Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man

Jonathan M Hazlehurst, Andrei I Oprescu, Nikolaos Nikolaou, Riccardo Di Guida, Annabel E K Grinbergs, Nigel P Davies, Robert B Flintham, Matthew J Armstrong, Angela E Taylor, Beverly A Hughes, Jinglei Yu, Leanne Hodson, Warwick B Dunn, Jeremy W Tomlinson

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

CONTEXT: 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.

DESIGN: 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.

SETTING: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom.

MAIN OUTCOME MEASURE: 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.

Original languageEnglish
Pages (from-to)103-113
Number of pages11
JournalThe Journal of clinical endocrinology and metabolism
Volume101
Issue number1
Early online date17 Nov 2015
DOIs
Publication statusPublished - Jan 2016

Fingerprint

Dive into the research topics of 'Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man'. Together they form a unique fingerprint.

Cite this