Cited by 276Hormonal Regulation and HypertensionAdrenal Hormones and DisordersStress Responses and Cortisol

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Urinary free cortisone and the assessment of 11β‐hydroxysteroid dehydrogenase activity in man

Palermo, Mario, Shackleton, Cedric H. L., Mantero, Franco, Stewart, Paul M.·1996·Clinical Endocrinology

DOI 10.1046/j.1365-2265.1996.00853.x

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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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Li, C., Zhang, Z., Liu, X., et al. (2017) · Journal of Chromatography B · doi:10.1016/j.jchromb.2017.07.012 · Cited by 14
Novel methods in adrenal research: a metabolomics approach
Papathomas, T. G., Sun, N., Chortis, V., Taylor, A. E., Arlt, W., Richter, S., Eisenhofer, G., Ruiz-Babot, G., Guasti, L., & Walch, A. K. (2019) · Histochemistry and Cell Biology · doi:10.1007/s00418-019-01772-w · Cited by 14
Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo
Nikolaou, N., Arvaniti, A., Appanna, N., Sharp, A., Hughes, B. A., Digweed, D., Whitaker, M. J., Ross, R. J. M., Arlt, W., Penning, T. M., et al. (2020) · Journal of Endocrinology · doi:10.1530/joe-19-0473 · Cited by 13
Can 11β-Hydroxysteroid Dehydrogenase Activity Predict the Sensitivity of Bone to Therapeutic Glucocorticoids in Inflammatory Bowel Disease?
Cooper, M. S., Kriel, M. H., Sayers, A. E., Fraser, W. D., Williams, A. M., Stewart, P. M., Probert, C. S., & Tobias, J. H. (2011) · Calcified Tissue International · doi:10.1007/s00223-011-9512-2 · Cited by 14
Self-citation
Dosagem de cortisol e cortisona livres urinários empregando cromatografia líquida associada a espectrometria de massa em tandem (LC-MS/MS)
Vieira, J. G. H., Nakamura, O. H., & Carvalho, V. M. (2005) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302005000200017 · Cited by 14
First in human randomised trial of J2H ‐1702: A novel 11β‐hydroxysteroid dehydrogenase type 1 inhibitor for non‐alcoholic steatohepatitis treatment
Kim, Y., Lee, S. W., & Lee, S. W. (2023) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.17726 · Cited by 13
“27 Our results demonstrated that J2H-1702 successfully inhibited the 11 β - HSD1 activity in the liver and the effect was long-lasting.”
BackgroundResult
LC-HRMS and GC-MS Profiling of Urine Free Cortisol, Cortisone, 6Β-, and 18-Hydroxycortisol for the Evaluation of Glucocorticoid and Mineralocorticoid Disorders
Casals, G., Vizoso, M. A. B., Zamora, A., Martínez, I., Fernández‐Varo, G., Mora, M., Hanzu, F. A., & Morales‐Ruiz, M. (2024) · Biomolecules · doi:10.3390/biom14050558 · Cited by 15
“A GC-MS method was also validated for measurement of the same steroids, and significant interference from 6 β -hydroxycortisol and cortisone was demonstrated in cortisol immunoassays, which may impact their reliability for monitoring in hypercortisolism medical therapies.”
Method
Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384
Katz, D. A., Liu, W., Locke, C., et al. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.67 · Cited by 13
Differential glucocorticoid metabolism in patients with persistent versus resolving inflammatory arthritis
Nanus, D. E., Filer, A. D., Yeo, L., Scheel‐Toellner, D., Hardy, R., Lavery, G. G., Stewart, P. M., Buckley, C. D., Tomlinson, J., Cooper, M. S., et al. (2015) · Arthritis Research & Therapy · doi:10.1186/s13075-015-0633-2 · Cited by 13
“Measurement of urinary corticosteroid metabolites Urinary corticosteroid metabolite levels were measured by gas chromatography/mass spectrometry (GC/MS) using a 5970 mass spectrometer (Hewlett-Packard, Houston, TX, USA) and a previously described method [10].”
MethodSelf-citation
A Semi-Physiologically Based Pharmacokinetic Pharmacodynamic Model for Glycyrrhizin-Induced Pseudoaldosteronism and Prediction of the Dose Limit Causing Hypokalemia in a Virtual Elderly Population
Xu, R., Liu, X., & Yang, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114049 · Cited by 13
“The observed value [50] is expressed as mean (SD).”
Background
Regulation of 11β-hydroxysteroid dehydrogenase 1 and 2 by IGF-1 in mice
Huang, Y., Li, X., Lin, H., Chu, Y., Chen, B., Lian, Q., & Ge, R. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.12.148 · Cited by 13
Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity
Bianzano, S., Heise, T., Jungnik, A., et al. (2021) · Clinical Diabetes and Endocrinology · doi:10.1186/s40842-021-00130-x · Cited by 12
The effects of piper sarmentosum water extract on the expression and activity of 11β-hydroxysteroid dehydrogenase type 1 in the bones with excessive glucocorticoids.
Ramli, E. S. M., Soelaiman, I. N., Othman, F. B., Ahmad, F., Shuib, A. N., Mohamed, N., Muhammad, N., & Suhaimi, F. H. (2012) · Europe PMC (PubMed Central) · Cited by 12
Increased central adiposity and decreased subcutaneous adipose tissue 11β‐hydroxysteroid dehydrogenase type 1 are associated with deterioration in glucose tolerance—A longitudinal cohort study
Crowley, R. K., Woods, C. P., Hughes, B. A., Gray, J., McCarthy, T., TAYLOR, A. E. R., Gathercole, L., Shackleton, C. H. L., Crabtree, N. J., Arlt, W., et al. (2019) · Clinical Endocrinology · doi:10.1111/cen.13939 · Cited by 13
Self-citation
In vivo activity of 11β‐hydroxysteroid dehydrogenase type 1 and free fatty acid‐induced insulin resistance
Mai, K., Kullmann, V., Bobbert, T., Maser‐Gluth, C., Möhlig, M., Bähr, V., Pfeiffer, A. F. H., Spranger, J., & Diederich, S. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02362.x · Cited by 12
No evidence of a relation between 11β-hydroxysteroid dehydrogenasetype 2 activity and salt sensitivity
Melander, O. (2003) · American Journal of Hypertension · doi:10.1016/s0895-7061(03)00981-6 · Cited by 12
GH effect on enzyme activity of 11βHSD in abdominal obesity is dependent on treatment duration
Sigurjónsdóttir, H. Á., Koranyi, J., Axelson, M., et al. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.02061 · Cited by 12
Salivary Cortisol and Cortisone Can Circumvent Confounding Effects of Oral Contraceptives in the Short Synacthen Test
Bäcklund, N., Lundstedt, S., Tornevi, A., Wihlbäck, A.-C., Olsson, T., Dahlqvist, P., & Brattsand, G. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad763 · Cited by 13
“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 11 β -HSD2 in the salivary glands (23, 47).”
Result
Role of Ketoconazole Treatment in Urinary-Free Cortisol-to-Cortisone and Tetrahydrocortisol-to-Tetrahydrocortisone Ratios in Nonectopic Cushing's Syndrome
Stiefel, P., Morillo, J. S. G., Jimenez, L., Pamies, E., Miranda, M. L., Ruiz, J. C., Villar, J. R., & Leal‐Cerro, A. (2002) · Endocrine · doi:10.1385/endo:18:3:279 · Cited by 9
Effect of AZD4017, a Selective 11β-HSD1 Inhibitor, on Bone Turnover Markers in Postmenopausal Osteopenia
Abbas, A., Schini, M., Ainsworth, G., Brown, S., Oughton, J. B., Crowley, R. K., Cooper, M. S., Fairclough, R. J., Eastell, R., & Stewart, P. M. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac100 · Cited by 11
Self-citation
Relationship between left ventricular mass index and 24-h urinary free cortisol and cortisone in essential arterial hypertension
Duprez, D. A., Buyzere, M. D., PAELINCK, M., Rubens, R., Dhooge, W., & Clement, D. L. (1999) · Journal of Hypertension · doi:10.1097/00004872-199917110-00012 · Cited by 11
Toxicités de l’exposition alimentaire à la réglisse : mise au point
Caré, W., Grenet, G., Schmitt, C., Michel, S., Langrand, J., Roux, G. L., & Vodovar, D. (2023) · La Revue de Médecine Interne · doi:10.1016/j.revmed.2023.03.004 · Cited by 11
Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats
Lauterburg, M., Escher, G., Dick, B., et al. (2012) · Journal of Endocrinology · doi:10.1530/joe-12-0200 · Cited by 10
Gitelman's syndrome with persistent hypokalemia - don't forget licorice, alcohol, lemon juice, iced tea and salt depletion: a case report
Knobel, U., Modarres, G., Schneemann, M., & Schmid, C. (2011) · Journal of Medical Case Reports · doi:10.1186/1752-1947-5-312 · Cited by 10
“The atypical constellation of a free cortisone level lower than the free cortisol level (reduced 11b-hydroxysteroid dehydrogenase activity) should raise clinical suspicions of pseudohyperaldosteronism [3].”
Background
Use of 11α-deuterium labeled cortisol as a tracer for assessing reduced 11β-HSD2 activity in vivo following glycyrrhetinic acid ingestion in a human subject
Kasuya, Y., Yokokawa, A., Takashima, S., Shibasaki, H., & Furuta, T. (2005) · Steroids · doi:10.1016/j.steroids.2004.10.006 · Cited by 10
11-Beta Dehydrogenase Type 2 Activity Is Not Reduced in Treatment Resistant Hypertension
Ghazi, L., Dudenbostel, T., Hachem, M. E., Siddiqui, M., Lin, C. P., Oparil, S., & Calhoun, D. A. (2017) · American Journal of Hypertension · doi:10.1093/ajh/hpx002 · Cited by 10
Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig
Quinkler, M. O., Troeger, H., Eigendorff, E., Maser‐Gluth, C., Stiglic, A., Oelkers, W., Bähr, V., & Diederich, S. (2003) · Journal of Endocrinology · doi:10.1677/joe.0.1760185 · Cited by 10
“We rather interpret this ratio as a marker for hepatic 11 -HSD-1 activity (Palermo et al. 1996, Quinkler et al. 2000).”
Background
Effect of Pomegranate Extract Consumption on Cardiovascular Disease RiskFactors, Stress Hormones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
Stockton, A. V. E., Al‐Dujaili, E. A. S., McDougall, G. J., Davidson, I., Drummond, S., & Wyness, L. (2015) · Queen Margaret University Publications Repository (Queen Margaret University) · Cited by 10
Raised urinary glucocorticoid and adrenal androgen precursors in the urine of young hypertensive patients: possible evidence for partial glucocorticoid resistance
Shamim, W. (2001) · Heart · doi:10.1136/heart.86.2.139 · Cited by 10
The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy
Dineen, R., Behan, L., Kelleher, G., Hannon, M. J., Brady, J. J., Rogers, B., Keevil, B. G., Tormey, W. P., Smith, D., Thompson, C. J., et al. (2020) · BMC Endocrine Disorders · doi:10.1186/s12902-020-00633-1 · Cited by 9
Self-citation
Decoding Monogenic Hypertension: A Review of Rare Hypertension Disorders
Gallegos, F. R., Delahunty, M., Hu, J., Yerigeri, S., Dev, V., Bhatt, G., & Raina, R. (2025) · American Journal of Hypertension · doi:10.1093/ajh/hpaf005 · Cited by 12
Altered cortisol metabolism in individuals with HNF1A‐MODY
Juszczak, A., Gilligan, L. C., Hughes, B. A., Hassan-Smith, Z. K., McCarthy, M. I., Arlt, W., Tomlinson, J., & Owen, K. R. (2020) · Clinical Endocrinology · doi:10.1111/cen.14218 · Cited by 9
The effect of water loading on the urinary ratio of cortisone to cortisol in healthy subjects and a new approach to the evaluation of the ratio as an index for in vivo human 11β-hydroxysteroid dehydrogenase 2 activity
Yokokawa, A., Takasaka, T., Shibasaki, H., Kasuya, Y., Kawashima, S., Yamada, A., & Furuta, T. (2012) · Steroids · doi:10.1016/j.steroids.2012.07.008 · Cited by 8

Authors: Palermo, M., Shackleton, C. H. L., Mantero, F., & Stewart, P. M.
Affiliations: Queen Elizabeth Hospital Birmingham (GB)
Corresponding author: Stewart, Paul M.
ORCID: Mantero, Franco
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
DOI: 10.1046/j.1365-2265.1996.00853.x
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 2553 d)
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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Urinary free cortisone and the assessment of 11β‐hydroxysteroid dehydrogenase activity in man

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