Endocannabinoid Regulation in Human Endometrium Across the Menstrual Cycle

Abstract

Humans produce endogenous cannabinoids (endocannabinoids), a group of molecules that activate the same receptors as tetrahydrocannabinol. Endocannabinoids play important roles in reproduction in multiple species, but data in human endometrium are limited. Because endocannabinoids such as anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) often act within tissues as paracrine factors, their effects can be modulated by changes in expression of locally produced synthetic and degradative/oxidative enzymes. The objective of this study was to localize and quantify expression of these key synthetic and degradative/oxidative enzymes for AEA and 2-AG in human endometrium throughout the menstrual cycle. Key synthetic enzymes include N-arachidonyl-phosphatidylethanolamine phospholipase-D (NAPE-PLD), diacylglycerol-lipase a (DAGL-α, and DAGL-β. Key degradative enzymes include fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL); cyclooxygenase 2 (COX2) is an oxidative enzyme. Endometrial samples were collected in 49 regularly cycling, normal women. Protein localization and expression were achieved by immunohistochemistry and messenger RNA (mRNA) expression by real-time reverse transcriptase polymerase chain reaction. No significant cycle-dependent mRNA expression was observed except that of COX2 (P = .002), which demonstrated maximum expression in the proliferative phase. During the secretory phase, NAPE-PLD protein had increased expression in luminal (P = .001), stromal (P = .007), and glandular (P = .04) epithelia, while FAAH had increased glandular (P = .009) and luminal (P = .01) expression. Increased expression in glandular epithelia was identified for MAGL (P = .03). The COX2 had increased luminal expression during the early secretory phase (P < .0001). In conclusion, maximal expression of degradatory/oxidative enzymes in the secretory phase may foster decreased endocannabinoid tone during implantation.

Endocannabinoids

“…In addition, these data are in keeping with recent observations that granulosa cells of the rat uterus lack CB receptors (Bagavandoss and Grimshaw 2010). Another recent study has monitored the expression of AEA and 2-AG catabolic enzymes in human endometrium during the menstrual cycle (Scotchie et al 2015). Maximal FAAH expression was detected in the middle secretory phase, whereas MAGL expression reached its highest level in the early secretory phase (Scotchie et al 2015).…”

“…Moreover, NAPE-PLD and FAAH are expressed in secondary and tertiary follicles and in the corpus luteum and albicans (El-Talatini et al 2009a). Data on the regulation of NAPE-PLD protein expression between the proliferative and secretory phases of the endometrium are conflicting, probably because of differences between studied patients Gebeh et al 2012;Scotchie et al 2015). However, published data on increased expression in the middle and late secretory phases are more consistent Gebeh et al 2012;Scotchie et al 2015).…”

“…Data on the regulation of NAPE-PLD protein expression between the proliferative and secretory phases of the endometrium are conflicting, probably because of differences between studied patients Gebeh et al 2012;Scotchie et al 2015). However, published data on increased expression in the middle and late secretory phases are more consistent Gebeh et al 2012;Scotchie et al 2015). Interestingly, AEA measured in the follicular fluid of women undergoing controlled ovarian hyperstimulation for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) is higher in follicles with mature oocytes than in those with immature oocytes (El-Talatini et al 2009a) (Fig.…”

“…Another recent study has monitored the expression of AEA and 2-AG catabolic enzymes in human endometrium during the menstrual cycle (Scotchie et al 2015). Maximal FAAH expression was detected in the middle secretory phase, whereas MAGL expression reached its highest level in the early secretory phase (Scotchie et al 2015). Furthermore, arachidonic acid, generated by the degradation of AEA and 2-AG, serves as a good substrate for COX-2, which is expressed in the cumulus oophorus but not in the egg cell.…”

Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium

“…Similarly to other TRP or cation channels of the endometrium (Ruan et al 2014, Singh et al 2015, TRPA1/TRPV1 may mediate homeostatic and barrier functions, Ca 2C signalling, cell proliferation/differentiation, endometrial receptivity, embryo implantation and sensory-immune interactions (Fernandes et al 2012). Non-neuronal TRPV1 can also be activated by the endocannabinoid anandamide in the rat reproductive system (Cella et al 2008, Scotchie et al 2014. These results are consistent with increased TRPA1 and TRPV1 expression in rat and human endometriosis demonstrated by our laboratory (unpublished results) and literature data (Hucho & Levine 2007, Ilie & Ilie 2013, Graham et al 2015.…”