Male development, fertility, and lifelong health are all androgen-dependent. Perturbed androgen action at any stage of life significantly impacts quality of life (1), and low androgens are an independent risk factor for all-cause early death (2). Thus, understanding the fundamental regulation of androgen production and action is essential if we are to support healthy ageing throughout life.
Androgens are synthesized by Leydig cells within the interstitial compartment. Testosterone can act (i) directly within the testis and local environment, and or (ii) indirectly, once secreted in the bloodstream, via the conversion into dihydrotestosterone (DHT). This route, the classical pathway, initiates masculinization and later promotes male fertility and health. Recently, an alternative metabolic route to DHT conversion, the backdoor pathway, was identified bypassing the testosterone step (3-4). However, how these pathways intersect both inside and outside of the testis, and the relative importance of each pathway for specific androgen-responsive endpoints during sexual development and throughout later life has not been dissected yet. Using different mouse models: a HSD17B3 knockout that results in classical pathway disruption, a SRD5A1 knockout that impairs the backdoor pathway, and a model inhibiting both pathways, along with cell culture systems and in vivo gene therapy, we are dissecting the roles and interactions between the classical and backdoor androgen pathways.
Our preliminary data shows that our understanding of the androgen signaling system is far from being fully comprehended. This highlights the importance of deciphering the fundamental role of both classical and backdoor pathways in male reproductive function and wider androgen-related conditions affecting male health, if we are to address many of the age-related comorbidities associated with perturbed androgen signaling.