N-Acylethanolamines in human reproductive fluids

Herbert Schuel,Lani J Burkman,Jack Lippes,Kent Crickard,Ellyn Forester,Daniele Piomelli,Andrea Giuffrida

doi:10.1016/s0009-3084(02)00158-5

Herbert Schuel, Lani J Burkman + Show 5 more

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https://doi.org/10.1016/s0009-3084(02)00158-5

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Abstract

N-Acylethanolamines (NAEs) are an important family of lipid-signaling molecules. Arachidonylethanolamide (anandamide) (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) are co-produced from similar phospholipid precursors when neurons are stimulated. AEA is an endogenous agonist (endocannabinoid) for cannabinoid receptors. It binds with higher affinity to type CB1 than to type CB2 cannabinoid receptors. PEA does not bind to CB1, while the hypothesis that it reacts with putative CB2-like receptors has been questioned. OEA does not activate currently known cannabinoid receptors, but it mimics the effects of AEA and cannabinoids in reducing the fertilizing capacity of sea urchin sperm. OEA and PEA also act as entourage compounds by inhibiting the hydrolysis of AEA by fatty acid amide hydrolase. Cannabinoid receptors and/or AEA are present in mammalian reproductive organs including the testis, epididymis, prostate, ovary, uterus, sperm, preimplantation embryo and placenta, as well as prostatic and mammary carcinomas. We now report that analysis by high-performance liquid chromatography/mass spectrometry (HPLC/MS) shows the presence of AEA, PEA, and OEA in human seminal plasma, mid-cycle oviductal fluid, follicular fluid, amniotic fluid, milk, and fluids from malignant ovarian cysts. Previous studies showed that AEA-signaling via cannabinoid receptors regulates capacitation and fertilizing potential of human sperm, early embryonic development and blastocyst implantation into the uterine mucosa of rodents, as well as proliferation of human mammary and prostatic carcinomas. Current results imply that NAEs also may modulate follicular maturation and ovulation, normal and pathological ovarian function, placental and fetal physiology, lactation, infant physiology, and behavior. Collectively, these findings suggest that NAEs in human reproductive fluids may help regulate multiple physiological and pathological processes in the reproductive system, and imply that exogenous cannabinoids delivered by marijuana smoke might impact these processes. This study has potential medical and public policy ramifications because of the incidence of marijuana abuse by adolescents and adults in our society, previously documented reproductive effects of marijuana, and the ongoing debate about medicinal use of marijuana and cannabinoids.

Highlights

Our results provide the first evidence that endocannabinoids can directly modulate sperm capacitation and fertilization in human, and imply that exogenous cannabinoids delivered by marijuana smoke might impact these processes
Co-administration of THC or 2-arachidonoyl glycerol (2-AG) protects pups from the adverse effects of SR141716 on suckling and survival, suggesting the involvement of CB1 receptors (Fride et al, 2001). These findings indicate that milk-derived endocannabinoids may influence infant physiology and behavior, a notion supported by common parental experience that nursing babies get sleepy as they become satiated
The discovery of functional cannabinoid receptors and their endogenous ligands has stimulated an explosive expansion of research during the past decade on their functions in reproduction and other physiological processes

Summary

Introduction

N -Acylethanolamines (NAEs) are lipid-signaling molecules that are widely distributed in plant, invertebrate, and mammalian tissues (Bachur et al, 1965; Berdyshev et al, 1996; Di Tomaso et al, 1996; Bisogno et al, 1997; Bezuglov et al, 1998; Piomelli et al, 1998; Berdyshev, 1999, 2000; Chapman, 2000; Hansen et al, 2000; Schmid, 2000; Stella and Piomelli, 2001). AEA, known as anandamide, was the first endogenous agonist for cannabinoid receptors to be identified (Devane et al, 1992) It mimics many of the pharmacological effects of ((/)D9-tetrahydrocannabinol (THC), the primary psychoactive substance in marijuana (Mechoulam and Hanus, 2000). 2-Arachidonoylglycerol (2-AG) is a potent endogenous ligand for cannabinoid receptors (Mechoulam et al, 1995; Stella et al, 1997; Mechoulam and Hanus, 2001; Sugiura et al, 1998; Sugiura and Waku, 2000).

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