Histomorphometric evaluation of cannabinoid receptor and anandamide modulating enzyme expression in the human endometrium through the menstrual cycle

Abstract

Plasma anandamide (AEA) levels fluctuate throughout the menstrual cycle and in early pregnancy in a pattern suggesting its involvement in implantation and early pregnancy maintenance through mechanisms that might involve its binding to cannabinoid receptors CB1 and CB2. Plasma AEA levels are maintained by the actions of the enzymes fatty acid amide hydrolase (FAAH) and N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD). All of these component parts of the 'endocannabinoid system' have been demonstrated in rodent but not in human uteri. This study aimed to demonstrate the presence of the endocannabinoid system in the human uterus and catalogue its modulation. Immunohistochemical techniques were employed to localise and determine the distribution of immunoreactive CB1, CB2, FAAH, and NAPE-PLD in well-characterised menstrual cycle biopsy samples. Immunoreactive CB1 and CB2 were widely distributed throughout the uterine tissue. In the myometrium and endometrium, smooth muscle cells were immunoreactive, although the vascular smooth muscle cells in both tissues were more so. In the endometrium, CB1 and CB2 immunoreactivity was primarily restricted to the glandular epithelium and expression was unrelated to the phase of the cycle. FAAH immunoreactivity in the endometrium was highest in the mid-proliferative gland and mid-secretory stroma, whilst NAPE-PLD immunoreactivity was down-regulated in the secretory epithelial gland compared to the proliferative epithelial gland and unaffected in the stroma. These data indicate that elements of the 'endocannabinoid system' coexist in many cell types within the uterus and may provide insight into the sites of action of endogenous and exogenous cannabinoids during endometrial transformation.

Endocannabinoid Signaling in Female Reproduction

“…52 Similar phenotype was also observed in humans in that FAAH expression is highest in midsecretory stroma, while levels of NAPE-PLD are lower in secretory glands. 53 These results suggest that lower levels of AEA and CNR1 are beneficial for implantation.…”

The endocannabinoid pathway and the female reproductive organs

“…Glandular expression of FAAH increases during the menstrual cycle reaching a peak during menstruation. Similarly, FAAH is also expressed in the stroma (Taylor et al 2010a). The expression of these two enzymes in the endometrium suggests that, during the menstrual cycle, they modulate AEA concentrations that are lower in the mid-luteal phase consistent with the idea that low levels are beneficial, and high levels detrimental, to blastocyst development , Taylor et al 2010b.…”

“…NAPE-PLD is intensively expressed in the menstrual, early-proliferative and late secretory glands with its lowest levels in the earlysecretory phase. This enzyme is also found in the stroma (Taylor et al 2010a). Glandular expression of FAAH increases during the menstrual cycle reaching a peak during menstruation.…”

“…These findings were not confirmed by Resuehr et al (2012) who recently reported a dramatic increase in CB1R mRNA and protein in normal endometrial samples in the secretory phase likely due to progesterone modulation. CB2R immunoreactivity is found in both glands and stroma; its expression is minimal at the beginning of the cycle and reaches a peak during the late proliferative phase (Taylor et al 2010a). NAPE-PLD is intensively expressed in the menstrual, early-proliferative and late secretory glands with its lowest levels in the earlysecretory phase.…”

“…The expression of the individual components of the endocannabinoid system was initially demonstrated in mice uteri (Das et al 1995, Paria et al 1999, 2001) and then also in humans, with both species expressing similar AEA levels (Taylor et al 2010a). According to Taylor et al (2010a) CB1R immunoreactivity is more intense in the glandular epithelium compared with the stroma and its expression is not regulated throughout the menstrual cycle. These findings were not confirmed by Resuehr et al (2012) who recently reported a dramatic increase in CB1R mRNA and protein in normal endometrial samples in the secretory phase likely due to progesterone modulation.…”