The Role of the Immune Microenvironment in Endometriosis-Associated Infertility: A Systematic Review

Rashi Sharma (University of Warwick),  Dr Joseph Clymer (George Eliot Hospital), Dr Joshua Odendaal (University Hospital Coventry and Warwickshire)

Introduction

Endometriosis is a reproductive disease characterised by ectopic endometrial tissue growth, primarily on the outer uterine walls and ovaries. It affects approximately 190 million women globally, around 10% of reproductive-age women (1).

 Many women are diagnosed only when they face subfertility, with endometriosis prevalence in infertile women as high as 50% (2). Studies examining the link between endometriosis and infertility examined structural changes caused by the disease and treatment options (3,4).  Endometriosis-associated infertility is a multifactorial condition, and several studies have postulated that an altered immune system could play a role in this due to the role of inflammation in the pathogenesis of endometriosis (1; 5; 6).

Aims

This systematic review aimed to explore the role of the localised immune microenvironment in endometriosis-associated infertility and propose mechanisms through which inflammation may contribute to infertility.

Discussion

The results demonstrated that the localised immune response in endometriosis-associated infertility centred around IL-6, and this inflammation could damage/impair fallopian tubes and sperm motility.

Clinical Applicability

• The common theme throughout all the results was IL-6. IL-6 plays a central role in the inflammatory microenvironment of endometriosis, whether through downregulating anti-inflammatory markers or upregulating reactive oxygen species.
  • This suggests that targeting IL-6 may lead to increased fertility.
• Monoclonal antibodies against IL-6 are already used in several autoimmune diseases, such as rheumatoid arthritis and juvenile idiopathic arthritis, and they are being investigated as effective treatments for more acute conditions( 7).
• The results suggest that blocking the IL-6 pathway helps reduce the burden of infertility or could be used as an adjunct to IVF to improve outcomes.
• Tocilizumab is a recombinant humanised anti-IL-6 receptor currently on the market that could be used for this purpose(8). This could reduce the number of IVF cycles needed, which would also have economic benefits.
• Studies looking at the effect of Tocilizumab in pregnancy showed no increased rates of adverse events in pregnancies (9).

References

(1) Horne, A. W., & Missmer, S. A. (2022). Pathophysiology, diagnosis, and management of endometriosis. BMJ, 379, e070750.

(2) Bulletti, C., Coccia, M. E., Battistoni, S., & Borini, A. (2010). Endometriosis and infertility. J Assist Reprod Genet, 27(8), 441-447.

(3) Filip, L., Duică, F., Prădatu, A., Crețoiu, D., Suciu, N., Crețoiu, S. M.,…Voinea, S. C. (2020). Endometriosis Associated Infertility: A Critical Review and Analysis on Etiopathogenesis and Therapeutic Approaches. Medicina (Kaunas), 56(9).

(4) Macer, M. L., & Taylor, H. S. (2012). Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am, 39(4), 535-549. Your paragraph text

(5) Lin, Y. H., Chen, Y. H., Chang, H. Y., Au, H. K., Tzeng, C. R., & Huang, Y. H. (2018). Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies. Int J Mol Sci, 19(8).

(6) Pašalić, E., Tambuwala, M. M., & Hromić-Jahjefendić, A. (2023). Endometriosis: Classification, pathophysiology, and treatment options. Pathology - Research and Practice, 251, 154847.

(7) Choy, E. H., De Benedetti, F., Takeuchi, T., Hashizume, M., John, M. R., & Kishimoto, T. (2020). Translating IL-6 biology into effective treatments. Nature Reviews Rheumatology, 16(6), 335-345.

(8) Sheppard, M., Laskou, F., Stapleton, P. P., Hadavi, S., & Dasgupta, B. (2017). Tocilizumab (Actemra). Hum Vaccin Immunother, 13(9), 1972-1988.

(9) Nakajima, K., Watanabe, O., Mochizuki, M., Nakasone, A., Ishizuka, N., & Murashima, A. (2016). Pregnancy outcomes after exposure to tocilizumab: A retrospective analysis of 61 patients in Japan. Mod Rheumatol, 26(5), 66