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.

The endocannabinoid 2-arachidonoylglycerol promotes endoplasmic reticulum stress in placental cells

“…Alterations in proliferation and exacerbation of trophoblast apoptosis have been associated with placental-related complications (Huppertz et al 2006, Heazell & Crocker 2008. On the other hand, dysregulation of the endocannabinoid levels might lead to adverse pregnancy outcomes, including impairment of implantation, inhibition of decidualization and compromised placentation (Maia et al 2020).…”

“…In women with endometriosis, there is a significant increase in plasmatic AEA and 2-AG levels. High AEA levels have also been shown to be related to failure in the in vitro fertilization embryo transfer and spontaneous miscarriage, while women with preeclampsia exhibit reduced levels of AEA ( Maia et al 2020 ). Moreover, we previously demonstrated that AEA and 2-AG impair the synthesis of proteins and hormones by the human syncytiotrophoblast ( Costa et al 2015 a , 2016 ).…”

(Endo)Cannabinoids and Gynaecological Cancers

“…In addition, growing evidence suggests that the ECS is a part of the diverse mechanisms that regulate the complexity of events that occur in the early stages of pregnancy, and especially within the placenta [ 51 ]. The first trimester trophoblast contains transcripts for both CB 1 and CB 2 [ 52 ], and their expression is important for the continuation of normal pregnancy [ 48 , 53 ].…”

“…Here, they play roles that include oocyte production [ 45 , 59 , 96 , 97 , 98 ], oviductal transport [ 98 , 99 , 100 ], and blastocyst maturity and implantation [ 101 ], as well as in preparing the endometrium for implantation [ 47 , 102 , 103 , 104 , 105 ]. When the ECS is dysfunctional or interfered with by, for example, cannabinoids [ 106 , 107 ], human fertility may be impaired (reviewed in [ 12 , 101 , 108 , 109 ]) and there may be associated reproductive-tissue-dependent pathologies, such as endometriosis, miscarriage, ectopic pregnancy, or pre-eclampsia [ 51 , 101 , 108 , 110 , 111 , 112 ]. Two recent reviews [ 12 , 38 ] on the ECS in the female reproductive tract summarise what is known on this topic, but crucially, these omit some important details on the main ECS components in gynaecological cancers, which we hope to address in this review (see Table 1 ).…”

“…In this context, the ECS has been studied the most in the human ovary [ 45 , 59 , 60 , 61 , 63 , 64 , 65 , 113 ], cervix [ 80 , 84 , 85 , 86 , 87 ], and endometrium [ 47 , 50 , 55 , 68 , 69 , 70 , 72 , 73 , 74 , 75 , 81 ], the most common gynaecological cancers ([ 95 , 114 , 115 ]); however, other female cancers have not been studied, as shown in Figure 2 . Although the presence and actions of the most commonly studied endogenous ligands (AEA, 2-AG, OEA, and PEA) in human reproductive tissues have been demonstrated, the presence and actions of others, such as SEA, virodhamine, stearamide, and monoolein [ 12 , 30 , 38 , 45 , 49 , 51 , 54 , 57 , 69 , 78 , 95 , 101 , 105 , 108 , 112 , 116 , 117 , 118 , 119 , 120 , 121 ,…”