Low Circulating Endocannabinoids May Affect Fertility

Marc Moulin November 27, 2018 0 comments

Research suggests that the endocannabinoid system regulates reproduction in both males and females. For couples who can’t get pregnant, could cannabis help?

Researchers discovered the endocannabinoid system (ECS) in the 1990s and originally thought it only existed in the brain and nerves. Since then, scientists have found endocannabinoid receptors in nearly every region of the human body. This vast system plays a role in many physiological and psychological processes including pain, stress, mood, memory, appetite, immune function, and sleep. It might surprise some that the ECS is also very much involved in regulating reproduction.[1]Maccarrone, M. (2009). Endocannabinoids: friends and foes of reproduction. Progress in Lipid Research48(6), 344-354. Research suggests that a dysfunctional ECS in both sexes can negatively affect pregnancy success. So, if a couple can’t get pregnant, could they supplement with exogenous cannabinoids?

Cannabinoid Receptors Key in Studies On Those Who Can’t Get Pregnant

A 2004 study published in Nature Medicine is an early example that demonstrated the importance of the ECS in reproduction. To understand how critical cannabinoid receptors are to the reproductive cycle, the researchers effectively ‘knocked-out’ the cannabinoid receptors in mice and assessed the effect that it had on successful pregnancy. The results showed that genetic or pharmacologic silencing of the cannabinoid receptor 1 (CB1) caused retention of a greater number of embryos in mice oviducts and eventually led to pregnancy loss. In other words – mice with no endocannabinoid system can’t easily get pregnant.[2]Wang, H., Guo, Y., Wang, D., Kingsley, P. J., Marnett, L. J., Das, S. K., … & Dey, S. K. (2004). Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nature … Continue reading

The findings suggest that endocannabinoid signaling coordinates oviductal smooth muscle contraction and relaxation that are crucial to normal oviductal embryo transport.

human embryonic development represented for those who can't get pregnant

Efficient ECS Functioning in Female Fertility Contributes to Wellness

Subsequently, a recent review published in Progress in Lipid Research (2020) found that the totality of evidence suggests that a finely tuned ECS in female fertility contributes to reproductive wellness and successful reproductive events.[3]Cecconi, S., Rapino, C., Di Nisio, V., Rossi, G., & Maccarrone, M. (2019). The (endo) cannabinoid signaling in female reproduction: What are the latest advances?. Progress in Lipid Research, … Continue reading On the other hand, dysregulation impairs reproductive performances by altering hormonal homeostasis or several essential reproductive steps. The authors stated that in this context, endocannabinoid-based drugs should be developed to treat female infertility.

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However, this does not necessarily mean women should start supplementing with exogenous cannabinoids like THC. Research into the effects of exogenous cannabinoids on female fertility is scarce, and some suggest an association with negative outcomes.

Cannabis Consumption Also Increases the Risk of Pregnancy Loss?

In a study published in Human Reproduction (2019), the researchers assessed the effects of cannabis consumption on the success of assisted reproductive technologies (ART). The results from over three hundred women with positive B-hCG hormone concentrations (indicating successful implantation and pregnancy) demonstrated that those women who self-reported as cannabis consumers were twice as likely overall to experience pregnancy loss.[4]Nassan, F. L., Arvizu, M., Mínguez-Alarcón, L., Gaskins, A. J., Williams, P. L., Petrozza, J. C., … & Chavarro, J. E. (2019). Marijuana smoking and outcomes of infertility treatment with … Continue reading

This suggests that although there is an association between an underperforming ECS and negative reproductive outcomes in women, achieving balance with exogenous cannabinoids (e.g. consuming lots of cannabis for pregnancy when you already have a healthy endocannabinoid system) might also not be the answer. Additionally, limiting these findings is the fact that it is unclear if these women seeking ART were having trouble conceiving because of a dysfunctional ECS.

Interestingly, cannabis consuming male partners within this same study showed the opposite effect. In twenty-three couples in which the male was a cannabis consumer, there was a greater probability of live births compared to couples in which the male was a past or never cannabis consumer. This finding is supported by research demonstrating the major role the ECS plays in male reproduction, but the real-world outcomes can be contradictory.

thos who can't get pregnant represented by sperm surrounding an egg

The ECS and Male Fertility

Moreover, research demonstrates that cannabinoid receptors and cannabinoid-based signaling are essential in the generation of sperm, as well as sperm viability and motility.[5]Francavilla, F., Battista, N., Barbonetti, A., Vassallo, M. R. C., Rapino, C., Antonangelo, C., … & Maccarrone, M. (2009). Characterization of the endocannabinoid system in human … Continue reading Furthermore, researchers have found that endocannabinoids affect sperm plasma membrane mechanisms and other molecular processes that affect the quality of sperm.[6]Battista, N., Meccariello, R., Cobellis, G., Fasano, S., Di Tommaso, M., Pirazzi, V., … & Maccarrone, M. (2012). The role of endocannabinoids in gonadal function and fertility along the … Continue reading Again, can exogenous cannabinoids help promote male fertility in a dysfunctional ECS? The findings suggest generally mixed results.

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Cannabis and Sperm 

A further study published in Biochemical Pharmacology (2018) investigated the effect of chronic THC administration on pregnancy outcomes in mice. The researchers gave one group of male mice ten milligrams of THC per kilogram of body weight a day for thirty days and the other male group acted as a control. They tested each group’s quality of sperm and their success at impregnating a female.

The results showed that there were no significant differences in sperm motility or concentration, nor any differences in pregnancy rates between the two groups. However, another study found that in mice exposed to THC, the THC binds to the cells responsible for sperm production and results in oddly shaped sperm. It is unclear if these altered sperm would be able to successfully fertilize an egg.[7]López-Cardona, A. P., Ibarra-Lecue, I., Laguna-Barraza, R., Pérez-Cerezales, S., Urigüen, L., Agirregoitia, N., … & Agirregoitia, E. (2018). Effect of chronic THC administration in the … Continue reading

In a recent review published in European Urology Focus (2018), the authors discussed the contradictory evidence surrounding cannabis and male fertility. Although the results have been mixed, they indicated that most studies associated cannabis consumption with low sperm concentrations, suggesting a negative effect on male fertility potential.[8]Hsiao, P., & Clavijo, R. I. (2018). Adverse effects of cannabis on mae reproduction. European Urology Focus4(3), 324-328. However, similar to the previously mentioned ART study, these studies were not looking at subjects known to have a dysfunctional ECS. Consequently, future research will need to focus on human subjects who are infertile and have a dysfunctional ECS.

We Need Endocannabinoid-Focused Studies on Couples Who Can’t Get Pregnant

Basically, the reader must remember that this reproductive research is new, and not yet well understood. There are many physiological processes concurrently involved in male and female fertility related to endocannabinoids. Based on current evidence, it is unclear if exogenous cannabinoids can help restore endocannabinoid balance and subsequently increase fertility in couples who can’t get pregnant.

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So, to better understand the relationship, researchers need to examine the endogenous cannabinoid levels in infertile humans. The next step would be to treat them in a controlled study environment with exogenous cannabinoids; and then evaluate the outcomes. Until then, the real-world implications of cannabinoid therapy on fertility will be unknown, despite the well-documented evidence of a relationship between fertility and the ECS.

References

1 Maccarrone, M. (2009). Endocannabinoids: friends and foes of reproduction. Progress in Lipid Research48(6), 344-354.
2 Wang, H., Guo, Y., Wang, D., Kingsley, P. J., Marnett, L. J., Das, S. K., … & Dey, S. K. (2004). Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nature Medicine10(10), 1074-1080.
3 Cecconi, S., Rapino, C., Di Nisio, V., Rossi, G., & Maccarrone, M. (2019). The (endo) cannabinoid signaling in female reproduction: What are the latest advances?. Progress in Lipid Research, 101019.
4 Nassan, F. L., Arvizu, M., Mínguez-Alarcón, L., Gaskins, A. J., Williams, P. L., Petrozza, J. C., … & Chavarro, J. E. (2019). Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies. Human Reproduction34(9), 1818-1829.
5 Francavilla, F., Battista, N., Barbonetti, A., Vassallo, M. R. C., Rapino, C., Antonangelo, C., … & Maccarrone, M. (2009). Characterization of the endocannabinoid system in human spermatozoa and involvement of transient receptor potential vanilloid 1 receptor in their fertilizing ability. Endocrinology150(10), 4692-4700.
6 Battista, N., Meccariello, R., Cobellis, G., Fasano, S., Di Tommaso, M., Pirazzi, V., … & Maccarrone, M. (2012). The role of endocannabinoids in gonadal function and fertility along the evolutionary axis. Molecular and Cellular Endocrinology355(1), 1-14.
7 López-Cardona, A. P., Ibarra-Lecue, I., Laguna-Barraza, R., Pérez-Cerezales, S., Urigüen, L., Agirregoitia, N., … & Agirregoitia, E. (2018). Effect of chronic THC administration in the reproductive organs of male mice, spermatozoa and in vitro fertilization. Biochemical Pharmacology157, 294-303.
8 Hsiao, P., & Clavijo, R. I. (2018). Adverse effects of cannabis on mae reproduction. European Urology Focus4(3), 324-328.

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