzi, N. Sonino, F. Dassie, P. Maffei, C. Martini, A. Paoletta, S. Iliceto, F. Tona, Coronary microvascular function in patients with Cushing’s syndrome. Endocrine 43(1), 206–213 (2013)

    Article  CAS  PubMed  Google Scholar 

  48. A. Gungunes, M. Sahin, T. Demirci, B. Ucan, E. Cakir, M.S. Arslan, I.O. Unsal, B. Karbek, M. Calıskan, M. Ozbek, E. Cakal, T. Delibasi, Cushing’s syndrome in type 2 diabetes patients with poor glycemic control. Endocrine 47(3), 895–900 (2014)

    Article  CAS  PubMed  Google Scholar 

  49. P.M. Toja, G. Branzi, F. Ciambellotti, P. Radaelli, M. De Martin, L.M. Lonati, M. Scacchi, G. Parati, F. Cavagnini, F.P. Giraldi, Clinical relevance of cardiac structure and function abnormalities in patients with Cushing’s syndrome before and after cure. Clin. Endocrinol. (Oxf). 76(3), 332–338 (2012)

    Article  CAS  PubMed  Google Scholar 

  50. M.J. Barahona, E. Resmini, D. Viladés, G. Pons-Lladó, R. Leta, T. Puig, S.M. Webb, Coronary artery disease detected by multislice computed tomography in patients after long-term cure of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 98(3), 1093–1099 (2013)

    Article  CAS  PubMed  Google Scholar 

  51. L. Manetti, G. Rossi, L. Grasso, V. Raffaelli, I. Scattina, S. Del Sarto, M. Cosottini, A. Iannelli, M. Gasperi, F. Bogazzi, E. Martino, Usefulness of salivary cortisol in the diagnosis of hypercortisolism: comparison with serum and urinary cortisol. Eur. J. Endocrinol. 168(3), 315–321 (2013)

    Article  CAS  PubMed  Google Scholar 

  52. N. Sonino, G.A. Fava, Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs 15(5), 361–373 (2001)

    Article  CAS  PubMed  Google Scholar 

  53. L.D. Dorn, E.S. Burgess, T.C. Friedman, B. Dubbert, P.W. Gold, G.P. Chrousos, The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J. Clin. Endocrinol. Metab. 82(3), 912–919 (1997)

    CAS  PubMed  Google Scholar 

  54. J.R. Seckl, B.R. Walker, 11b-Hydroxysteroid dehydrogenase type 1-a tissue-specific amplifier of glucocorticoid action. Endocrinology 142(4), 1371–1376 (2001)

    CAS  PubMed  Google Scholar 

  55. V. Morelli, F. Donadio, C. Eller-Vainicher, V. Cirello, L. Olgiati, C. Savoca, E. Cairoli, A.S. Salcuni, P. Beck-Peccoz, I. Chiodini, Role of glucocorticoid receptor polymorphism in adrenal incidentalomas. Eur. J. Clin. Invest. 40(9), 803–811 (2010)

    Article  CAS  PubMed  Google Scholar 

  56. H. Masuzaki, J. Paterson, H. Shinyama, N.M. Morton, J.J. Mullins, J.R. Seckl, J.S. Flier, A transgenic model of visceral obesity and the metabolic syndrome. Science 294(5549), 2166–2170 (2001)

    Article  CAS  PubMed  Google Scholar 

  57. D.J. Wake, B.R. Walker, 11 beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. Mol. Cell. Endocrinol. 215(1–2), 45–54 (2004)

    Article  CAS  PubMed  Google Scholar 

  58. N.M. Morton, M.C. Holmes, C. Fievet, B. Staels, A. Tailleux, J.J. Mullins, J.R. Seckl, Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11β-hydroxysteroid dehydrogenase type 1 null mice. J. Biol. Chem. 276(44), 41293–41300 (2001)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the RIMEDRI project for supporting V. Guarnotta.

Author information

Authors and Affiliations

  1. Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Sezione di Endocrinologia, Diabetologia e Malattie Metaboliche, Università degli Studi di Palermo, Palermo, Italy

    Valentina Guarnotta, Marco C. Amato, Alessandro Ciresi, Roberto Citarrella & Carla Giordano

  2. Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy

    Rosario Pivonello, Davide Iacuaniello, Chiara Simeoli & Annamaria Colao

  3. Clinica di Endocrinologia e del Metabolismo, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy

    Giorgio Arnaldi, Laura Trementino & Grazia Michetti

Authors
  1. Valentina Guarnotta
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Marco C. Amato
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Rosario Pivonello
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Giorgio Arnaldi
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Alessandro Ciresi
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Laura Trementino
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Roberto Citarrella
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Davide Iacuaniello
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Grazia Michetti
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Chiara Simeoli
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Annamaria Colao
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Carla Giordano
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Carla Giordano.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guarnotta, V., Amato, M.C., Pivonello, R. et al. The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome. Endocrine 55, 564–572 (2017). https://doi.org/10.1007/s12020-016-0914-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-0914-9

Keywords

Profiles

  1. Giorgio Arnaldi View author profile