TY - JOUR
T1 - Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Kidney Disease Disrupts 11-Oxygenated Androgen Biosynthesis
AU - Tomkins, Maria
AU - McDonnell, Tara
AU - Cussen, Leanne
AU - Sagmeister, Michael S.
AU - Oestlund, Imken
AU - Shaheen, Fozia
AU - Harper, Lorraine
AU - Hardy, Rowan S.
AU - Taylor, Angela E.
AU - Gilligan, Lorna C.
AU - Arlt, Wiebke
AU - McIlroy, Marie
AU - De Freitas, Declan
AU - Conlon, Peter
AU - Magee, Colm
AU - Denton, Mark
AU - O'Seaghdha, Conall
AU - Snoep, Jacky L.
AU - Storbeck, Karl Heinz
AU - Sherlock, Mark
AU - O'Reilly, Michael W.
N1 - Publisher Copyright:
© 2024 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2025/6
Y1 - 2025/6
N2 - 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.
AB - 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.
KW - 11-oxygenated androgens
KW - 11β-hydroxysteroid dehydrogenase type 2
KW - chronic kidney disease
KW - steroid biosynthesis
UR - https://www.scopus.com/pages/publications/105005731007
UR - https://www.scopus.com/inward/citedby.url?scp=105005731007&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgae714
DO - 10.1210/clinem/dgae714
M3 - Article
C2 - 39382395
AN - SCOPUS:105005731007
SN - 0021-972X
VL - 110
SP - 1701
EP - 1715
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 6
ER -