SFEIES24 Poster Presentations Adrenal & Cardiovascular (40 abstracts)
Impaired 11β-hydroxysteroid dehydrogenase type 2 activity in chronic kidney disease disrupts 11-oxygenated androgen biosynthesis
Maria Tomkins 1,2 , Tara McDonnell 1,2 , Leanne Cussen 1,2 , Michael S. Sagmeister 3 , Imken Oestlund 4 , Fozia Shaheen 3 , Lorraine Harper 5 , Rowan S. Hardy 3 , Angela E. Taylor 3 , Lorna C. Gilligan 3 , Wiebke Arlt 3,6,7 , Marie McIlroy 1 , Declan de Freitas 8 , Peter Conlon 8 , Colm Magee 8 , Mark Denton 8 , Conall O’Seaghdha 8 , Jacky L. Snoep 4,9 , Karl-Heinz Storbeck 4 , Mark Sherlock 1,2 & Michael W. O’Reilly 1,2
1Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Royal College of Surgeons in Ireland, Dublin, Ireland; 2Department of Endocrinology, Beaumont Hospital, Dublin, Ireland; 3Steroid Metabolome Analaysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom; 4Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa; 5Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; 6Medical Research Council Laboratory of Medical Sciences, London, United Kingdom; 7Institute of Clinical Sciences, Imperial College London, London, United Kingdom; 8Department of Nephrology, Beaumont Hospital, Dublin, Ireland; 9Molecular Cell Biology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
In vitro data highlight a potential role for 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11β-hydroxyandrostenedione (11OHA4) 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. In this cross-sectional multicentre cohort study of patients with CKD and healthy controls, serum concentrations of 11-oxygenated androgens, classic androgens and glucocorticoids were measured by tandem mass spectrometry. Cortisol (F)/cortisone (E) ratios, validated surrogate markers of HSD11B2 activity, were calculated. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant. We included 85 patients with CKD [65% male, median age 64 years, median eGFR 22ml/min] and 56 healthy controls [11% male, median age 34 years, median eGFR 103ml/min]. HSD11B2 activity declined with eGFR, with higher F/E ratios in CKD patients than controls [serum F/E 10.7 vs 5.8; urinary F/E 0.8 vs 0.6 (P < 0.01)]. Serum concentrations of E, 11KA4, 11KT and 11β-hydroxytestosterone (11OHT) were significantly lower in patients with CKD compared to controls (P < 0.01 for each). Patients with CKD had an increased ratio of 11OHA4/(11KA4+11KT+11OHT), reflective of reduced HSD11B2-mediated activation of 11-oxygenated androgens. A computational model based on enzyme kinetic parameters of HSD11B2, 11β-hydroxysteroid dehydrogenase type 1, 17β-hydroxysteroid dehydrogenase type 2 and aldoketoreductase 1C3 accurately predicted HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR. This is the first in vivo study to confirm a central role for renal HSD11B2 in the peripheral activation of 11-oxygenated androgens. Further research is required to determine the clinical implications of this observation for patients with CKD.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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