Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Kidney Disease Disrupts 11-Oxygenated Androgen Biosynthesis.

Leanne Cussen, Mark Denton, Colm Magee, Imken Oestlund, Michael S Sagmeister, Michael W O'Reilly, Wiebke Arlt, Karl-Heinz Storbeck, Mark Sherlock, Marie McIlroy, Fozia Shaheen, Rowan S Hardy, Angela E Taylor, Tara McDonnell, Lorna C Gilligan, Lorraine Harper, Jacky L Snoep, Declan de Freitas, Peter Conlon, Conall O'Seaghdha, Maria Tomkins

Journal: The Journal of clinical endocrinology and metabolism 2025;110(6):1701-1715

PMID: 39382395

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Abstract

CONTEXT

11-Oxygenated androgens are a group of adrenal-derived steroids that require peripheral activation. In vitro data highlight a putative role for 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11β-hydroxyandrostenedione to 11-ketoandrostenedione (11KA4), the direct precursor of the potent androgen 11-ketotestosterone (11KT). As the kidney is the major site of HSD11B2 expression, we hypothesized that patients with chronic kidney disease (CKD) would have reduced 11-oxygenated androgen biosynthesis due to impaired HSD11B2 activity.

OBJECTIVE

To determine the role of HSD11B2 in 11-oxygenated androgen biosynthesis using a human CKD cohort alongside complementary cell culture and computational modeling approaches.

METHODS

Cross-sectional observational study of patients with CKD (n = 85) and healthy controls (n = 46) measuring serum and urinary concentrations of glucocorticoids, and classic and 11-oxygenated androgens by liquid chromatography tandem mass spectrometry. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant.

RESULTS

HSD11B2 activity declined with estimated glomerular filtration rate (eGFR), evidenced by higher cortisol/cortisone (E) ratios in patients with CKD than in controls (P < .0001). Serum concentrations of E, 11KA4, 11KT, and 11β-hydroxytestosterone were lower in patients with CKD than in controls (P < .0001 for each). A computational model based on enzyme kinetic parameters of HSD11B2, 11β-hydroxysteroid dehydrogenase type 1, 17β-hydroxysteroid dehydrogenase type 2, and aldo-keto reductase 1C3 confirmed HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR.

CONCLUSION

This is the first in vivo study to confirm a central role for renal HSD11B2 in 11-oxygenated androgen biosynthesis. Determining the clinical implications of this observation for patients with CKD requires further research.

Address: Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland.; Department of Endocrinology, Beaumont Hospital, Dublin, D09 V2N0, Ireland.; Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK.; Department of Nephrology, Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK.; Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa.; Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK.; Department of Nephrology, Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK.; Institute of Clinical Sciences, University of Birmingham, Birmingham, B15 2TT, UK.; Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK.; Medical Research Council Laboratory of Medical Sciences, London, W12 0HS, UK.; Institute of Clinical Sciences, Imperial College London, London, SW7 2AZ, UK.; Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland.; Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland.; Department of Nephrology, Beaumont Hospital/RCSI, Dublin, D09 V2N0, Ireland.; Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa.; Molecular Cell Biology, Vrije Universiteit Amsterdam, Amsterdam, 1081 HV, The Netherlands.; Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa.; Medical Research Council Laboratory of Medical Sciences, London, W12 0HS, UK.

DOI: 10.1210/clinem/dgae714

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MeSH Terms: Humans, Male, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Cross-Sectional Studies, Middle Aged, Female, Androgens, Aged, Renal Insufficiency, Chronic, Testosterone, Adult, Androstenedione, Case-Control Studies