Skip to main content

Advertisement

Log in

Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma

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

Abstract

Background and aim

Impaired cortisol rhythm is a characteristic feature of Cushing’s Syndrome, nevertheless late night salivary cortisol (LNSC) is not suitable to detect subclinical hypercortisolism in patients with adrenal incidentaloma (AI). We studied daily salivary cortisol (F) and cortisone (E) rhythm in patients with AI.

Materials and methods

Six saliva samples were collected from awakening to night in 106 patients with AI and 40 controls. F and E were measured with LC-MS/MS and daily F exposure was calculated with the area under the curve (AUC).

Results

Patients with serum cortisol after dexamethasone suppression test (DST) > 50 nmol/L showed higher morning F (15.5 ± 14.5 vs. 8.6 ± 5.5 nmol/L, p = 0.001), suppressed corticotropin levels (76 vs. 35%, p < 0.001) and increased daily F exposure (3795 ± 1716 vs. 2898 ± 1478, p = 0.012), especially in the morning (2035 ± 1267 vs. 1365 ± 777, p = 0.003), otherwise LNSC levels were similar. Salivary E and AUC levels were higher in patients with DST > 50 nmol/L. AUC was not correlated with urinary cortisol levels or adenoma size. F and E levels were similar among patients with unilateral or bilateral adenoma, or considering the presence of hypertension, dyslipidemia, diabetes, or cardiovascular events.

Conclusion

Daily cortisol exposure, evaluated with AUC from multiple saliva collections, is increased in AI patients with serum cortisol > 50 nmol/L after DST, especially in the morning, leading to reduced corticotropin levels. Cortisol rhythm is preserved in patients with AI, remarking that LNSC is not a screening test for subclinical hypercortisolism.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. M. Terzolo, A. Stigliano, I. Chiodini, P. Loli, L. Furlani, G. Arnaldi, G. Reimondo, A. Pia, V. Toscano, M. Zini, G. Borretta, E. Papini, P. Garofalo, B. Allolio, B. Dupas, F. Mantero, A. Tabarin, Italian association of clinical endocrinologists. AME position statement on adrenal incidentaloma. Eur. J. Endocrinol. 6, 851–870 (2011). https://doi.org/https://doi.org/10.1530/EJE-10-1147

    Article  CAS  Google Scholar 

  2. M. Fassnacht, W. Arlt, I. Bancos, H. Dralle, J. Newell-Price, A. Sahdev, A. Tabarin, M. Terzolo, S. Tsagarakis, O.M. Dekkers, 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, G1–G34 (2016). https://doi.org/10.1530/EJE-16-0467

    Article  CAS  PubMed  Google Scholar 

  3. F. Ceccato, G. Antonelli, A.C. Frigo, D. Regazzo, M. Plebani, M. Boscaro, C. Scaroni, First-line screening tests for Cushing’s syndrome in patients with adrenal incidentaloma: the role of urinary free cortisol measured by LC-MS/MS. J. Endocrinol. Invest. 40, 753–760 (2017). https://doi.org/10.1007/s40618-017-0644-8.

    Article  CAS  PubMed  Google Scholar 

  4. 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, 4462–4470 (2014). https://doi.org/10.1210/jc.2014-3007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. G. Di Dalmazi, V. Vicennati, S. Garelli, E. Casadio, E. Rinaldi, E. Giampalma, C. Mosconi, R. Golfieri, A. Paccapelo, U. Pagotto, R. Pasquali, 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, 396–405 (2014). https://doi.org/10.1016/S2213-8587(13)70211-0

    Article  Google Scholar 

  6. 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, 1526–1540 (2008). https://doi.org/10.1210/jc.2008-0125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. M. Boscaro, G. Arnaldi, Approach to the patient with possible Cushing’s syndrome. J. Clin. Endocrinol. Metab. 94, 3121–3131 (2009). https://doi.org/10.1210/jc.2009-0612

    Article  CAS  PubMed  Google Scholar 

  8. L. Plat, R. Leproult, M. L’Hermite-Baleriaux, F. Fery, J. Mockel, K.S. Polonsky, E. Van Cauter, Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. J. Clin. Endocrinol. Metab. 84, 3082–3092 (1999)

    CAS  PubMed  Google Scholar 

  9. B. Masserini, V. Morelli, S. Bergamaschi, F. Ermetici, C. Eller-Vainicher, A.M. Barbieri, M.A. Maffini, A. Scillitani, B. Ambrosi, P. Beck-Peccoz, I. Chiodini, The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma. Eur. J. Endocrinol. 160, 87–92 (2009). https://doi.org/10.1530/EJE-08-0485

    Article  CAS  PubMed  Google Scholar 

  10. S. Palmieri, V. Morelli, E. Polledri, S. Fustinoni, R. Mercadante, L. Olgiati, C. Eller Vainicher, E. Cairoli, V.V. Zhukouskaya, P. Beck-Peccoz, I. Chiodini, The role of salivary cortisol measured by liquid chromatography-tandem mass spectrometry in the diagnosis of subclinical hypercortisolism. Eur. J. Endocrinol. 168, 289–296 (2013). https://doi.org/10.1530/EJE-12-0803

    Article  CAS  PubMed  Google Scholar 

  11. H. Raff, Measurement of Salivary Cortisone to assess the adequacy of hydrocortisone replacement. J. Clin. Endocrinol. Metab. 101, 1350–1352 (2016). https://doi.org/10.1210/jc.2016-1228

    Article  CAS  PubMed  Google Scholar 

  12. F. Ceccato, G. Antonelli, M. Barbot, M. Zilio, L. Mazzai, R. Gatti, M. Zaninotto, F. Mantero, M. Boscaro, M. Plebani, C. Scaroni, 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, 1–7 (2014). https://doi.org/10.1530/EJE-14-0061

    Article  CAS  PubMed  Google Scholar 

  13. J.W. Funder, R.M. Carey, F. Mantero, M.H. Murad, M. Reincke, H. Shibata, M. Stowasser, W.F. Young Jr., The management of primary aldosteronism: Case detection, diagnosis, and treatment: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 1889–1916 (2016). https://doi.org/10.1210/jc.2015-4061

    Article  CAS  PubMed  Google Scholar 

  14. J.W. Lenders, Q.Y. Duh, G. Eisenhofer, A.P. Gimenez-Roqueplo, S.K. Grebe, M.H. Murad, M. Naruse, K. Pacak, W.F. Young Jr, Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 1915–1942 (2014). https://doi.org/10.1210/jc.2014-1498

    Article  CAS  PubMed  Google Scholar 

  15. G. Antonelli, C. Artusi, M. Marinova, L. Brugnolo, M. Zaninotto, C. Scaroni, R. Gatti, F. Mantero, M. Plebani, Cortisol and cortisone ratio in urine: LC-MS/MS method validation and preliminary clinical application. Clin. Chem. Lab. Med. 52, 213–220 (2014). https://doi.org/10.1515/cclm-2013-0471

    Article  CAS  PubMed  Google Scholar 

  16. F. Ceccato, M. Barbot, M. Zilio, A.C. Frigo, N. Albiger, V. Camozzi, G. Antonelli, M. Plebani, F. Mantero, M. Boscaro, C. Scaroni, Screening tests for cushing’s syndrome: Urinary free cortisol role measured by LC-MS/MS. J. Clin. Endocrinol. Metab. 100, 3856–3861 (2015). https://doi.org/10.1210/jc.2015-2507

    Article  CAS  PubMed  Google Scholar 

  17. G. Antonelli, A. Padoan, C. Artusi, M. Marinova, M. Zaninotto, M. Plebani, Automated saliva processing for LC-MS/MS: Improving laboratory efficiency in cortisol and cortisone testing. Clin Biochem. 49, 518–520 (2016). https://doi.org/10.1016/j.clinbiochem.2015.12.006

    Article  CAS  PubMed  Google Scholar 

  18. J.C. Pruessner, C. Kirschbaum, G. Meinlschmid, D.H. Hellhammer, Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 28, 916–931 (2003)

    Article  CAS  Google Scholar 

  19. H. Raff, Cushing’s syndrome: diagnosis and surveillance using salivary cortisol. Pituitary 15, 64–70 (2012). https://doi.org/10.1007/s11102-011-0333-0

    Article  PubMed  Google Scholar 

  20. F. Ceccato, M. Barbot, M. Zilio, S. Ferasin, G. Occhi, A. Daniele, S. Mazzocut, M. Iacobone, C. Betterle, F. Mantero, C. Scaroni, Performance of salivary cortisol in the diagnosis of Cushing’s syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur. J. Endocrinol. 169, 31–36 (2013). https://doi.org/10.1530/EJE-13-0159

    Article  CAS  PubMed  Google Scholar 

  21. R. Bou Khalil, C. Baudry, L. Guignat, C. Carrasco, J. Guibourdenche, S. Gaillard, X. Bertagna, J. Bertherat, Sequential hormonal changes in 21 patients with recurrent Cushing’s disease after successful pituitary surgery. Eur. J. Endocrinol. 165, 729–737 (2011). https://doi.org/10.1530/EJE-11-0424

    Article  CAS  PubMed  Google Scholar 

  22. I.I. Androulakis, G.A. Kaltsas, G.E. Kollias, A.C. Markou, A.K. Gouli, D.A. Thomas, K.I. Alexandraki, C.M. Papamichael, D.J. Hadjidakis, G.P. Piaditis, Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion. J. Clin. Endocrinol. Metab. 99, 2754–2762 (2014). https://doi.org/10.1210/jc.2013-4064

    Article  CAS  PubMed  Google Scholar 

  23. D.A. Vassiliadi, G. Ntali, E. Vicha, S. Tsagarakis, High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management. Clin. Endocrinol. 74, 438–444 (2011). https://doi.org/10.1111/j.1365-2265.2010.03963.x

    Article  Google Scholar 

  24. 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, 37–45 (2014). https://doi.org/10.1530/EJE-13-0848

    Article  CAS  PubMed  Google Scholar 

  25. V. Morelli, S. Palmieri, A.S. Salcuni, C. Eller-Vainicher, E. Cairoli, V. Zhukouskaya, A. Scillitani, P. Beck-Peccoz, I. Chiodini, Bilateral and unilateral adrenal incidentalomas: biochemical and clinical characteristics. Eur. J. Endocrinol. 168, 235–241 (2013). https://doi.org/10.1530/EJE-12-0777

    Article  CAS  PubMed  Google Scholar 

  26. L. Petramala, G. Cavallaro, M. Galassi, C. Marinelli, G. Tonnarini, A. Concistrè, U. Costi, M. Bufi, P. Lucia, G. De Vincentis, G. Iannucci, G. De Toma, C. Letizia, Clinical benefits of unilateral adrenalectomy in patients with subclinical hypercortisolism due to adrenal incidentaloma: Results from a single center. High Blood Press Cardiovasc. Prev. 24, 69–75 (2017). https://doi.org/10.1007/s40292-017-0182-7

    Article  PubMed  Google Scholar 

  27. S.A. Paschou, E. Kandaraki, F. Dimitropoulou, D.G. Goulis, A. Vryonidou, Subclinical Cushing’s syndrome in patients with bilateral compared to unilateral adrenal incidentalomas: a systematic review and meta-analysis. Endocrine 51, 225–235 (2016). https://doi.org/10.1007/s12020-015-0776-6

    Article  CAS  PubMed  Google Scholar 

  28. 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, 388–391 (2009). https://doi.org/10.1097/SLA.0b013e31819a47d2

    Article  PubMed  Google Scholar 

  29. M. Iacobone, M. Citton, G. Viel, R. Boetto, I. Bonadio, I. Mondi, S. Tropea, D. Nitti, G. Favia, Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing’s syndrome. Surgery 152, 991–997 (2012). https://doi.org/10.1016/j.surg.2012.08.054

    Article  PubMed  Google Scholar 

  30. I. Perogamvros, D.A. Vassiliadi, O. Karapanou, E. Botoula, M. Tzanela, S. Tsagarakis, Biochemical and clinical benefits of unilateral adrenalectomy in patients with subclinical hypercortisolism and bilateral adrenal incidentalomas. Eur. J. Endocrinol. 173, 719–725 (2015). https://doi.org/10.1530/EJE-15-0566

    Article  CAS  PubMed  Google Scholar 

  31. I. Chiodini, A. Albani, A.G. Ambrogio, M. Campo, M.C. De Martino, G. Marcelli, V. Morelli, B. Zampetti, A. Colao, R. Pivonello, A.B.C. Group, Six controversial issues on subclinical Cushing’s syndrome. Endocrine 56, 262–266 (2017). https://doi.org/10.1007/s12020-016-1017-3

    Article  CAS  PubMed  Google Scholar 

  32. H. Raff, J.W. Findling, Biomarkers: Salivary cortisol or cortisone? Nat. Rev. Endocrinol. 6, 658–660 (2010). https://doi.org/10.1038/nrendo.2010.192

    Article  CAS  PubMed  Google Scholar 

  33. 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, 4951–4958 (2010). https://doi.org/10.1210/jc.2010-1215

    Article  CAS  PubMed  Google Scholar 

  34. M. Debono, R.F. Harrison, M.J. Whitaker, D. Eckland, W. Arlt, B.G. Keevil, R.J. Ross, Salivary cortisone reflects cortisol exposure under physiological conditions and after hydrocortisone. J. Clin. Endocrinol. Metab. 101, 1469–1477 (2016). https://doi.org/10.1210/jc.2015-3694

    Article  CAS  PubMed  Google Scholar 

  35. G.Å. Ueland, P. Methlie, R. Kellmann, M. Bjørgaas, B.O. Åsvold, K. Thorstensen, O. Kelp, H.B. Thordarson, G. Mellgren, K. Løvås, E.S. Husebye, Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test. Eur. J. Endocrinol. 176, 705–713 (2017). https://doi.org/10.1530/EJE-17-0078

    Article  CAS  PubMed  Google Scholar 

  36. H. Raff, R.J. Singh, Measurement of late-night salivary cortisol and cortisone by LC-MS/MS to assess preanalytical sample contamination with topical hydrocortisone. Clin. Chem. 58, 947–948 (2012). https://doi.org/10.1373/clinchem.2012.182717

    Article  CAS  PubMed  Google Scholar 

  37. E. Valassi, I. Crespo, B.G. Keevil, A. Aulinas, E. Urgell, A. Santos, P.J. Trainer, S.M. Webb, Affective alterations in patients with Cushing’s syndrome in remission are associated with decreased BDNF and cortisone levels. Eur. J. Endocrinol. 176, 221–231 (2017). https://doi.org/10.1530/EJE-16-0779

    Article  CAS  PubMed  Google Scholar 

  38. S.A. Morgan, Z.K. Hassan-Smith, G.G. Lavery, Mechanisms in endocrinology: Tissue-specific activation of cortisol in Cushing’s syndrome. Eur. J. Endocrinol. 175, R83–R89 (2016). https://doi.org/10.1530/EJE-15-1237

    Article  CAS  PubMed  Google Scholar 

  39. B. Mariniello, V. Ronconi, S. Rilli, P. Bernante, M. Boscaro, F. Mantero, G. Giacchetti, Adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing’s syndrome. Eur. J. Endocrinol. 155, 435–441 (2006). https://doi.org/10.1530/eje.1.02228

    Article  CAS  PubMed  Google Scholar 

  40. J.E. Adaway, B.G. Keevil, L.J. Owen, Liquid chromatography tandem mass spectrometry in the clinical laboratory. Ann. Clin. Biochem. 52, 18–38 (2015). https://doi.org/10.1177/0004563214557678

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Filippo Ceccato.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ceccato, F., Barbot, M., Albiger, N. et al. Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma. Endocrine 59, 510–519 (2018). https://doi.org/10.1007/s12020-017-1421-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-017-1421-3

Keywords

Navigation