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

Research output: Contribution to journalArticle

Authors

  • Lise Barnard
  • Nikolaos Nikolaou
  • Carla Louw
  • Hylton Gibson
  • Elena Gangitano
  • Jacky Snoep

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.

Details

Original languageEnglish
Article number105724
JournalThe Journal of Steroid Biochemistry and Molecular Biology
Early online date3 Jul 2020
Publication statusE-pub ahead of print - 3 Jul 2020

Keywords

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