Hepatic metabolism of 11-oxygenated androgens in humans: an integrated in vivo and ex vivo approach
Author(s)
Type
Journal Article
Abstract
Objective
Excess production of adrenal-derived 11-oxygenated androgens is observed in congenital adrenal hyperplasia, premature adrenarche, and polycystic ovary syndrome. 11-Ketotestosterone is equipotent to testosterone but does not decline with age. To date, the precise hepatic metabolism of 11-oxygenated androgens and subsequent urinary metabolite excretion have not been characterised.
Design
We employed an integrated approach combining an in vivo oral androgen challenge with an ex vivo normothermic machine liver perfusion (NMLP) model to characterise human hepatic 11-oxygenated androgen metabolism.
Methods
Women with polycystic ovary syndrome were randomised to receive 150 mg of either oral dehydroepiandrosterone or 11-ketoandrostenedione (11KA4) for 7 days (n = 10 for each), with collection of 24-hour urine samples for multi-steroid profiling by liquid chromatography-tandem mass spectrometry pre- and post-intervention. We employed human liver tissue explants (n = 3) alongside a whole human liver NMLP model (n = 3) to characterise ex vivo 11-oxygenated androgen metabolism.
Results
In ex vivo studies, the main metabolites identified were 11β-hydroxyandrosterone and 11β-hydroxyetiocholanolone. In vivo priming of the 11-oxygenated pathway with oral 11KA4 resulted in significant increases of urinary 11β-hydroxyandrosterone, 11β-hydroxyetiocholanolone, and 11-ketoetiocholanolone, all known to overlap with glucocorticoid metabolism. In addition, we observed significant increases in the urinary excretion of 11-ketoandrosterone (11KAn).
Conclusions
Using in vivo and ex vivo approaches, we report the predominance of 11β-hydroxy metabolites, highlighting the pivotal role of hepatic 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) activity in 11-oxygenated androgen metabolism. We identify 11KAn as the only metabolite without overlap with glucocorticoid metabolism, underscoring its specificity and biomarker potential. NMLP represents a novel integrated model to study human hepatic steroid metabolism.
Excess production of adrenal-derived 11-oxygenated androgens is observed in congenital adrenal hyperplasia, premature adrenarche, and polycystic ovary syndrome. 11-Ketotestosterone is equipotent to testosterone but does not decline with age. To date, the precise hepatic metabolism of 11-oxygenated androgens and subsequent urinary metabolite excretion have not been characterised.
Design
We employed an integrated approach combining an in vivo oral androgen challenge with an ex vivo normothermic machine liver perfusion (NMLP) model to characterise human hepatic 11-oxygenated androgen metabolism.
Methods
Women with polycystic ovary syndrome were randomised to receive 150 mg of either oral dehydroepiandrosterone or 11-ketoandrostenedione (11KA4) for 7 days (n = 10 for each), with collection of 24-hour urine samples for multi-steroid profiling by liquid chromatography-tandem mass spectrometry pre- and post-intervention. We employed human liver tissue explants (n = 3) alongside a whole human liver NMLP model (n = 3) to characterise ex vivo 11-oxygenated androgen metabolism.
Results
In ex vivo studies, the main metabolites identified were 11β-hydroxyandrosterone and 11β-hydroxyetiocholanolone. In vivo priming of the 11-oxygenated pathway with oral 11KA4 resulted in significant increases of urinary 11β-hydroxyandrosterone, 11β-hydroxyetiocholanolone, and 11-ketoetiocholanolone, all known to overlap with glucocorticoid metabolism. In addition, we observed significant increases in the urinary excretion of 11-ketoandrosterone (11KAn).
Conclusions
Using in vivo and ex vivo approaches, we report the predominance of 11β-hydroxy metabolites, highlighting the pivotal role of hepatic 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) activity in 11-oxygenated androgen metabolism. We identify 11KAn as the only metabolite without overlap with glucocorticoid metabolism, underscoring its specificity and biomarker potential. NMLP represents a novel integrated model to study human hepatic steroid metabolism.
Date Issued
2025-09-01
Date Acceptance
2025-08-01
Citation
European Journal of Endocrinology (EJE), 2025, 193 (3), pp.340-347
ISSN
0804-4643
Publisher
Oxford University Press
Start Page
340
End Page
347
Journal / Book Title
European Journal of Endocrinology (EJE)
Volume
193
Issue
3
Copyright Statement
© The Author(s) 2025. Published by Oxford University Press on behalf of European Society of Endocrinology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40795393
PII: 8228637
Subjects
11 beta-hydroxysteroid dehydrogenase type 1
11-oxygenated androgens
Endocrinology & Metabolism
hepatic steroid metabolism
Life Sciences & Biomedicine
Science & Technology
steroid biosynthesis
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2025-08-08