Pathogenesis of ectopic pregnancy : is there a role for the endocannabinoid system in modulating embryo-tubal transport?

• Main Author: Gebeh, Alpha Karim
• Other Authors: Willets, Jonathon; Konje, Justin
• Published: University of Leicester 2013
• Subjects: 618.3
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.574123

Background: The molecular mechanisms of ectopic pregnancy remain unclear. Studies from knockout mice suggest that perturbations in oviductal endocannabinoid levels, endocannabinoid receptors (CB1) or endocannabinoid degrading enzyme (fatty acid amide hydrolase, FAAH) expression result in infertility secondary to physical trapping of embryos in their oviducts. Perturbations in endocannabinoid metabolism and action may therefore underlie ectopic pregnancy. Aims: To (1) quantify plasma and tubal endocannabinoid levels (2) evaluate blood activity of FAAH and the endocannabinoid degrading enzyme N-acylphosphatidyl-ethanolamine phospholipase-D (NAPE-PLD) and relate that to β-hCG levels (3) evaluate the expression of cannabinoid receptors (CB1, CB2), FAAH and NAPE-PLD in Fallopian tubes and (4) examine the effect of endocannabinoids [N-arachidonoylethanolamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA)] on cilia beat frequency (CBF) in tubal epithelial cells ex-vivo. Methods: Whole blood collected from women with ectopic pregnancy and suitable controls were used for quantification of endocannabinoids by UHPLCMS/MS and FAAH and NAPE-PLD activity by HPLC methods. Fallopian tubes were fixed in formalin for immunohistochemistry and had RNA and protein extracted for RT-qPCR and immunoblotting respectively. Fallopian tube explants were exposed to endocannabinoids and changes in CBF evaluated using highspeed digital camera. Results: Plasma AEA, OEA, PEA and tubal AEA were significantly higher (p < 0.05) in ectopic pregnancy compared to controls. Tubal OEA and PEA showed a similar trend though the results were not statistically significant. Blood FAAH but not NAPE-PLD activity was attenuated (p < 0.05) in ectopic pregnant women consistent with the higher endocannabinoid level observed in plasma. CB1 and FAAH were localised in Fallopian tube and showed significant attenuation (p < 0.05) in ectopic pregnancy compared to luteal phase controls. Exposure of Fallopian tube epithelial cells to OEA unlike methanandamide and PEA resulted in a significant reduction (p < 0.05) in CBF. Conclusion: The results implicate ECS dysfunction in the pathogenesis of ectopic pregnancy.