Mechanisms of endometriosis pain

Inflammation, neurogenic inflammation, neuroangiogenesis, peripheral sensitization and central sensitization all contribute to chronic pain in endometriosis, according to a review in the journal Frontiers in Cellular Neuroscience.

“Whilst many studies focus on retrograde menstruation, and the formation and development of lesions in the pathogenesis of endometriosis, the mechanisms underlying the associated pain remain poorly described,” wrote the Australian authors.1

Because endometriosis patients also have comorbidities like irritable bowel syndrome and overactive bladder syndrome, common nerve pathways innervating the colon, bladder and female reproductive tract can contribute to comorbidity via cross-organ sensitization.

Surgical removal of endometrial lesions can successfully alleviate pain, thus implicating these lesions in chronic pain; however, inconsistencies exist between pain severity and lesion score. Chronic pain also often returns within 12 months of lesion removal, despite the absence of lesion regeneration.

In fact, some reports indicate 20% to 28% of patients do not attain pain relief following surgery.

Growing evidence suggests that a chronic remodeling of the nervous system occurs in shared sensory neural pathways to induce a state of protracted peripheral and central sensitization and chronic pain in endometriosis patients.

More recent revelations of the mechanisms underlying the development of a chronic pain state in endometriosis point to cyclical bleeding from lesions and subsequent inflammation at lesion sites and in the peritoneal cavity. These proinflammatory responses result in sensory nerve activation and altered activation of nociceptive pathways.

An increase in extra-uterine debris during menstruation exacerbated by additional retrograde menstruation induces an enhanced inflammatory response within the peritoneum. This allows for the interaction of these immune cells with sensory nerves to induce chronic pelvic pain.

Long-term exposure to proinflammatory cytokines may activate and sensitize sensory nerves present in endometriotic lesions, thus initiating the transfer of pain to the central nervous system (CNS).

According to several studies, once endometrial fragments adhere to a peritoneal location and become lesions, they undergo a process of neoangiogenesis, whereby a new blood supply is created by generating new blood vessels to support growth and survival, along with synchronized innervation by nerve fibers (neurogenesis).

Studies have found that endometriosis-associated menstrual pain is greatest in women whose endometriotic lesions had increased nerve fiber innervation.

Adding to the pro-nociceptive environment induced by endometrial lesions in the peritoneal cavity, the accumulation of degraded tissue byproducts can directly sensitize sensory nerve fibers through receptors on nociceptive afferent nerves located within lesions. Sensitized sensory nerve fibers also maintain inflammation by a positive feedback loop known as neurogenic inflammation.

Chronic sensitization of peripheral sensory nerve fibers could induce sensitization of the CNS in endometriosis. Recent studies conclude that exposure to chronic stress early in life can increase the likelihood of chronic pelvic pain later in life, whereas episodes of acute stress can trigger or worsen symptoms.

This review offered evidence of an overall heterogeneity in endometriosis, as opposed to a “one size fits all” approach, indicating personalized treatment based on etiology and symptomatology.1

“Shifting the paradigm of lesion-specific and cyclical inflammatory pain will continue to open up further areas to expand treatment opportunities,” wrote the authors.1

The next step is to clarify disease-specific changes and their targets at the lesion, dorsal root ganglion (DRG), spinal cord, and brain levels.

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Reference

  1. Maddern J, Grundy L, Castro J, et al. Pain in endometriosis. Front Cell Neurosci. Published online October 6, 2020. doi:10.3389/fncel.2020.590823