Regulating the Endocannabinoid System with CBD To Improve Women’s Health

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

By Chris D. Meletis, N.D.

The endocannabinoid system plays an important and often underrecognized role in women’s health. Endocannabinoids are endogenously produced ligands that act on cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The two primary endocannabinoids are anandamide and 2-arachidonoylglycerol. Endocannabinoids, their receptors, enzymes, and downstream signaling targets make up the endocannabinoid system. An abundance of evidence indicates the endocannabinoid system is important in oocyte maturation and fertility, as well as other aspects of women’s health.1 The endocannabinoid system is found in areas of the hypothalamus involved in producing gonadotropin-releasing hormone (GnRH), which regulates various aspects of female reproduction through the hypothalamic-pituitary-ovarian (HPO) axis.

Researchers have also detected the presence of the endocannabinoid system within ovaries.3 CB1 and CB2 receptors as well as the enzyme fatty acid amide hydrolase (FAAH), which breaks down the endocannabinoid anandamide, have all been found within human ovarian follicles.3 Additionally, an increase in ovarian levels of anandamide occurs during ovulation, indicating it may play a role in folliculogenesis.However, while higher anandamide levels in the follicles permit ovulation, lower plasma and intrauterine levels must be lower to permit implantation of a fertilized oocyte.4 Too high concentrations of cannabinoids, such as those that occur when consuming the psychoactive cannabinoid THC, can inhibit ovulation.1 Balance here is key, in order to avoid overwhelming the endocannabinoid system.

There is bidirectional communication between the endocannabinoid system and female sex hormones. Estrogen is involved in endocannabinoid system expression in the female reproductive tract.5 When estradiol is given to ovariectomized rats, there is upregulation of cannabinoid receptors 1 and 2 (CB1 and CB2) as well as FAAH.5 These effects occurred through estrogen receptors. Anandamide levels also rose in the plasma after the rats were treated with estradiol. The researchers reported, “Thus, estradiol may have a direct regulatory role in the modulation of ECS [the endocannabinoid system] in female reproductive tissues.”

The Endocannabinoid System and Uterine Health

A new study has found that the phytocannabinoid CBD may support the health of women with endometriosis who are experiencing pelvic discomfort.6 Armour and colleagues studied the strategies Australian women used to manage their pelvic discomfort due to endometriosis. The techniques used by the women included 11 different self-care or lifestyle strategies. Out of these techniques, the women rated the use of hemp/CBD oil as being among several of the most effective strategies for relieving or reducing their pelvic discomfort. A third of the women using CBD or hemp oil reduced their endometriosis medication by 50% or more.

The Endocannabinoid System and Ovarian Health

As noted earlier in this article, the endocannabinoid system plays an important role in ovary health. Further evidence indicates a dysfunctional endocannabinoid system is involved in ovarian and related pathologies. For example, women with polycystic ovary syndrome and non-alcoholic fatty liver disease (NAFLD) are more likely to have a polymorphism in the CB1 gene compared with women with PCOS who do not have NAFLD.7 That same gene is associated with an increased susceptibility to obesity and comorbid conditions.7 An impaired endocannabinoid system is also associated with ovarian cancer.8 In human ovarian tumors, Messalli and associates found benign and borderline ovarian tumors had weak to moderate CB1 expression.8 Conversely, invasive tumors had moderate to strong CB1 expression.8 It has been suggested that the higher CB1 expression occurring in malignant tumors allows exogenous cannabinoids to have a greater probability of initiating apoptosis in the cells by interacting with those increased receptors.1  

Menopause and The Endocannabinoid System

Evidence indicates the endocannabinoid system is involved in menopause. The endocannabinoid system’s regulation of GnRH secretion may be a means by which this system can influence the onset of menopause.2 Furthermore, higher circulating levels of the endocannabinoid 2-arachidonoylglycerol occur in post-menopausal women who are obese and insulin resistant compared to insulin sensitive obese  postmenopausal women.9 Weight loss in these women is associated with an increase in palmitoylethanolamide (PEA), a lipid that belongs to the same family of compounds as anandamide.9 This indicates the endocannabinoid system may regulate post-menopausal metabolic pathways. Anecdotal reports and experience in my clinical practice also indicate that the phytocannabinoid CBD may suppress hot flashes in menopausal women. 

The Endocannabinoid System and Breast Health

Due to the interaction between estrogen and the endocannabinoid system, it is logical that this system has been studied for its involvement in breast health. CB1 expression is moderate in breast cancer cell lines, but CB2 expression is high and is associated with the aggressiveness of tumors. In cell culture samples of human breast cancer, CB1 immunoreactivity was detected in 28% of samples and CB2 in 72%.10 In normal breast tissue, there was no notable CB1 and CB2 immunoreactivity.10 Increased expression of CB2 receptors occurs in estrogen- and/or progesterone receptor-negative tumors, which are more aggressive than tumors expressing steroid-hormone receptors.10 Higher CB2 receptor expression almost always occurs in triple-negative tumors that are difficult to treat such as tumors that lack the expression of receptors for steroid hormones and HER2/neu.10 This has led Kisková and colleagues to suggest, “To treat these tumor entities, targeting CB [cannabinoid]-associated pathways could be a promising treatment option and might also work in patients suffering from a relapse with an anti-HER2 targeted therapy.”10 

The phytocannabinoid cannabidiol (CBD) supports cellular health during in vitro studies of breast cancer cells by changing the mitochondrial membrane potential.11,12 In vitro, CBD also has improved the treatment response to the chemotherapy drugs cytarabine and vincristine in cancer cells.10 Some evidence indicates CBD is more effective when combined with radiation therapy.10  

Conclusion

The endocannabinoid system is involved in various aspects of women’s health. Supporting this system without overwhelming it by using CBD can lead to enhanced ovarian, uterine, and breast health. It may also support a healthy menopausal transition. 

References:

  1. Walker OS, Holloway AC, Raha S. The role of the endocannabinoid system in female reproductive tissues. J Ovarian Res. 2019:12:3.
  2. Gammon CM, Freeman GM Jr, Xie W, et al. Regulation of gonadotropin-releasing hormone secretion by cannabinoids.Endocrinology. 2005 Oct;146(10):4491-9.
  3. El-Talatini MR, Taylor AH, Elson JC, et al. Localisation and function of the endocannabinoid system in the human ovary. PLoS One. 2009;4(2):e4579.
  4. Maccarrone M. Endocannabinoids: friends and foes of reproduction.Prog Lipid Res. 2009 Nov;48(6):344-54. 
  5. Maia J, Almada M, Silva A. The endocannabinoid system expression in the female reproductive tract is modulated by estrogen. J Steroid Biochem Mol Biol. 2017 Nov;174:40-7.
  6. Armour M, Sinclair J, Chalmers KJ, Smith CA. Self-management strategies amongst Australian women with endometriosis: a national online survey. BMC Complement Altern Med. 2019 Jan;19:17. 
  7. Plaksej JK, Laczmanski L, Milewicz A, Lenarcik-Kabza A, et al. Cannabinoid Receptor 1 Gene Polymorphisms and Nonalcoholic Fatty Liver Disease in Women with Polycystic Ovary Syndrome and in Healthy Controls. Int J Endocrinol. 2014;2014:232975. 
  8. Messalli EM, Grauso F, Luise R, et al. Cannabinoid receptor type 1 immunoreactivity and disease severity in humanepithelial ovarian tumors.Am J Obstet Gynecol. 2014 Sep;211(3):234.e1-6.
  9. Abdulnour J, Yasari S, Rabasa-Lhoret R, et al. Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study.Obesity (Silver Spring). 2014 Jan;22(1):211-6.
  10. Kisková T, Mungenast F, Suváková M, et al. Future Aspects for Cannabinoids in Breast Cancer Therapy. Int J Mol Sci. 2019 Apr;20(7):1673. 
  11. Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy.Mol Cancer Ther. 2011 Jul;10(7):1161-72.
  12. Takeda S, Okajima S, Miyoshi H, et al. Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration.Toxicol Lett. 2012 Nov 15;214(3):314-9.