Abstract
BackgroundIn early pregnancy, increased plasma levels of the endocannabinoid anandamide (AEA) are associated with miscarriage through mechanisms that might affect the developing placenta or maternal decidua.MethodsIn this study, we compare AEA levels in failed and viable pregnancies with the levels of the trophoblastic hormones (beta-human chorionic gonadotrophin (beta-hCG), progesterone (P4) and (pregnancy-associated placental protein-A (PAPP-A)) essential for early pregnancy success and relate that to the expression of the cannabinoid receptors and enzymes that modulate AEA levels.ResultsThe median plasma AEA level in non-viable pregnancies (1.48 nM; n = 20) was higher than in viable pregnancies (1.21 nM; n = 25; P = 0.013), as were progesterone and beta-hCG levels (41.0 vs 51.5 ng/mL; P = 0.052 for P4 and 28,650 vs 6,560 mIU/L; P = 0.144 for beta-hCG, respectively, but were not statistically significant). Serum PAPP-A levels in the viable group were approximately 6.8 times lower than those in the non-viable group (1.82 vs 12.25 mg/L; P = 0.071), but again these differences were statistically insignificant. In the spontaneous miscarriage group, significant correlations between P4 and beta-hCG, P4 and PAPP-A and AEA and PAPP-A levels were observed. Simultaneously, immunohistochemical distributions of the two main cannabinoid receptors and the AEA-modifying enzymes, fatty acid amide hydrolase (FAAH) and N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), changed within both the decidua and trophoblast.ConclusionsThe association of higher AEA levels with early pregnancy failure and with beta-hCG and PAPP-A, but not with progesterone concentrations suggest that plasma AEA levels and pregnancy failure are linked via a mechanism that may involve trophoblastic beta-hCG, and PAPP-A, but not, progesterone production. Although the trophoblast, decidua and embryo contain receptors for AEA, the main AEA target in early pregnancy failure remains unknown.
Highlights
In early pregnancy, increased plasma levels of the endocannabinoid anandamide (AEA) are associated with miscarriage through mechanisms that might affect the developing placenta or maternal decidua
The endocannabinoid system consists of several natural ligands; i.e. AEA, 2-arachidonylglycerol (2-AG), N-oleoylethanolamine (OEA), N-palmitoylethanolamine (PEA) and virodhamine, their cognate and related receptors; i.e. cannabinoid receptors 1 (CB1) and 2 (CB2), the orphan receptor G-protein coupled receptor 55 (GPR55), peroxisome proliferatoractivated receptor-a (PPAR-a) and the Ca2+ channel vanilloid receptor 1 (TRPV1), and the enzymes that modulate the ligand concentrations; i.e. N-acyl transferase (NAT), N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), fatty acid amide hydrolase (FAAH), diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) [14,15]
Alterations in the levels of AEA at the endometrium have resulted in failed implantation and/or failure to maintain pregnancy [19], suggesting that a decrease in the activation pathways for anandamide mainly via its G-proteincoupled receptor CB1 is essential for early pregnancy success
Summary
In early pregnancy, increased plasma levels of the endocannabinoid anandamide (AEA) are associated with miscarriage through mechanisms that might affect the developing placenta or maternal decidua. Anandamide, originally isolated and characterised in 1992 [16], and four years after the cannabinoid receptors were identified [17], has been shown to be a key molecule that is important to the hormone-cytokine dialogue between the blastocyst and the endometrium in experimental animals, ensuring that the latter is ‘tuned’ to receive the former [11,18] In such animals, alterations in the levels of AEA at the endometrium have resulted in failed implantation and/or failure to maintain pregnancy [19], suggesting that a decrease in the activation pathways for anandamide mainly via its G-proteincoupled receptor CB1 is essential for early pregnancy success. Experiments have demonstrated that female CB1 receptor knock-out mouse models exhibit impaired fertility and suffer from impaired oviductal transport with resultant ectopic pregnancies [20], indicating that AEA signalling through the CB1 receptor is important in this aspect of mouse fertility
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