The fundamental role of the endocannabinoid system in endometrium and placenta: implications in pathophysiological aspects of uterine and pregnancy disorders

Abstract

Background: The endocannabinoid system (ECS) consists of the cannabinoid receptors CB1 and CB2, the main endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their metabolic enzymes N-acylphosphatidylethanolamine-specific phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase and monoacylglycerol lipase. This system is involved in the modulation of essential physiological processes. Its role in the reproductive system has become significantly important in recent years, given its major role in events such as gametogenesis, decidualisation, implantation and placentation.

Objective and rationale: In this paper, we review the literature and summarize the role of the ECS elements in reproduction and their potential as early markers for diagnosis of reproductive disorders or as pharmacological targets for treatment.

Search methods: Original research and review papers published from 1964 to June 2019 were selected in terms of relevance, reliability and quality by searching PubMed, MEDLINE and Web of Science, using the following search terms: endocannabinoid system and endometriosis; endocannabinoid system and ectopic pregnancy; endocannabinoid system and miscarriage; endocannabinoid system and pre-eclampsia; endocannabinoid system and endometrial cancer; endocannabinoid system and reproduction; endocannabinoid, endometrium; placenta; N-acylethanolamines; anandamide; 2-arachidonoylglycerol; and cannabinoids.

Outcomes: This review demonstrates relevant information concerning ECS alterations in endometriosis, ectopic pregnancy, miscarriage, pre-eclampsia and endometrial cancer. We highlight the importance of the endocannabinoids in endometrial and placental physiology and pathophysiology, from studies in vitro and in vivo and in clinical observations. The most studied of the endogenous cannabinoids is AEA. The levels of AEA were increased in plasma of patients with endometriosis and miscarriage, as well as in the fallopian tube of women with ectopic pregnancy and in endometrial biopsies of endometrial cancer. Changes in the pattern of expression of the cannabinoid receptor CB1 were also observed in endometrial biopsies of endometriosis, fallopian tube and decidua of patients with ectopic pregnancy and pre-eclamptic placenta. Moreover, alterations in CB2 expression have been reported in association with endometrial cancer. In general, studies on the cannabinoid signalling through CB2 and on the biological activities of the other major endocannabinoid, namely 2-AG, as well as its metabolic enzymes are scarce and avidly required.

Wider implications: The pathophysiological mechanisms involved in the described endometrial and placental pathologies are still unclear and lack the means for an early diagnosis. Based on current evidence, though alterations in ECS are demonstrated at tissue level, it is difficult to associate plasmatic changes in AEA with specific endometrial and placental diseases. Thus, pairing alterations in AEA levels with 2-AG and/or other endocannabinoid-like molecules may provide more accurate and early diagnoses. In addition, patients may benefit from new therapies that target the ECS and endocannabinoid signalling.

Keywords: ectopic pregnancy; endocannabinoid system; endocannabinoids; endometrial cancer; endometriosis; endometrium; miscarriage; placenta; pre-eclampsia; pregnancy.

Figure 1. The elements of the endocannabinoid system and related receptors . The endocannabinoid system (ECS) is composed of its two main endocannabinoids AEA and 2-AG, which activate their primary targets CB1 and CB2 as well as their secondary targets GPR55, PPAR and TRPV1, among others. AEA is synthesised from cell membrane lipids by NAPE-PLD and is degraded primarily by FAAH. 2-AG is synthesised also from membrane lipid precursors by the DAGL enzyme and is degraded by MAGL and, also, to a minor extent, by ABHD6 and ABHD12. Besides their proposed ability to move to and from the cell by diffusion, the existence of an endocannabinoid specific transporter, the EMT, has been proposed that eases this bidirectional flow. 2-AG, 2-arachydonoylglycerol; ABHD6, α/β-hydrolase-6; ABHD12, α/β-hydrolase-12, AEA, anandamide; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; DAGL, diacylglycerol lipase; EMT, endocannabinoid membrane transporter; FAAH, fatty acid amide hydrolase; GPR55, G-protein-coupled receptor 55; GPR119, G-protein-coupled receptor 119; MAGL, monoacylglycerol lipase; NAPE-PLD, N-acylphosphatidylethanolamine-specific phospholipase D; PPAR, peroxisome proliferator-activated receptors; TRPV1, transient receptor potential vanilloid 1. This image contains some elements adapted from the Servier Medical Art Image Bank (Servier Laboratories (Aust) Pty Ltd) licensed under a Creative Commons Attribution 3.0 Unported Licence.

Figure 2. Cannabinoid receptor signalling. Cannabinoids exert their effects by binding to specific G-protein-coupled receptors. The major pathways and channels activated by CB1 receptor are depicted. These include inhibition of the adenylyl cyclase (AC)–cyclic AMP–protein kinase A (PKA) pathway; inhibition of voltage-operated Ca²⁺ channels and activation of K⁺ inwardly rectifying channels; activation of mitogen-activated protein kinase cascades (ERK; JNK, p38 and FAK); ceramide generation and β-arrestin recruitment. This image contains some elements adapted from the Servier Medical Art Image Bank (Servier Laboratories (Aust) Pty Ltd) licensed under a Creative Commons Attribution 3.0 Unported Licence.

Figure 3. Crosstalk between the endocannabinoid and eicosanoid system pathways. FAAH is the main enzyme responsible for the hydrolysis of AEA into arachidonic acid (AA) and ethanolamine (EA). 2-AG is mainly degraded by MAGL and, to a smaller extent, by ABHD6 and ABHD12 into AA and glycerol (G). AA is metabolised by cyclooxygenase 2 (COX-2) leading to the formation of the endoperoxide PGH₂. Tissue specific metabolism of PGH₂ by PG synthases (PGS) yields the different prostanoids: prostaglandins (PGD₂, PGE₂ and PGF_2α), prostacyclin (PGI₂) and thromboxane A2 (TXA₂). AEA and 2-AG are also metabolised by COX-2 to produce prostaglandins–ethanolamides (or prostamides) and prostaglandin glycerol esters, respectively. However, as yet the molecular targets of these lipid mediators have not been totally elucidated. This image contains some elements adapted from the Servier Medical Art Image Bank (Servier Laboratories (Aust) Pty Ltd) licensed under a Creative Commons Attribution 3.0 Unported Licence.

Figure 4. Alterations in the ECS elements in endometrial and placental diseases. Main findings regarding alterations in members of the ECS in endometriosis, miscarriage, ectopic pregnancy, pre-eclampsia and endometrial cancer. This image contains some elements adapted from the Servier Medical Art Image Bank (Servier Laboratories (Aust) Pty Ltd) licensed under a Creative Commons Attribution 3.0 Unported Licence.