Exploring the contributions of human seminal extracellular vesicles to reproduction and fertility

Abstract Declining reproductive health and fertility are global public health issues affecting an estimated 15% of reproductive-aged couples worldwide. The reasons for declining fertility are complex. However, a male contribution is thought to occur in approximately 50% of infertile couples. Deficits in sperm number and/or function are undeniably a major cause of infertility, but compelling evidence suggests that additional factors in the male ejaculate also play an influential and underappreciated role. In this review, we focus specifically on extracellular vesicles within human seminal plasma and explore their emerging roles in reproduction and fertility. These seminal extracellular vesicles are nano-sized membrane structures secreted by various cell lineages in virtually all regions of the male reproductive tract and exert key roles in intercellular communication. Consideration is given to the well-characterised effects of seminal extracellular vesicles in supporting sperm as they transit through the female reproductive tract, and their recently identified ability to modulate the immune environment within the female reproductive tract. Building on these important roles, we also detail the emerging links between dysregulated seminal extracellular vesicle production and male fertility status and highlight the potential utility of leveraging these vesicles to improve fertility and reproductive outcomes in infertile couples. Altogether, this review highlights how expanding knowledge of seminal extracellular vesicles is providing a new perspective on the complexity of seminal fluid physiology and the underlying aetiology of male infertility.