title: Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man.
abstract: BACKGROUND
  5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified.
  
  
  OBJECTIVE
  Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism.
  
  
  METHODS
  We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3-week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry.
  
  
  METHODS
  The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom.
  
  
  METHODS
  Incorporation of hepatic lipid was measured with MRS.
  
  
  RESULTS
  Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism.
  
  
  CONCLUSIONS
  Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Hazlehurst
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Oprescu
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Nikolaou
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Di Guida
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Annabel E K
authors.initials: AE
authors.lastname: Grinbergs
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Davies
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Flintham
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Armstrong
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Taylor
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Hughes
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Jinglei
authors.initials: J
authors.lastname: Yu
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Leanne
authors.initials: L
authors.lastname: Hodson
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Warwick B
authors.initials: WB
authors.lastname: Dunn
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.M.H., N.N., L.H., J.W.T.), National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, United Kingdom; Centre for Diabetes, Endocrinology, and Metabolism (A.I.O., A.E.T., B.A.H.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, School of Biosciences and Regional Phenome Centre (R.D.G., W.B.D.), Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit (M.J.A.), and School of Sports and Exercise Sciences (J.Y.), University of Birmingham, Birmingham B15 2TH, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility (A.E.K.G.), Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom; and Department of Medical Physics (N.P.D., R.B.F.), Queen Elizabeth Hospital, Birmingham B15 2GW, United Kingdom.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D050260:Carbohydrate Metabolism / Q000187:drug effects; D000068538:Dutasteride / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D055442:Metabolome / Q000187:drug effects; D013256:Steroids / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D008565:Membrane Proteins; D013256:Steroids; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548467:SRD5A1 protein, human; C548468:SRD5A2 protein, human; D000068538:Dutasteride