Endometriosis and infertility: A complex web involving oocyte quality, the innate immune system and the uterine microbiome

Endometriosis is a common but poorly understood condition, impacting on quality of life and fertility. Diagnosis is also invasive, requiring surgery. Treatment for endometriosis symptoms is suboptimal, relying on analgesia and hormonal suppression. This presents difficulties for women who are trying to conceive. While ART is an effective option for endometriosis-related infertility, poorer outcomes are seen compared to those without the disease. Whether endometriosis-related infertility is the result of oocyte or endometrial dysfunction is debated. The immune system has been implicated in endometriosis pathogenesis and reproductive consequences. Further understanding of the immune profile in endometriosis may offer future diagnostic and treatment options. While the innate immune system is known to be crucial in successful embryo implantation, the interplay between the embryo and the endometrial immune components is only partially understood. AMPs comprise an important part of female reproductive defence. The role they play in the endometrium, in embryo implantation, and their interaction with the endometrial microbiome, is not clear. Methods: To investigate the role of the oocyte, innate immune system and FRT microbiome in endometriosis, we adopted a multi-pronged approach. A retrospective review first analysed data from time lapse embryo incubators, comparing embryo development morphokinetic variables in patients with endometriosis and unexplained infertility. A retrospective study expanded on previous work looking at IL-17A levels and ART outcomes by examining oocyte and embryo parameters in women with low (50pg/ml) serum IL-17A. A prospective approach was used to study the endometrial innate immune profile in patients with endometriosis and infertility, focusing on expression of AMPs and IL-17A in endometrial biopsies. A pilot study also examined microbiota in the female reproductive tract using a Q-PCR protocol. Results: A retrospective analysis of over 900 embryos using time lapse incubator data revealed a significant difference in early time points between the control group and endometriosis, specifically the time of pronuclei disappearance (tPNf) and the time taken to reach 2 discrete cells(t2), 3 cells (t3), 4 cells (t4), and 6 cells (t6). A subgroup analysis, excluding cases of sperm abnormalities from the endometriosis cohort, found that only the differences in tPNf, t2 and t3 persisted as significant. A retrospective analysis from previous work in our group shows that a mean fertilisation rate for oocytes retrieved from women with a serum IL-17A level of 50pg/ml (0.5857; n=11). Prospective studies then analysed the innate immune milieu in the endometrium in endometriosis and infertility. Using a Q-PCR approach, we found that endometrial expression of the AMPs elafin, SLPI, Human Beta defensin 1 and S100A9 were reduced in cases of endometriosis. There was no significant difference in levels of IL-17A protein in the endometrium in endometriosis (p= 0.3636), or between stages of disease. A weak negative correlation between IL-17A protein and expression of S100A9, Elafin, SLPI, S100A8 and S100A9 was found, but was not significant. An evaluation of the FRT microbiome in endometriosis using a Q-PCR approach was also performed. Bacterial phyla were detected in the low biomass compartments of the endometrium and peritoneal cavity. A negative correlation between SLPI and s100A9 and Lactobacillus genus was also found. Conclusion: Endometriosis impacts on various aspects of fertility, including embryo development and the endometrium. Aspects of the innate immune system of the endometrium, including AMPs, are altered in endometriosis. The interaction between the endometrial microbiome and innate immune system warrants further study.