The role of the endocannabinoid system in fertility control
thesisposted on 2013-12-23, 09:49 authored by Tülay Karasu
Endocannabinoids are endogenous ligands for cannabinoid receptors that play a pivotal role in fertilisation, embryo development, transport, implantation and pregnancy maintenance. The endocannabinoid system (ECS) consists of ligands (e.g. anandamide, AEA), receptors (e.g. CB1, CB2 and TRPV1) and ligand modulating enzymes (e.g. NAPEPLD and FAAH). The ECS interacts with sex steroid hormones and cytokines to regulate reproduction. Progesterone (P4), essential for pregnancy maintenance, increases FAAH activity in human lymphocytes, keeping AEA levels low. An elevated plasma AEA level is detrimental for implantation and pregnancy maintenance and any ECS dysregulation adversely affects pregnancy outcome. The hypothesis therefore was that manipulating the ECS could be an effective way of interrupting implantation. (a) The effect of RU486, a P4 antagonist used to initiate medical termination of pregnancy (MTOP), on plasma AEA levels and levels of AEA and the ECS in trophoblast were investigated. These were examined using UHPLC-MS/MS, immunohistochemistry, qRT-PCR and Western Blotting. (b) The effect of exogenously administered AEA to female rats during the implantation window was studied. The results show that ethnicity and BMI can affect the ECS, increasing AEA levels. RU486 administration causes a rise in plasma (p=0.005) and trophoblast (p=0.0062) AEA levels. Trophoblast NAPE-PLD (p=0.0006), FAAH (p=0.021), TRPVR1 (p=0.042) and CB1 (p=0.03) are significantly elevated at the mRNA level but not at the protein level though protein levels were generally higher. Exogenous administration of AEA to rats, around the day of implantation causes a reduction in viable implantation sites and an increase in resorbed units. At gestation day 14 there was a significant correlation between number of viable embryos and plasma AEA levels (p=0.0091). The complete ECS was detected in implantation, interimplantation and resorbed units at day 14. These studies have shown that manipulating the ECS can interrupt implantation showing the importance of this system in pregnancy maintenance.
Supervisor(s)Marczylo, Timothy; Konje, Justin; Oloto, Emeka
Date of award2013-11-01
Awarding institutionUniversity of Leicester