ECE2024 Poster Presentations Reproductive and Developmental Endocrinology (45 abstracts)
Renal 11β-hydroxysteroid dehydrogenase type 2 is of central importance for 11-oxygenated androgen biosynthesis and is disrupted in chronic kidney disease
Maria Tomkins 1,2 , Tara McDonnell 1,2 , Leanne Cussen 1,2 , Michael S Sagmeister 3 , Imken Oestlund 4 , Fozia Shaheen 3 , Lorraine Harper 3 , Rowan S Hardy 3 , Angela E Taylor 3 , Lorna C Gilligan 3 , Wiebke Arlt 3,5,6 , Marie McIlroy 1 , Declan de Freitas 7 , Peter Conlon 7 , Colm Magee 7 , Mark Denton 7 , Conall O’Seaghdha 7 , Jacky Snoep 4 , Karl Heinz-Storbeck 4 , Mark Sherlock 1,2 & Michael W O’Reilly 1,2
1Royal College of Surgeons in Ireland, Academic Division of Endocrinology, Department of Medicine, Dublin, Ireland; 2Beaumont Hospital, Department of Endocrinology, Dublin, Ireland; 3University of Birmingham, Institute of Metabolism and Systems Research, United Kingdom; 4Stellenbosch University, Department of Biochemistry, Stellenbosch, South Africa; 5MRC Laboratory of Medical Sciences, London, United Kingdom; 6Institute of Clinical Sciences, Imperial College London, London, United Kingdom; 7Beaumont Hospital, Department of Nephrology, Dublin, Ireland
11-oxygenated androgens are a group of adrenal-derived C19 steroids that require activation in peripheral tissues. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) has been shown in vitro to be essential for 11-oxygenated androgen activation, 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 activation due to impaired renal HSD11B2 activity. In this cross-sectional multicentre cohort study of patients with CKD and healthy controls, serum and urinary multi-steroid profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to measure 11-oxygenated androgens, classic androgens and glucocorticoids. Serum and urinary cortisol/cortisone ratios, previously established as validated surrogate markers of HSD11B2 activity, were calculated. A computational model of peripheral 11-oxygenated biosynthesis was fitted to the serum data and used to calculate relative HSD11B2 expression levels for each patient and control. We performed serum and urinary multi-steroid profiling in 90 patients with CKD [65% male, median age 64 (IQR 52-70) years, median estimated glomerular filtration ratio (eGFR) 23 (IQR 13-39) ml/min] and 56 healthy controls [11% male, median age 34 (IQR 30 – 41) years, median eGFR 103 (IQR 90 – 119) ml/min]. HSD11B2 activity declined with reducing eGFR. Serum concentrations of cortisone, 11KA4, 11KT and 11β-hydroxytestosterone (11OHT) were all significantly lower in patients with CKD compared to controls (P<0.01 for each). There was a strong correlation between eGFR and HSD11B2-dependent steroids in serum [cortisone (r=0.77, P<0.01), 11KA4 (r=0.48, P<0.01), 11OHT (r=0.35, P<0.01) and 11KT (r=0.58, P<0.01)], and urine [cortisone (r=0.59, P<0.01), 11β-hydroxyandrosterone (r=0.32, P<0.01) and 11-oxoandrosterone (r=0.39, P<0.01)]. Significant associations between classic androgens and eGFR were not observed. Patients with CKD had an increased ratio of 11OHA4 /(11KA4 + 11KT + 11OHT), reflective of reduced HSD11B2 activation of 11-oxygenated androgens. This ratio declined significantly across each stage of CKD from III-V (P<0.01). Using a computational model based on enzyme kinetic parameters of 11β-hydroxysteroid dehydrogenase type 1, HSD11B2, 17β-hydroxysteroid dehydrogenase type 2 and aldoketoreductase 1C3, we accurately predicted HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen activation in CKD, with predicted HSD11B2 expression correlated with eGFR. This is the first study to demonstrate impaired 11-oxygenated androgen biosynthesis in patients with CKD. It confirms a central role for renal HSD11B2 in the activation of 11OHA4 to the potent 11-oxygenated androgen 11KT.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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