The effect of mifepristone (RU486) on the endocannabinoid system in human plasma and first-trimester trophoblast of women undergoing termination of pregnancy.

INTRODUCTION: High anandamide (AEA) concentrations are detrimental for implantation and early pregnancy. Progesterone, essential for pregnancy, may keep AEA levels low by increasing fatty acid amide hydrolase (FAAH) expression. Here the effect of RU486, a P4 antagonist used to initiate medical termination of pregnancy (MTOP), on plasma AEA concentrations and the endocannabinoid system (ECS) in trophoblasts was examined. OBJECTIVE: Quantification of the endocannabinoid concentrations and expression of the ECS in trophoblast tissue of MTOP women and women undergoing surgical termination of pregnancy (STOP). DESIGN AND SETTING: A prospective study at the University Hospitals of Leicester National Health Service Trust. PATIENTS AND METHODS: AEA, N-oleoylethanolamine (OEA), and N-palmitolylethanolamine (PEA) concentrations in trophoblast tissues and blood samples from 68 MTOP and 15 STOP were analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry. ECS expression was determined by immunohistochemistry, quantitative RT-PCR, and Western blotting. RESULTS: Concentrations of AEA, OEA, and PEA were significantly higher in MTOP than STOP trophoblasts (P = .0062, P = .016, and P = .0029, respectively), whereas no significant differences in plasma AEA, OEA, and PEA concentrations were observed even though plasma AEA and PEA concentrations were significantly (P = .005 and P = .025, respectively) increased the day after RU486 administration in women undergoing MTOP. Changes in the immunohistochemical densities of the AEA modifying enzymes N-acylphophatidylethanolamine-phospholipase D (NAPE-PLD) and FAAH, and the cannabinoid receptors (CB1 and CB2) were observed with increased NAPE-PLD, FAAH, and CB1 expression seen in the trophoblast of MTOP patients. CONCLUSIONS: Trophoblast after MTOP demonstrated high AEA concentrations with increased expression of NAPE-PLD, FAAH, and CB1.

Endocannabinoids and pregnancy.

Acylethanolamides such as anandamide (AEA), and monoacylglycerols like 2-arachidonoylglycerol are endocannabinoids that bind to cannabinoid, vanilloid and peroxisome proliferator-activated receptors. These compounds, their various receptors, the purported membrane transporter(s), and related enzymes that synthesize and degrade them are collectively referred to as the "endocannabinoid system (ECS)". Poorly defined cellular and molecular mechanisms control the biological actions of the ECS. Over the last decade evidence has been emerging to suggest that the ECS plays a significant role in various aspects of human reproduction. In this review, we summarize our current understanding of this role especially the involvement of AEA and related ECS elements in regulating oogenesis, embryo oviductal transport, blastocyst implantation, placental development and pregnancy outcomes, and sperm survival, motility, capacitation and acrosome reaction. Additionally, the possibility that plasma and tissue AEA and other cannabinoids may represent reliable diagnostic markers of natural and assisted reproduction and pregnancy outcomes in women will be discussed.

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

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.