Multiple salivary cortisol measurements are a useful tool to optimize metyrapone treatment in patients with Cushing's syndromes treatment: case presentations
Open accessAbstract
Measuring salivary cortisol is both convenient and noninvasive for patients; however, its usefulness as marker for monitoring medical therapy has not yet been established. The aim of this study is to assess the utility of multiple salivary cortisol measurements in patients with Cushing’s syndrome (CS) during medical therapy. Six patients with CS (3 with cortisol-secreting adrenocortical adenoma, and 3 with ACTH-secreting pituitary adenoma) were recruited. Samples for morning serum cortisol, urinary free cortisol (UFC), and multiple salivary cortisol levels were collected before and during metyrapone treatment. The area under the curve (AUC) and mean value (MV) of daily salivary cortisol were calculated. Five out of 6 patients, UFC were normalized; however, multiple salivary cortisol measurement revealed an impaired diurnal cortisol rhythm in these patients. To verify the usefulness of multiple salivary cortisol measurements, we performed a prospective case study of a patient in whom the excess secretion of cortisol was not controlled (UFC 211µg/day) with 2250mg/day in 4 divided doses of metyrapone. Multiple measurements of salivary cortisol revealed that cortisol levels elevated before the next administration. Accordingly, we shortened the interval by increasing the number of administration from 4 to 5 times per day, with a slight increment of daily dose of 2500mg. These optimizations resulted in a drastic improvement of diurnal pattern as well as UFC level (101 µg/day). Changes in both the MV and AUC of salivary cortisol were more correlated to those in UFC (Correlation coefficient 0.75, p = 0.007, and 0.70, p = 0.017) than those in morning serum cortisol level (0.42, p = 0.200), indicating that multiple salivary cortisol measurement reflects more precisely the excess secretion of cortisol. Our preliminary data suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone during the treatment in patients with CS.
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Normalization of the cortisol circadian rhythm after most medical therapies has rarely been investigated and is not routinely measured to assess treatment response.
“Although this can be achieved after successful surgery selectively removing the source of excess ACTH or cortisol, normalization of the cortisol circadian rhythm after most medical therapies has rarely been investigated and is not routinely measured to assess treatment response (39-44).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [41]
The Introduction says that monitoring during medical therapy has few useful biomarkers, and the Discussion explains that urinary free cortisol cannot assess diurnal rhythm. This supports the point that rhythm is not captured by commonly described monitoring measures, but the paper does not establish how rarely normalization has been investigated or whether rhythm is routinely measured across most medical therapies. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMeasuring cortisol circadian rhythm via salivary samples offers a non-invasive tool to monitor and adjust therapy in real time, as samples can be collected in outpatient settings.
“This method of measuring the cortisol circadian rhythm offers a non-invasive tool to monitor and adjust therapy in real time, as salivary samples can be collected in outpatient settings.”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [41]
The Introduction and Discussion say that salivary sampling is feasible in outpatient clinics and that multiple measurements can reveal diurnal cortisol patterns and help optimize metyrapone treatment. The claim’s “in real time” qualifier is not supported: the Saliva Collection methods describe storing samples at −20°C until measurement, not immediate monitoring or adjustment. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEvidence suggests that restoring cortisol circadian rhythm may improve disease control and alleviate symptoms.
“However, evidence suggests that restoring cortisol circadian rhythm may improve disease control and alleviate symptoms (39-43).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [41]
Multiple salivary cortisol assessments can evaluate cortisol circadian rhythm and guide adjustments in metyrapone dose and frequency.
“Additionally, a prospective study in a single patient utilized multiple salivary cortisol assessments to evaluate the cortisol circadian rhythm and successfully guide adjustments in metyrapone dose and frequency.”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [41]
Multiple salivary cortisol measurements detected disrupted cortisol circadian rhythms in patients despite normalized UFC levels.
“Through 6 case presentations, they demonstrated that multiple salivary cortisol measurements detected disrupted cortisol circadian rhythms in patients despite normalized UFC levels.”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [41]
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Cites
The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline.
Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0125 · Cited by 2,718 · see citing works
Ketoconazole in Cushing's disease: is it worth a try?
Castinetti, F., Guignat, L., Giraud, P., Muller, M., Kamenicky, P., Drui, D., Caron, P., Luca, F., Donadille, B., Vantyghem, M. C., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3628 · Cited by 285 · see citing works
Long‐term stability of salivary cortisol
Garde, A. H., & Hansen, Å. M. (2005) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365510510025773 · Cited by 260 · see citing works
Daniel, E., Aylwin, S., Mustafa, O., Ball, S., Munir, A., Boelaert, K., Chortis, V., Cuthbertson, D. J., Daousi, C., Rajeev, S. P., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2616 · Cited by 231 · see citing works
The effect of storage conditions on salivary cortisol concentrations using an Enzyme Immunoassay
Nalla, A. A., Thomsen, G., Knudsen, G. M., & Frokjaer, V. G. (2015) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365513.2014.985252 · Cited by 44 · see citing works
Flagged first, then by citations
Research works printed but not linked: 10
- [1]Arnaldi G Angeli A Atkinson AB Bertagna X Cavagnini F Chrousos GP Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab (2003) 88(12): 5593– 602. 10.1210/jc.2003-030871 14671138 · DOI · Paper page
- [2]Fukuoka H Takeuchi T Matsumoto R Bando H Suda K Nishizawa H D-dimer as a significant marker of deep vein thrombosis in patients with subclinical or overt Cushing’s syndrome. Endocr J (2014) 61(10): 1003– 10. 10.1507/endocrj.EJ14-0102 25100148 · DOI
- [5]Bertagna X Pivonello R Fleseriu M Zhang Y Robinson P Taylor A LCI699, a potent 11beta-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab (2014) 99(4): 1375– 83. 10.1210/jc.2013-2117 24423285 · DOI
- [6]Fleseriu M Pivonello R Young J Hamrahian AH Molitch ME Shimizu C Osilodrostat, a potent oral 11beta-hydroxylase inhibitor: 22-week, prospective, phase II study in Cushing’s disease. Pituitary (2016) 19(2): 138– 48. 10.1007/s11102-015-0692-z 26542280 PMC4799251 · DOI
- [7]Biller BM Grossman AB Stewart PM Melmed S Bertagna X Bertherat J Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab (2008) 93(7): 2454– 62. 10.1210/jc.2007-2734 18413427 PMC3214276 · DOI · Paper page
- [8]Morris D Grossman A. The medical management of Cushing’s syndrome. Ann N Y Acad Sci (2002) 970: 119– 33. 10.1111/j.1749-6632.2002.tb04418.x 12381547 · DOI
- [11]Boscaro M Arnaldi G Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab (2009) 94(9): 3121– 31. 10.1210/jc.2009-0612 19734443 · DOI
- [13]Kageyama K Oki Y Sakihara S Nigawara T Terui K Suda T Evaluation of the diagnostic criteria for Cushing’s disease in Japan. Endocr J (2013) 60(2): 127– 35. 10.1507/endocrj.EJ12-0299 23171704 · DOI
- [14]Iacobone M Citton M Scarpa M Viel G Boscaro M Nitti D Systematic review of surgical treatment of subclinical Cushing’s syndrome. Br J Surg (2015) 102(4): 318– 30. 10.1002/bjs.9742 25640696 · DOI
- [15]Trainer PJ Eastment C Grossman AB Wheeler MJ Perry L Besser GM The relationship between cortisol production rate and serial serum cortisol estimation in patients on medical therapy for Cushing’s syndrome. Clin Endocrinol (1993) 39(4): 441– 3. 10.1111/j.1365-2265.1993.tb02391.x 8287570 · DOI
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Sorted by citations
Ferrari, D., Bonaventura, I., Simeoli, C., Tomaselli, A., Vincenzi, L., De Alcubierre, D., Sciarra, F., Rizzo, F., Cerroni, L., Di Paola, N., et al. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf206 · Cited by 28 · see citing works
What is the role of medical therapy in adrenal-dependent Cushing’s syndrome?
Braun, L. T., & Reincke, M. (2020) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2020.101376 · Cited by 21 · see citing works
Diurnal salivary cortisol profiles in patients with Cushing's syndrome
Braun, L. T., Vogel, F., Zopp, S., Rubinstein, G., Schilbach, K., Künzel, H., Beuschlein, F., & Reincke, M. (2022) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1719-5381 · Cited by 8 · see citing works
Hamidi, O., St-Jean, M., Lacroix, A., & Bancos, I. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag095 · Cited by 5 · see citing works
- Authors
- Yoshida, K., Fukuoka, H., Odake, Y., Nakajima, S., Tachibana, M., Ito, J., Hosokawa, Y., Yamada, T., Miura, H., Suematsu, N., Matsumoto, R., Bando, H., Suda, K., Nishizawa, H., Iguchi, G., Ogawa, W., & Takahashi, Y.
- Affiliations
- Kobe University Hospital (JP)
- Kobe University (JP)
- Corresponding author
- Fukuoka, Hidenori
- ORCID
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2018-01-11
- Volume
- 8
- Pages
- 375-375
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC5768610
- OpenAlex
- W2783836782
- Cited by
- 23
- References
- 5
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 4 · 2018: 1
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (acceptedVersion, cc-by)
- Kobe University Repository Kernel (Kobe University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (23591354, 18K08514, 15K09432, 17K19684, 16H05332, 24790945, 23659477)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- salivary cortisol, metyrapone, Cushing's syndrome, Cushing's disease, diurnal cortisol rhythm, urinary free cortisol, treatment monitoring, dose optimization, non-invasive biomarkers
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