Endocannabinoid Regulation in Human Endometrium Across the Menstrual Cycle

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.