From Fertilisation to Implantation in Mammalian Pregnancy—Modulation of Early Human Reproduction by the Endocannabinoid System

Abstract

There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol) in early reproduction.

(Endo)Cannabinoids and Gynaecological Cancers

“…Although it is composed of multiple receptors, the female reproductive tract is stimulated by numerous exogenous cannabinoids and eCBs, and multiple metabolic enzymes that regulate eCB levels and activity are known; knowledge on the various roles that each of these components have on the initiation, development, and progression of benign and malignant tumours of the female reproductive tract is lacking, or, at best, at an early stage. Much is still unknown ( Table 1 ), and although many studies over the past two decades have highlighted the critical role of the ECS in maintaining key aspects of human and animal reproduction, including immune modulation, inflammation, cell proliferation, and differentiation [ 101 , 165 , 183 ], the precise roles of these factors in common reproductive tract cancers remain poorly defined. The roles, if any, in less common reproductive cancers (such as those of the vagina, vulva, and trophoblast/placenta) are untested and could provide fertile ground for subsequent studies.…”

“…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 ,…”

“…The function of the female reproductive tract is to support the embryo and fetus during its development into an independent offspring ( Figure 1 ). In order to do this, the coordinated actions of many interacting factors need to take place, of which the ECS is an integral part [ 101 , 108 , 111 , 163 , 164 , 165 , 166 ]. A key tissue in human reproduction is the fetoplacental unit.…”

Characterization of the endocannabinoid system, CB1 receptor signalling and desensitization in human myometrium

“…It is however, interesting to note that endocannabinoids are also able to mediate their effects through alternative signalling pathways (O'Sullivan, 2007). Endocannabinoids are unsaturated bioactive fatty acid amides and esters, with multiple signalling roles in different tissues, controlling a plethora of physiological processes as diverse as neuronal development, inflammation, energy metabolism and reproduction (Bambang et al ., 2010; Taylor et al ., 2010). The two most studied endocannabinoids are N ‐arachidonylethanolamine (anandamide, AEA) and 2‐arachidonoylglycerol (2‐AG), with quantified levels of 2‐AG reportedly 10‐fold greater than AEA in human tissues (Taylor et al ., 2010).…”