In mouse oocytes, CB1, CB2, and GPR55 mRNAs occurring from germinal vesicle to metaphase II, CB2 and GPR55 protein contents increased during the same period. In germinal vesicles, only CB1 was localized in oolemma, but it completely disappeared at metaphase I. TRPV1 was always undetectable. When oocytes were in vitro matured with CB1 and CB2 but not GPR55 antagonists, a significant delay of germinal vesicle breakdown occurred, sustained by elevated intra-oocyte cAMP concentration. Although CB1/2 antagonists did not affect polar body I emission or chromosome alignment, GPR55 antagonist impaired in ~75% of oocytes the formation of normal-sized metaphase I and metaphase II spindles (Cecconi et al., 2019). These results suggest a prominent role for the ECS in oocyte maturation.
Mice lacking CB1 and CB2 had significantly reduced ovary area and volume, fewer ovarian follicles and abnormal oocyte maturation (Totorikaguena et al., 2020).
In cats, CB1 was detected only in tertiary follicle granulosa cells while more immature follicles were negative. FAAH was found in ovarian pre-antral follicles, the oocyte cytoplasm, and in granulosa cells of primary, secondary and tertiary follicles. Luteal cells were immunopositive for both CB1 and FAAH. Because CB1 in oviduct was found only in ciliated cells, it might represent a specific marker at least in cats. In contrast, FAAH immunoreactivity was observed in both ciliated and non-ciliated cells (Pirone et al., 2017).
In anterior pituitary explants from anestrous ewes it was found that AEA inhibits the secretion of Gonadotropin Releasing Hormone and stimulated the secretion of Luteinizing Hormone and Follicle Stimulating Hormone (Tomaszewska-Zaremba et al., 2020). These effects might be mediated by CB1, which is present in the anterior pituitary.
In pre-estrous rats, application of THC (2 mg i.p.) between 12.00 and 16.00 suppressed the rise of Luteinizing Hormone, Follicle Stimulating Hormone, prolactin and prostaglandin E, causing a 24h delay in ovulation. This effect was reduced with application in the morning or late afternoon (Ayalon et al., 1977). Please note that this is a very high dose for human standards.
In virgin mice oral THC (0, 1, 5, or 25 mg/kg) or cannabis extract (0, 3, 15, or 75 mg/kg) for 70 days delays entry into pre-estrus (all doses), depress serum progesterone (75 mg/kg extract) and inhibits female receptiveness (25 mg/kg THC and 75 mg/kg extract). Estrous cycle length or mating was not significantly different but full-term pregnancies were reduced by 32 and 68% for medium and high doses respectively. Successful pregnancies were largely restored after a 30-day washout period (Kostellow et al., 1980). Please note that the used doses are very high for human standards.
In human ovaries, the ECS is widely expressed in medulla and cortex with CB2 more abundant than CB1 in the granulosa cells of primordial, primary, secondary and tertiary follicles, corpus luteum and corpus albicans. NAPE-PLD and FAAH were observed in growing secondary and tertiary follicles and in corpora lutea and albicantes. AEA is more abundant in mature than in immature follicles and was predictive for oocyte maturity suggesting a role in ovulation (El-Talatini et al., 2009).
cannabinoid-degrading enzymes and the cannabinoid CB1 receptor are present in human oocytes. Specifically, FAAH is detected in the periphery of the oocyte from the GV to MI stage and co-localized with CB1. Later, by the MII stage, FAAH spreads within the oocyte, whereas MAGL immunostaining is homogeneous across the oocyte at all stages of maturation and only overlaps with CB1 at the GV stage (Agirregoitia et al., 2015, 2016).
In the human menstrual cycle AEA levels in the late follicular phase were slightly higher than those in the early follicular phase. Subsequently, AEA levels peaked at the time of ovulation in both two cohorts. Finally, the lowest AEA levels were measured in the luteal phase. Moreover, there were highly significant positive correlations between the plasma AEA concentration and the serum levels of FSH, LH and E2, whereas the AEA level was not correlated with P during the normal menstrual cycle (Cui et al., 2017).
In human oocytes in vitro maturation (as part of the in vitro fertilization process) is accelerated by THC (at nM to M concentration), leading to increased blastocyst formation/success rate (Totorikaguena et al., 2019). The results suggest THC might be useful in some forms/aspects of in vitro fertilization.
Agirregoitia, E., Ibarra-Lecue, I., Totorikaguena, L., Mendoza, R., Expósito, A., Matorras, R., Urigüen, L., and Agirregoitia, N. (2015). Dynamics of expression and localization of the cannabinoid system in granulosa cells during oocyte nuclear maturation. Fertil. Steril. 104, 753–760.
Agirregoitia, E., Totorikaguena, L., Expósito, A., Mendoza, R., Matorras, R., and Agirregoitia, N. (2016). Dynamic of expression and localization of cannabinoid-degrading enzymes FAAH and MGLL in relation to CB1 during meiotic maturation of human oocytes. Cell Tissue Res. 365, 393–401.
Ayalon, D., Nir, I., Cordova, T., Bauminger, S., Puder, M., Naor, Z., Kashi, R., Zor, U., Harell, A., and Lindner, H.R. (1977). Acute effect of delta1-tetrahydrocannabinol on the hypothalamo-pituitary-ovarian axis in the rat. Neuroendocrinology 23, 31–42.
Cecconi, S., Rossi, G., Oddi, S., Di Nisio, V., and Maccarrone, M. (2019). Role of Major endocannabinoid-Binding Receptors during Mouse Oocyte Maturation. Int. J. Mol. Sci. 20.
Cui, N., Wang, L., Wang, W., Zhang, J., Xu, Y., Jiang, L., and Hao, G. (2017). The correlation of Anandamide with gonadotrophin and sex steroid hormones during the menstrual cycle. Iran. J. Basic Med. Sci. 20, 1268–1274.
El-Talatini, M.R., Taylor, A.H., Elson, J.C., Brown, L., Davidson, A.C., and Konje, J.C. (2009). Localisation and function of the endocannabinoid system in the human ovary. PloS One 4, e4579.
Kostellow, A.B., Ziegler, D., Kunar, J., Fujimoto, G.I., and Morrill, G.A. (1980). Effect of cannabinoids on estrous cycle, ovulation and reproductive capacity of female A/J mice. Pharmacology 21, 68–75.
Pirone, A., Lenzi, C., Briganti, A., Abbate, F., Levanti, M., Abramo, F., and Miragliotta, V. (2017). Spatial distribution of cannabinoid receptor 1 and fatty acid amide hydrolase in the cat ovary and oviduct. Acta Histochem. 119, 417–422.
Tomaszewska-Zaremba, D., Wojtulewicz, K., Paczesna, K., Tomczyk, M., Biernacka, K., Bochenek, J., and Herman, A.P. (2020). The Influence of Anandamide on the Anterior Pituitary Hormone Secretion in Ewes-Ex Vivo Study. Anim. Open Access J. MDPI 10.
Totorikaguena, L., Olabarrieta, E., López-Cardona, A.P., Agirregoitia, N., and Agirregoitia, E. (2019). Tetrahydrocannabinol Modulates in Vitro Maturation of Oocytes and Improves the Blastocyst Rates after in Vitro Fertilization. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 53, 439–452.
Totorikaguena, L., Olabarrieta, E., Lolicato, F., Romero-Aguirregomezcorta, J., Smitz, J., Agirregoitia, N., and Agirregoitia, E. (2020). The endocannabinoid system modulates the ovarian physiology and its activation can improve in vitro oocyte maturation. J. Cell. Physiol.