The endocannabinoid system (ECS) is a complex signaling network of receptors, enzymes, and endocannabinoids that helps regulate various physiological processes, including reproduction. The ECS is composed of cannabinoid receptors (CB₁, CB₂, and GPR55 are the most common), endogenous ligands (endocannabinoids), and enzymes responsible for endocannabinoid synthesis and degradation. Recent research has highlighted the significant impact of the ECS on the female reproductive system, affecting fertility, pregnancy, and other reproductive functions.
Endocannabinoids are naturally occurring molecules that bind to cannabinoid receptors in the body, including CB₁ and CB₂ receptors. CB₁ receptors are highly expressed in the female reproductive system, including the ovaries, uterus, and fallopian tubes. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are synthesized by these reproductive tissues and are involved in several reproductive processes, including ovulation, implantation, and placentation. The ECS has been shown to aid in modulating the release of gonadotropins and sex hormones, affecting the menstrual cycle, and the development and function of the placenta.
Researchers confirmed in a 2019 article from the Journal of Ovarian Research that the ECS plays a major role in critical modulators of the female reproductive system, where it affects folliculogenesis, oocyte maturation and ovarian endocrine secretion. According to the authors, there "is a complex interplay between the ECS and the hypothalamic-pituitary-ovarian axis and an intricate crosstalk between the ECS and steroid hormone production and secretion." One recent study published in Reproduction found that levels of the endocannabinoid anandamide fluctuate throughout the menstrual cycle, with the highest levels occurring during the follicular phase. Anandamide has been shown to bind to CB₁ receptors in the ovary, where it helps regulate follicle development and ovulation.
The ECS has also been shown to play a crucial role in preimplantation development and implantation. In a review article published in the International Journal of Endocrinology, Meccariello et al. (2014) discuss how the ECS interacts with embryo development, implantation, and placental function. The authors found that CB₁ and CB₂ receptors are expressed in the human endometrium, and that endocannabinoids are involved in promoting embryo implantation and maintaining pregnancy. Researchers also discovered that alterations in cannabinoid receptors could lead to implantation failure, miscarriage, or endometrial tissue disorders. These studies highlight the potential therapeutic applications of ECS modulation in improving pregnancy outcomes in women with recurrent implantation failure and infertility.
In addition to the regulation of female reproductive health, the ECS has also been implicated in a variety of reproductive disorders. For example, a study published in the Journal of Ovarian Research found that women with polycystic ovary syndrome (PCOS) have alterations in their endocannabinoid system. Women with PCOS were found to have higher levels of anandamide and CB₁ receptors in their ovaries, possibly contributing to hormonal imbalances and other symptoms associated with the disorder. The study highlighted the essential role of the ECS in regulating folliculogenesis, ovulation, and corpus luteum function. The authors also highlighted the potential therapeutic applications of ECS modulation in ovarian diseases such as polycystic ovary syndrome (PCOS) and ovarian cancer.
Another article published in Molecules by Almeida et al. investigated the expression of cannabinoid receptors in breast cancer. Endocannabinoid concentrations and expression levels of cannabinoids, and their metabolic enzymes, are typically associated with cancer aggressiveness, reinforcing their involvement in cancer development. CB₂ receptors are overexpressed in breast cancer, mainly observed in HER2+ tumors (>90%), while CB₁ is present in significant lower quantities. Comparatively, the impact of the ECS in male reproduction has been well-documented. However, recent research on the impact of the ECS on sperm biology and male fertility is investigating the role of the ECS in human sperm biology, highlighting the potential therapeutic applications of ECS modulation in improving male fertility.
Overall, these studies suggest that the ECS is crucial in regulating many aspects of human reproductive health, and that disruptions to this system can contribute to a variety of reproductive disorders. Further research is needed to fully understand the mechanisms of ECS modulation in the female reproductive system and to develop targeted therapies for women with reproductive health problems.