The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1

Lise Barnard; Nikolaos Nikolaou; Carla Louw; Lina Schiffer; Hylton Gibson; Lorna C. Gilligan; Elena Gangitano; Jacky Snoep; Wiebke Arlt; Jeremy W. Tomlinson; Karl Heinz Storbeck

doi:10.1016/j.sbmb.2020.105724

The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1

Lise Barnard, Nikolaos Nikolaou, Carla Louw, Lina Schiffer, Hylton Gibson, Lorna C. Gilligan, Elena Gangitano, Jacky Snoep, Wiebke Arlt, Jeremy W. Tomlinson, Karl Heinz Storbeck^*

^*Corresponding author for this work

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Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.

Original language	English
Article number	105724
Pages (from-to)	1-10
Number of pages	10
Journal	Journal of Steroid Biochemistry and Molecular Biology
Volume	202
Early online date	3 Jul 2020
DOIs	https://doi.org/10.1016/j.sbmb.2020.105724
Publication status	Published - Sept 2020

Funding

This work was supported by the Wellcome Trust (Investigator Grant WT209492/Z/17/Z , to W.A.), the Academy of Medical Sciences UK (Newton Advanced Fellowship NAF0041002 , to K.-H.S), the National Research Foundation (NRF) of South Africa ( 111622 , to L.B), SARChI DST/NRF grant ( 82813 , to J.S), the European Society of Endocrinology (ESE) (Short-Term Fellowship to E.G), the Medical Research Council, UK (programme grant to J.W.T. MR/P011462/1 ), and the NIHR Oxford Biomedical Research Centre (J.W.T.). W.A. receives support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (Grant Reference Number BRC-1215-20009). The views expressed are those of the author(s) and not necessarily those of the NIHR UK, the Department of Health and Social Care UK or the NRF of South Africa.

Funders	Funder number
Wellcome Trust	WT209492/Z/17/Z
European Society of Endocrinology
University Hospitals Birmingham NHS Foundation Trust
Medical Research Council	MR/P011462/1
National Institute for Health Research
Department of Health and Social Care
Academy of Medical Sciences	NAF0041002
University of Birmingham	BRC-1215-20009
National Research Foundation	111622
Department of Science and Technology, Republic of South Africa	82813
NIHR Oxford Biomedical Research Centre
Birmingham Biomedical Research Centre

Keywords

11-ketoetiocholanolone
11-ketotestosterone
11-oxygenated androgens
steroid 5α-reductase
steroid 5β-reductase
steroid metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.sbmb.2020.105724

https://www.sciencedirect.com/science/article/pii/S0960076020302491

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Barnard, L., Nikolaou, N., Louw, C., Schiffer, L., Gibson, H., Gilligan, L. C., Gangitano, E., Snoep, J., Arlt, W., Tomlinson, J. W., & Storbeck, K. H. (2020). The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1. Journal of Steroid Biochemistry and Molecular Biology, 202, 1-10. Article 105724. https://doi.org/10.1016/j.sbmb.2020.105724

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title = "The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1",

abstract = "Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.",

keywords = "11-ketoetiocholanolone, 11-ketotestosterone, 11-oxygenated androgens, steroid 5α-reductase, steroid 5β-reductase, steroid metabolism",

author = "Lise Barnard and Nikolaos Nikolaou and Carla Louw and Lina Schiffer and Hylton Gibson and Gilligan, {Lorna C.} and Elena Gangitano and Jacky Snoep and Wiebke Arlt and Tomlinson, {Jeremy W.} and Storbeck, {Karl Heinz}",

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doi = "10.1016/j.sbmb.2020.105724",

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Barnard, L, Nikolaou, N, Louw, C, Schiffer, L, Gibson, H, Gilligan, LC, Gangitano, E, Snoep, J, Arlt, W, Tomlinson, JW & Storbeck, KH 2020, 'The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1', Journal of Steroid Biochemistry and Molecular Biology, vol. 202, 105724, pp. 1-10. https://doi.org/10.1016/j.sbmb.2020.105724

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T1 - The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1

AU - Barnard, Lise

AU - Nikolaou, Nikolaos

AU - Louw, Carla

AU - Schiffer, Lina

AU - Gibson, Hylton

AU - Gilligan, Lorna C.

AU - Gangitano, Elena

AU - Snoep, Jacky

AU - Arlt, Wiebke

AU - Tomlinson, Jeremy W.

AU - Storbeck, Karl Heinz

PY - 2020/9

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N2 - Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.

AB - Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.

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KW - steroid 5β-reductase

KW - steroid metabolism

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The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1

Abstract

Funding

Keywords

UN SDGs

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