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.

Cannabinoids in Gynecological Diseases

“…These findings are in accordance with previously published studies showing TRPV1 expression in ectopic endometrial epithelial cells [101]. The presence of this receptor in endometrial tissue and the elevated levels of eCB in patients with endometriosis may therefore be associated with the development of chronic inflammatory pain [99]. …”

“…There were, however, no changes in CB 1 expression in endometrial stromal cells during the menstrual cycle of the women with endometriosis, although in the healthy controls (and in contrast to findings by Bilgic et al [100]) an upregulation of CB 1 was found in the S-phase [99]. TRPV1, an ECS-related receptor, was found to be expressed at comparable levels in ectopic endometrial stromal cells from both healthy controls and women with endometriosis [99]. These findings are in accordance with previously published studies showing TRPV1 expression in ectopic endometrial epithelial cells [101].…”

“…Since the mechanisms for endometriosis-related pain can be divided into 3 categories (nociceptive, inflammatory, and neuropathic), each of which is linked to the ECS, it is not surprising that the ECS represents a big field of research for the development of new therapeutic tools in the management of this disorder. Sanchez et al [99] recently reported elevated plasma levels of AEA and 2-AG in women with endometriosis. There were, however, no changes in CB 1 expression in endometrial stromal cells during the menstrual cycle of the women with endometriosis, although in the healthy controls (and in contrast to findings by Bilgic et al [100]) an upregulation of CB 1 was found in the S-phase [99].…”

“…Sanchez et al [99] recently reported elevated plasma levels of AEA and 2-AG in women with endometriosis. There were, however, no changes in CB 1 expression in endometrial stromal cells during the menstrual cycle of the women with endometriosis, although in the healthy controls (and in contrast to findings by Bilgic et al [100]) an upregulation of CB 1 was found in the S-phase [99]. TRPV1, an ECS-related receptor, was found to be expressed at comparable levels in ectopic endometrial stromal cells from both healthy controls and women with endometriosis [99].…”

Endocannabinoids and Related Lipids in Chronic Pain: Analytical and Clinical Aspects

“…Elevated microdialysate levels of PEA and SEA sampled from the trapezius muscle have been reported in subjects with chronic neck/shoulder pain (n=11) compared to healthy controls (n=11) [135]. Finally, one study found that endometriosis (n=27) was associated with elevated plasma levels of AEA, OEA, and 2-AG compared to controls (n=29) [136]. To the best of my knowledge, with the exception of the two studies included in this thesis, only two previous studies have investigated EC and NAE plasma levels in CWP/FMS.…”