An Exploration into the Role of the Endocannabinoid System in Endometrial Receptivity

While it is clear that the control of implantation is multifactorial, one emerging component that appears to be important in the success or failure of embryo implantation is the endocannabinoid system. The primary ligand of the endocannabinoid system (ECS) is anandamide (AEA) which is synthesised by a N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and degraded by fatty acid amide hydrolase (FAAH). A careful balance in the activities of NAPE-PLD and FAAH is required to ensure the appropriate levels of AEA are available during implantation. The purpose of this thesis was to explore further the role of the ECS, specifically its role in uterine receptivity using both in-vivo and in-vitro models. In-vivo models were used to study the expression of the ECS by measuring plasma concentrations of AEA, along with OEA and PEA (two other ligands of the ECS). A statistically significant change in plasma PEA concentrations was noted when comparing urine pregnancy test results. No significant differences in either AEA or OEA plasma concentrations were demonstrated. In-vitro models were used to investigate the interactions between galectin 3, integrin β3 and the ECS. The results show that while galectin 3 did not have any effect on the ECS, up-regulation of the expression of integrin β3 in receptive endometrial cells both increased the expression of FAAH and decreased the expression on NAPE-PLD in a dose-dependent manner. However, no effect was demonstrated in non-receptive endometrial cells, suggesting that integrin β3 expression, in collaboration with the ECS, plays an important role in endometrial receptivity. Overall, this work gives us further insight into the immensely complex processes involved in ensuring the endometrium is receptive to an embryo. Most importantly, it has suggested a link between the expression of integrin β3 and the enzymes of the ECS that is absent in the non-receptive endometrium.