ECE2015 Guided Posters Steroids (9 abstracts)
Dual 5α-reductase inhibition causes hepatic lipid accumulation in man
Jonathan Hazlehurst 1 , Andrei Oprescu 2 , Nikolaos Nikolaou 1 , Annabel Grinbergs 3 , Nigel Davies 4 , Robert Flintham 4 , Beverley Hughes 2 , Angela Taylor 2 , Jinglei Yu 5 , Anton Wagenmakers 5 & Jeremy Tomlinson 1
1OCDEM, University of Oxford, Oxford, UK; 2CEDAM, University of Birmingham, Birmingham, UK; 3NIHR/Wellcome Trust Research Facility, University Hospitals Birmingham, Birmingham, UK; 4MRI Physics, University Hospitals Birmingham, Birmingham, UK; 5School of Sport and Exercise Science, University of Birmingham, Birmingham, UK.
5α reductases 1 and 2 (SRD5A1 and SRD5A2) metabolise cortisol into inactive 5α-dihydrocortisol contributing to the regulation of cortisol availability in addition to their established role in the generation of dihydrotestosterone from testosterone. Dutasteride and finasteride are commonly prescribed to patients with benign prostatic hyperplasia but their potential metabolic effects have only recently been identified. Dutasteride inhibits both SRD5A1and SRD5A2 whilst finasteride inhibits SRD5A2 alone. Importantly, mice with deletion of SRD5A1 are more susceptible to hepatic steatosis and fibrosis. We conducted a randomised, double-blind study in 12 healthy male volunteers (age 36.3±4.4 years, BMI (kg/m2) 26.6±1.2). Volunteers underwent hepatic magnetic resonance spectroscopy to evaluate intrahepatic lipid content and a series of detailed metabolic assessments including adipose microdialysis and a hyperinsulinaemic–euglycaemic clamp incorporating stable isotopes to measure lipogenesis and glucose handling. Subjects were then randomised to receive either finasteride (5 mg OD) or dutasteride (0.5 mg OD) for 21 days then all investigations were repeated. Dutasteride, not finasteride increased hepatic glucose output (EGP (mg/kg per min) D: 0.609±0.07, 0.924±0.14, P=0.046; F: 0.711±0.12, 0.539±0.08, P=0.19). Neither, impacted peripheral glucose disposal. Adipose tissue interstitial release of glycerol was decreased by dutasteride in the presence of insulin (AUC glycerol (μmol/l) D: 203±30.6, 104.5±22.1, P=0.01; F: 151.02±36.9, 160.7±21.7, P=0.83). Although, dutasteride increased de novo lipogenesis, this did not reach statistical significance. (D: 1.21±0.36, 6.50±2.7%, P=0.14; F: 1.55±0.51, 1.33±0.33%, P=0.64). Intrahepatic lipid increased after dutasteride, but not finasteride treatment (PDFF%: D: 0.88±0.49, 1.15±0.57, P=0.04; F: 3.05±2.24, 3.69±2.84, P=0.36). Furthermore, there was a positive correlation between change in DNL and change in hepatic steatosis in those treated with dutasteride (R2, P<0.01). In conclusion, inhibiting SRD5A1 with dutasteride promotes an adverse metabolic phenotype resulting in increased intrahepatic lipid and endorses previous observations in rodent studies. Further detailed studies are needed in patients prescribed 5α-reductase inhibitor therapy.
Disclosure: This work was supported by the Medical Research Council (Senior Clinical Fellowship G0802765, to J Tomlinson). Additional equipment was provided through Advantage West Midlands Science City.
Volume 37
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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