The Role of the Endocannabinoid System in Human Gametogenesis

Abstract

The endocannabinoid system (ECS) is a complex endocrine network involved in maintaining body homeostasis. It comprises endocannabinoids, their receptors (CB1 and CB2), and the enzymes and transporters responsible for their synthesis and degradation. While the ECS's role in the nervous system is well established, its functions in other organs and peripheral tissues, including the cardiovascular, gastrointestinal, and reproductive systems, remain incompletely understood. With the increasing use of marijuana, particularly among individuals of reproductive age, concerns have emerged regarding its potential impact on male and female fertility. Phytocannabinoids (∆9tethrahydrocannabinol and cannabidiol), as well as synthetic cannabimimetic drugs, interact with the ECS, influencing sperm and oocyte physiology and reproductive outcomes. Recent research has identified ECS-related biomarkers with potential applications in infertility diagnosis, particularly in assessing male fertility with greater precision. Furthermore, emerging evidence suggests that ECS signaling pathways are involved in epigenetic modifications, which may influence health maintenance, disease susceptibility, and transgenerational inheritance patterns. These findings highlight the therapeutic potential of ECS modulation in reproductive disorders and broader medical applications. This narrative review aims to elucidate the role of the ECS in human reproduction, with a particular focus on the influence of endocannabinoids on gametogenesis. While current research underscores the critical role of the ECS in fertility, further investigations are needed to fully elucidate its underlying mechanisms and its broader implications for reproductive health and therapeutic interventions.

Keywords: endocannabinoid system; gametogenesis; human reproduction.

Figure 1

Levels of expression of receptors and synthesis and degradation enzymes of endocannabinoid system throughout the spermatogenesis. Abbreviations used: CB1: cannabinoid receptor type 1; CB2: cannabinoid receptor type 2; FAAH: fatty acid amide hydrolase; MGLL: monoacylglycerol lipase; NAPE-PLD: N-acyl phosphatidylethanolamine-specific phospholipase D.

Figure 2

Pattern of expression of CB1 receptor, FAAH, and MGLL enzymes throughout oogenesis. The distribution of CB1, FAAH, and MGLL, studied with immunofluorescent analysis, varies through the different stages of maturation of oocytes. Abbreviations used: CB1: cannabinoid receptor type 1; FAAH: fatty acid amide hydrolase; GV: germinal vesicle; MGLL: monoacylglycerol lipase; MI: meiosis I; MII: meiosis II.

Figure 3

Expression of CB1 receptor, FAAH, and NAPE-PLD enzymes during preimplantation embryo development and migration through the fallopian tube. The high expression of CB1 receptors and NAPE-PLD enzyme in the oviduct, corresponding to a high endocannabinoid tone, protects against the ectopic implantation of the embryo during development and migration to the uterine cavity. The high expression of FAAH enzyme by the embryo counteracts the cytotoxic effect of anandamide. Abbreviations used: AEA: anandamide; CB1: cannabinoid receptor type 1; FAAH: fatty acid amide hydrolase; NAPE-PLD: N-acyl phosphatidylethanolamine-specific phospholipase D.