The ovary has two main purposes: to produce female gametes and to secrete various endocrine factors such as estrogen and progesterone [17, 42]. Estrogen enhances the responsiveness of the follicles to gonadotropic hormones and signals the release of GnRH [42, 48], while progesterone, mostly expressed by the corpus luteum [42], slows ovarian follicular growth [50]. In response to the gonadotropins, FSH and LH, these hormones work together to ensure successful oocyte development [17].

While components of the ECS have been identified in female reproductive fluids and in plasma [51], the majority of our knowledge about the effects of cannabinoids on ovarian function is derived from in vitro and animal studies, as well as studies in cannabis users. In 2009, El-Talatini et al reported the presence of the entire ECS within the ovary [1]. Using immunohistochemical staining, CB1, CB2, FAAH, and NAPE-PLD were shown to be localized within human ovarian follicles. They also presented data which suggests that AEA acts by autocrine mechanisms in the follicular cells to stimulate changes that have yet to be determined [1]. Interestingly, CB2 was present at greater levels in the ovarian follicles as compared to CB1 [1]. This finding may suggest a greater immunological role for the ECS in ovarian function. Moreover, FAAH and NAPE-PLD were found to be expressed in the secondary and tertiary follicles, the corpus luteum and corpus albicans, which suggests that AEA may be produced by developing follicles, but not from oocytes, thus serving a role in folliculogenesis [1].

Though AEA fluctuations occur during the ovarian cycle, a surge is reported in the ovary leading up to the time of ovulation, making it possible that endocannabinoid signaling may help to regulate follicular maturation and development [1]. As an example, high intrafollicular levels of AEA allow for ovulation, while the plasma and intrauterine levels must be lowered to allow for implantation of a fertilized oocyte [9]. However, excessively high levels of cannabinoids can impair the processes leading up to and including ovulation, acting not only at the hypothalamic level, but also at the level of the ovarian granulosa cells. Perturbations to the biosynthesis and/or degradation of AEA leading to a net increase in the concentration of AEA has been associated with several human pathologies, including neuroinflammatory diseases, eating disorders [7, 52], and polycystic ovarian syndrome [52, 53].

AEA has been identified in ovarian follicular fluids obtained at the time of oocyte retrieval for in vitro fertilization (IVF), which further suggests that it may play a role in follicular/oocyte maturation [9]. In vitro studies using rat granulosa cells have demonstrated that THC exerts a direct inhibitory effect on folliculogenesis and ovulation [1]. Ovulation is dependent on the accumulation of cAMP, an effect that is inhibited by THC, as demonstrated in rat follicular cells [54]. In support of these findings, in humans, a direct negative effect on the ovary has been demonstrated since occasional [17] and heavy-moderate [38] cannabis users present with anovulatory cycles leading to primary infertility. However, the development of tolerance in chronic cannabis users needs to be considered, as this can present as a source of variability in interpreting the data [55]. Furthermore, when these cannabis users undergo IVF treatment, they produce poor quality oocytes and have lower pregnancy rates when compared to non-cannabis users [1]. Interestingly, El-Talatini et al have identified an optimal cut-off point of AEA concentrations in follicular fluid, at 1.09 nM [1], which positively correlated with follicular size and the presence of a mature oocyte. AEA concentrations were higher in follicles in which mature oocytes were retrieved, suggesting that AEA is involved in the maturation of the follicles and/or the oocyte [1]. Mechanistically, estrogen, produced by developing follicles has been shown to inhibit FAAH resulting in increased AEA signaling [36], contributing to its role in folliculogenesis and ovulation. Following ovulation, estrogen levels decline [43], thus releasing the inhibition on FAAH, so it follows that AEA is enzymatically degraded post-ovulation (Fig. 2). THC, unlike AEA, is slowly metabolized and accumulates within adipose tissue, thus mimicking a situation of excess endocannabinoids, or when re-uptake or degradation of the endogenous ligands are impaired [36]. Given that AEA is an agonist at cannabinoid receptors, one might suppose that THC from cannabis would not serve as a detriment to ovulation. However, THC has been shown in several studies to block the release of LH [6, 56–58], which is critical for ovulation, and this may potentiate the probability of infertility.

Using cultured rat granulosa cells, Adashi et al examined the effects of cannabinoids on ovarian function [59]. Their chief finding was that THC, or its metabolites, inhibited FSH-stimulated accumulation of estrogen and progesterone, along with the FSH-stimulated increase in LH receptors. This direct effect of THC was determined to occur at a point downstream of the formation of cAMP and involves the inhibition of steroidogenesis [59]. Indeed, they found that THC reduced the conversion of pregnenolone to progesterone [59]. These effects were shown to be selective, as THC did not produce a negative impact on cell viability nor protein content [59]. These findings suggest that a perturbed ECS, either by exogenous cannabinoids [59], or elevated serum AEA, both of which act via CB1, may contribute to ovarian dysfunction [52].