Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?

Abstract

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Keywords: endometriosis; inflammation; nerve signalling; neurogenic inflammation; neuroimmune modulation; non-hormonal treatment; peripheral nerve.

Figure 1

Main pathways involved in the pathogenesis of inflammatory pain in endometriosis. Endometrial fragments in the peritoneum lead to peritoneal inflammation. The same immune response is seen at endometriotic lesions, where the increased production of cytokines, chemokines, growth factors and immune cells also contributes to an enhanced inflammatory environment present in the peritoneal cavity of women with EM. Of these inflammatory mediators, PGE2, tumour necrosis factor-α (TNFα), nerve growth factor (NGF), RANTES and interleukins are also able to stimulate sensory nerve endings and activate a positive feedback loop, further increasing proinflammatory modulator production. The expression of pain receptors is also increased in EM patients’ nerve fibres. The enhanced stimulation and activation of peripheral nerve endings in the peritoneal cavity increase the painful stimuli, initiating and maintaining chronic pelvic pain.