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Saliva versus serum cortisol to identify subclinical hypercortisolism in adrenal incidentalomas: simplicity versus accuracy

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Abstract

Purpose

Subclinical hypercortisolism (SCH) leads to metabolic derangements and increased cardiovascular risk. Cortisol autonomy is defined by the overnight 1 mg dexamethasone suppression test (DST). Saliva cortisol is an easier, stress-free, and cost-effective alternative to serum cortisol. We compared 23 h and post-1 mg DST saliva with serum cortisol to identify SCH in adrenal incidentalomas (AI).

Methods

We analyzed 359 DST obtained retrospectively from 226 AI subjects (173F/53 M; 19–83 years) for saliva and serum cortisol. We used three post-DST serum cortisol cutoffs to uncover SCH: 1.8, 2.5, and 5.0 μg/dL. We determined post-DST and 23 h saliva cortisol cutoffs by ROC curve analysis and calculated their sensitivities (S) and specificities (E).

Results

The sensitive 1.8 μg/dL cutoff defined 137 SCH and 180 non-functioning adenomas (NFA): post-DST and 23 h saliva cortisol S/E were: 75.2%/74.4% and 59.5%/65.9%, respectively. Using the specific 5.0 μg/dL cortisol cutoff (22 SCH/295 NFA), post-DST and 23 h saliva cortisol S/E were 86.4%/83.4% and 66.7%/80.4%, respectively. Using the intermediate 2.5 μg/dL cutoff (89 SCH/228 NFA), post-DST and 23 h saliva cortisol S/E were 80.9%/68.9% and 65.5%/62.8%, respectively.

Conclusion

Saliva cortisol showed acceptable performance only with the 5.0 μg/dL cortisol cutoff, as in overt Cushing’s syndrome. Lower cutoffs (1.8 and 2.5 μg/dL) that identify larger samples of patients with poor metabolic outcomes are less accurate for screening. These results may be attributed to pre-analytical factors and inherent patient conditions. Thus, saliva cortisol cannot replace serum cortisol to identify SCH among patients with AI for screening DST.

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References

  1. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM (2016) 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

    CAS  PubMed  Google Scholar 

  2. Chiodini I, Morelli V (2016) Subclinical hypercortisolism: how to deal with it? Front Horm Res 46:28–38

    PubMed  Google Scholar 

  3. Mazzuco TL, Bourdeau I, Lacroix A (2009) Adrenal incidentalomas and subclinical Cushing’s syndrome: diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes 16:203–210

    CAS  PubMed  Google Scholar 

  4. Debono M, Newell-Price J (2015) Subclinical hypercortisolism in adrenal incidentaloma. Curr Opin Endocrinol Diabetes Obes 22:185–192

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Midorikawa S, Sanada H, Hashimoto S, Suzuki T, Watanabe T, Sasano H (2001) Analysis of cortisol secretion in hormonally inactive adrenocortical incidentalomas: study of in vitro steroid secretion and immunohistochemical localization of steroidogenic enzymes. Endocr J 48:167–174

    CAS  PubMed  Google Scholar 

  7. Bernini G, Moretti A, Argenio G, Salvetti A (2002) Primary aldosteronism in normokalemic patients with adrenal incidentalomas. Eur J Endocrinol 146:523–529

    CAS  PubMed  Google Scholar 

  8. Erbil Y, Ademog˘lu E, Ozbey N, Barbaros U, Ozbey N, Yanik BT, Salmasliog˘lu A, Bozbora A, Ozarmag˘an S (2006) Evaluation of the cardiovascular risk in patients with subclinical Cushing syndrome before and after surgery. World J Surg 30:1665–1671

    PubMed  Google Scholar 

  9. Tsuiki M, Tanabe A, Takagi S, Naruse M, Takano K (2008) Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing’s syndrome. Endocr J 55:737–745

    CAS  PubMed  Google Scholar 

  10. Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E (2009) Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg 249:388–391

    PubMed  Google Scholar 

  11. Chiodini I, Morelli V, Salcuni AS, Eller-Vainicher C, Torlontano M, Coletti F, Iorio L, Cuttitta A, Ambrosio A, Vicentini L, Pellegrini F, Copetti M, Beck-Peccoz P, Arosio M, Ambrosi B, Trischitta V, Scillitani A (2010) Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J Clin Endocrinol Metab 95:2736–2745

    CAS  PubMed  Google Scholar 

  12. Giorgi RB, Correa MV, Costa-Barbosa FA, Kater CE (2019) Cyclic subclinical hypercortisolism: a previously unidentified hypersecretory form of adrenal incidentalomas. J Endocr Soc 3:678–686

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Terzolo M, Stigliano A, Chiodini I, Loli P, Furlani L, Arnaldi G, Reimondo G, Pia A, Toscano V, Zini M, Borretta G, Papini E, Garofalo P, Allolio B, Dupas B, Mantero F, Tabarin A (2011) AME position statement on adrenal incidentaloma. Eur J Endocrinol 164:851–870

    CAS  PubMed  Google Scholar 

  14. Tateishi Y, Kouyama R, Mihara M, Doi M, Yoshimoto T, Hirata Y (2012) Evaluation of salivary cortisol measurements for the diagnosis of subclinical Cushing’s syndrome. Endocr J 59:283–289

    CAS  PubMed  Google Scholar 

  15. Chiodini I, Albani A, Ambrogio AG, Campo M, De Martino MC, Marcelli G, Morelli V, Zampetti B, Colao A, Pivonello R (2017) Six controversial issues on subclinical Cushing’s syndrome. Endocrine 56:262–266

    CAS  PubMed  Google Scholar 

  16. Ceccato F, Barbot M, Albiger N, Antonelli G, Zilio M, Todeschini M, Regazzo D, Plebani M, Lacognata C, Iacobone M, Mantero F, Boscaro M, Scaroni C (2018) Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma. Endocr 59:510–519

    CAS  Google Scholar 

  17. Liddle GW (1960) Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 20:1539–1560

    CAS  PubMed  Google Scholar 

  18. Nugent CA, Nichols T, Tyler FH (1965) Diagnosis of Cushing’s syndrome—single dose dexamethasone suppression test. Arch Intern Med 116:172–176

    CAS  PubMed  Google Scholar 

  19. Pavlatos FC, Smilo RP, Forsham PH (1965) A rapid screening test for Cushing’s syndrome. JAMA 193:720–723

    CAS  PubMed  Google Scholar 

  20. Mattingly D (1962) A simple fluorimetric method for the estimation of free 11-hydroxycorticosteroids in human plasma. J Clin Pathol 15:374–379

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Shannon IL, Prigmore JR, Brooks RA, Feller RP (1959) The 17-hydroxycorticosteroids of parotid fluid, serum and urine following intramuscular administration of repository corticotropin. J Clin Endocrinol Metab 19:1477–1480

    CAS  PubMed  Google Scholar 

  22. Katz FH, Shannon IL (1969) Adrenal corticosteroids in submaxillary fluids. J Dental Res 48:448–451

    CAS  Google Scholar 

  23. Walker RF, Riad-Fahrny D, Read GF (1978) Adrenal status assessed by direct radioimmunoassay of cortisol in whole saliva or parotid saliva. Clin Chem 24:1460–1463

    CAS  PubMed  Google Scholar 

  24. Vining RF, McGinley RA, Maksvytis JJ, Ho KY (1983) Salivary cortisol: a better measure of adrenal cortical function than serum cortisol. Ann Clin Biochem 20:329–335

    CAS  PubMed  Google Scholar 

  25. Tabarin A, Bardet S, Bertherat J, Dupas B, Chabre O, Hamoir E, Laurent F, Tenenbaum F, Cazalda M, Lefebvre H, Valli N, Rohmer V (2008) Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus. Ann Endocrinol 69:487–500

    CAS  Google Scholar 

  26. Zeiger MA, Thompson GB, Duh QY, Hamrahian AH, Angelos P, Elaraj D, Fishman E, Kharlip J (2009) The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr Pract 15:1–20

    PubMed  Google Scholar 

  27. Masserini B, Morelli V, Bergamaschi S, Ermetici F, Eller-Vainicher C, Barbieri AM, Maffini MA, Scillitani A, Ambrosi B, Beck-Peccoz P, Chiodini I (2009) 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

    CAS  PubMed  Google Scholar 

  28. Nunes ML, Vattaut S, Corcuff JB, Rault A, Loiseau H, Gatta B, Valli N, Letenneur L, Tabarin A (2009) Late-night salivary cortisol for diagnosis of overt and subclinical Cushing’s syndrome in hospitalized and ambulatory patients. J Clin Endocrinol Metab 94:456–462

    CAS  PubMed  Google Scholar 

  29. Huayllas MKP, Netzel BC, Singh RJ, Kater CE (2018) Serum cortisol levels via radioimmunoassay vs liquid chromatography mass spectrophotometry in healthy control subjects and patients with adrenal incidentalomas. Lab Med 49(3):259–267

    PubMed  Google Scholar 

  30. Tonetto-Fernandes V, Lemos-Marini SH, Kuperman H, Ribeiro-Neto LM, Verreschi IT, Kater CE (2006) Serum 21-deoxycortisol, 17-Hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and hormonal correlations and identification of patients with 11beta-hydroxylase deficiency among a large group with alleged 21-hydroxylase deficiency. J Clin Endocrinol Metab 91:2179–2184

    CAS  PubMed  Google Scholar 

  31. Ceccato F, Antonelli G, Frigo AC, Regazzo D, Plebani M, Boscaro M, Scaroni C (2017) 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

    CAS  PubMed  Google Scholar 

  32. Eller-Vainicher C, Morelli V, Salcuni AS, Battista C, Torlontano M, Coletti F, Iorio L, Cairoli E, Beck-Peccoz P, Arosio M, Ambrosi B, Scillitani A, Chiodini I (2010) Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma. Eur J Endocrinol 163:925–935

    CAS  PubMed  Google Scholar 

  33. Eller-Vainicher C, Morelli V, Salcuni AS, Torlontano M, Coletti F, Iorio L, Cuttitta A, Ambrosio A, Vicentini L, Carnevale V, Beck-Peccoz P, Arosio M, Ambrosi B, Scillitani A, Chiodini I (2010) Postsurgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery? Eur J Endocrinol 162:91–99

    PubMed  Google Scholar 

  34. Morelli V, Masserini B, Salcuni AS, Eller-Vainicher C, Savoca C, Viti R, Coletti F, Guglielmi G, Battista C, Iorio L, Beck-Peccoz P, Ambrosi B, Arosio M, Scillitani A, Chiodini I (2010) Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Clin Endocrinol (Oxf) 73:161–166

    CAS  Google Scholar 

  35. Morelli V, Scillitani A, Arosio M, Chiodini I (2017) Follow–up of patients with adrenal incidentaloma, in accordance with the European society of endocrinology guidelines: could we be safe? J Endocrinol Invest 40:331–333

    CAS  PubMed  Google Scholar 

  36. Ueland GA, Methlie P, Kellmann R, Bjorgaas M, Asvold BO, Thorstensen K, Kelp O, Thordarson HB, Mellgren G, Løvås K, Husebye ES (2017) Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test. Eur J Endocrinol 176:705–713

    CAS  PubMed  Google Scholar 

  37. Nickelsen T, Lissner W, Schoffling K (1989) The dexamethasone suppression test and long-term contraceptive treatment: measurement of ACTH or salivary cortisol does not improve the reliability of the test. Exp Clin Endocrinol 94:275–280

    CAS  PubMed  Google Scholar 

  38. Qureshi AC, Bahri A, Breen LA, Barnes SC, Powrie JK, Thomas SM, Carroll PV (2007) The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol. Clin Endocrinol (Oxf) 66:632–635

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Klose M, Lange M, Rasmussen AK, Skakkebaek NE, Hilsted L, Haug E, Andersen M, Feldt-Rasmussen U (2007) Factors influencing the adrenocorticotropin test: role of contemporary cortisol assays, body composition, and oral contraceptive agents. J Clin Endocrinol Metab 92:1326–1333

    CAS  PubMed  Google Scholar 

  41. Hamrahian AH, Oseni TS, Arafah BM (2004) Measurements of serum free cortisol in critically ill patients. N Engl J Med 350:1629–1638

    CAS  PubMed  Google Scholar 

  42. Tan T, Chang L, Woodward A, McWhinney B, Galligan J, Macdonald GA, Cohen J, Venkatesh B (2010) Characterizing adrenal function using directly measured plasma free cortisol in stable severe liver disease. J Hepatol 53:841–848

    CAS  PubMed  Google Scholar 

  43. Ho JT, Al-Musalhi H, Chapman MJ, Quach T, Thomas PD, Bagley CJ, Lewis JG, Torpy DJ (2006) Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab 91:105–114

    CAS  PubMed  Google Scholar 

  44. Arafah B, Nishiyama F, Tlaygeh H, Hejal R (2007) Measurement of salivary cortisol concentration in the assessment of adrenal function in critically ill subjects: a surrogate marker of the circulating free cortisol. J Clin Endocrinol Metab 92:2965–2971

    CAS  PubMed  Google Scholar 

  45. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Doi SA, Clark J, Russell AW (2013) Concordance of the late night salivary cortisol in patients with Cushing’s syndrome and elevated urine-free cortisol. Endocrine 43:327–333

    CAS  PubMed  Google Scholar 

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Acknowledgements

Marcelo Vieira-Correa received a fellowship grant from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), Brazil.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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Authors and Affiliations

  1. From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo School of Medicine (Escola Paulista de Medicina/Universidade Federal de São Paulo), Rua Pedro de Toledo, 781-13th Floor, São Paulo, SP, 04039-032, Brazil

    M. Vieira-Correa, R. B. Giorgi, K. C. Oliveira, L. F. Hayashi, F. A. Costa-Barbosa & C. E. Kater

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  1. M. Vieira-Correa
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  2. R. B. Giorgi
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  3. K. C. Oliveira
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  4. L. F. Hayashi
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  5. F. A. Costa-Barbosa
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  6. C. E. Kater
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Correspondence to C. E. Kater.

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Vieira-Correa, M., Giorgi, R.B., Oliveira, K.C. et al. Saliva versus serum cortisol to identify subclinical hypercortisolism in adrenal incidentalomas: simplicity versus accuracy. J Endocrinol Invest 42, 1435–1442 (2019). https://doi.org/10.1007/s40618-019-01104-8

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