Role of the endocannabinoid system in the pathophysiology of endometriosis and therapeutic implications

Harshavardhan Lingegowda, Williams BJ, Bailey J. Williams, Katherine G. Spiess, Spiess KG, Danielle J Sisnett, Alan Lomax, Alan E Lomax, Lomax AE, Madhuri Koti, Koti M, Tayade C, Chandrakant Tayade
Journal of cannabis research · 2022 · vol. 4(1) , pp. 54 · doi:10.1186/s42238-022-00163-8 · PMID:36207747 · PMC9540712 · W4303411537
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This review examines the role of the endocannabinoid system in endometriosis pathophysiology, exploring its potential for managing pain and inflammation and presenting therapeutic avenues targeting this system.

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This 2022 review studied the role of the endocannabinoid system (ECS) in endometriosis pathophysiology and evaluated therapeutic implications of cannabinoid-based approaches for endometriosis-associated pain, inflammation, and lesion-related processes. Drawing together prior mechanistic and preclinical literature, the authors describe ECS components (e.g., AEA, 2-AG, CB1/CB2 and related targets) and discuss how they may influence key endometriosis features such as nociceptive/neuropathic pain signaling, inflammatory pathways, proliferation, and vascularization, while noting that evidence for cannabinoid use remains limited or inconsistent. A major caveat emphasized is the lack of thorough and reliable evidence to support or refute cannabinoid treatment efficacy and concerns raised by prior analyses regarding potential fertility and cognitive effects. This paper is centrally about endometriosis — it reviews how the ECS may contribute to endometriosis-associated pain and inflammatory/lesion biology and discusses therapeutic implications of cannabinoid targeting.

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Abstract

Endometriosis patients experience debilitating chronic pain, and the first-line treatment is ineffective at managing symptoms. Although surgical removal of the lesions provides temporary relief, more than 50% of the patients experience disease recurrence. Despite being a leading cause of hysterectomy, endometriosis lacks satisfactory treatments and a cure. Another challenge is the poor understanding of disease pathophysiology which adds to the delays in diagnosis and overall compromised quality of life. Endometriosis patients are in dire need of an effective therapeutic strategy that is both economical and effective in managing symptoms, while fertility is unaffected. Endocannabinoids and phytocannabinoids possess anti-inflammatory, anti-nociceptive, and anti-proliferative properties that may prove beneficial for endometriosis management, given that inflammation, vascularization, and pain are hallmark features of endometriosis. Endocannabinoids are a complex network of molecules that play a central role in physiological processes including homeostasis and tissue repair, but endocannabinoids have also been associated in the pathophysiology of several chronic inflammatory diseases including endometriosis and cancers. The lack of satisfactory treatment options combined with the recent legalization of recreational cannabinoids in some parts of the world has led to a rise in self-management strategies including the use of cannabinoids for endometriosis-related pain and other symptoms. In this review, we provide a comprehensive overview of endocannabinoids with a focus on their potential roles in the pathophysiology of endometriosis. We further provide evidence-driven perspectives on the current state of knowledge on endometriosis-associated pain, inflammation, and therapeutic avenues exploiting the endocannabinoid system for its management.
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The

The analgesic effects of plant-derived or phytocannabinoids are well recorded throughout history, but we have only just begun to manipulate endogenous cannabinoids (the body’s natural pain killers). Pain relief remains a key area of research in EMS and novel analgesic treatments are continuously being investigated. Various components of the ECS are identified throughout peripheral nerve terminals (on both pre- and post-synaptic neurons), such as neurons in the dorsal root ganglia (DRG) and trigeminal ganglia and extending up to supraspinal sites that comprise nociceptive pathways (Hohmann 2002 ). Emerging research points out the therapeutic utility of DRG stimulation in select neuropathic pain scenarios (Berger et al. 2021 ; Liem et al. 2016 ). As previously mentioned, CB1 receptors are found throughout the CNS and can be specifically localized in regions involved in pain transmission including the spinal dorsal horn and periaqueductal gray (Herkenham et al. 1991 ; Tsou et al. 1998 ). This localization of components throughout the nociceptive system makes the ECS an attractive target for analgesic treatments. The ECS has been well-characterized in inflammatory pain. Mice with cutaneous chemical damage displayed reduced nociceptive behavior upon administration with AEA and subsequent interaction with CB1 receptors. When treated with CB1/CB2 antagonists, mice displayed both prolonged and enhanced nociceptive behavior because of tissue damage (Calignano et al. 1998 ). Comparable results are reported with 2-AG through the stimulation of CB2 receptors (Guindon et al. 2007 ). EMS-associated pain stems from multiple pathways such as nociception, neuropathic, and inflammatory, all of which are regulated and modulated by the ECS to a certain extent. It has been proposed that some chronic pain conditions are potentially a cause of clinical endocannabinoid deficiency (CED), where ECS signaling has been dysregulated compared to individuals without chronic pain (Russo 2016 ). The peritoneal microenvironment is a defining factor in the establishment and progression of EMS. It is well established that levels of inflammatory cytokines (IL-1β, IL-6, and TNFα) are significantly higher in the peritoneal fluid of EMS patients. Higher levels of these cytokines fuel hyperalgesia which is further sustained through altered expression of TRPV1 in the peritoneum of EMS patients (Rocha et al. 2011 ). In a mouse model of EMS, we demonstrated significantly reduced expression of TRPV1 in lumbar DRGs upon exposure to WIN 55,212-2 as compared to sham mice (without EMS-like lesions), suggesting that nociceptive pain might be modulated by DRGs whose terminals are in proximity to EMS lesions (Lingegowda et al. 2021b ). Similarly, a study using a rat model of EMS also showed that the stimulation of the CB1 and CB2 receptors using WIN 55,212-2 significantly reduced abdominal nociception and vaginal hyperalgesia in a CB1 receptor-dependent manner (Dmitrieva et al. 2010 ). Correlations have also been drawn between the levels of ECs in the plasma and peritoneal fluid, to identify their role in EMS-associated inflammatory pain. One such study showed that the levels of 2-AG and AEA were significantly higher in the peritoneal fluid of EMS patients as compared to individuals without EMS, which was also correlated to higher abdominal pain experienced by patients. Although the authors suggest that the ECs identified in their study are involved in deepening the abdominal inflammatory pain, low sample size and unaccounted comorbidities should be considered when correlating ECS involvement in driving the inflammatory pain in the peritoneum (Andrieu et al. 2022 ). Nevertheless, these findings demonstrate a complex and at times contradictory role of the ECS in pain modulation and management. Given the complex regulation of endogenous production of ECS, enzymes modulating endogenous levels, specific receptor engagement, teasing out cause and effect becomes a significant challenge. Most of the reported studies therefore points out to association of ECS dysregulation with disease or inflammatory state rather than causing it. More research is warranted in this domain.

Current

Due to the well-established relationship between EMS and the ECS, research into the potential therapeutic effects of manipulating this system is of great interest. The use of cannabinoids (both natural and synthetic) in the treatment of EMS has varying results. It has been suggested that EC agonists are beneficial in disease profiles where stimulation of EC receptors has protective effects, such as diabetic nephropathy (Barutta et al. 2011 ). In EMS, this is complex as receptor activation has contradicting impacts on disease pathogenesis. A study using palmitoylethanolamide-polydatin combination treatment of four patients reported pain relief after 1 month following treatment and patients were found to be taking fewer analgesics than before treatment. They also reported that the lesions were improving, as measured with imaging techniques (Indraccolo and Barbieri 2010 ). Although this study was preliminary, the impact on lesion growth aligns with literature suggesting anti-proliferative actions of cannabinoids to reduce lesion growth and manage pain associated with EMS. Similarly, another open-label study investigated the use of ultramicronized-palmitoylethanolamide (um-PEA) and co-micronized palmitoylethanolamide/polydatin m (PEA/PLD) for pelvic pain in a group of 30 EMS patients. The results showed a decrease in pain symptoms between baseline and end of treatment. Additionally, PEA treatment resulted in improved quality of life and psychological wellbeing when measured by the 36-Item Short Form Health Survey questionnaire and Symptom Check list-90 questionnaire, respectively (Loi et al. 2019 ). It is evident that pain relief is a major factor that EMS patients seek in their treatment, as discussed here. Based on patient surveys and preliminary studies, some cannabinoids seem to be effective in this domain, as well as showing efficacy against EM-associated gastrointestinal, sleep, and mood symptoms (Sinclair et al. 2020 ; Sinclair et al. 2021a ). EMS patients using cannabis have been able to reduce dosages of other medications like non-opioid and opioid analgesics, antineuropathics, antidepressants, and antianxiety medications by at least 50% (Armour et al. 2021 ; Sinclair et al. 2021b ). It is important to note, however, that cannabinoids can have adverse effects and abuse potential, which must be considered before undergoing treatment (Volkow et al. 2014 ). Additional concerns about safety and legal repercussions (places where cannabis is an illegal substance) should be considered by patients. Several patients do not disclose the use of cannabis to their doctors due to legal concerns and societal judgment fears, which can lead to negative health effects as use is unregulated and unaccounted (Sinclair et al. 2021b ). Some cannabinoids like Δ 9 -THC have neurological effects that can impair cognitive function. This is because Δ 9 -THC binds to CB1 receptors, present in the nervous system, where it can alter neurotransmitter release in synapses (Kendall and Yudowski 2017 ). Although less is known about the mechanism, CBD does not have neurological effects, which means that it could be a preferred treatment option, should it be proven to be effective. Interestingly, long-term exposure to cannabinoids in females has been shown to delay sexual maturation, cause menstrual cycle disruption, dysregulate ovarian follicular maturation, and reduce serum concentrations of luteinizing hormone and other sex hormones, making it contraindicated for those trying to conceive (Field and Tyrey 1990 ; Park et al. 2004 ; Gammon et al. 2005 ). Notably, AEA has become of great interest in the context of pregnancy and fertility, particularly in the elucidation of its role in pregnancy complications (Maia et al. 2020 ; Ezechukwu et al. 2020 ). The potential of manipulating the ECS therapeutically in EMS is vast but more research is needed on the exact role that ECS plays in the pathogenesis of the disease to favorably alter the system for patients with minimal side effects (Fig. 3 ). This is particularly relevant to EMS patients, who often suffer from infertility.

Conclusion

As presented in this review, the ECS system plays an important role in both normal physiological functions and in some inflammatory disorders including EMS. EMS is a complex, hormone-dependent, inflammatory disorder where the etiology is likely multifactorial. Several molecules of the ECS such as the ligands, receptors, and enzymes are reported to be involved in the complex mechanisms of EMS both systemically and in the lesions. This observation mostly stems from dysregulated levels of ECS members in localized and systemic environments. One of the most perceived utilities of ECS is to treat EMS-associated pain; however, careful considerations are needed in targeting specific pathways since ECS is directly involved in pregnancy outcomes. Even though efforts from several researchers have contributed to the overall understanding of ECS in the context of EMS, several unanswered questions exist. Are endocannabinoids involved in endometriosis lesion proliferation, survival, inflammation, and associated pain? Are cannabinoids capable of being a mainstream therapy for EMS? Will targeting endocannabinoids affect the female reproductive system and what impact it will have on fertility and pregnancy outcomes? The current knowledge and scientific evidence available till date suggest that cannabinoid compounds have therapeutic potential for various diseases including endometriosis. However, the ECS system needs to be carefully evaluated in the future to identify (1) their direct role in the pathogenesis of EMS, (2) if ECS is exhausted given the constant inflammatory state of the lesions and hence dysregulated phenotype, and (3) selective inhibition or stimulation of ECs and their receptors for therapeutic intervention. An ideal treatment for EMS would be to eliminate lesion, and prevention of lesion recurrence (a long-term solution), while sparing fertility with minimum side effects. Current treatments have not yet met all these expectations and disease recurrence is a major problem for patients. Although there is a major knowledge gap surrounding the ECS due to its complex network and function, the cannabis research landscape is swiftly evolving on both therapeutic fronts. Like any prescription medication, cannabinoids must also be regulated to manage daily intake before it can be considered as a prescription medication for EMS management, among other regulatory and safety requirements. Despite this need for regulation, most of the self-management strategies employed by EMS patients are currently nonspecific. One of the unexplored avenues of therapeutic potential is to boost the innate production of EC ligands such as palmitoylethanolamide (PEA), which is known to be anti-inflammatory in nature. Unfortunately, the knowledge of ECs has not yet caught up to the fast-paced pharmaceutical world and this presents a challenge for its future use in therapeutics. With the growing establishment of cannabis-dedicated research institutes, we can anticipate that the knowledge gap that exists today will be closed in the near future and provide clear ideas on the therapeutic potential of cannabinoids in EMS and other disorders.

Introduction

Endometriosis (EMS) is an inflammatory condition characterized by the abnormal growth of endometrial-like tissue outside of the uterus, mainly in the peritoneal cavity (Matarese et al. 2003 ). The condition is estimated to be prevalent in 10% of women of reproductive age (Viganò et al. 2004 ). The disease is heterogenous in presentation, not only for symptoms but also the lesion types ranging from superficial to deep infiltrating lesions and is associated with severe pelvic pain as well as infertility (Zondervan et al. 2018 ; Giudice 2010 ). Although the etiology of EMS is not entirely known, there are several theories for the pathogenesis of endometriotic lesions, such as retrograde menstruation, metaplasia, immune dysfunction, and stem cells (extensively reviewed here (Sourial et al. 2014 ; Laganà et al. 2019 ; Symons et al. 2018 )). Sampson’s theory of retrograde menstruation is one of the oldest theories that is debated to be the root cause of EMS, given that retrograde menstruation is common among menstruating individuals (Zondervan et al. 2018 ; Halme et al. 1984 ). This theory postulates that endometrial tissue shed during menstruation is refluxed into the peritoneal cavity via the fallopian tubes, where it implants and develops as EMS lesions (Sampson 1927 ). Sampson’s theory, however, does not explain cases in those who do not menstruate and in cases of endometriotic lesions outside of the peritoneal cavity. It is plausible that retrograde menstruation combined with hormonal imbalance, genetic and epigenetic modifications, immune dysfunction, and environmental factors contribute to the complex pathogenesis of EMS (Barbosa et al. 2011 ; Montgomery et al. 2008 ; Bellelis et al. 2011 ). This complexity in pathophysiology and associated symptoms likely contribute to the difficulty of diagnosis and treatment of EMS. Currently, diagnosis of EMS is achieved through laparoscopy which has an average diagnostic delay of 7 to 11 years from the onset of the disease (Nnoaham et al. 2011 ). EMS patients do not have access to a treatment option that manages both pain and lesion growth, while leaving fertility intact and hence management of EMS often involves a multidisciplinary approach through a combination of nonsteroidal anti-inflammatory drugs, hormone treatment, and/or surgical excision of lesions. Clearly, this hormone-targeted therapy poses a challenge for individuals trying to conceive. One of the major goals of EMS research is to elucidate the mechanisms of lesion establishment and survival so we can develop a new generation of therapeutics to circumvent some of the challenges. Another goal is to find an ideal treatment that will not only eliminate EMS lesions but also prevent their recurrence and do so with minimal side effects (Tanaka et al. 2020 ). In recent years, the endocannabinoid system (ECS) has become a topic of great interest in the field of EMS. The expanding legalization of recreational cannabinoids has led to a recent surge in the use of cannabinoids as a form of self-management therapy for many diseases, including EMS (Carrubba et al. 2021 ; Sinclair et al. 2019 ). Several articles in the past have thoroughly discussed the use and effectiveness of cannabinoids for pain management in EMS patients and the broad role of ECS in reproductive disorders (Mistry et al. 2022 ; Bouaziz et al. 2017 ; Maia et al. 2020 ). One of the recent meta-analyses conducted by Mistry et al. reviewed the effects of cannabis-based products on female reproductive health in the context of EMS and chronic pelvic pain and suggested that fertility complications and long-term cognitive functions might be affected. Additionally, the authors also acknowledge the lack of thorough and reliable evidence to support or dismiss the use of cannabinoids to treat EMS symptoms (Mistry et al. 2022 ). Similarly, a study conducted by Bouaziz et al. in 2017 summarized the role of ECS in EMS-associated pain symptoms and the potential use of cannabinoids as therapeutic agents, where they concluded that pain mechanisms are heterogenous in EMS patients and the use of cannabinoids for the treatment of EMS needs to be evaluated carefully (Bouaziz et al. 2017 ). The focus of this review is on the involvement of ECS with nociceptive pain, neuropathic pain, and inflammatory pain and they elegantly summarized the mechanisms of peripheral and central sensitization leading to pain amplification and psychological effects (Bouaziz et al. 2017 ). Even though similarities exist in some of the narrative, in this review, we specifically focus our efforts on the role of ECS in the female reproductive system in general, and we summarize current knowledge about its involvement in the pathophysiology of EMS. We address emerging literature on ECS in endometriosis lesion microenvironment and their influence on inflammation, proliferation, and vascularization. Finally, we provide insights into the potential utility of cannabinoid therapeutics in EMS.

Endocannabinoids

EMS is characterized by pelvic pain and a dysfunctional immune response. As the ECS is involved in the regulation of both processes, it is no surprise that there are alterations in this system in those with EMS. The role of the ECS in EMS is yet to be fully elucidated, but studies have begun to show that there are differences in the ECS in patients with EMS compared to individuals without EMS (Fig. 3 ). Fig. 3 The endocannabinoid system in endometriosis pathophysiology. EMS has been associated with endocannabinoid dysregulation and deficiency that contributes to increased pain sensitivity, compromised decidualization, infertility, and related complications. Endometriotic lesions produce differential levels of endocannabinoids (ECs) but their role in disease progression versus bystander effect is not entirely known. In vivo studies have shown that synthetic cannabinoids and some ECs (palmitoylethanolamide-PEA) have anti-inflammatory effects and inhibit the proliferation of endometriosis (EMS)-like lesions in mice The endocannabinoid system in endometriosis pathophysiology. EMS has been associated with endocannabinoid dysregulation and deficiency that contributes to increased pain sensitivity, compromised decidualization, infertility, and related complications. Endometriotic lesions produce differential levels of endocannabinoids (ECs) but their role in disease progression versus bystander effect is not entirely known. In vivo studies have shown that synthetic cannabinoids and some ECs (palmitoylethanolamide-PEA) have anti-inflammatory effects and inhibit the proliferation of endometriosis (EMS)-like lesions in mice Systemically, EMS patients have elevated levels of AEA and 2-AG as well as their structural analogues, PEA and OEA as compared to women without EMS (Sanchez et al. 2016 ). Plasma levels of AEA, 2-AG, and OEA were also elevated in the secretory phase compared to the proliferative phase in EMS patients (Sanchez et al. 2016 ). Studies from our group revealed that endometriotic lesions produce members of ECS and that levels of PEA in EMS lesions were significantly higher when compared to eutopic endometrium from EMS patients (Lingegowda et al. 2021a ). EMS patients presenting with moderate to severe dysmenorrhea showed higher levels of AEA and PEA when compared to those with low-to-moderate pain symptoms (Sanchez et al. 2016 ). These findings partly explain some of the pain symptoms in EMS as elevated levels of AEA and PEA are correlated with pain levels. Hence, several clinical trials are focused on using PEA alone or in combination with other anti-inflammatory drugs to assess the feasibility and efficacy of PEA therapy to treat EM-associated pain (reviewed elsewhere extensively) (Bouaziz et al. 2017 ). Alterations in the ECS were also reported within the eutopic endometrium in patients with EMS. CB1 mRNA and protein was decreased in endometrial tissue in EMS patients compared to controls (Resuehr et al. 2012 ). While most of these findings on ECS dysregulation, including that from our lab, are correlative, this provides a basis that the interplay between levels of circulating and localized ECs with specific receptor expression within the EMS microenvironment may contribute to the disease pathogenesis and associated symptoms. Specific cause and effect experiments using knockout mice for each EC component and receptor will be required to address the causal role the ECS plays in EMS pathogenesis. There are several ECs and receptor alterations in the endometriotic lesions of EMS patients. A study of adenomyosis and EMS found significantly lower CB1 and CB2 receptor expression in glandular and SCs compared to the eutopic endometrium of EMS patients and individuals without EMS (Bilgic et al. 2017 ). Similarly, we also showed that CB2 receptor expression in ectopic lesions was significantly lower than both eutopic endometrium from EMS patients and endometrium from individuals without EMS. The increased EC levels seen systemically may contribute to this observed decrease in CB1 and CB2 receptor expression in a negative feedback mechanism, which could impair pain modulation in this system (Sanchez et al. 2016 ). As signaling via these receptors typically induces anti-inflammatory effects, it can be deduced that lower levels of CB1 and CB2 receptors in endometriotic lesions contribute to a lack of anti-inflammatory effects in lesions. In contrast, other studies found equal expression of CB1 and CB2 receptors in EMS compared to controls (Leconte et al. 2010 ). A decrease in FAAH, NAPE-PLD, MAGL, and DAGL enzymes has been reported in both endometriotic and adenomyotic tissues compared to healthy controls (Bilgic et al. 2017 ). These lower levels of catabolizing enzymes in the stromal and epithelial compartments of the lesions likely contribute to slower synthesis and degradation of AEA, resulting in higher AEA levels reported in patient plasma samples (Bilgic et al. 2017 ). There is also a significant elevation in TRPV1 and TRPA1 mRNA levels in ectopic endometrial tissue in patients with deep infiltrating EMS compared to autologous eutopic endometrium and healthy control endometrium (Bohonyi et al. 2017 ). Stromal immunoreactivities of these receptors are correlated with the severity of pain symptoms in patients, notably dysmenorrhea. These receptors are found on sensory nerve terminals and non-neuronal structures and are stimulated by pro-inflammatory molecules in the lesion environment which further triggers pain in EMS (Bohonyi et al. 2017 ). EC signaling via the CB1 receptor in a mouse model has been shown to play a vital role in the symptoms associated with EMS. The sensory and sympathetic neurons that innervate and play a role in the nociceptive aspect of EMS lesions express CB1 receptors on their somata and fibers (Dmitrieva et al. 2010 ). A rat model exploring the impact of CB1 receptor signaling in EMS symptoms found that CB1 receptor agonists decrease EMS-associated pain, whereas CB1 receptor antagonists increase EMS-associated pain (Dmitrieva et al. 2010 ). Signaling via the CB1 receptor may also contribute to the initial development of EMS lesions. Synthetic CB1 receptor agonists, such as methandamide, stimulated ESC migration through activation of PI3K and ERK1/2 pathways in a dose-dependent manner via CB1 receptors (Gentilini et al. 2010 ). As endometrial cell migration is a key aspect in the pathogenesis of EMS, these results suggest the potential involvement of EC signaling, more specifically CB1 receptor signaling and ERK1/2 P13K activation, in lesion establishment (Gentilini et al. 2010 ). Although CB1 receptor expression has been identified in EMS lesions, where neuronal innervations are observed, it is challenging to identify if CB1 expressed in the lesion (stromal and epithelial compartments) or on the innervated neurons participate in nociceptive episodes. CB1 receptor agonists have a favorable effect on limiting cell proliferation and managing EMS-associated pain. Notably, both CB1 and CB2 receptor agonists have an anti-proliferative and pro-apoptotic effect on endometriotic SCs (Bilgic et al. 2017 ), suggesting that ECs increase apoptosis in EMS and offer a potential therapeutic avenue. Taken together, these findings further suggest that the ECS may play an important role in the mechanism underlying EMS pathogenesis and maintenance (Table 1 ). Table 1 Summary of endocannabinoid (EC) molecules identified in circulation and tissues of endometriosis (EMS) patients. Most prominent ECs in circulation such as N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were found to be altered in circulation. PEA, fatty acid amide hydrolase (FAAH), and N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) were also found to be altered in the EMS lesions, along with cannabinoid receptors 1 (CB1) and (CB2) 2 and transient receptor potential cation channel subfamily V member 1 (TRPV1) Area Endocannabinoid system component Levels Significance Systemic AEA/2-AG (Sanchez et al. 2016 ) Elevated Correlates with pain levels PEA/OEA (Sanchez et al. 2016 ) Elevated Peritoneal fluid AEA/2-AG a (Andrieu et al. 2022 ) Elevated/reduced Inflammation Follicular fluid AEA (Fonseca et al. 2021 ) Elevated Inflammation Eutopic endometrium CB1 receptor (Resuehr et al. 2012 ) Decreased Regardless of the cycle phase CB1 receptor/CB2 receptor (Shen et al. 2019a ) Decreased TRPV1 (Bohonyi et al. 2017 ) Increased Impact on pain Ectopic lesion PEA (Lingegowda et al. 2021a ) Increased Anti-inflammatory CB1 receptor/CB2 receptor (Lingegowda et al. 2021a ; Bilgic et al. 2017 ; Shen et al. 2019a ) Decreased Inflammation FAAH/NAPE-PLD (Bilgic et al. 2017 ) Decreased Higher AEA levels TRPV1/TRPA1 (Bohonyi et al. 2017 ) Increased Increased pain Myometrium CB1 receptor/CB2 receptor (Shen et al. 2019b ) Increased Correlates with pain levels a During the proliferative phase of the menstrual cycle only Summary of endocannabinoid (EC) molecules identified in circulation and tissues of endometriosis (EMS) patients. Most prominent ECs in circulation such as N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were found to be altered in circulation. PEA, fatty acid amide hydrolase (FAAH), and N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) were also found to be altered in the EMS lesions, along with cannabinoid receptors 1 (CB1) and (CB2) 2 and transient receptor potential cation channel subfamily V member 1 (TRPV1) a During the proliferative phase of the menstrual cycle only

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