Skip to main content

Advertisement

Log in

Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background and aim

Dexamethasone Suppression Test (DST), recommended for Cushing’s Syndrome (CS) diagnosis, explores the pituitary feedback to glucocorticoids. Its diagnostic accuracy could be affected by dexamethasone bioavailability, and therefore, we have developed and validated a dexamethasone threshold after 1-mg DST.

Materials and methods

We studied 200 subjects: 125 patients were considered retrospectively and 75 were enrolled prospectively as the validation cohort. Serum dexamethasone, Late Night Salivary Cortisol (LNSC), and Urinary Free Cortisol (UFC) were measured with LC–MS/MS. Normal LNSC and UFC levels were used to exclude CS. The lower 2.5th percentile of dexamethasone distribution in non-CS patients with cortisol ≤ 50 nmol/L after 1-mg DST was used as threshold.

Results

16 patients were CS and 184 non-CS (108 adrenal incidentaloma and 76 excluded CS); 4.5 nmol/L resulted the calculated threshold. Cortisol after 1-mg DST confirmed high sensitivity (100% at 50 nmol/L cut-off) and moderate–low specificity (63%, increased to 91% at 138 nmol/L) to diagnose CS in the whole cohort of patients. We could reduce the number of false-positive results (from 10 to 6 and from 7 to 4 in AI and excluded CS) considering adequate dexamethasone levels. Dexamethasone levels were not affected by hypercortisolism, age, gender, smoke, weight, and creatinine. 6% of non-CS patients did not achieve adequate dexamethasone levels (40% of tests with serum cortisol > 138 nmol/L after 1-mg DST).

Conclusions

We developed and validated the routine dexamethasone measurement during 1-mg DST: it is independent from patient’s clinical presentation, and it should be used to increase the specificity of serum cortisol levels.

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

Similar content being viewed by others

References

  1. Nieman LK, Biller BMK, Findling JW et al (2008) The diagnosis of cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93(5):1526–1540. https://doi.org/10.1210/jc.2008-0125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ceccato F, Boscaro M (2016) Cushing’s syndrome: screening and diagnosis. High Blood Press Cardiovasc Prev 23(3):209–215. https://doi.org/10.1007/s40292-016-0153-4

    Article  CAS  PubMed  Google Scholar 

  3. Boscaro M, Arnaldi G (2009) Approach to the patient with possible cushing’s syndrome. J Clin Endocrinol Metab 94(9):3121–3131. https://doi.org/10.1210/jc.2009-0612

    Article  CAS  PubMed  Google Scholar 

  4. Shimon I (2015) Screening for cushing’s syndrome: is it worthwhile? Pituitary 18(2):201–205. https://doi.org/10.1007/s11102-015-0634-9

    Article  PubMed  Google Scholar 

  5. Ceccato F, Marcelli G, Martino M et al (2018) The diagnostic accuracy of increased late night salivary cortisol for Cushing’s syndrome: a real-life prospective study. J Endocrinol Invest 42(3):327–335. https://doi.org/10.1007/s40618-018-0921-1

    Article  CAS  PubMed  Google Scholar 

  6. Omura M, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T (2004) Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 27(3):193–202. https://doi.org/10.1291/hypres.27.193

    Article  PubMed  Google Scholar 

  7. Terzolo M, Reimondo G, Chiodini I et al (2012) Screening of Cushing’s syndrome in outpatients with type 2 diabetes: results of a prospective multicentric study in Italy. J Clin Endocrinol Metab 97(10):3467–3475. https://doi.org/10.1210/jc.2012-1323

    Article  CAS  PubMed  Google Scholar 

  8. Terzolo M, Stigliano A, Chiodini I et al (2011) AME position statement on adrenal incidentaloma. Eur J Endocrinol 164(6):851–870. https://doi.org/10.1530/EJE-10-1147

    Article  CAS  PubMed  Google Scholar 

  9. Fassnacht M, Arlt W, Bancos I et al (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(2):G34. https://doi.org/10.1530/EJE-16-0467

    Article  Google Scholar 

  10. Elamin MB, Murad MH, Mullan R et al (2008) Accuracy of diagnostic tests for Cushing’s syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab 93(5):1553–1562. https://doi.org/10.1210/jc.2008-0139

    Article  CAS  PubMed  Google Scholar 

  11. Pecori Giraldi F, Ambrogio AG, De Martin M, Fatti LM, Scacchi M, Cavagnini F (2007) Specificity of first-line tests for the diagnosis of Cushing’s syndrome: assessment in a large series. J Clin Endocrinol Metab 92(11):4123–4129. https://doi.org/10.1210/jc.2007-0596

    Article  CAS  PubMed  Google Scholar 

  12. Raff H (2009) Utility of salivary cortisol measurements in Cushing’s syndrome and adrenal insufficiency. J Clin Endocrinol Metab 94(10):3647–3655. https://doi.org/10.1210/jc.2009-1166

    Article  CAS  PubMed  Google Scholar 

  13. Nunes M-L, Vattaut S, Corcuff J-B et al (2009) Late-night salivary cortisol for diagnosis of overt and subclinical Cushing’s syndrome in hospitalized and ambulatory patients. J Clin Endocrinol Metab 94(2):456–462. https://doi.org/10.1210/jc.2008-1542

    Article  CAS  PubMed  Google Scholar 

  14. Ceccato F, Barbot M, Zilio M et al (2013) Performance of salivary cortisol in the diagnosis of Cushing’s syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur J Endocrinol 169(1):31–36. https://doi.org/10.1530/EJE-13-0159

    Article  CAS  PubMed  Google Scholar 

  15. Petersenn S, Newell-Price J, Findling JW et al (2014) High variability in baseline urinary free cortisol values in patients with Cushing’s disease. Clin Endocrinol 80(2):261–269. https://doi.org/10.1111/cen.12259

    Article  CAS  Google Scholar 

  16. Sandouk Z, Johnston P, Bunch D et al (2018) Variability of late-night salivary cortisol in Cushing disease: a prospective study. J Clin Endocrinol Metab 103(3):983–990. https://doi.org/10.1210/jc.2017-02020

    Article  PubMed  Google Scholar 

  17. Ceccato F, Antonelli G, Frigo AC et al (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(7):753–760. https://doi.org/10.1007/s40618-017-0644-8

    Article  CAS  PubMed  Google Scholar 

  18. 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(3):331–333. https://doi.org/10.1007/s40618-016-0558-x

    Article  CAS  PubMed  Google Scholar 

  19. Guthrie S (1991) The impact of dexamethasone pharmacokinetics on the DST: a review. Psychopharmacol Bull 27(4):565–576. https://www.ncbi.nlm.nih.gov/pubmed/1813902

  20. Ueland GÅ, Methlie P, Kellmann R et al (2017) Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test. Eur J Endocrinol 176(6):705–713. https://doi.org/10.1530/EJE-17-0078

    Article  CAS  PubMed  Google Scholar 

  21. Meikle AW, Lagerquist LG, Tyler FH (1975) Apparently normal pituitary-adrenal suppressibility in Cushing’s syndrome: dexamethasone metabolism and plasma levels. J Lab Clin Med 86(3):472–478. https://www.ncbi.nlm.nih.gov/pubmed/1151162

  22. Meikle AW (1982) Dexamethasone suppression tests: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin Endocrinol 16(4):401–408. https://www.ncbi.nlm.nih.gov/pubmed/7094363

  23. Sasaki Y, Katabami T, Asai S, Fukuda H, Tanaka Y (2017) In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing’s syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry. Endocr J 64(9):833–842. https://doi.org/10.1507/endocrj.EJ17-0083

    Article  CAS  PubMed  Google Scholar 

  24. Ceccato F, Antonelli G, Barbot M et al (2014) 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. https://doi.org/10.1530/EJE-14-0061

    Article  CAS  PubMed  Google Scholar 

  25. Antonelli G, Ceccato F, Artusi C, Marinova M, Plebani M (2015) Salivary cortisol and cortisone by LC-MS/MS: validation, reference intervals and diagnostic accuracy in Cushing’s syndrome. Clin Chim Acta 451:247–251. https://doi.org/10.1016/j.cca.2015.10.004

    Article  CAS  PubMed  Google Scholar 

  26. Valassi E, Swearingen B, Lee H et al (2009) Concomitant medication use can confound interpretation of the combined dexamethasone-corticotropin releasing hormone test in Cushing’s syndrome. J Clin Endocrinol Metab 94(12):4851–4859. https://doi.org/10.1210/jc.2009-1500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. A clinical and laboratory standards institute (CLSI), liquid chromatography-mass spectrometry methods; approved guidelines for Clinical Chemistry, available online at https://clsi.org/media/1346/c62a_sample.pdf

  28. Horowitz GL In: Lewis MA (ed) Defining, establishing, and verifying reference intervals in the clinical laboratory; Approved guidelines for Clinical Chemistry, available online https://clsi.org/media/1421/ep28a3c_sample.pdf

  29. Ceccato F, Barbot M, Zilio M et al (2015) Screening tests for cushing’s syndrome: urinary free cortisol role measured by LC-MS/MS. J Clin Endocrinol Metab 100(10):3856–3861. https://doi.org/10.1210/jc.2015-2507

    Article  CAS  PubMed  Google Scholar 

  30. Raff H (2012) Cushing’s syndrome: diagnosis and surveillance using salivary cortisol. Pituitary 15(1):64–70. https://doi.org/10.1007/s11102-011-0333-0

    Article  PubMed  Google Scholar 

  31. de Graaf AJ, Mulder AL, Krabbe JG (2019) Retrospective analysis of repeated dexamethasone suppression tests—the added value of measuring dexamethasone. Ann Clin Biochem Int J Lab Med 56(6):708–710. https://doi.org/10.1177/0004563219870834

    Article  CAS  Google Scholar 

  32. Mayo clinic. https://www.mayocliniclabs.com/test-catalog/Overview/91956

  33. Miller BS, Ignatoski KM, Daignault S et al (2011) A quantitative tool to assess degree of sarcopenia objectively in patients with hypercortisolism. Surgery 150(6):1178–1185. https://doi.org/10.1016/j.surg.2011.09.020

    Article  PubMed  Google Scholar 

  34. Di Dalmazi G, Vicennati V, Garelli S et al (2014) 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. https://doi.org/10.1016/S2213-8587(13)70211-0

    Article  PubMed  Google Scholar 

  35. Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J (2014) Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin Endocrinol Metab 99(12):4462–4470. https://doi.org/10.1210/jc.2014-3007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Morelli V, Reimondo G, Giordano R et al (2014) Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab 99(3):827–834. https://doi.org/10.1210/jc.2013-3527

    Article  CAS  PubMed  Google Scholar 

  37. Masserini B, Morelli V, Bergamaschi S et al (2009) 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. https://doi.org/10.1530/EJE-08-0485

    Article  CAS  PubMed  Google Scholar 

  38. Palmieri S, Morelli V, Polledri E, et al (2013) The role of salivary cortisol measured by liquid chromatography-tandem mass spectrometry in the diagnosis of subclinical hypercortisolism. Eur J Endocrinol 168(3):289. https://www.ncbi.nlm.nih.gov/pubmed/23211572

  39. Ceccato F, Barbot M, Albiger N et al (2017) Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma. Endocrine. https://doi.org/10.1007/s12020-017-1421-3

    Article  PubMed  Google Scholar 

  40. Fassnacht M, Dekkers OM, Else T et al (2018) European society of endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol 179(4):G1–G46. https://doi.org/10.1530/EJE-18-0608

    Article  CAS  PubMed  Google Scholar 

  41. Trementino L, Appolloni G, Concettoni C, Cardinaletti M, Boscaro M, Arnaldi G (2012) 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. https://doi.org/10.1530/EJE-11-0722

    Article  CAS  PubMed  Google Scholar 

  42. van Rossum EFC, Koper JW, van den Beld AW, et al (2003) Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin Endocrinol 59(5):585–592. https://www.ncbi.nlm.nih.gov/pubmed/14616881

  43. Di Blasio AM, van Rossum EFC, Maestrini S, et al (2003) The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients. Clin Endocrinol 59(1):68–74. https://www.ncbi.nlm.nih.gov/pubmed/12807506

  44. Tzanela M, Mantzou E, Saltiki K et al (2012) Clinical and biochemical impact of BCL1 polymorphic genotype of the glucocorticoid receptor gene in patients with adrenal incidentalomas. J Endocrinol Invest 35(4):395–400. https://doi.org/10.3275/7840

    Article  CAS  PubMed  Google Scholar 

  45. Plebani M (2010) The detection and prevention of errors in laboratory medicine. Ann Clin Biochem 47(Pt 2):101–110. https://doi.org/10.1258/acb.2009.009222

    Article  PubMed  Google Scholar 

  46. Plebani M (2016) Towards a new paradigm in laboratory medicine: the five rights. Clin Chem Lab Med 54(12):1881–1891. https://doi.org/10.1515/cclm-2016-0848

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

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

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F. Ceccato.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest that might be perceived as influencing the impartiality of the reported research.

Ethical approval

The study was performed in accordance with the guidelines in the Declaration of Helsinki, the study was approved by the Ethics Committee of Padova University-Hospital.

Informed consent

All patients gave informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ceccato, F., Artusi, C., Barbot, M. et al. Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation. J Endocrinol Invest 43, 1105–1113 (2020). https://doi.org/10.1007/s40618-020-01197-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01197-6

Keywords

Navigation