Abstract
BackgroundEmbryo retention in the Fallopian tube (FT) is thought to lead to ectopic pregnancy (EP), a considerable cause of morbidity. In mice, genetic/pharmacological silencing of cannabinoid receptor Cnr1, encoding CB1, causes retention of embryos in the oviduct. The role of the endocannabinoids in tubal implantation in humans is not known.Methods and FindingsTimed FT biopsies (n = 18) were collected from women undergoing gynecological procedures for benign conditions. Endometrial biopsies and whole blood were collected from women undergoing surgery for EP (n = 11); management of miscarriage (n = 6), and termination of pregnancy (n = 8). Using RT-PCR and immunohistochemistry, CB1 mRNA and protein expression levels/patterns were examined in FT and endometrial biopsies. The distribution of two polymorphisms of CNR1 was examined by TaqMan analysis of genomic DNA from the whole blood samples. In normal FT, CB1 mRNA was higher in luteal compared to follicular-phase (p<0.05). CB1 protein was located in smooth muscle of the wall and of endothelial vessels, and luminal epithelium of FT. In FT from women with EP, CB1 mRNA expression was low. CB1 mRNA expression was also significantly lower (p<0.05) in endometrium of women with EP compared to intrauterine pregnancies (IUP). Although of 1359G/A (rs1049353) polymorphisms of CNR1 gene suggests differential distribution of genotypes between the small, available cohorts of women with EP and those with IUP, results were not statistically significant.ConclusionsCB1 mRNA shows temporal variation in expression in human FT, likely regulated by progesterone. CB1 mRNA is expressed in low levels in both the FT and endometrium of women with EP. We propose that aberrant endocannabinoid-signaling in human FT leads to EP. Furthermore, our finding of reduced mRNA expression along with a possible association between polymorphism genotypes of the CNR1 gene and EP, suggests a possible genetic predisposition to EP that warrants replication in a larger sample pool.
Highlights
Tubal ectopic pregnancy remains a common cause of morbidity and occasional mortality [1]
CB1 mRNA is expressed in low levels in both the Fallopian tube (FT) and endometrium of women with ectopic pregnancy (EP)
We propose that aberrant endocannabinoidsignaling in human FT leads to EP
Summary
Tubal ectopic pregnancy remains a common cause of morbidity and occasional mortality [1]. Exposure to marijuana and its cannabinoid derivatives is reported to have many adverse effects on reproductive functions, including reduced fertilizing capacity of sperm, retarded development of the embryo, fetal loss and pregnancy failure [6,7,8,9,10,11]. Both the exogenous and endogenous cannabinoids (endocannabinoids) act through their G protein-coupled cannabinoid receptors (CB1 and CB2) but the exact mechanism by which their wide-ranging effects are mediated has yet to be defined [11,12]. The role of the endocannabinoids in tubal implantation in humans is not known
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