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

doi:10.1210/jc.2015-2928

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 journal › Article › peer-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 language	English
Pages (from-to)	103-113
Number of pages	11
Journal	The Journal of clinical endocrinology and metabolism
Volume	101
Issue number	1
Early online date	17 Nov 2015
DOIs	https://doi.org/10.1210/jc.2015-2928
Publication status	Published - Jan 2016

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10.1210/jc.2015-2928

Glucocorticoid Metabolism and the Control of Metabolic Phenotype
Tomlinson, J.
Medical Research Council
1/10/09 → 30/09/14
Project: Research Councils

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Hazlehurst, J. M., Oprescu, A. I., Nikolaou, N., Di Guida, R., Grinbergs, A. E. K., Davies, N. P., Flintham, R. B., Armstrong, M. J., Taylor, A. E., Hughes, B. A., Yu, J., Hodson, L., Dunn, W. B., & Tomlinson, J. W. (2016). Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man. The Journal of clinical endocrinology and metabolism, 101(1), 103-113. https://doi.org/10.1210/jc.2015-2928

@article{d269b4f8913840c996b821d708b8d4a3,

title = "Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man",

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.",

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

year = "2016",

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doi = "10.1210/jc.2015-2928",

language = "English",

volume = "101",

pages = "103--113",

journal = "The Journal of clinical endocrinology and metabolism",

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publisher = "Endocrine Society",

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Hazlehurst, JM, Oprescu, AI, Nikolaou, N, Di Guida, R, Grinbergs, AEK, Davies, NP, Flintham, RB, Armstrong, MJ, Taylor, AE, Hughes, BA, Yu, J, Hodson, L, Dunn, WB & Tomlinson, JW 2016, 'Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man', The Journal of clinical endocrinology and metabolism, vol. 101, no. 1, pp. 103-113. https://doi.org/10.1210/jc.2015-2928

TY - JOUR

T1 - Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man

AU - Hazlehurst, Jonathan M

AU - Oprescu, Andrei I

AU - Nikolaou, Nikolaos

AU - Di Guida, Riccardo

AU - Grinbergs, Annabel E K

AU - Davies, Nigel P

AU - Flintham, Robert B

AU - Armstrong, Matthew J

AU - Taylor, Angela E

AU - Hughes, Beverly A

AU - Yu, Jinglei

AU - Hodson, Leanne

AU - Dunn, Warwick B

AU - Tomlinson, Jeremy W

PY - 2016/1

Y1 - 2016/1

N2 - 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.

AB - 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.

U2 - 10.1210/jc.2015-2928

DO - 10.1210/jc.2015-2928

M3 - Article

C2 - 26574953

SN - 0021-972X

VL - 101

SP - 103

EP - 113

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 1

ER -

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

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Glucocorticoid Metabolism and the Control of Metabolic Phenotype

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