Localisation and Function of the Endocannabinoid System in the Human Ovary

Abstract

BackgroundAlthough anandamide (AEA) had been measured in human follicular fluid and is suggested to play a role in ovarian follicle and oocyte maturity, its exact source and role in the human ovary remains unclear.Methods and FindingsImmunohistochemical examination of normal human ovaries indicated that the endocannabinoid system was present and widely expressed in the ovarian medulla and cortex with more intense cannabinoid receptor 2 (CB2) than CB1 immunoreactivity in the granulosa cells of primordial, primary, secondary, tertiary follicles, corpus luteum and corpus albicans. The enzymes, fatty acid amide hydrolase (FAAH) and N-acyclphosphatidylethanolamine-phospholipase D (NAPE-PLD), were only found in growing secondary and tertiary follicles and corpora lutea and albicantes. The follicular fluid (FF) AEA concentrations of 260 FF samples, taken from 37 infertile women undergoing controlled ovarian hyperstimulation for in vitro fertilisation and intracytoplasmic sperm injection with embryo transfer, were correlated with ovarian follicle size (P = 0.03). Significantly higher FF AEA concentrations were also observed in mature follicles (1.43±0.04 nM; mean±SEM) compared to immature follicles (1.26±0.06 nM), P = 0.0142 and from follicles containing morphologically assessed mature oocytes (1.56±0.11 nM) compared to that containing immature oocytes (0.99±0.09 nM), P = 0.0011. ROC analysis indicated that a FF AEA level of 1.09 nM could discriminate between mature and immature oocytes with 72.2% sensitivity and 77.14% specificity, whilst plasma AEA levels and FF AEA levels on oocyte retrieval day were not significantly different (P = 0.23).ConclusionsThese data suggest that AEA is produced in the ovary, is under hormonal control and plays a role in folliculogenesis, preovulatory follicle maturation, oocyte maturity and ovulation.

Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility

“…CB1 receptors These GPCRs are found primarily in the central nervous system [36][37][38][39]. It is also located in the ovary, uterine endometrium, testis, vas deferens, urinary bladder among others [19,32,[40][41][42]. In the brain, CB1 receptors seem to be located in the preoptic area of the hypothalamus which is also the home of luteinizing hormone releasing hormone (LHRH) secreting neurons [43].…”

“…Human seminal plasma, mid-cycle fallopian tubal fluid as well as follicular fluid contains AEA which suggests that human spermatozoa are sequentially exposed to AEA, indicating a potential modulatory role for the ECS on sperm function [40,65,66]. Even more profound is the fact that small amounts of THC have been shown to be secreted by the vagina into the vaginal fluid in women who regularly use marijuana, leading to stimulation of spermatozoa and possibly affecting sperm function [4,110].…”

Flagellar ion channels of sperm: similarities and differences between species

“…Electrophysiological data have shown that Hv1 is potentiated by micromolar concentrations of anandamide, an endogenous cannabinoid found in male and female reproductive fluid and thought to interact directly with Hv1 [17]. The physiological relevance of this effect has been the subject of controversy as the physiological concentration of anandamide in the male and female reproductive tract are much lower than the EC 50 for Hv1 [134,135]. However, the cumulus cells surrounding the oocyte synthesize anandamide [134], therefore exposing sperm to higher concentrations during their transit through the cumulus mass [19,48].…”

“…The physiological relevance of this effect has been the subject of controversy as the physiological concentration of anandamide in the male and female reproductive tract are much lower than the EC 50 for Hv1 [134,135]. However, the cumulus cells surrounding the oocyte synthesize anandamide [134], therefore exposing sperm to higher concentrations during their transit through the cumulus mass [19,48]. Hv1 is also activated by capacitation [17], the process during which tyrosine phosphorylation of sperm proteins occurs.…”

The endocannabinoid pathway and the female reproductive organs

“…Recently, it has been reported that the entire endocannabinoid system is active at the ovarian level and CB1R and CB2R, NAPE-PLD and AEA, have been identified in ovarian tissue (El-Talatini et al 2009). Immunostaining shows expression of CB1R and CB2R in the medulla and cortex of the ovary.…”