Endometriosis is a chronic inflammatory disease associated with an impaired immune response at the site of lesion implantation. The ability of macrophages to respond to changes in their environment is critical for an effective immune response. However, the existing knowledge of the peritoneal immune cell populations, their activation state and contribution to the immunological changes that occur in endometriosis are still controversial and inconclusive. In this study, we have examined the relative abundance of peritoneal macrophage subtypes, in women with (n = 21) versus without (n = 18) endometriosis and disease-associated changes in the adaptive T cell response. Using flow cytometry, we showed that peritoneal fluid monocyte/macrophages are composed of two populations of cells that exhibit major differences in the levels of the CD14 and CD68 markers, which we classified as the CD14^+low/CD68^+low and CD14^+high/CD68^+high subpopulations. Moreover, endometriosis-associated changes in the macrophage subtypes occurred only in the CD14^+low/CD68^+low subpopulation. In this subpopulation, we found an increased macrophage type 2 response that was coupled with an increase in peritoneal T-helper 2 and T-regulatory cell populations in women with endometriosis, compared with controls. In summary, this study resolves conflicting data in the literature regarding changes in the peritoneal immune cell population in endometriosis and identifies CD14^+low/CD68^+low macrophages as the subpopulation that changes in response to the disease.

Endometriosis is a chronic gynecological disorder affecting the quality of life and fertility of many women around the world. Heterogeneous and non-specific symptoms may lead to a delay in diagnosis, with treatment options limited to surgery and hormonal therapy. Hence, there is a need to better understand the pathogenesis of the disease to improve diagnosis and treatment. Long non-coding RNAs (lncRNAs) have been increasingly shown to be involved in gene regulation but remain relatively under investigated in endometriosis. Mutational and transcriptomic studies have implicated lncRNAs in the pathogenesis of endometriosis. Single-nucleotide polymorphisms (SNPs) in lncRNAs or their regulatory regions have been associated with endometriosis. Genome-wide transcriptomic studies have identified lncRNAs that show deregulated expression in endometriosis, some of which have been subjected to further experiments, which support a role in endometriosis. Mechanistic studies indicate that lncRNAs may regulate genes involved in endometriosis by acting as a molecular sponge for miRNAs, by directly targeting regulatory elements via interactions with chromatin or transcription factors or by affecting signaling pathways. Future studies should concentrate on determining the role of uncharacterized lncRNAs revealed by endometriosis transcriptome studies and the relevance of lncRNAs implicated in the disease by in vitro and animal model studies.

Endometriosis is a chronic disease characterized by the implantation and proliferation of endometrial tissue outside of the uterine cavity. The nonspecific nature of the symptoms and the lack of sensitive, noninvasive diagnostic methods often lead to a significant delay in diagnosis, highlighting the need for diagnostic biomarkers. The correlation of circulating miRNAs with altered inflammatory signals seen in patients with endometriosis has raised the possibility that miRNAs can serve as biomarkers for the disease. In our study, we analyzed miRNA expression in saliva of women with and without endometriosis using a FireFly custom multiplex circulating miRNA assay. This focused panel included 28 human miRNAs, 25 of which have been previously found to be differentially expressed either in plasma, serum, and/or blood of women with endometriosis, compared to controls. We found that hsa-mir-135a was expressed significantly higher in the saliva of women with endometriosis, independent of disease stage and menstrual cycle phase. We confirmed that hsa-mir-135a also showed significantly elevated expression in the plasma of endometriosis patients. This indicates that hsa-mir-135a is a putative noninvasive biomarker of endometriosis in both saliva and plasma, but further validation studies are required to assess its clinical value as a biomarker.

Endometriosis is one of the most common gynecological illnesses causing extensive psychological, physical and social impact on patient’s life and exerts negative effects on health-related quality of Life (HRQoL). However, the effects of surgery on the postoperative HRQoL in the different endometriosis subgroups have not been fully evaluated. We performed a comparative retrospective study between 2014 and 2018 at the Medical University of Vienna, including all patients with surgically confirmed endometriosis who had completed the standardized Endometriosis Health Profile-30 (EHP-30) questionnaire 1 day after surgery (the questions refer to the 4 weeks preoperatively) and 6–10 weeks postoperatively. Compared to preoperative values, we found significant benefits, regarding postoperative conditions, in our study group (n = 115) in all five categories, “pain” (HR 0.78, p < 0.001); “self-determination” (HR 0.92, p < 0.001); “emotional health” (HR 0.83, p < 0.001);” social environment” (HR 0.67, p < 0.001); and “self-image” (HR 0.47, p < 0.001). Patients with only peritoneal endometriosis had the lowest preoperative clinical symptoms and there were no significant changes in any of the categories. In the subgroups deep infiltrating endometriosis (DIE) and DIE + ovarian endometrioma, surgical intervention results in a significantly greater improvement in all categories of EHP 30 compared to ovarian endometrioma without DIE or peritoneal endometriosis. Our study shows, that especially women with DIE—with or without ovarian endometrioma—demonstrate a more pronounced benefit from surgical therapy compared to patients with peritoneal endometriosis or endometrioma without DIE.

MLLT11 is a gene implicated in cell differentiation and the development and progression of human cancers, but whose role in the pathogenesis of endometriosis is still unknown. Using quantitative RT-PCR and immunohistochemistry, we analyzed 37 women with and 33 women without endometriosis for differences in MLLT11 expression. We found that MLLT11 is reduced in the ectopic stroma cells of women with advanced stage endometriosis compared to women without endometriosis. MLLT11 knockdown in control stroma cells resulted in the downregulation of their proliferation accompanied by G1 cell arrest and an increase in the expression of p21 and p27. Furthermore, the knockdown of MLLT11 was associated with increased apoptosis resistance to camptothecin associated with changes in BCL2/BAX signaling. Finally, MLLT11 siRNA knockdown in the control primary stroma cells led to an increase in cell adhesion associated with the transcriptional activation of ACTA2 and TGFB2. We found that the cellular phenotype of MLLT11 knockdown cells resembled the phenotype of the primary endometriosis stroma cells of the lesion, where the levels of MLLT11 are significantly reduced compared to the eutopic stroma cells of women without the disease. Overall, our results indicate that MLLT11 may be a new clinically relevant player in the pathogenesis of endometriosis.

Endometriosis appears to share certain cancer-related processes, such as cell attachment, invasion, proliferation and neovascularization, some of which can also be found in other healthy tissues. In order to better understand the altered milieu of the peritoneal cavity, while acknowledging the reported similarities between endometriosis and neoplastic processes, we applied a multiplex oncology panel to search for specific biomarker signatures in the peritoneal fluid of women with endometriosis, women with deep-infiltrating endometriosis (DIE), as well as controls. In total, 84 patients were included in our study, 53 women with endometriosis and 31 controls. Ninety-two proteins were measured in prospectively collected peritoneal fluid (PF) samples, using the “Proseek^® Multiplex Oncology I Panel”. We first compared patients with endometriosis versus controls, and in a second step, DIE versus endometriosis patients without DIE. Out of the 92 analyzed proteins, few showed significant differences between the groups. In patients with endometriosis, ICOS ligand, Endothelial growth factor, E-selectin, Receptor tyrosine-protein kinase erbB-2, Interleukin-6 receptor alpha, Vascular endothelial growth factor receptor 2, Fms-related tyrosine kinase 3 ligand, C-X-C motif chemokine 10, Epididymal secretory protein E4 and Folate receptor-alpha were decreased, while Interleukin-6 and Interleukin-8 were increased compared to controls. Looking at patients with DIE, we found Chemokine ligand 19, Stem cell factor, Vascular endothelial growth factor D, Interleukin-6 receptor alpha and Melanoma inhibitory activity to be increased compared to endometriosis patients without DIE. We have shown a distinct regulation of the immune response, angiogenesis, cell proliferation, cell adhesion and inhibition of apoptosis in PF of patients with endometriosis compared to controls. The specific protein pattern in the PF of DIE patients provides new evidence that DIE represents a unique entity of extrauterine endometriosis with enhanced angiogenetic and pro-proliferative features.