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Regulation of cortisol bioavailability—effects on hormone measurement and action

Nature Reviews Endocrinology volume 8, pages 717–727 (2012)Cite this article

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Abstract

Routine assessment of the hypothalamic–pituitary–adrenal axis relies on the measurement of total serum cortisol levels. However, most cortisol in serum is bound to corticosteroid-binding globulin (CBG) and albumin, and changes in the structure or circulating levels of binding proteins markedly affect measured total serum cortisol levels. Furthermore, high-affinity binding to CBG is predicted to affect the availability of cortisol for the glucocorticoid receptor. CBG is a substrate for activated neutrophil elastase, which cleaves the binding protein and results in the release of cortisol at sites of inflammation, enhancing its tissue-specific anti-inflammatory effects. Further tissue-specific modulation of cortisol availability is conferred by corticosteroid 11β-dehydrogenase. Direct assessment of tissue levels of bioavailable cortisol is not clinically practicable and measurement of total serum cortisol levels is of limited value in clinical conditions that alter prereceptor glucocorticoid bioavailability. Bioavailable cortisol can, however, be measured indirectly at systemic, extracellular tissue and cell levels, using novel techniques that have provided new insight into the transport, metabolism and biological action of glucocorticoids. A more physiologically informative approach is, therefore, now possible in the assessment of the hypothalamic–pituitary–adrenal axis, which could prove useful in clinical practice.

Key Points

  • Only the unbound (free) fraction of cortisol is biologically active

  • Current hypothalamic–pituitary–adrenal axis assessment relies on measurement of total serum cortisol levels, which are a surrogate for free serum cortisol concentrations

  • Prereceptor regulation of cortisol involves binding to corticosteroid-binding globulin and cortisol–cortisone interconversion, which both affect cortisol bioavailability for the glucocorticoid receptor

  • Various conditions and medications affect protein binding and total, but not bioavailable, cortisol levels; total serum cortisol levels are inappropriately used as a biochemical end point and can be misleading

  • Novel methodologies have led to a transition from total serum cortisol measurement by immunoassays to free serum cortisol measurement by liquid chromatography and tandem mass spectrometry

  • Tissue microdialysis and glucocorticoid bioassays could be used in the future to clarify the relationship of circulating to tissue and cell levels of available cortisol

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Figure 1: Prereceptor regulation of cortisol bioavailability and its relationship to methods of glucocorticoid measurement.
Figure 2: CBG as a substrate for neutrophil elastase.
Figure 3: The effect of CBG saturation on free cortisol levels in individuals with altered serum cortisol binding capacity.

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References

  1. Lewis, J. G., Bagley, C. J., Elder, P. A., Bachmann, A. W. & Torpy, D. J. Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. Clin. Chim. Acta 359, 189–194 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Mendel, C. M. The free hormone hypothesis: a physiologically based mathematical model. Endocr. Rev. 10, 232–274 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Htun, H., Barsony, J., Renyi, I., Gould, D. L. & Hager, G. L. Visualization of glucocorticoid receptor translocation and intranuclear organization in living cells with a green fluorescent protein chimera. Proc. Natl Acad. Sci. USA 93, 4845–4850 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rhen, T. & Cidlowski, J. A. Anti-inflammatory action of glucocorticoids—new mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Chrousos, G. P. Stress and disorders of the stress system. Nat. Rev. Endocrinol. 5, 374–81 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Mendel, C. M. The free hormone hypothesis. Distinction from the free hormone transport hypothesis. J. Androl. 13, 107–116 (1992).

    CAS  PubMed  Google Scholar 

  7. Mendel, C. M. et al. Uptake of cortisol by the perfused rat liver: validity of the free hormone hypothesis applied to cortisol. Endocrinology 124, 468–476 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Hryb, D. J. et al. Specific binding of human corticosteroid-binding globulin to cell membranes. Proc. Natl Acad. Sci. USA 83, 3253–3256 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nakhla, A. M., Khan, M. S. & Rosner, W. Induction of adenylate cyclase in a mammary carcinoma cell line by human corticosteroid-binding globulin. Biochem. Biophys. Res. Commun. 153, 1012–1018 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Willnow, T. E. & Nykjaer, A. Cellular uptake of steroid carrier proteins—mechanisms and implications. Mol. Cell Endocrinol. 316, 93–102 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Rosner, W., Hryb, D. J., Kahn, S. M., Nakhla, A. M. & Romas, N. A. Interactions of sex hormone-binding globulin with target cells. Mol. Cell Endocrinol. 316, 79–85 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Cameron, A. et al. Temperature-responsive release of cortisol from its binding globulin: a protein thermocouple. J. Clin. Endocrinol. Metab. 95, 4689–4695 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Westphal, U. Steroid–protein interaction: from past to present. J. Steroid Biochem. 19, 1–15 (1983).

    Article  CAS  PubMed  Google Scholar 

  14. Cooper, M. S. & Stewart, P. M. 11β-Hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus–pituitary–adrenal axis, metabolic syndrome, and inflammation. J. Clin. Endocrinol. Metab. 94, 4645–4654 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Edwards, C. R. et al. Localisation of 11 β-hydroxysteroid dehydrogenase—tissue specific protector of the mineralocorticoid receptor. Lancet 2, 986–989 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Smith, R. E. et al. Localization of 11 β-hydroxysteroid dehydrogenase type II in human epithelial tissues. J. Clin. Endocrinol. Metab. 81, 3244–3248 (1996).

    CAS  PubMed  Google Scholar 

  17. Stewart, P. M. Cortisol as a mineralocorticoid in human disease. J. Steroid Biochem. Mol. Biol. 69, 403–408 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Hammond, G. L., Smith, C. L. & Underhill, D. A. Molecular studies of corticosteroid binding globulin structure, biosynthesis and function. J. Steroid Biochem. Mol. Biol. 40, 755–762 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Pugeat, M. M., Dunn, J. F. & Nisula, B. C. Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J. Clin. Endocrinol. Metab. 53, 69–75 (1981).

    Article  CAS  PubMed  Google Scholar 

  20. Dunn, J. F., Nisula, B. C. & Rodbard, D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J. Clin. Endocrinol. Metab. 53, 58–68 (1981).

    Article  CAS  PubMed  Google Scholar 

  21. Lightman, S. L. & Conway-Campbell, B. L. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat. Rev. Neurosci. 11, 710–718 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Pugeat, M. M. et al. Plasma cortisol transport and primate evolution. Endocrinology 115, 357–361 (1984).

    Article  CAS  PubMed  Google Scholar 

  23. Lin, H. Y., Muller, Y. A. & Hammond, G. L. Molecular and structural basis of steroid hormone binding and release from corticosteroid-binding globulin. Mol. Cell Endocrinol. 316, 3–12 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Pemberton, P. A., Stein, P. E., Pepys, M. B., Potter, J. M. & Carrell, R. W. Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336, 257–258 (1988).

    Article  CAS  PubMed  Google Scholar 

  25. Hammond, G. L., Smith, C. L., Paterson, N. A. & Sibbald, W. J. A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J. Clin. Endocrinol. Metab. 71, 34–39 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Emptoz-Bonneton, A., Crave, J. C., Lejeune, H., Brebant, C. & Pugeat, M. Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells. J. Clin. Endocrinol. Metab. 82, 3758–3762 (1997).

    CAS  PubMed  Google Scholar 

  27. Tsigos, C., Kyrou, I., Chrousos, G. P. & Papanicolaou, D. A. Prolonged suppression of corticosteroid-binding globulin by recombinant human interleukin-6 in man. J. Clin. Endocrinol. Metab. 83, 3379 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Ho, J. T. et al. Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J. Clin. Endocrinol. Metab. 91, 105–114 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Bernier, J., Jobin, N., Emptoz-Bonneton, A., Pugeat, M. M. & Garrel, D. R. Decreased corticosteroid-binding globulin in burn patients: relationship with interleukin-6 and fat in nutritional support. Crit. Care Med. 26, 452–460 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Zouaghi, H. et al. Total and unbound cortisol-, progesterone-, oestrone- and transcortin-binding activities in sera from patients with myocardial infarction: evidence for differential responses of good and bad prognostic cases. Eur. J. Clin. Invest. 15, 365–370 (1985).

    Article  CAS  PubMed  Google Scholar 

  31. Westphal, U. Steroid–protein interactions. Monogr. Endocrinol. 4, 1–567 (1971).

    Article  CAS  PubMed  Google Scholar 

  32. Lin, H. Y. et al. High frequency of SERPINA6 polymorphisms that reduce plasma corticosteroid-binding globulin activity in Chinese subjects. J. Clin. Endocrinol. Metab. 94, E678–E686 (2012).

    Article  CAS  Google Scholar 

  33. Gagliardi, L., Ho, J. T. & Torpy, D. J. Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations. Mol. Cell. Endocrinol. 316, 24–34 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Musa, B. U., Seal, U. S. & Doe, R. P. Elevation of certain plasma proteins in man following estrogen administration: a dose–response relationship. J. Clin. Endocrinol. Metab. 25, 1163–1166 (1965).

    Article  CAS  PubMed  Google Scholar 

  35. Sandberg, A. A. & Slaunwhite, W. R. Transcortin: a corticosteroid-binding protein of plasma. II. Levels in various conditions and the effects of estrogens. J. Clin. Invest. 38, 1290–1297 (1959).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mitchell, E., Torpy, D. J. & Bagley, C. J. Pregnancy-associated corticosteroid-binding globulin: high resolution separation of glycan isoforms. Horm. Metab. Res. 36, 357–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Strel'chyonok, O. A. & Avvakumov, G. V. Specific steroid-binding glycoproteins of human blood plasma: novel data on their structure and function. J. Steroid Biochem. 35, 519–534 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Nader, N. et al. Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J. Clin. Endocrinol. Metab. 91, 2165–2170 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Alexandraki, K. I. et al. Assessment of serum-free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study. Clin. Endocrinol. (Oxf.) 72, 305–311 (2010).

    Article  CAS  Google Scholar 

  40. Klose, M. et al. Factors influencing the adrenocorticotropin test: role of contemporary cortisol assays, body composition, and oral contraceptive agents. J. Clin. Endocrinol. Metab. 92, 1326–1333 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Perogamvros, I., Keevil, B. G., Ray, D. W. & Trainer, P. J. Salivary cortisone is a potential biomarker for serum free cortisol. J. Clin. Endocrinol. Metab. 95, 4951–4958 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Plumpton, F. S. & Besser, G. M. The adrenocortical response to surgery and insulin-induced hypoglycemia in corticosteroid-treated and normal subjects. Br. J. Surg. 55, 857 (1968).

    Article  CAS  PubMed  Google Scholar 

  43. Widmer, I. E. et al. Cortisol response in relation to the severity of stress and illness. J. Clin. Endocrinol. Metab. 90, 4579–4586 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Vogeser, M. et al. Corticosteroid-binding globulin and free cortisol in the early postoperative period after cardiac surgery. Clin. Biochem. 32, 213–216 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Vogeser, M., Briegel, J. & Zachoval, R. Dialyzable free cortisol after stimulation with Synacthen. Clin. Biochem. 35, 539–543 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Christ-Crain, M. et al. Measurement of serum free cortisol shows discordant responsivity to stress and dynamic evaluation. J. Clin. Endocrinol. Metab. 92, 1729–1735 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Thomson, A. H. et al. Variability in hydrocortisone plasma and saliva pharmacokinetics following intravenous and oral administration to patients with adrenal insufficiency. Clin. Endocrinol. (Oxf.) 66, 789–796 (2007).

    Article  CAS  Google Scholar 

  48. Wong, V., Yan, T., Donald, A. & McLean, M. Saliva and bloodspot cortisol: novel sampling methods to assess hydrocortisone replacement therapy in hypoadrenal patients. Clin. Endocrinol. (Oxf.) 61, 131–137 (2004).

    Article  CAS  Google Scholar 

  49. Nieman, L. K. et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Raff, H. Utility of salivary cortisol measurements in Cushing's syndrome and adrenal insufficiency. J. Clin. Endocrinol. Metab. 94, 3647–3655 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Baid, S. K., Sinaii, N., Wade, M., Rubino, D. & Nieman, L. K. Radioimmunoassay and tandem mass spectrometry measurement of bedtime salivary cortisol levels: a comparison of assays to establish hypercortisolism. J. Clin. Endocrinol. Metab. 92, 3102–3107 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Annane, D. et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288, 862–871 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Marik, P. E. et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit. Care Med. 36, 1937–1949 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Annane, D., Sébille, V., Troché, G., Raphaël, J. C., Gajdos, P. & Bellissant, E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283, 1038–1045.

  55. Mickelson, K. E., Forsthoefel, J. & Westphal, U. Steroid–protein interactions. Human corticosteroid binding globulin: some physicochemical properties and binding specificity. Biochemistry 20, 6211–6218 (1981).

    Article  CAS  PubMed  Google Scholar 

  56. Vogeser, M. & Briegel, J. Effect of temperature on protein binding of cortisol. Clin. Biochem. 40, 724–727 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Hammond, G. L. Molecular properties of corticosteroid binding globulin and the sex-steroid binding proteins. Endocr. Rev. 11, 65–79 (1990).

    Article  CAS  PubMed  Google Scholar 

  58. Sprung, C. L. et al. Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358, 111–124 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Hamrahian, A. H., Oseni, T. S. & Arafah, B. M. Measurements of serum free cortisol in critically ill patients. N. Engl. J. Med. 350, 1629–1638 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Cohen, J. et al. Serial changes in plasma total cortisol, plasma free cortisol and tissue cortisol activity in patients with septic shock: an observational study. Shock 37, 28–33 (2011).

    Article  CAS  Google Scholar 

  61. Zimmerman, J. J. et al. Real-time free cortisol quantification among critically ill children. Pediatr. Crit. Care Med. 12, 525–531 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Arafah, B. M., Nishiyama, F. J., Tlaygeh, H. & Hejal, R. 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 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Duplessis, C., Rascona, D., Cullum, M. & Yeung, E. Salivary and free serum cortisol evaluation. Mil. Med. 175, 340–346 (2010).

    Article  PubMed  Google Scholar 

  64. Cohen, J. et al. Measurement of tissue cortisol levels in patients with severe burns: a preliminary investigation. Crit. Care 13, R189 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ilias, I. et al. Interstitial cortisol levels obtained by adipose tissue microdialysis in mechanically ventilated septic patients: correlations with total and free serum cortisol. Endocr. Abstr. 26, P15 (2011).

    Google Scholar 

  66. Llompart-Pou, J. A. et al. Correlation between brain interstitial and total serum cortisol levels in traumatic brain injury. A preliminary study. J. Endocrinol. Invest. 33, 368–372 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Marik, P. E., Gayowski, T. & Starzl, T. E. The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit. Care Med. 33, 1254–1259 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  68. O'Beirne, J. et al. Adrenal insufficiency in liver disease—what is the evidence? J. Hepatol. 47, 418–423 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Harry, R., Auzinger, G. & Wendon, J. The effects of supraphysiological doses of corticosteroids in hypotensive liver failure. Liver Int. 23, 71–77 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Tan, T. et al. Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease. J. Hepatol. 53, 841–848 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Brien, T. G. Pathophysiology of free cortisol in plasma. Ann. NY Acad. Sci. 538, 130–136 (1988).

    Article  CAS  PubMed  Google Scholar 

  72. Galbois, A. et al. Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred. J. Hepatol. 52, 839–845 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Thevenot, T. et al. Assessment of adrenal function in cirrhotic patients using concentration of serum-free and salivary cortisol. Liver Int. 31, 425–433 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Fede, G. et al. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology 55, 1282–1291 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Perogamvros, I. et al. Novel corticosteroid-binding globulin variant that lacks steroid binding activity. J. Clin. Endocrinol. Metab. 95, E142–E150 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Emptoz-Bonneton, A. et al. Novel human corticosteroid-binding globulin variant with low cortisol-binding affinity. J. Clin. Endocrinol. Metab. 85, 361–367 (2000).

    CAS  PubMed  Google Scholar 

  77. Torpy, D. J. et al. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J. Clin. Endocrinol. Metab. 86, 3692–3700 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Torpy, D. J. et al. CBG Santiago: a novel CBG mutation. J. Clin. Endocrinol. Metab. 97, E151–E155 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Van Baelen, H., Brepoels, R. & De, M. P. Transcortin Leuven: a variant of human corticosteroid-binding globulin with decreased cortisol-binding affinity. J. Biol. Chem. 257, 3397–3400 (1982).

    CAS  PubMed  Google Scholar 

  80. Perogamvros, I., Aarons, L., Miller, A. G., Trainer, P. J. & Ray, D. W. Corticosteroid-binding globulin regulates cortisol pharmacokinetics. Clin. Endocrinol. (Oxf.) 74, 30–36 (2011).

    Article  CAS  Google Scholar 

  81. Brossaud, J., Barat, P., Gualde, D. & Corcuff, J. B. Cross reactions elicited by serum 17-OH progesterone and 11-desoxycortisol in cortisol assays. Clin. Chim. Acta 407, 72–74 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Monaghan, P. J. et al. Comparison of serum cortisol measurement by immunoassay and liquid chromatography–tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone. Ann. Clin. Biochem. 48, 441–446 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. O'Shaughnessy, I. M., Raff, H. & Findling, J. W. Factitious Cushing's syndrome: discovery with use of a sensitive immunoradiometric assay for corticotropin. Endocr. Pract. 1, 327–329 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Roberts, R. F. & Roberts, W. L. Performance characteristics of five automated serum cortisol immunoassays. Clin. Biochem. 37, 489–493 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Siemens Healthcare Diagnostics Inc. Advia Centaur® Immunoassay Systems Customer Bulletin http://www.medical.siemens.com (2008).

  86. Carvalho, V. M. The coming of age of liquid chromatography coupled to tandem mass spectrometry in the endocrinology laboratory. J. Chromatogr. B. Analyt. Technol. Biomed. Life. Sci. 883–884, 50–58 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Hammond, G. L., Nisker, J. A., Jones, L. A. & Siiteri, P. K. Estimation of the percentage of free steroid in undiluted serum by centrifugal ultrafiltration-dialysis. J. Biol. Chem. 255, 5023–5026 (1980).

    CAS  PubMed  Google Scholar 

  88. Jerkunica, I., Sophianopoulos, J. & Sgoutas, D. Improved ultrafiltration method for determining unbound cortisol in plasma. Clin. Chem. 26, 1734–1737 (1980).

    CAS  PubMed  Google Scholar 

  89. Lentjes, E. G. et al. Free cortisol in serum assayed by temperature-controlled ultrafiltration before fluorescence polarization immunoassay. Clin. Chem. 39, 2518–2521 (1993).

    CAS  PubMed  Google Scholar 

  90. Vogeser, M., Mohnle, P. & Briegel, J. Free serum cortisol: quantification applying equilibrium dialysis or ultrafiltration and an automated immunoassay system. Clin. Chem. Lab. Med. 45, 521–525 (2007).

    CAS  PubMed  Google Scholar 

  91. Pretorius, C. J., Galligan, J. P., McWhinney, B. C., Briscoe, S. E. & Ungerer, J. P. Free cortisol method comparison: ultrafiltation, equilibrium dialysis, tracer dilution, tandem mass spectrometry and calculated free cortisol. Clin. Chim. Acta 412, 1043–1047 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Vining, R. F., McGinley, R. A. & Symons, R. G. Hormones in saliva: mode of entry and consequent implications for clinical interpretation. Clin. Chem. 29, 1752–1756 (1983).

    CAS  PubMed  Google Scholar 

  93. Katz, F. H. & Shannon, I. L. Parotid fluid cortisol and cortisone. J. Clin. Invest. 48, 848–855 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Perogamvros, I., Owen, L. J., Keevil, B. G., Brabant, G. & Trainer, P. J. Measurement of salivary cortisol with liquid chromatography–tandem mass spectrometry in patients undergoing dynamic endocrine testing. Clin. Endocrinol. (Oxf.) 72, 17–21 (2010).

    Article  CAS  Google Scholar 

  95. Umeda, T. et al. Use of saliva for monitoring unbound free cortisol levels in serum. Clin. Chim. Acta 110, 245–253 (1981).

    Article  CAS  PubMed  Google Scholar 

  96. Vining, R. F., McGinley, R. A., Maksvytis, J. J. & Ho, K. Y. Salivary cortisol: a better measure of adrenal cortical function than serum cortisol. Ann. Clin. Biochem. 20 (Pt 6), 329–335 (1983).

    Article  CAS  PubMed  Google Scholar 

  97. Chu, F. W. & Ekins, R. P. Detection of corticosteroid binding globulin in parotid fluids: evidence for the presence of both protein-bound and non-protein-bound (free) steroids in uncontaminated saliva. Acta Endocrinol. (Copenh.) 119, 56–60 (1988).

    Article  CAS  Google Scholar 

  98. Hammond, G. L. & Langley, M. S. Identification and measurement of sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) in human saliva. Acta Endocrinol. (Copenh.) 112, 603–608 (1986).

    Article  CAS  Google Scholar 

  99. Qureshi, A. C. et al. The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol. Clin. Endocrinol. (Oxf.) 66, 632–635 (2007).

    Article  CAS  Google Scholar 

  100. Simunková, K. et al. Comparison of total and salivary cortisol in a low-dose ACTH (Synacthen) test: influence of three-month oral contraceptives administration to healthy women. Physiol. Res. 57 (Suppl. 1), S193–S199 (2008).

    PubMed  Google Scholar 

  101. Meulenberg, P. M. & Hofman, J. A. Differences between concentrations of salivary cortisol and cortisone and of free cortisol and cortisone in plasma during pregnancy and postpartum. Clin. Chem. 36, 70–75 (1990).

    CAS  PubMed  Google Scholar 

  102. Sandeep, T. C. et al. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 54, 872–879 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Li, Y., Peris, J., Zhong, L. & Derendorf, H. Microdialysis as a tool in local pharmacodynamics. AAPS J. 8, E222–E235 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Schäfer-Korting, M., Korting, H. C., Hiemstra, S. & Mutschler, E. Does cantharides blister fluid provide access to the peripheral compartment? Eur. J. Clin. Pharmacol. 23, 327–330 (1982).

    Article  PubMed  Google Scholar 

  105. Brunner, M. et al. Direct assessment of peripheral pharmacokinetics in humans: comparison between cantharides blister fluid sampling, in vivo microdialysis and saliva sampling. Br. J. Clin. Pharmacol. 46, 425–431 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Necela, B. M. & Cidlowski, J. A. Development of a flow cytometric assay to study glucocorticoid receptor-mediated gene activation in living cells. Steroids 68, 341–350 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Perogamvros, I., Kayahara, M., Trainer, P. J. & Ray, D. W. Serum regulates cortisol bioactivity by corticosteroid-binding globulin dependent and independent mechanisms, as revealed by combined bioassay and physicochemical assay approaches. Clin. Endocrinol. (Oxf.), 75, 31–38 (2011).

    Article  CAS  Google Scholar 

  108. Raivio, T., Palvimo, J. J., Kannisto, S., Voutilainen, R. & Jänne, O. A. Transactivation assay for determination of glucocorticoid bioactivity in human serum. J. Clin. Endocrinol. Metab. 87, 3740–3744 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Vermeer, H. et al. A novel specific bioassay for the determination of glucocorticoid bioavailability in human serum. Clin. Endocrinol. (Oxf.) 59, 49–55 (2003).

    Article  CAS  Google Scholar 

  110. Baumann, G., Rappaport, G., Lemarchand-Béraud, T. & Felber, J. P. Free cortisol index: a rapid and simple estimation of free cortisol in human plasma. J. Clin. Endocrinol. Metab. 40, 462–469 (1975).

    Article  CAS  PubMed  Google Scholar 

  111. Coolens, J. L., Van, B. H. & Heyns, W. Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J. Steroid Biochem. 26, 197–202 (1987).

    Article  CAS  PubMed  Google Scholar 

  112. le Roux., C. W. et al. Free cortisol index as a surrogate marker for serum free cortisol. Ann. Clin. Biochem. 39, 406–408 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Ho, J. T. et al. Reduced maternal corticosteroid-binding globulin and cortisol levels in pre-eclampsia and gamete recipient pregnancies. Clin. Endocrinol. (Oxf.) 66, 869–877 (2007).

    Article  CAS  Google Scholar 

  114. Pugeat, M. et al. Decreased immunoreactivity and binding activity of corticosteroid-binding globulin in serum in septic shock. Clin. Chem. 35, 1675–1679 (1989).

    CAS  PubMed  Google Scholar 

  115. Vogeser, M., Groetzner, J., Küpper, C. & Briegel, J. Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography–tandem mass spectrometry. Clin. Chem. Lab. Med. 41, 146–151 (2003).

    CAS  PubMed  Google Scholar 

  116. Loriaux, L. Glucocorticoid therapy in the intensive care unit. N. Engl. J. Med. 350, 1601–1602 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. McMaster, A. et al. Ultradian cortisol pulsatility encodes a distinct, biologically important signal. PLoS ONE 6, e15766 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Stavreva, D. A. et al. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat. Cell Biol. 11, 1093–1102 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sakai, F. et al. Increases in steroid binding globulins induced by tamoxifen in patients with carcinoma of the breast. J. Endocrinol. 76, 219–226 (1978).

    Article  CAS  PubMed  Google Scholar 

  120. Crave, J. C., Lejeune, H., Brebant, C., Baret, C. & Pugeat, M. Differential effects of insulin and insulin-like growth factor I on the production of plasma steroid-binding globulins by human hepatoblastoma-derived (Hep G2) cells. J. Clin. Endocrinol. Metab. 80, 1283–1289 (1995).

    CAS  PubMed  Google Scholar 

  121. Mihrshahi, R., Lewis, J. G. & Ali, S. O. Hormonal effects on the secretion and glycoform profile of corticosteroid-binding globulin. J. Steroid Biochem. Mol. Biol. 101, 275–285 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Caron, P., Bennet, A., Barousse, C., Nisula, B. C. & Louvet, J. P. Effects of hyperthyroidism on binding proteins for steroid hormones. Clin. Endocrinol. (Oxf.) 31, 219–224 (1989).

    Article  CAS  Google Scholar 

  123. Feldman, D., Mondon, C. E., Horner, J. A. & Weiser, J. N. Glucocorticoid and estrogen regulation of corticosteroid-binding globulin production by rat liver. Am. J. Physiol. 237, E493–E499 (1979).

    CAS  PubMed  Google Scholar 

  124. Schlechte, J. A. & Hamilton, D. The effect of glucocorticoids on corticosteroid binding globulin. Clin. Endocrinol. (Oxf.) 27, 197–203 (1987).

    Article  CAS  Google Scholar 

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  1. Endocrine Sciences Research Group, School of Medicine, University of Manchester, A. V. Hill Building, Oxford Road, M13 9PT, Manchester, UK

    Ilias Perogamvros, David W. Ray & Peter J. Trainer

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  1. Ilias Perogamvros
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I. Perogamvros researched data for the article, contributed to content discussions, wrote and edited the manuscript. D. W. Ray and P. J. Trainer contributed substantially to discussions of the content and review or editing of the manuscript.

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Perogamvros, I., Ray, D. & Trainer, P. Regulation of cortisol bioavailability—effects on hormone measurement and action. Nat Rev Endocrinol 8, 717–727 (2012). https://doi.org/10.1038/nrendo.2012.134

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