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Endocrine Abstracts (2015) 38 OC2.1 | DOI: 10.1530/endoabs.38.OC2.1

1Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; 2Centre for Diabetes, Endocrinology and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK; 3School of Biosciences and Regional Phenome Centre, University of Birmingham, Birmingham, UK; 4NIHR/Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, UK; 5Medical Physics, Queen Elizabeth Hospital, Birmingham, UK; 6Centre for Liver Research and NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK; 7School of Sports and Exercise Sciences, University of Birmingham, Birmingham, UK.


Background and aims: 5α reductase 1 and 2 (SRD5A1 (expressed in liver and adipose), SRD5A2 (expressed in liver) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of dihydrotestosterone and therefore regulate the tissue availability of cortisol. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and Finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified. Our principle objective is to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact upon hepatic lipid metabolism and the serum metabolome.

Methods: We conducted a randomised study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after 3-weeks treatment with Finasteride (5 mg od) or Dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) to evaluate intrahepatic lipid and 2-step-hyperinsulinaemic euglycaemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate tissue-specific carbohydrate and lipid flux. In addition, analysis of the serum metabolome was performed using ultra high performance liquid chromatography-mass spectrometry.

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 mobilisation was decreased by Dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, Dutasteride had a significant effect on the metabolome with significant changes in 123 metabolites (compared to 11 by Finasteride) in particular there were markedly increased glycerophospholipids. Finasteride and Dutasteride blunted the effects of insulin on the serum metabolome.

Conclusions: SRD5A has an important role in lipid regulation and dual SRD5A inhibition with Dutasteride is metabolically disadvantageous by direct effects on the liver and adipose tissue. These changes to the lipid profile with dual SRD5A inhibition promotes hepatic lipid accumulation an established precursor to more serious liver disease.

Volume 38

Society for Endocrinology BES 2015

Edinburgh, UK
02 Nov 2015 - 04 Nov 2015

Society for Endocrinology 

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