Modulation of the endocannabinoid system in viable and non-viable first trimester pregnancies by pregnancy-related hormones

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.

The role of endocannabinoids in pregnancy

“…The expression of NAPE-PLD was not significantly altered in the trophoblast, mesenchymal core or decidua of placentae from spontaneous miscarriage compared with that in placentae from elective surgical termination (Taylor et al 2011). Conversely, the expression of NAPE-PLD mRNA is at least twofold higher in the first-trimester (weeks 9-12) placentae from elective surgical termination than in those from spontaneous miscarriage ).…”

“…This suggests that anandamide concentrations in the placenta are lower prior to spontaneous miscarriage. In direct contrast with these observations, several studies have found that plasma anandamide concentrations measured in the first trimester of women at risk of miscarriage are up to threefold higher in those who subsequently miscarried than in those who progressed to term (Habayeb et al 2004, Taylor et al 2011. A recent study, however, has failed to demonstrate a difference between plasma anandamide concentrations in women with normal pregnancies and those in women who subsequently miscarried (Tong et al 2012).…”

“…In addition, Trabucco et al found that the immunostaining of the CB1 receptor is poorly detected in placental villi from elective surgical terminations, which supports earlier observations from our laboratory that the expression of CB1 receptor mRNA and protein is not readily detected in the first-trimester placentae (weeks 9-13 of gestation; Helliwell et al 2004). However, for gestational age-matched placentae of weeks 7-8, the expression of CB1 receptor protein in the trophoblast, mesenchymal core and decidua was approximately twofold lower in spontaneous miscarriage than in elective surgical termination (Taylor et al 2011). The difference in results could be due to the tissue source as Trabucco et al did not indicate which part of the placenta was analysed.…”

“…Immunohistochemical studies have characterised changes in the expression of endocannabinoid-producing and -metabolising enzymes as well as cannabinoid receptors in first-trimester gestational tissue. The expression of human FAAH and CB1 proteins increases at weeks 9-10 of gestation before returning to basal levels (Habayeb et al 2008, Taylor et al 2011. The implication of these changes is that the expression of the CB1 receptor and FAAH is dramatically elevated (week 9) prior to the commencement of blood flow to the intervillous space (gestation weeks 10-12).…”

“…The expression of the CB2 receptor in trophoblast cells and decidua is greatly up-regulated in placentae from spontaneous abortion compared with those from surgical terminations (Taylor et al 2011). The significance of this is unknown, given that the effects of anandamide appear to be primarily dependent on the function of the CB1 receptor.…”