Nerves and endometriosis

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“Endometriosis lesions are known to be hyperinnervated” (Liu, Yan, & Guo, 2019). People with endometriosis have abnormal nerve growth and nerve fibers close to endometriosis lesions (Zheng, Zhang, Leng, & Lang, 2019). Pain with endometriosis is multifactorial, including irritation of nerves in the pelvis, new nerve growth, heightened sensitivity to pain, inflammation in the pelvis, and pain producing agents in the pelvic fluid (Ferrero, Vellone, & Barra, 2019).  The interplay between nerves and inflammation is believed to play a significant role in pain. There are increased levels of multiple inflammatory factors in and around endometriosis lesions (Wei et al., 2020). Endometriosis “can also directly irritate and infiltrate pelvic nerves promoting endometriosis-associated pain” (Ferrero, Vellone, & Barra, 2019) and can lead “to corresponding neurological symptoms or deficits” (Working group of ESGE et al., 2020).

Studies:

“Endometriotic lesions are known to be hyperinnervated due to neurogenesis resulting from neutrophins secreted by endometriotic lesions and possibly platelets. These neutrophins seem to preferentially favour production of sensory neurons at the expense of sympathetic neurons….Since sensory nerves are known to be important in wound healing and fibrogenesis, our findings also give more credence to the notion that endometriotic lesions are wounds undergoing repeated tissue injury and repair.”

“…endometriosis is certainly a chronic inflammation disorder [4]. The levels and concentrations of active macrophages; interleukin (IL)-1β, IL-6, IL-8; nerve growth factor (NGF); other immune cells; and inflammatory factors are increased in peritoneal fluid (PF) and endometriotic lesions [4,5,6]. These changes are believed to contribute to serious symptoms of pain such as chronic pelvic pain, dysmenorrhea, and dyspareunia [7]. Notably in deep infiltrating endometriosis (DIE) and intestinal endometriosis, the anatomical distribution of lesions is normally more closely related to pelvic pain symptoms [2]. Abnormal innervations are observed in most endometriotic lesions: an increased number of total intact nerve fibers, increased sensory and decreased sympathetic nerve fiber density (NFD) [6], the occurrence of cholinergic and unmyelinated nerve fibers, etc. [8] In various studies, these abnormal phenomena have been correlated with endometriosis-associated pain [6, 8,9,10]. More importantly, sympathetic and parasympathetic systems have different inflammation-related effects in different stages of inflammation [10].”

“A growing body of evidence attests that patients with endometriosis endure pain associated with abnormal angiogenesis and the growth of novel nerve fibers in close proximity to ectopic lesions. Endometriotic lesions create an inflammatory environment and change the quality or quantity of inflammatory mediators or neurotransmitters, thereby stimulating peripheral nerve sensitization by remodeling the structure of peripheral synapses and accelerating conduction along nerve fibers…. Endometriosis-related pain is currently considered a form of neuropathic or neuroinflammatory pain.”

“The pathophysiology of the association between pain and endometriosis is still enigmatic. The cause of pain is likely to be multifactorial (Table 1) (9,10). In patients with severe endometriosis with large ovarian cysts and DIE, pain can be caused by the distortion of the pelvic anatomy and by the presence of extensive adhesions (involving the uterus, the ovaries and the rectosigmoid) (Figure 1) (10). However, there is a poor correlation between the degree of pain and the severity of endometriosis. Some patients with intense pain symptoms have only small endometriotic implants on the peritoneal surface while other patients with severe endometriosis are almost asymptomatic….patients with endometriosis have an inflammatory process within the peritoneal cavity. In fact, women with endometriosis have increased concentration of inflammatory cells (macrophages and T lymphocytes), chemokines (MCP1, RANTES), inflammatory cytokines (IL1β, IL6, IL8, TNFα) and inflammatory molecules in the peritoneal fluid (11). These molecules and cells can sensitize peripheral nerves promoting the generation of pain (12). In addition, some pain-inducing molecules (such as prostaglandins) have elevated concentration in peritoneal fluid of women with endometriosis. Finally, endometriotic nodule can also directly irritate and infiltrate pelvic nerves promoting endometriosis-associated pain (13).”

  • Working group of ESGE, ESHRE, and WES, Keckstein, J., Becker, C. M., Canis, M., Feki, A., Grimbizis, G. F., … & Tanos, V. (2020). Recommendations for the surgical treatment of endometriosis. Part 2: deep endometriosis. Human Reproduction Open2020(1), hoaa002. Retrieved from https://academic.oup.com/hropen/article/2020/1/hoaa002/5733057

“Endometriosis close to the sympathetic and parasympathetic nerve fibres (hypogastric plexus and splanchnic nerves) can lead to a dysfunction of pelvic organs (e.g. dysfunction of the bladder as well as disturbance of vaginal lubrication and intestinal dysfunction) (Possover, 2014). Involvement of somatic nerves, such as the sacral plexus and the sciatic nerve, leads to corresponding neurological symptoms or deficits.”

References

Ferrero, S., Vellone, V. G., & Barra, F. (2019). Pathophysiology of pain in patients with peritoneal endometriosis. Annals of translational medicine7(Suppl 1). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462618/

Liu, X., Yan, D., & Guo, S. W. (2019). Sensory nerve-derived neuropeptides accelerate the development and fibrogenesis of endometriosis. Human Reproduction34(3), 452-468. Retrieved from https://academic.oup.com/humrep/article-abstract/34/3/452/5303712

Wei, Y., Liang, Y., Lin, H., Dai, Y., & Yao, S. (2020). Autonomic nervous system and inflammation interaction in endometriosis-associated pain. Journal of Neuroinflammation17(1), 1-24. Retrieved from https://link.springer.com/article/10.1186/s12974-020-01752-1

Working group of ESGE, ESHRE, and WES, Keckstein, J., Becker, C. M., Canis, M., Feki, A., Grimbizis, G. F., … & Tanos, V. (2020). Recommendations for the surgical treatment of endometriosis. Part 2: deep endometriosis. Human Reproduction Open2020(1), hoaa002. Retrieved from https://academic.oup.com/hropen/article/2020/1/hoaa002/5733057

Zheng, P., Zhang, W., Leng, J., & Lang, J. (2019). Research on central sensitization of endometriosis-associated pain: a systematic review of the literature. Journal of pain research12, 1447. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514255/