Evolutionarily speaking, if the endocannabinoid system of receptors and ligands were not critical to human life, it would have disappeared early in the course of human development. If the system is not necessary, humans and mammals that genetically mutated to lack endocannabinoid receptors would have existed, and in fact, would have had better luck as a result of not wasting energy. Although we tend to forget, the body consumes energy by building receptors, producing enzymes, and creating natural endocannabinoids. This energy might otherwise be used for important functions such as repairing muscle or fortifying the immune system. Of course, a clever reader may ask, “What about the appendix? If what you’re saying is true, why hasn’t that disappeared?” Although the appendix no longer serves a function, it did at one point during human development. The appendix is like an old bridge that was once critical and is now unused. It is entirely possible that the endocannabinoid system once played a greater function, however, we’ve already confirmed multiple current functions and our understanding of its importance continues to grow. This month, we’re taking a look at the various ways in which the endocannabinoid system affects the human reproductive system. In the past, we’ve covered the interaction with estrogen and the female reproductive cycle. However, lately we’ve learned that sperm motility and production is associated with the endocannabinoid system as well.

In the first area of interaction, cannabinoids affect hypothalamic-pituitary control of reproduction in the brain. In normal sex hormone production, gonadotropin-releasing-hormone (GnRH) is synthesized by hypothalamic neurons and releases a string of interactions that ends in the up-regulation of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These intermediary sex hormones lead to direct synthesis of gonadal steroid hormones (such as estrogen, progesterone, etc.). Since multiple studies have confirmed that endocannabinoids modulate both GnRH and the cells in the reproductive region of the brain in general, this therefore means cannabinoids can cause changes in progesterone and estrogen. Specifically, an increase in cannabinoids and endocannabinoids decreases GnRH release, which ultimately also decreases progesterone. This holds up to general testing in which THC application reduces the circulating amount of both intermediary gonadal hormones, FSH and LH. Additionally, this holds across multiple species of mammals and even extends partially to amphibians!

Clearly the brain is wired to accept cannabinoids as a signaling mechanism for sex hormone production.

However, beyond influencing the brain, endocannabinoids can also influence gonads directly. Gonad cells synthesize endocannabinoids, which in turn help create the right conditions to produce sperm. In fact, a specific balance of endocannabinoid level, known as “endocannabinoid tone”, is needed for sperm production in males and follicle maturation in females. This balance is not only necessary for sperm vitality, but also for “sperm functions related to fertilization”, such as sperm mobility. In support of this concept, we notice that both too much and too little cannabinoid level can equally affect sperm quality. For instance, on the one hand, external application of THC decreases sperm quality. On the other hand, cannabinoid receptor knockout mice, or mice that have no genes to process THC at all, also have lower quality sperm. Sperm produced without endocannabinoid signaling has low mobility and less probability of fertilization once at the egg. The optimal balance of cannabinoids, neither too much or too little, rises and falls in a predictable pattern during each stage of sperm creation.

The bad news:

While we continue to investigate the endocannabinoid system, men attempting to conceive should perhaps reduce cannabis intake temporarily to create the best possible chance of fertilization. However, we have no evidence of any long-term impact, and cannabis use does not appear to damage sperm production over time. Furthermore, cannabidiol (CBD) has actually been cited to increase sperm production, with effects opposite to THC.

The good news:

We now have another avenue for fertility drug development. According to Dr. Paola Grimaldi, from the University of Rome, “tailored treatment of patients with the right dose of activators of [cannabinoid receptors] could help to reset progression of a normal spermatogenesis in infertile or subfertile patients, thus improving male reproductive health.”

While that statement is a mouthful, Dr. Grimaldi is essentially stating that the endocannabinoid regulation of sperm production could perhaps be adjusted with a specific cannabinoid, ideally one that is capable of influencing gonad-related function, while leaving other functions alone. Additionally, the issue is not so simple as merely deactivating cannabinoid receptors since the knockout mice that genetically lacked receptors in the first place showed issues with sperm production as well. The answer seems to be some sort of partial activation at specific times. Since we are still at the very beginning of understanding how to precisely control endocannabinoid signaling and receptors, scientists have their work cut out in terms of developing a fertility drug based on the endocannabinoid system. However, due to the apparently strong connection between this system and reproductive health, we are confident that useful applications will eventually stem from such research.

 

Works Cited

Patrizia Bovolin, Erika Cottone, Valetina Pomatto, et al. “Endocannabinoids are involved in male vertebrate reproduction: regulatory mechanisms at central and gonadal level”. (2014). Frontiers in Endocrinology (2014) 5:54, 1-8.

MedicalResearch.com. “Mouse Study Suggests Marijuana May Affect Male Fertility”. Published 20 April 2016. Accessed 20 September 2016. <http://medicalresearch.com/author-interviews/mouse-study-suggest-marijuana-may-affect-male-fertility/23610/>.