title: Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis.
abstract: Cannabinoids and modulators of the endocannabinoid system affect specific mechanisms that are critical to the establishment and development of endometriosis. The aim of this study was to measure the systemic levels of endocannabinoids and related mediators in women with and without endometriosis and to investigate whether such levels correlated with endometriosis-associated pain. Plasma and endometrial biopsies were obtained from women with a laparoscopic diagnosis of endometriosis (n = 27) and no endometrial pathology (n = 29). Plasma levels of endocannabinoids (N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]) and related mediators (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]), messenger RNA expression of some of their receptors (cannabinoid receptor type 1 [CB1], CB2, transient receptor potential vanilloid type [TRPV1]), and the enzymes involved in the synthesis (N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D [NAPE-PLD]) and degradation (fatty acid amide hydrolase 1 [FAAH]) of AEA, OEA, and PEA were evaluated in endometrial stromal cells. The systemic levels of AEA, 2-AG, and OEA were elevated in endometriosis in the secretory phase compared to controls. The expression of CB1 was higher in secretory phase endometrial stromal cells of controls versus endometriosis. Similar expression levels of CB2, TRPV1, NAPE-PLD, and FAAH were detected in controls and endometriosis. Patients with moderate-to-severe dysmenorrhea and dyspareunia showed higher AEA and PEA levels than those with low-to-moderate pain symptoms, respectively. The association of increased circulating AEA and 2-AG with decreased local CB1 expression in endometriosis suggests a negative feedback loop regulation, which may impair the capability of these mediators to control pain. These preliminary data suggest that the pharmacological manipulation of the action or levels of these mediators may offer an alternative option for the management of endometriosis-associated pain.
authors.affiliation: Division of Genetics and Cell Biology, Reproductive Sciences Laboratory, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Sanchez
authors.affiliation: Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cioffi
authors.affiliation: Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Viganò
authors.affiliation: Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Candiani
authors.affiliation: Endocannabinoid Research Group, CNR, Pozzuoli, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Verde
authors.affiliation: Endocannabinoid Research Group, CNR, Pozzuoli, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: Endocannabinoid Research Group, CNR, Pozzuoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Garavaglia
authors.affiliation: Division of Genetics and Cell Biology, Reproductive Sciences Laboratory, IRCCS Ospedale San Raffaele, Milan, Italy panina.paola@hsr.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Panina-Bordignon
mesh_terms: D000328:Adult; D000577:Amides; D000581:Amidohydrolases / Q000378:metabolism; D001095:Arachidonic Acids / Q000097:blood*; D063388:Endocannabinoids / Q000097:blood*; D004715:Endometriosis / Q000097:blood*; D004983:Ethanolamines / Q000097:blood*; D005260:Female; D005989:Glycerides / Q000097:blood*; D006801:Humans; D008597:Menstrual Cycle / Q000097:blood*; D008875:Middle Aged; D009829:Oleic Acids / Q000097:blood*; D010169:Palmitic Acids / Q000097:blood*; D010739:Phospholipase D / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000097:blood; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D009829:Oleic Acids; D010169:Palmitic Acids; D010739:Phospholipase D; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C588309:CNR2 protein, human; C494482:TRPV1 protein, human; C033595:N-oleoylethanolamine; C005958:palmidrol; C094503:glyceryl 2-arachidonate; C581518:NAPEPLD protein, human; C078814:anandamide
keywords: endocannabinoids; endometriosis; pain