Machairiotis, N., Vasilakaki, S., & Thomakos, N. (2021). Inflammatory Mediators and Pain in Endometriosis: A Systematic Review. Biomedicines, 9(1). https://doi.org/10.3390/biomedicines9010054
Machairiotis N, Vasilakaki S, Thomakos N. Inflammatory Mediators and Pain in Endometriosis: A Systematic Review. Biomedicines. 2021;9(1). doi:10.3390/biomedicines9010054
Machairiotis, Nikolaos, et al. "Inflammatory Mediators and Pain in Endometriosis: A Systematic Review." Biomedicines, vol. 9, no. 1, 2021.
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RRM Academy Synopsis
Inflammatory Mediators Contribute to Pain in Endometriosis
A systematic review of 56 studies finds that inflammatory mediators contribute to endometriosis pain, partly by promoting blood vessel and nerve growth. The review suggests active roles in pain for CXC chemokines, fractalkine and prostaglandin E2 (PGE2), with IL-1β and IL-6 appearing to be leading interleukins. The authors call factors that promote this growth promising treatment targets.
Key Findings
Searches of PubMed, Scopus and Europe PMC for 1 January 2016 to 31 December 2020 returned 1871 articles, and 56 met the eligibility criteria for the review.
IL-1β appeared to be the main interleukin stimulating most of the factors that promote neuroangiogenesis, the parallel growth of nerves and blood vessels, with IL-6 alongside it.
Four studies in the review showed IL-6 overexpressed in endometriosis, with its expression depending on disease severity.
In an endometriosis animal model, fractalkine and its receptor were upregulated in ectopic endometrium and linked to pain conduction. Rodent work associated PGE2 regulation with vaginal hyperalgesia severity.
IL-1β induced nerve injury-induced protein 1 (Ninj1) expression in endometriotic stromal cells, and nerve fibers occupied Ninj1-positive areas of lesions. IL-1β also stimulated BDNF synthesis in eutopic endometriosis stromal cells.
Interpretation
The review follows the PRISMA reporting guideline and is registered with PROSPERO. Two authors screened the articles and extracted data independently. The included studies, published from 2016 to 2020, include work on samples from patients with endometriosis, cell cultures and rodent models. The findings describe biological pathways and associations. The authors note that how inflammation produces pain remains unclear and that reported cytokine profiles conflict.
RRM Context
Restorative reproductive medicine (RRM) seeks the cause of endometriosis pain. The review describes nerve fibers near lesions and inflammatory signals in nearby fluid. It identifies hormonal suppression as first-line medical treatment. Suppressive medications control symptoms and leave the lesions in place. Excision, the surgical standard, removes the tissue linked to nerve growth and inflammatory signaling.
Our editorial summary of this paper, not the article's abstract.
Abstract
Background
pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients' personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are disruptive events for patients. Hence, there is an urgency for the development of a sufficient non-invasive medical treatment. Inflammation is one of the causative factors of pain in endometriosis. It is well established that inflammatory mediators promote angiogenesis and interact with the sensory neurons inducing the pain signal; the threshold of pain varies and it depends on the state and location of the disease. The inhibition of inflammatory mediators' synthesis might offer a novel and effective treatment of the pain that is caused by inflammation in endometriosis.
Objectives
patients with endometriosis experience chronic pelvic pain, which is moderate to severe in terms of intensity. The objective of this systematic review is to highlight the inflammatory mediators that contribute to the induction of pain in endometriosis and present their biological mechanism of action. In addition, the authors aim to identify new targets for the development of novel treatments for chronic pelvic pain in patients with endometriosis.
Data Sources
three databases (PubMed, Scopus, and Europe PMC) were searched in order to retrieve articles with the keywords 'inflammation, pain, and endometriosis' between the review period of 1 January 2016 to 31 December 2020. This review has been registered with PROSPERO (registry number: CRD42020171018).
Study Eligibility Criteria
only original articles that presented the regulation of inflammatory mediators and related biological molecules in endometriosis and their contribution in the stimulation of pain signal were included.
Data Extraction
two authors independently extracted data from articles, using predefined criteria.
Results
the database search yielded 1871 articles, which were narrowed down to 56 relevant articles of interest according to the eligibility criteria.
Conclusions
inflammatory factors that promote angiogenesis and neuroangiogenesis are promising targets for the treatment of inflammatory pain in endometriosis. Specifically, CXC chemokine family, chemokine fractalkine, and PGE2 have an active role in the induction of pain. Additionally, IL-1β appears to be the primary interleukin (IL), which stimulates the majority of the inflammatory factors that contribute to neuroangiogenesis along with IL-6. Finally, the role of Ninj1 and BDNF proteins needs further investigation.
