Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer

Maccarrone, Mauro; Bisogno, Tiziana; Valensise, H.; Lazzarin, Natalia; Fezza, Filomena; Manna, Claudio; Marzo, Vincenzo Di; Finazzi‐Agrò, Alessandro

doi:10.1093/molehr/8.2.188

Cited by 166 publications

(106 citation statements)

References 37 publications

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“…For example, while AEA at a low concentration (7 nM) activates ERK signaling via CB1, higher AEA levels (28nM) fail to activate ERK, but instead inhibit Ca 2+ mobilization [44]. These results, combined with evidence that women with elevated peripheral AEA levels have spontaneous pregnancy loss [87,88],demonstrate that endocannabinoid signaling is at least one of the pathways determining the fate of implantation and ultimately successful pregnancy.…”

Section: Endocannabinoid Signaling and Implantationmentioning

confidence: 98%

Aspects of endocannabinoid signaling in periimplantation biology

Sun

Dey

2008

Molecular and Cellular Endocrinology

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Physiological roles of endocannabinoids, a group of endogenously produced cannabinoid-like lipid molecules that activate G-protein coupled cannabinoid receptors, are being increasingly appreciated in female reproduction. Adverse effects of cannabinoids on female fertility have been suspected for decades; however, underlying molecular and genetic bases by which they exert these effects were not clearly understood. The discovery of cannabinoid receptors (CB1 and CB2), endocannabinoid ligands (anandamide and 2-acylglycerol) as well as their key synthetic and hydrolytic pathways has helped to better understand the roles of cannabinoid/endocannabinoid signaling in preimplantation embryo development, oviductal embryo transport, embryo implantation and postimplantation embryonic growth. This review focuses on various aspects of the endocannabinoid system in female fertility based on studies that used knockout mouse models. The information generated from studies in mice is likely to shed deeper insight into fertility regulation in women.

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Section: Endocannabinoid Signaling and Implantationmentioning

confidence: 98%

Aspects of endocannabinoid signaling in periimplantation biology

Sun

Dey

2008

Molecular and Cellular Endocrinology

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“…Thus, an aberrant expression and activity of either these key synthetic and hydrolytic enzymes in the uterus may constrain early pregnancy events. This study is clinically relevant, since elevated endocannabinoid levels in peripheral circulation are associated with spontaneous pregnancy loss in women [59,60]. Levels of anandamide (A) and 2-AG (B) in the periimplantation mouse uterus.…”

Section: Faah or Cox-2 Deficiency Modulates Uterine Anandamide And 2-mentioning

confidence: 99%

Differential regulation of endocannabinoid synthesis and degradation in the uterus during embryo implantation

Wang

Xie

Sun

et al. 2007

Prostaglandins & Other Lipid Mediators

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Preimplantation embryo development to the blastocyst stage and uterine differentiation to the receptive state are prerequisites for embryo implantation. Burgeoning evidence suggests that endocannabinoid signaling is critical to early pregnancy events. Anandamide (Narachidonoylethanolamine) and 2-AG (2-arachidonoylglycerol) are two major endocannabinoids that bind to and activate G-protein coupled cannabinoid receptors CB1 and CB2. We have previously shown that a physiological tone of anandamide is critical to preimplantation events in mice, since either silencing or amplification of anandamide signaling causes retarded development and oviductal retention of embryos via CB1, leading to deferred implantation and compromised pregnancy outcome. Whether 2-AG, which also influences many biological functions, has any effects on early pregnancy remains unknown. Furthermore, mechanisms by which differential uterine endocannabinoid gradients are established under changing pregnancy state is not clearly understood. We show here that 2-AG is present at levels one order of magnitude higher than those of anandamide in the mouse uterus, but with similar patterns as anandamide, i.e. lower levels at implantation sites and higher at interimplantation sites. We also provide evidence that region-and stage-specific uterine expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), and sn-1-diacylglycerol (DAG) lipase fα (DAGLfα) and monoacylglycerol lipase (MAGL) for synthesis and hydrolysis of anandamide and 2-AG, respectively, creates endocannabinoid gradients conducive to implantation. Our genetic evidence suggests that FAAH is the major degrading enzyme for anandamide, whereas COX-2, MAGL and to some extent COX-1 participate in metabolizing 2-AG in the pregnant uterus. The results suggest that aberrant functioning of these pathways impacting uterine anandamide and/or 2-AG levels would compromise pregnancy outcome.

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“…4 In women undergoing in vitro fertilization and embryo transfer, high plasma anandamide level at 6 weeks after embryo transfer was associated with failure to achieve an ongoing pregnancy. 5 We therefore investigated whether plasma anandamide levels could predict outcome in women presenting with threatened miscarriage. The data are grouped according to those who proceeded to have a live birth and those who miscarried and are shown as individual cases.…”

mentioning

confidence: 99%

Plasma Anandamide Concentration and Pregnancy Outcome in Women With Threatened Miscarriage

2008

JAMA

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We do not recommend routine pretransplantation chemotherapy for patients who have received treatment in the past. Our recommendation to treat patients with impending immunosuppression (from human immunodeficiency virus infection, induction for organ transplant, or other etiologies) who have not previously received antitrypanosomal therapy should be interpreted in the context of our overall BII recommendation for T cruzi-infected adults up to age 50 years without advanced heart disease. The major objective of etiologic treatment in this setting is to prevent development or progression of cardiomyopathy.Our intention in explicitly listing anticipated immunosuppressionasapatientcategoryfortreatmentwastolendadditional weight to the recommendation since we assume that antitrypanosomal therapy would be better tolerated, and theoretically more effective, before immunosuppression develops or is induced.Althoughdataarelackingonthispoint,asecondarytheoretical benefit is a possible reduction in the risk of reactivation. Advanced renal, hepatic, or cardiac dysfunction would certainly complicate therapy and constitutes a contraindication.We agree with Altclas et al that posttransplantation monitoring is indicated whether or not a course of antitrypanosomal treatment was completed prior to transplant. As stated in the Clinical Review, we recommend that treatment decisions be individualized for all adult patients with Chagas disease, balancing the potential benefit vs the risk of drug toxicity.

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Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer

Cited by 166 publications

References 37 publications

Aspects of endocannabinoid signaling in periimplantation biology

Aspects of endocannabinoid signaling in periimplantation biology

Differential regulation of endocannabinoid synthesis and degradation in the uterus during embryo implantation

Plasma Anandamide Concentration and Pregnancy Outcome in Women With Threatened Miscarriage

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