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Review
. 2022 Oct 7;4(1):54.
doi: 10.1186/s42238-022-00163-8.

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

Harshavardhan Lingegowda  1 , Bailey J Williams  1 , Katherine G Spiess  1 , Danielle J Sisnett  1 , Alan E Lomax  1   2 , Madhuri Koti  1   3   4 , Chandrakant Tayade  5
Affiliations
Review

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

Harshavardhan Lingegowda et al. J Cannabis Res. .

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.

Keywords: Endocannabinoids; Endometriosis; Hyperalgesia; Infertility; Inflammation; Phytocannabinoids.

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Conflict of interest statement

The authors have no conflict of interest and consent for publication.

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Summary of the role of the endocannabinoid system in the context of endometriosis. Cannabinoid receptors 1 (CB1) and 2 (CB2) are considered as classical receptors and orphan G protein-coupled receptors (GPRs) and transient receptor potential (TRP) channels as nonclassical receptors of the endocannabinoid system (ECS). Arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are the predominant molecules of the ECS, while palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are found in a lesser extent. Molecules of the ECS are biosynthesized by, but not limited to, N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL) depending on the microenvironment. Degradation of the endocannabinoids (ECs) by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) is rapid. Together, the ECS is involved in a variety of physiological processes such as nociception, inflammation, and immune modulation
Fig. 2
Fig. 2
The endocannabinoid system signaling cascade. Arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are biosynthesized by N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL), respectively. Fatty acid amide hydrolase (FAAH) and MAGL are the metabolizing enzymes that degrade AEA to produce arachidonic acid (AA) and ethanolamine (ETA), and 2-AG to AA and glycerol. AEA and 2-AG are transported in and out of a cell through the putative endocannabinoid membrane transporters (EMTs). AEA and 2-AG bind to G protein-coupled receptors (GRPs), such as cannabinoid receptors 1 (CB1) and 2 (CB2), at varying affinities and to a lesser extent with the orphan GPR and transient receptor potential (TRP) channels. The endocannabinoid system (ECS) mainly targets the protein kinase A (PKA) signaling cascade via inhibition of adenylyl cyclase (AC)-cyclic adenosine monophosphate (AMP) that has direct inhibitory effects on β-catenin which affects epithelial-mesenchymal transition. Activation of the mitogen-activated protein kinase signaling cascades, such as extracellular signal-regulated kinase ½ (ERK ½), protein kinase B or Akt, phosphatidylinositol-3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and mammalian target of rapamycin (mTOR), is involved in cellular processes such as autophagy, apoptosis, cell cycle, and proliferation
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
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