Investigating the effects of neuropeptides on human sperm function and fertility

An ever-growing body of research has reported decreasing trends in male fertility globally. In particular a recent meta-regression analysis demonstrated a significant decline in sperm count occurring over the past 40 years warranting further investigation. This study sought to investigate the role of the neuropeptides, oxytocin and vasopressin on sperm function and fertility. Neuropeptides have major functions in reproduction that are well documented. They are essential for normal function in the hypothalamic-pituitary-gonadal (HPG) axis, influencing the activity of the reproductive endocrine system, fecundity and sexual behaviour. Despite the involvement of neuropeptides in reproduction, little is known about their effects on sperm function and within the follicular fluid, an essential microenvironment where the oocyte matures. This study used in vitro assays to elucidate concentrations of neuropeptides in follicular fluid and semen, investigate their effects on sperm function and to investigate oxytocin receptor methylation in sperm. Regression analyses were used to investigate the relationship between the neuropeptides and the clinical outcomes in the patient cohorts of men and women undergoing assisted reproductive technology (ART). This study demonstrated that the neuropeptides vasopressin and oxytocin have a role in fertility. It is the first to discover the vasopressin receptor 2 on the acrosome region of human sperm and demonstrate a role for vasopressin in sperm motility, hyperactivation, calcium response, mitochondrial respiration and glycolysis. In the clinical cohorts of men and women undergoing in vitro fertilisation (IVF), increasing concentrations of oxytocin in follicular fluid was found to be negatively associated with fertilisation of oocytes in women and increasing concentrations of oxytocin in semen was negatively associated with sperm count and concentration in men. In sperm, increases in the oxytocin receptor methylation at CpG sites 924 and 934 were negatively associated with sperm concentration. The data presented in this thesis is highly suggestive of a novel role for vasopressin and oxytocin in sperm function, spermatogenesis, fertilisation and potentially indicating epigenetic effects for the oxytocin receptor and warrants further investigation.