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

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.

Antioxidant vitamins supplementation reduce endometriosis related pelvic pain in humans: a systematic review and meta-analysis

“…Endometriosis is associated with clinically significant symptoms in approximately 75–80% of individuals, with chronic pelvic pain being the most common and impactful symptom on patients' quality of life [ 40 ]. Pain in endometriosis can be nociceptive (including inflammatory), neuropathic, or a combination of both [ 41 ]. Aberrant inflammation and dysregulation of inflammatory factors play a major role in endometriosis-associated pain [ 42 ].…”

Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response

“…The ECS is involved in several physiological processes including (but not limited to) pain perception, immune regulation, and reproductive functions 31 ; CNR1 and CNR2 are expressed in immune cells, nerve tissues, and serve as critical regulators of reproductive processes including decidualization and embryo implantation 32,33 . The etiology of EM has been speculated to be routed in defective decidualization and retrograde menstruation of the endometrial fragments combined with ECS dysregulation 8,9,34 . While it is plausible that decreased ECS function influences EM lesion initiation, progression, and severe pain experience, it is not clear whether ECS dysfunction actively contributes to EM pathogenesis, or whether it represents a secondary consequence of alterations occurring within the refluxed endometrial tissue, leading to establishment of EM lesions.…”

“…CNR1 and CNR2 are primarily expressed in nerve tissues, immune cells, and reproductive tissues, where they regulate various physiological processes, including pain perception, immune responses, and reproductive functions 6 . Consequently, EM pathogenesis has been postulated as a consequence of EC deficiency 7,8 .…”

Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response

“…The ECS is involved in several physiological processes including (but not limited to) pain perception, immune regulation, and reproductive functions 30 ; CNR1 and CNR2 are expressed in immune cells, nerve tissues, and serve as critical regulators of reproductive processes including decidualization and embryo implantation 31,32 . The etiology of EM has been speculated to be routed in defective decidualization and retrograde menstruation of the endometrial fragments combined with ECS dysregulation 8,9,33 . While it is plausible that decreased ECS function influences EM lesion initiation, progression, and severe pain experience, it is not clear whether ECS dysfunction actively contributes to EM pathogenesis, or whether it represents a secondary consequence of alterations occurring within the refluxed endometrial tissue, leading to establishment of EM lesions.…”