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.

睾丸激素及其5α还原形式5α-二氢睾丸激素以前被认为是人类中唯一的活性雄激素。但是，最近的研究表明，源自肾上腺雄激素前体11β-羟基雄烯二酮的有效雄激素11-酮睾酮实际上可以充当健康女性的主要雄激素。然而，尽管最近对这些类固醇重新产生了兴趣，但它们的下游代谢仍未确定。因此，我们着手通过表征5α-或5β-还原作用的步骤研究11-酮睾酮的代谢。我们显示11-酮睾酮的失活主要是由AKR1D1驱动的，AKR1D1有效催化11-酮睾酮的5β还原，使其终止于11-酮乙胆醇酮的代谢途径。我们证明SRD5A2催化5α-还原的11-酮睾酮，但不是SRD5A1，并终止于11-酮雄甾酮，但仅负责少数11-酮睾酮的失活。但是，由于糖皮质激素可的松的代谢也会产生11-酮乙胆醇酮，因此11-酮雄甾酮应被视为11-酮睾酮生成的更具体的泌尿标志物。