ESPEYB25 14. The Year in Science and Medicine Metabolomics, Steroidomics (5 abstracts)
14.16. Impaired 11[beta]-hydroxysteroid dehydrogenase type 2 activity in kidney disease disrupts 11-oxygenated androgen biosynthesis
Maria Tomkins , Tara McDonnell , Leanne Cussen , Michael S Sagmeister , Imken Oestlund , Fozia Shaheen , Lorraine Harper , Rowan S Hardy , Angela E Taylor , Lorna C Gilligan , Wiebke Arlt , Marie McIlroy , Declan de Freitas , Peter Conlon , Colm Magee , Mark Denton , Conall O’Seaghdha , Jacky L Snoep , Karl-Heinz Storbeck , Mark Sherlock & Michael W O’Reilly
The Journal of Clinical Endocrinology & Metabolism. 110, 1701–1715 (2025) doi: 10.1210/clinem/dgae714
Brief Summary: This study demonstrates that chronic kidney disease (CKD) impairs the activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), which is essential for the biosynthesis of active 11-oxygenated androgens. Using a combination of clinical data (e.g. cross-sectional, observational study of serum and urinary steroid profiles of 85 patients and 46 healthy controls), enzyme kinetics, and computational modeling, the authors show that reduced HSD11B2 activity in CKD leads to decreased conversion of 11β-hydroxyandrostenedione (11OHA4) to its active metabolites, including 11-ketotestosterone (11KT).
This is the first in vivo study to confirm the critical role of renal HSD11B2 in the biosynthesis of 11-oxygenated androgens, a class of potent androgens increasingly recognized for their role in health and disease. Estimated HSD11B2 expression was positively correlated with estimated glomerular filtration rate and could be clustered based on the disease stage. In addition, the relative contribution of 11OHA4 to the total circulating 11-oxygenated androgen pool increased with progression of CKD disease stage, indicating a build-up of precursor due to impaired HSD11B2 activity. These findings confirm that the kidney is a major site of HSD11B2 expression and activity. The decrease in circulating 11-oxygenated androgens might play a role in the progression of CKD and should be investigated in the future. The computational model developed could be used to monitor disease progression or predict endocrine outcomes in CKD.
In a broader context, the study establishes a novel link between kidney function and peripheral androgen metabolism. It suggests that 11-oxygenated androgen deficiency may contribute to CKD-associated conditions such as anemia, sarcopenia, and frailty.
Study limitations include a) age and sex differences between CKD and control groups, b) urinary steroid measurements may be less reliable in advanced CKD due to altered renal excretion, c) cross-sectional study design limits causal inference regarding androgen deficiency and clinical outcomes.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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