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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 |
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Article number | 105724 |
Journal | The Journal of Steroid Biochemistry and Molecular Biology |
Volume | 202 |
Early online date | 3 Jul 2020 |
DOIs | |
Publication status | Published - Sept 2020 |
Bibliographical note
Funding Information: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.
Publisher Copyright:
© 2020 The Authors
Keywords
- 11-ketoetiocholanolone
- 11-ketotestosterone
- 11-oxygenated androgens
- steroid 5α-reductase
- steroid 5β-reductase
- steroid metabolism
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Endocrinology
- Clinical Biochemistry
- Cell Biology
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Dissecting Androgen excess and metabolic dysfunction - an Integrated SYstems approach to PolyCystic Ovary Syndrome (DAISY-PCOS)
Dunn, W., Tino, P., Deeks, J., Arlt, W., Manolopoulos, K., O'Reilly, M. & Afford, S.
1/04/18 → 1/10/24
Project: Research