Endometriosis is a gynecological disorder characterized by the growth of endometrial tissue (glands and stroma) outside the uterus, mainly in the peritoneal cavity, ovaries, and intestines. This condition shows estrogen dependency and progesterone resistance, and it has been associated with chronic inflammation, severe pain, and infertility, which negatively affect the quality of life in reproductive women. The molecular mechanisms involved in the pathogenesis of endometriosis are not completely understood; however, inflammation plays a key role in the pathophysiology of the disease, mainly by altering the function of immune cells (macrophages, natural killer, and T cells) and increasing levels of pro-inflammatory mediators in the peritoneal cavity, endometrium, and blood. These immune alterations inhibit apoptotic pathways and promote adhesion and proliferation of endometriotic cells, as well as angiogenesis and neurogenesis in endometriotic lesions. It has been demonstrated that hormonal alterations in endometriosis are related to the inflammatory unbalance in this disease. Particularly, steroid hormones (mainly estradiol) promote the expression and release of pro-inflammatory factors. Excessive inflammation in endometriosis contributes to changes of hormonal regulation by modulating sex steroid receptors expression and increasing aromatase activity. In addition, dysregulation of the inflammasome pathway, mediated by an alteration of cellular responses to steroid hormones, participates in disease progression through preventing cell death, promoting adhesion, invasion, and cell proliferation. Furthermore, inflammation is involved in endometriosis-associated infertility, which alters endometrium receptivity by impairing biochemical responses and decidualization. The purpose of this review is to present current research about the role of inflammasome in the pathogenesis of endometriosis as well as the molecular role of sex hormones in the inflammatory responses in endometriosis.

Please cite this paper as: Mier‐Cabrera J, Jiménez‐Zamudio L, García‐Latorre E, Cruz‐Orozco O, Hernández‐Guerrero C. Quantitative and qualitative peritoneal immune profiles, T‐cell apoptosis and oxidative stress‐associated characteristics in women with minimal and mild endometriosis. BJOG 2011;118:6–16. Objectives  To assess immunological variables, T‐cell apoptosis and oxidative stress markers in the peripheral blood and peritoneal fluid of women with (WEN) and without (WWE) endometriosis. Design  Observational and transverse case–control study. Setting  National Institute of Perinatology, Mexico City, Mexico. Population and sample  Peripheral blood and peritoneal fluid obtained from 30 WWE and 32 WEN. Methods  Blood was drawn before surgery and peritoneal fluid was collected during surgery but before any surgical procedure had been carried out. Flow cytometry, spectrophotometry, high‐performance liquid chromatography and multiplex immunoassay analyses were performed. Main outcome measures  Peripheral and peritoneal lymphocyte subpopulations (CD3+, CD4+ CD3+, CD8+ CD3+, CD16+ CD56+, human leucocyte antigen‐DR+ CD3+ and CD19+), intracellular CD4+ CD3+ and CD8+ CD3+ cytokine synthesis (interleukin‐2 [IL‐2] and interferon‐γ [IFN‐γ]), CD3+ apoptosis, malondialdehyde and ascorbate concentrations and peritoneal cytokine concentrations. Results  No differences were found in peripheral and peritoneal lymphocyte subsets between the groups. Peritoneal T lymphocytes from WEN produced less IL‐2 and IFN‐γ than those from WWE. Peritoneal malondialdehyde concentrations were higher and ascorbate concentrations were lower in WEN than in WWE. Higher peritoneal concentrations of pro‐inflammatory cytokines (IL‐1β, tumour necrosis factor‐α and IL‐6) and chemokines (IL‐10, IL‐8, eotaxin, vascular endothelial growth factor, monocyte chemotactic protein‐1 and regulated upon activation, normal T‐cell expressed, and secreted) and lower concentrations of IFN‐γ, IL‐1 receptor antagonist and IL‐15 were found in WEN. No statistical differences were found in IL‐2, IL‐4, IL‐12 and IL‐13 concentrations. Conclusion  The alterations observed in WEN were associated with a diminished peritoneal T helper type 1 immune response. Pro‐inflammatory, chemotactic, angiogenic and oxidative stress markers were altered in the peritoneal milieu of WEN. These changes appeared to contribute to the peritoneal immune alterations found.

Endometriosis is one of the most frequent gynecological diseases in reproductive age women, but its etiology is not completely understood. Endometriosis is characterized by progesterone resistance, which has been explained in part by a decrease in the expression of the intracellular progesterone receptor in the ectopic endometrium. Progesterone action is also mediated by nongenomic mechanisms via membrane progesterone receptors (mPRs) that belong to the class II members of the progesterone and adipoQ receptor (PAQR) family. The aim of the present study was to evaluate the expression at mRNA and protein levels of mPR members in the eutopic and ectopic endometrium of women with endometriosis. Total RNA and total protein were isolated from control endometrium (17 samples), eutopic endometrium (17 samples), and ectopic endometrium (9 samples). The expression of PAQR7 (mPRα), PAQR8 (mPRβ), and PAQR6 (mPRδ) at mRNA and protein levels was evaluated by RT-qPCR and Western blot, whereas PAQR5 (mPRγ) gene expression was evaluated by RT-qPCR. Statistical analysis between comparable groups was performed using one-way ANOVA followed by Tukey’s multiple comparisons test with a confidence interval of 95 %. The analysis of gene expression showed that PAQR7 and PAQR5 expression was lower in both eutopic and ectopic endometrium as compared to the endometrium of women without endometriosis, whereas the expression of PAQR8 and PAQR6 was only reduced in eutopic endometrium. Furthermore, mPRα and mPRβ protein content was decreased in the ectopic endometrium of women with endometriosis. Our results demonstrate a decrease in the expression and protein content of mPRs in eutopic and ectopic endometrium of patients with endometriosis, which could contribute to the progesterone resistance observed in patients with this disease.

Objetives: The goal of this study was to determine if systemic and peritoneal oxidative stress biomarkers are related to each other and to retrograde menstruation in endometriosis. Methods: Plasma and peritoneal fluid oxidative stress biomarkers and hemoglobin and erythrocytes in peritoneal fluid as retrograde menstruation indicators, were measured in 28 patients with endometriosis and 23 without endometriosis. Results: In the peritoneal fluid, carbonyls and lipohydroperoxides, indicative of protein and lipid oxidative damage, were higher in endometriosis group (21%, p = 0.016 and 46%, p = 0.009, respectively). However, these biomarkers were not different in the blood plasma of both groups, and only protein dityrosine, was increased in the plasma of endometriosis group (31%, p = 0.04). The peritoneal fluid hemoglobin content was not higher in the endometriosis group, nor related to carbonyls and lipohydroperoxides. Additionally, the peritoneal fluid oxidative biomarkers were not correlated with the blood plasma ones, and only malondialdehyde, and ischemia-modified albumin were almost two times higher in peritoneal fluid. Discussion: Our results show a peritoneal and systemic oxidative stress biomarkers increase in endometriosis, but not related to each other, and do not support the hypothesis of an increase in hemoglobin-iron supply towards the peritoneal cavity that causes oxidative damage.

Background Endometriosis is an estrogen-dependent and chronic inflammatory disease affecting up to 10% of women. It is the result of a combined interaction of genetic, epigenetic, environmental, lifestyle, reproductive and local inflammatory factors. In this study, we investigated whether single nucleotide polymorphisms (SNPs) mapping to TNF-alpha (TNF, rs1800629) and IL-1beta (IL1B, rs1143634) and variable number tandem repeat polymorphism mapping to IL1-Ra (IL1RN intron 2, rs2234663) genetic loci are associated with risk for endometriosis in a Mexican mestizo population. Methods This study included 183 women with confirmed endometriosis (ENDO) diagnosed after surgical laparoscopy and 186 women with satisfied parity and without endometriosis as controls (CTR). PCR/RFLP technique was used for genotyping SNPs (rs1800629 and rs1143634); PCR for genotyping rs2234663. Results We found no statistical differences in age between groups nor among stages of endometriosis and the CTR group. We observed no difference in genotype and allele frequencies, nor carriage rate between groups in none of the three studied polymorphisms. The prevalence of TNF*2-allele heterozygotes (p = 0.025; OR 3.8), TNF*2-allele (p = 0.029; OR 3.4), IL1B*2-allele heterozygotes (p = 0.044; OR 2.69) and its carriage rate (p = 0.041; OR 2.64) in endometriosis stage IV was higher than the CTR group. Surprisingly, the carriage rate of IL1RN*2-allele (ENDO: p = 0.0004; OR 0.4; stage I: p = 0.002, OR 0.38; stage II: p = 0.002, OR 0.35; stage III: p = 0.003, OR 0.33), as well as the IL1RN*2-allele frequencies (ENDO: p = 0.0008, OR 0.55; I: p = 0.037, OR 0.60; II: p = 0.002, OR 0.41; III: p = 0.003, OR 0.38) were lower than the CTR group. Women with endometriosis stage IV (severe) had frequencies more alike to the CTR group in the IL1RN*2 allele frequency (31.2% vs. 27.2%) and carriage rate (37.5% vs. 41.9%). Conclusion Although these polymorphisms are not associated with the risk of endometriosis, Mexican mestizo women with severe stage of endometriosis have higher frequencies of TNF*2-, IL1B*2- and IL1RN*2-alleles, which may explain a possible correlation with disease severity rather than predisposition or risk.