New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice

Abstract

Androgens such as testosterone and dihydrotestosterone (DHT) are essential for male sexual development, masculinisation, and fertility. Testosterone is produced via the canonical androgen production pathway and is essential for normal masculinisation and testis function. Disruption to androgen production can result in disorders of sexual development (DSD). In the canonical pathway, 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) is viewed as a critical enzyme in the production of testosterone, performing the final conversion required. HSD17B3 deficiency in humans is associated with DSD due to low testosterone concentration during development. Individuals with HSD17B3 mutations have poorly masculinised external genitalia that can appear as ambiguous or female, whilst having internal Wolffian structures and testes. Recent studies in mice deficient in HSD17B3 have made the surprising finding that testosterone production is maintained, male mice are masculinised and remain fertile, suggesting differences between mice and human testosterone production exist. We discuss the phenotypic differences observed and the possible other pathways and enzymes that could be contributing to testosterone production and male development. The identification of alternative testosterone synthesising enzymes could inform the development of novel therapies to endogenously regulate testosterone production in individuals with testosterone deficiency.

Gene expression of male pathway genes sox9 and amh during early sex differentiation in a reptile departs from the classical amniote model

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Four novel mutations identification in 17 beta-hydroxysteroid dehydrogenase-3 deficiency and our clinical experience: possible benefits of early treatment

“…Based on our findings, it is possible for patients with 17β-HSD3 deficiency to exhibit a T/AND ratio above 0.8 following an HCG test. This phenomenon is likely attributed to isoenzymes (e.g., 17β-HSD5) ( 9 , 16 , 19 ), residual enzyme activity ( 20 – 24 ), and individual variations in extra-testicular enzyme activity ( 9 , 16 , 19 ). Therefore, additional molecular testing is particularly crucial for confirming the diagnosis of this condition.…”

Recent advances in reproductive research in Australia and New Zealand: highlights from the Annual Meeting of the Society for Reproductive Biology, 2022

“…Dr Diane Rebourcet (University of Newcastle) and colleagues have developed a technology to target testicular cells in adult mice to provide a novel approach to regulating steroid production. Using a Hsd17b3 knockout mouse model that displays altered androgen production (Lawrence et al 2022), Dr Rebourcet validated the effectiveness of lentiviral and adeno-associated virus 9 (AAV9)-mediated gene therapy in restoring classical androgen production. However, steroid production relies upon a pulsatile regulation from the hypothalamus-pituitary axis; therefore, to refine such approaches Dr Rebourcet has combined the fields of optogenetics and endocrinology.…”