Urinary free cortisone and the assessment of 11β‐hydroxysteroid dehydrogenase activity in man
Abstract
OBJECTIVE: Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyse the interconversion of cortisol to hormonally inactive cortisone; defects in the 11 beta-HSD2 isoform result in hypertension. The kidney, expressing high levels of 11 beta-HSD2, is the principal source of cortisone in man. We have validated the measurement of urinary free cortisone (UFE) excretion in normals and in patients with disorders of the pitultary-adrenal axis in an attempt to more accurately measure the activity of 11 beta-HSD2 in vivo. SUBJECTS: Forty-one normal adults, 12 normal children < 12 years of age, 15 patients with Cushing's syndrome, 12 with hypopitultarism on replacement hydrocortisone, 12 with the syndrome of apparent mineralocorticoid excess (AME) and 7 volunteers consuming liquorice. MEASUREMENTS: A complete 24-hour urine collection was analysed by gas chromatography/mass spectrometry for "A-ring' reduced cortisol and cortisone metabolites, i.e. tetrahydrocortisols (THF and allo-THF) and tetrahydrocortisone (THE). In addition, urinary free cortisol (UFF) and urinary free cortisone were quantified using deuterium-labelled internal standards. RESULTS: In normal adults and children, UFE excretion exceeded that of UFF (UFF 30.4 +/- 2.4 micrograms/24h (mean +/- SE), UFE 54.6 +/- 4.1 micrograms/24h, adults) (for conversion to nmol/24h multiply E by 2.78 and F by 2.76 respectively). Thus the normal UFF/UFE ratio was 0.54 +/- 0.05 in contrast to the (THF + allo-THF)/THE ratio of 1.21 +/- 0.06. UFE excretion was normal in hypopituitary patients on replacement hydrocortisone. Although UFE was elevated in all forms of Cushing's syndrome, the UFF/UFE ratio was grossly elevated in patients with the ectopic ACTH syndrome (14.0 +/- 6.7, n = 6). UFE was below the lower limit of the assay (< 1 microgram/24h) in most patients with the so-called type 1 variant of AME and significantly reduced in 4 patients described as having the type 2 variant of AME (10.5 +/- 3.5 micrograms/h, P < 0.05) and in 7 volunteers consuming liquorice (26.8 +/- 10.0 micrograms/24h, P < 0.01). In ectopic ACTH syndrome, AME, and liquorice ingestion the UFF/UFE ratio was more deranged than the (THF + allo-THF)/THE ratio. CONCLUSION: In normals the discrepant THF + allo-THF/ THE and UFF/UFE ratio suggests that much more of the UFE is derived from the kidney. Reduction in UFE excretion is seen following liquorice ingestion and in both variants of AME, though it is more profound in AME1. The high UFF/UFE ratio in the mineralocorticoid excess state seen in the ectopic ACTH syndrome is compatible with substrate-saturation of renal 11 beta-HSD2. The measurement of UFE and the UFF/UFE ratio is a significant advance in the analysis of human 11 beta-HSD activity in vivo; in particular, the UFF/UFE ratio appears to be a more sensitive index than the (THF + allo-THF)/THE ratio of renal 11 beta-HSD2 activity.
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Higher levels of cortisol overwhelm the capacity of 11β-HSD2 in the salivary glands, as shown by higher salivary cortisol:cortisone ratios with increasing concentrations.
“The present study and previous data show higher salivary cortisol:cortisone ratios with increasing concentrations, indicating that higher levels of cortisol overwhelm the capacity of 11β-HSD2 in the salivary glands (23, 47).”
From Salivary Cortisol and Cortisone Can Circumvent Confounding Effects of Oral Contraceptives in the Short Synacthen Test (2024) · cites this paper as [47]
The urinary free cortisol-to-urinary free cortisone ratio has emerged as a more sensitive marker for apparent mineralocorticoid excess than the ratio of (THF+5α-THF)/THE.
“The urinary free cortisol–to–urinary free cortisone ratio has emerged as a more sensitive marker for AME than the ratio of (THF+5α-THF)/THE (100), as A-ring reduction to tetrahydro metabolites takes place mainly in the liver and their ratio may not accurately reflect renal HSD11B2 activity.”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [100]
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“We and others have previously demonstrated that GH does not alter the urinary free cortisol to cortisone ratio, indicating that the changes in Fm/Em and THF plus 5aTHF/THE ratios due to GH are specific to 11bHSD1 (1, 9 ).”
BackgroundMutants of 11β-Hydroxysteroid Dehydrogenase (11-HSD2) With Partial Activity
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Self-citationSensitivity of bone to glucocorticoids
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“Most investigators relied upon measuring urinary free cortisol–to–cortisone ratios as an index of renal 11bHSD2 activity (33,34) or on urinary cortisol–to–cortisone metabolite ratios, which reflect predominantly intrahepatic steroid levels.”
BackgroundExpression and putative role of 11 beta-hydroxysteroid dehydrogenase isozymes within the human eye.
Rauz, S., Walker, E. A., Shackleton, C. H. L., Hewison, M., Murray, P. I., & Stewart, P. M. (2001) · PubMed · Cited by 61 · see citing works
Self-citationEsche, J., Shi, L., Sánchez‐Guijo, A., Hartmann, M. F., Wudy, S. A., & Remer, T. (2016) · Kidney International · doi:10.1016/j.kint.2016.02.033 · Cited by 62 · see citing works
Cortisol Metabolism in Depressed Patients and Healthy Controls
Römer, B., Lewicka, S., Kopf, D., Lederbogen, F., Hamann, B., Gilles, M., Schilling, C., Onken, V., Frankhauser, P., & Deuschle, M. (2009) · Neuroendocrinology · doi:10.1159/000235904 · Cited by 63 · see citing works
Toogood, A. A., Taylor, N., Shalet, S. M., & Monson, J. P. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.4.6505 · Cited by 61 · see citing works
Walker, E. A., Ahmed, A., Lavery, G. G., Tomlinson, J., Kim, S. Y., Cooper, M. S., Ride, J. P., Hughes, B. A., Shackleton, C. H. L., McKiernan, P. J., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704144200 · Cited by 60 · see citing works
Self-citationHenschkowski, J., Stuck, A. E., Frey, B. M., Gillmann, G., Dick, B., Frey, F. J., & Mohaupt, M. (2008) · American Journal of Hypertension · doi:10.1038/ajh.2008.152 · Cited by 60 · see citing works
Glycyrrhizic acid suppresses type 2 11β-hydroxysteroid dehydrogenase expression in vivo
Tanahashi, T., Mune, T., Morita, H., Tanahashi, H., Isomura, Y., Suwa, T., Daido, H., Gómez-Sánchez, C. E., & Yasuda, K. (2002) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(02)00033-x · Cited by 59 · see citing works
Ceccato, F., Antonelli, G., Barbot, M., Zilio, M., Mazzai, L., Gatti, R. D., Zaninotto, M., Mantero, F., Boscaro, M., Plebani, M., et al. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0061 · Cited by 56 · see citing works
Self-citationCure of Apparent Mineralocorticoid Excess by Kidney Transplantation
Palermo, M., Cossu, M. L., & Shackleton, C. H. L. (1998) · New England Journal of Medicine · doi:10.1056/nejm199812103392414 · Cited by 54 · see citing works
Self-citationTargeting Human Urinary Metabolome by LC–MS/MS: A Review
Rodríguez-Morató, J., Pozo, Ó. J., & Marcos, J. (2018) · Bioanalysis · doi:10.4155/bio-2017-0285 · Cited by 53 · see citing works
“Precursor/product ratios have proved to be the best markers for the diagnosis of many conditions [59-61].”
BackgroundClassic and Nonclassic Apparent Mineralocorticoid Excess Syndrome
Carvajal, C. A., Tapia-Castillo, A., Vecchiola, A., Baudrand, R. F., & Fardella, C. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz315 · Cited by 51 · see citing works
Painovich, J., SHUFELT, C. L., Azziz, R., Yang, Y., Goodarzi, M. O., Braunstein, G. D., Karlan, B. Y., Stewart, P. M., & Merz, C. N. B. (2011) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0b013e31821f9171 · Cited by 52 · see citing works
“THF, 5>-THF, cortolones, and cortols), along with the concentrations of free F and free estrodial, was used as an assessment of the total daily F production, as previously validated.(29)”
MethodSelf-citationHawley, J. M., & Keevil, B. G. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.05.014 · Cited by 52 · see citing works
Swords, F. M., Carroll, P., Kisalu, J., Wood, P. J., Taylor, N., & Monson, J. P. (2003) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2003.01894.x · Cited by 52 · see citing works
Ontogeny and sexual dimorphic expression of mouse type 2 11β-hydroxysteroid dehydrogenase
Condon, J. C., Ricketts, M., Whorwood, C. B., & Stewart, P. M. (1997) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(97)04000-8 · Cited by 51 · see citing works
Self-citationQuinkler, M. O., Zehnder, D., Lepenies, J., Petrelli, M., Moore, J. S., Hughes, S. V., Cockwell, P., Hewison, M., & Stewart, P. M. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.01954 · Cited by 51 · see citing works
Self-citationMariniello, B., Ronconi, V., Sardu, C., et al. (2005) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2005.02.020 · Cited by 51 · see citing works
“Moreover an increased UFF/ UFE ratio, an index of 11 -HSD2 activity, has also been noted in salt-sensitive hypertensive patients.(22,24) The increased excretion of urinary cortisol metabolites in some patients with essential hypertension also argues for the involvement of 11 -HSD2 in hypertension.”
BackgroundMethodResultSelf-citationBuning, J. W., van Faassen, M. H. J. R., Brummelman, P., Dullaart, R. P. F., van den Berg, G., van der Klauw, M. M., Kerstens, M. N., Stegeman, C. A., Kobold, A. C. M., Kema, I. P., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-2216 · Cited by 50 · see citing works
Woods, C. P., Corrigan, M., Gathercole, L., TAYLOR, A. E. R., Hughes, B. A., Gaoatswe, G., Manolopoulos, K. N., Hogan, A. E., O’Connell, J., Stewart, P. M., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-4120 · Cited by 47 · see citing works
“Participants completed a 24-hour urine collection for cortisol, cortisone, and glucocorticoid metabolite analysis (38) before surgery and again after surgery, following weight loss.”
MethodSelf-citationTokarz, J., Mindnich, R., Norton, W., Möller, G., Hrabé de Angelis, M., & Adamski, J. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.10.022 · Cited by 48 · see citing works
Odermatt, A., Dick, B., Arnold, P., Zaehner, T., Plueschke, V., Deregibus, M. N., Repetto, H. A., Frey, B. M., Frey, F. J., & Ferrari, P. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.3.7334 · Cited by 47 · see citing works
Khelil, M. B., Tegethoff, M., Meinlschmidt, G., Jamey, C., Ludes, B., & Raul, J. (2011) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-011-5172-3 · Cited by 46 · see citing works
“23) recently determined by HPLC combined with fluorescence derivatization [32], indicating that the cortisol/cortisone ratio measured in nail may reflect the same physiological processes as the urinary ratio, above all the net balance of corticosteroid 11-betadehydrogenase isozyme 1 (HSD11B1) and corticosteroid 11-bet…”
Effect of Polyphenol-Rich Dark Chocolate on Salivary Cortisol and Mood in Adults
Tsang, C., Hodgson, L., Bussu, A., Farhat, G., & Al‐Dujaili, E. A. S. (2019) · Antioxidants · doi:10.3390/antiox8060149 · Cited by 47 · see citing works
“The ratio of cortisol to cortisone is well accepted by many researchers as indicative of 11β-HSD type 1 activity [29,36].”
BackgroundBäcklund, N., Brattsand, G., Israelsson, M., Ragnarsson, O., Burman, P., Edén Engström, B., Høybye, C., Berinder, K., Wahlberg, J., Olsson, T., et al. (2020) · European Journal of Endocrinology · doi:10.1530/eje-19-0872 · Cited by 46 · see citing works
Mini-review of hair cortisol concentration for evaluation of Cushing syndrome
Hodes, A., Meyer, J., Lodish, M. B., Stratakis, C. A., & Zilbermint, M. (2018) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2018.1517043 · Cited by 46 · see citing works
Campino, C., Carvajal, C. A., Cornejo, J., Martín, B. S., Olivieri, O., Guidi, G. C., Faccini, G., Pasini, F., Sateler, J., Baudrand, R. F., et al. (2009) · Endocrine · doi:10.1007/s12020-009-9269-9 · Cited by 46 · see citing works
Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients
Hoshiro, M., Ohno, Y., Masaki, H., et al. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02412.x · Cited by 44 · see citing works
Cortisol as a mineralocorticoid in human disease
Stewart, P. M. (1999) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(99)00072-2 · Cited by 43 · see citing works
Self-citationKerstens, M. N., Riemens, S. C., Sluiter, W. J., Pratt, J. J., Wolthers, B. G., & Dullaart, R. P. F. (2000) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2000.00975.x · Cited by 43 · see citing works
Cohen, J., Lassig‐Smith, M., Deans, R., Pretorius, C. J., Ungerer, J. P. J., Tan, T. C. H., Jones, M., & Venkatesh, B. (2011) · Shock · doi:10.1097/shk.0b013e318239b809 · Cited by 43 · see citing works
Yamashita, K., Nakagawa, R., Okuyama, M., Honma, S., Takahashi, M., & Numazawa, M. (2008) · Steroids · doi:10.1016/j.steroids.2008.02.009 · Cited by 41 · see citing works
Genetic manipulation of 11β-hydroxysteroid dehydrogenases in mice
Paterson, J. M., Seckl, J. R., & Mullins, J. J. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00017.2005 · Cited by 41 · see citing works
- Authors
- Palermo, M., Shackleton, C. H. L., Mantero, F., & Stewart, P. M.
- Affiliations
- Queen Elizabeth Hospital Birmingham (GB)
- Corresponding author
- Stewart, Paul M.
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 1996-11
- Volume
- 45
- Issue
- 5
- Pages
- 605-611
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2019500301
- Cited by
- 276
- References
- 0
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 11 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 12
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- urinary free cortisol, 11β-hydroxysteroid dehydrogenase type 2, tetrahydrocortisone, tetrahydrocortisol, Cushing's syndrome, ectopic ACTH syndrome, hypopituitarism, hydrocortisone replacement, apparent mineralocorticoid excess, licorice, hypertension, pituitary-adrenal axis
- MeSH terms
- Adult, Child, Cortisone, Cushing Syndrome, Female, Glycyrrhiza, Humans, Hydrocortisone, Hydroxysteroid Dehydrogenases, Hypopituitarism, Male, Gas Chromatography-Mass Spectrometry, Middle Aged, Mineralocorticoids, Pituitary-Adrenal System, Plants, Medicinal, Tetrahydrocortisol, Tetrahydrocortisone, 11-beta-Hydroxysteroid Dehydrogenases
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