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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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“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]
In the citing paper
“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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Items 201–274 of 274
Zuckerman‐Levin, N., Tsivlin, L., Knopf, C. F., Flor, O., Shen‐Orr, Z., Levin, M., & Hochberg, Z. (2011) · Pediatric Research · doi:10.1203/pdr.0b013e3182226a0c · Cited by 8
“5 reductase activity was calculated by An/Et, 11-OH-An/11-OH-Et, allo THB/THB, and allo THF/THF where An denotes androsterone; Et, etiocholanalone; 11-OH-An, 11-hydroxyandrosterone; 11-OH-Et, 11-hydroxy etiocholanalone; and allo THB, 5 tetrahydrocorticosterone) (34,35).”
Urinary free cortisone, but not cortisol, is associated with urine volume in severe obesity
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Apparent Mineralocorticoid Excess – Update
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Urinary steroid metabolites in a case of florid Ectopic Cushing’s syndrome and clinical correlations
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Decreased cortisol production in male type 1 diabetic patients
Kerstens, M. N., Luik, P. T., van der Kleij, F. G. H., Boonstra, A. H., Breukelman, H., Sluiter, W. J., Navis, G. J., & Dullaart, R. P. F. (2003) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2003.01171.x · Cited by 6
Angiotensin administration stimulates renal 11β-hydroxysteroid dehydrogenase activity in healthy men
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“The ratio of UFF to UFE was used as an index of 11βHSD type 2 activity in viv”
MethodGrowth hormone and cortisol metabolism
Monson, J. P. (1998) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1998.00547.x · Cited by 6
Beentjes, J. (2001) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365510152379003 · Cited by 6
Low Cortisone as a Novel Predictor of the Low-Renin Phenotype
Tapia-Castillo, A., Carvajal, C. A., Pérez, J. A., Sandoval, A., Allende, F. A., Solari, S., & Fardella, C. (2024) · Journal of the Endocrine Society · doi:10.1210/jendso/bvae051 · Cited by 5
“…global population serum cortisone is associated with age (r = − 0.3; P < .0001), but not cortisol or F/E. Similar to observations by Palermo et al [33], reduced 11 β HSD2 activity correlates with decreased urinary excretion of free cortisone rather than increased urinary free cortisol excretion…”
ResultInfluentialDesenvolvimento e caracterização de método para a dosagem de cortisol livre urinário
Vieira, J. G. H., Noguti, K. O., Rayol, M. D. P., & Maciel, R. M. B. (2000) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302000000300008 · Cited by 5
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“Gas chromatography–mass spectrometry (GC–MS) based techniques have been extensively used for the determination of cortisol and its metabolites (Palermo et al. 1996; Furuta et al. 2000; Kasuya, Shibasaki, and Furuta 2000; Choi et al. 2002; Cooper et al. 2003; Tiosano et al. 2003; Casals et al.…”
MethodBertholf, R. L., Jialal, I., & Winter, W. E. (2012) · Tietz Textbook of Clinical Chemistry and Molecular Diagnostics · doi:10.1016/b978-1-4160-6164-9.00054-8 · Cited by 5
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Self-citationBianzano, S., Schepers, C., Wolff, M., et al. (2022) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1932-3136 · Cited by 4
“The Author(s) (aTHF + THF)/THE ratio is still a relevant non-invasive indirect measure of 11beta-HSD1 enzyme inhibition in the liver [18].”
Ramchandran, R., Verma, S., Dasgupta, R., & Thomas, N. (2018) · BMJ Case Reports · doi:10.1136/bcr-2018-225686 · Cited by 3
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Urinary Steroid Excretion Rates in Acromegaly
Vierhapper, H., Nowotny, P., & Waldhäusl, W. K. (2005) · Hormone Research in Paediatrics · doi:10.1159/000085840 · Cited by 4
Gómez, C., Alimajstorovic, Z., Othonos, N., Winter, D. V., White, S. J., Lavery, G. G., Tomlinson, J., Sinclair, A. J., & Odermatt, A. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16251 · Cited by 3
“This ratio is also influenced by 11 β -HSD2 that converts cortisol to cortisone, mainly in the kidney and the colon, exemplified by the highly elevated ( α THF + THF)/THE ratio in urines from patients with genetic defects in 11 β -HSD2 (Odermatt et al., 2001; Palermo et al., 1996; Shackleton, 1993).”
BackgroundSystematic approach to the diagnosis and management of endocrine hypertension
Stowasser, M., Jansen, P. M., & Wolley, M. J. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-96120-2.00009-1 · Cited by 4
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Kerstens, M. (2004) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2003.11.008 · Cited by 3
Physiologie et exploration des sécrétions de cortisol et d'androgènes par la surrénale
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“Second, urine steroid profiling was measured by liquid chromatography-tandem mass spectrometry high-resolution accurate mass to calculate the urinary (THF + allo-THF)/ THE ratio, in historical data, steroids and metabolites were measured by gas chromatography/mass spectrometry [11].”
BackgroundMethodInfluentialKufukihara, R., Takeda, T., Hakozaki, K., Yasumizu, Y., Tanaka, N., Matsumoto, K., Morita, S., Kosaka, T., Mizuno, R., 浅沼, 宏., et al. (2022) · International Journal of Urology · doi:10.1111/iju.15007 · Cited by 2
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Carey, R. M., & Padia, S. H. (2010) · Elsevier eBooks · doi:10.1016/b978-1-4160-5583-9.00107-6 · Cited by 1
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Hypertension With Hypokalemia: A Quiz
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“1) and results in a urinary cortisone to cortisol ratio of 2:1.(2) Careful history was taken to rule out consumption of licorice products, such as in some chewing tobacco, and antifungal drugs.”
BackgroundApparent Mineralocorticoid Excess
Carvajal, C. A., Tapia-Castillo, A., Uslar, T., & Fardella, C. (2023) · Endocrinology · doi:10.1007/978-3-031-27119-9_11 · Cited by 1
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“7% for the cortisol / cortisone-ratio (normal ranges determined by isotope-dilution GC-MS [13] are <100 nmol/24h for cortisol, and <170 nmol/24h for cortisone (mean +2xSD); own results in healthy volunteers (n=7): cortisol 34-87 nmol/24h; cortisone 70-153 nmol/24h).”
BackgroundInfluentialDoes a reduced 11betaHSD type 2 activity contribute to sodium retention in the nephrotic syndrome?
Kerstens, M. N. (2003) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/18.3.620 · Cited by 1
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“This enabled us to estimate the activity of 11-1i-HSD2, given as urinary cortisol and cortisone ratio [14].”
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Author’s Response: In Vivo Measurements of Renal 11β-Hydroxysteroid Dehydrogenase Type 2 Activity
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Corticosteroids in advanced cancer : Epidemiology, symptom relief and patient experiences
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revisão Apparent Mineralocorticoid Excess Syndrome: An Overview
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Title of dissertation: HIGH SUCROSE, FRUCTOSE, AND GLUCOSE DIETS AND GLUCOCORTICOID DYSREGULATION IN
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“In adults, the urinary (allo-THF + THF)/THE (F/E) ratio and 11βHSD type 2 activity were inversely proportional, implying that the higher the F/E ratio, the lower the 11βHSD type 2 activity [3,4].”
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Metadata
- 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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