Onset Of Endometriosis Research Articles

Western diet promotes endometriotic lesion growth in mice and induces depletion of Akkermansia muciniphila in intestinal microbiota.

Endometriosis, affecting 10% of women in their reproductive years, remains poorly understood. Both individual and environmental unexplained factors are implicated in this heterogenous condition. This study aims to examine the influence of a Western diet on endometriosis lesion development in mice and to uncover the mechanisms involved. Mice were fed either a control diet or a Western diet (high in fatty acids and low in fiber) for 4weeks. Endometriosis was then surgically induced, and lesion development was monitored by ultrasound. After 7weeks, the mice were sacrificed for analysis of lesion characteristics through RT-qPCR, immunohistochemistry, and flow cytometry. Additionally, the intestinal microbiota was assessed using 16S rRNA gene sequencing. Mice on the Western diet developed lesions that were significantly twice as large compared to those on the control diet. These lesions exhibited greater fibrosis and proliferation, alongside enhanced macrophage activity and leptin pathway expression. Changes in the intestinal microbiota were significantly noted after endometriosis induction, regardless of diet. Notably, mice on the Western diet with the most substantial lesions showed a loss of Akkermansia Muciniphila in their intestinal microbiota. A Western diet significantly exacerbates lesion size in a mouse model of endometriosis, accompanied by metabolic and immune alterations. The onset of endometriosis also leads to substantial shifts in intestinal microbiota, suggesting a potential link between diet, intestinal health, and endometriosis development.

The potential role of gut microbiota in the occurrence and development of endometriosis.

Endometriosis (EMT) has a significant impact on women's physical and mental health. In this study, high-throughput sequencing technology was employed to detect differences in gut microbiota between EMT patients and healthy individuals (CTL). Additionally, Spearman correlation analysis was utilized to analyze the correlation between different bacterial genera and EMT biomarkers (CA125 and CA199). The results demonstrated that at the phylum level, the relative abundances of Proteobacteria and Desulfobacterota_G_459546 in the EMT group were significantly higher than those in the CTL group, while the relative abundances of Bacteroidota and Firmicutes_A in the EMT group were significantly lower than those in the CTL group. At the genus level, the relative abundances of Burkholderiales and Sphingomonadales in the EMT group were significantly higher than those in the CTL group, while the relative abundances of Bacteroidales and Roseburia in the EMT group were significantly lower than those in the CTL group. The correlation analysis results show that CA125 and CA199 are significantly positively correlated with Burkholderiales and Sphingomonadales, and significantly negatively correlated with Bacteroidales, Oscillospirales, and Roseburia. The PICRUSt2 results show that the relative abundance in the cell motility and xenobiotics biodegradation and metabolism pathways in the EMT group was higher than that in the CTL group, while the relative abundance in the translation, replication and repair, folding, sorting and degradation, metabolism of terpenoids and polyketides and metabolism of cofactors and vitamins pathways in the EMT group was lower than that in the CTL group. In brief, there is a close correlation between the imbalance of gut microbiota and the onset of EMT. The intestinal microbiota has great significance broad prospects for the prevention, diagnosis and treatment of EMT.

The interplay between systemic inflammatory factors and endometriosis: A bidirectional mendelian randomization study

ObjectiveTo utilize vast genetic data to reveal the interplay between 41 systemic inflammatory factors and endometriosis. DesignBidirectional Mendelian randomization study. Mains outcome measuresThis study obtained believable genetic instrumental variables for systemic inflammatory factors. The effect of systemic inflammatory factors on different endometriosis phenotypes, and the effect of endometriosis on the concentrations of systemic inflammatory factors were investigated. ResultsIn this mendelian randomization study, we found 20 causal relationships involving 18 systemic inflammatory factors and it was shown that Monocyte chemotactic protein-1, Macrophage inflammatory protein-1a, Granulocyte colony-stimulating factor, Macrophage migration inhibitory factor, Interleukin-4, Interleukin-5, Interleukin-8, Interleukin-9, Interleukin-12p70, Interleukin-16, and Interleukin-17 may be the upstream causes of endometriosis (P<0.05). Additionally, if the definition of exposure in the mendelian randomization was endometriosis, it could suggestively cause an increase in Eotaxin, cutaneous T-cell attracting chemokine, and Interferon gamma-induced protein 10 levels, and a decrease in growth-regulated oncogene-alpha, Interleukin-2 receptor, alpha subunit, platelet-derived growth factor BB, and Interleukin-18 (P<0.05). Reverse causality was not observed between a single systemic inflammatory factor and endometriosis. ConclusionsOur findings indicate that several systemic inflammatory factors may act as the initiator at the onset of endometriosis. Additionally, several other inflammatory factors are far more probable to involved downstream during disease development.

Molecular and Epigenetic Impacts of Pesticides on the Female Reproductive System: A Review

Pesticides, primarily originating from agricultural activities, have raised environmental and health concerns due to their suspected effects on the female reproductive system. Despite their widespread application, a significant research void exists concerning their implications for human female reproductive health. This review provides comprehensive information on the adverse effects of pesticides on female reproduction, focusing on their molecular and epigenetic mechanisms. In general, these adverse outcomes include ovarian dysfunction, hormonal irregularities, the onset of endometriosis, and an increased risk of stillbirths. From a mechanistic perspective, pesticides can interfere with the endocrine system, catalyze the formation of reactive oxygen species, and induce oxidative stress. At the molecular level, certain pesticides can act as hormone mimics, disrupting the normal hormonal balance. Moreover, they can trigger epigenetic shifts, leading to alterations in non-coding RNAs, histone configurations, and DNA methylation patterns. These epigenetic alterations not only have an immediate impact but can also be passed on to subsequent generations. Highlighting these concerns, this review underscores the urgent need for stringent regulations and aims to catalyze future in-depth studies on the relationship between pesticides and female reproductive health.

Sphingosine 1-phosphate signaling axis mediates neuropeptide S-induced invasive phenotype of endometriotic cells.

Endometriosis is a chronic gynecological syndrome characterized by endometrial cell invasion of the extra-uterine milieu, pelvic pain and infertility. Treatment relies on either symptomatic drugs or hormonal therapies, even though the mechanism involved in the onset of endometriosis is yet to be elucidated. The signaling of sphingolipid sphingosine 1-phosphate (S1P) is profoundly dysregulated in endometriosis. Indeed, sphingosine kinase (SK)1, one of the two isoenzymes responsible for S1P biosynthesis, and S1P1, S1P3 and S1P5, three of its five specific receptors, are more highly expressed in endometriotic lesions compared to healthy endometrium. Recently, missense coding variants of the gene encoding the receptor 1 for neuropeptide S (NPS) have been robustly associated with endometriosis in humans. This study aimed to characterize the biological effect of NPS in endometriotic epithelial cells and the possible involvement of the S1P signaling axis in its action. NPS was found to potently induce cell invasion and actin cytoskeletal remodeling. Of note, the NPS-induced invasive phenotype was dependent on SK1 and SK2 as well as on S1P1 and S1P3, given that the biological action of the neuropeptide was fully prevented when one of the two biosynthetic enzymes or one of the two selective receptors was inhibited or silenced. Furthermore, the RhoA/Rho kinase pathway, downstream to S1P receptor signaling, was found to be critically implicated in invasion and cytoskeletal remodeling elicited by NPS. These findings provide new information to the understanding of the molecular mechanisms implicated in endometriosis pathogenesis, establishing the rationale for non-hormonal therapeutic targets for its treatment.

P-353 possible correlation between the second-to-four digit ratio (2d:4d) and endometriosis: a case-control study

Abstract Study question This study investigates a possible association between the second-to-four digit ratio and endometriosis. Summary answer There is an association between a higher 2D:4D ratio and the presence of endometriosis. What is known already Endometriosis is characterised by the presence of endometrium epithelium and/or stroma outside the uterus. Recent findings suggest that endocrine disruptors during intrauterine life could determine the onset of the disease.The ratio between the length of the index finger (2D) and the ring finger (4D) is a sexually dimorphic feature. Moreover, it has been proposed as a marker of prenatal hormonal exposure since high level of androgens results in a lower 2D:4D ratio, whereas a prenatal oestrogenic environment results in a higher one. Therefore, a longer 2D:4D ratio could be considered as a silent sign of the disease. Study design, size, duration This study was conducted at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. Participants were recruited from July 2021 to October 2022. Cases included women with a past surgical diagnosis of endometriosis or with a current nonsurgical diagnosis of the disease. Women attending the outpatient clinics for periodic visits, contraception, severe male infertility, and cervical cancer screening programme and without a previous clinical or surgical diagnosis of endometriosis were enrolled as the control group. Participants/materials, setting, methods Women with endometriosis were divided into two groups: deep infiltrating endometriosis (DIE) and ovarian endometrioma (OMA) depending on the lesion localization. Among controls, endometriosis was excluded based on gynaecological history, pelvic transvaginal ultrasound, gynaecological bimanual examination and vaginal inspection.The digit lengths were measured on the right hand's ventral surface because previous studies suggested that the right hand is more sensitive to androgens. In addition, other clinical details were collected on standardised forms. Main results and the role of chance A total of 424 participants (endometriosis n = 212; controls n = 212) were recruited for this study. The group of cases included 114 women with ovarian endometriomas and 98 patients with deep infiltrating endometriosis.Although the median age in the endometriosis group was 37 years, significantly higher than controls (p &amp;lt; 0.01), other variables (such as BMI, ethnicity, smoking habit, age at menarche, parity, previous miscarriages and previous IVF) did not differ between the study groups.The right hand 2D:4D digit ratio resulted significantly higher in women with endometriosis compared to controls with 2D:4D ratio of 1.00 [0.97 - 1.03] and 0.99 [0.96 - 1.02] respectively (p = 0.002).The significant association remained when exclusively focussing on women with ovarian endometriomas (p = 0.002). In contrast, the association was no more significant when the analysis was restricted to women with deep infiltrating forms (p = 0.07).These findings support the potential role of intrauterine exposure of estrogen in the pathogenesis of the disease. A low ratio of testosterone-to-estradiol during fetal life may play a crucial role in endometriosis onset and progression. Limitations, reasons for caution The selection of controls may represent a source of bias since endometriosis was ruled out based on gynaecological and ultrasonography examination. Therefore, it could not be excluded having inadvertently included some cases among controls. Wider implications of the findings In conclusion, there is an association between a higher 2D:4D ratio and the presence of endometriosis. Our results support the hypothesis claiming potential influences of intrauterine hormonal and endocrine disruptors exposure during fetal life on the onset of the disease. Trial registration number not applicable

P-344 Prevalence and maternal risk factors for neonatal uterine bleeding (NUB): a possible origin of endometriosis?

Abstract Study question What is the prevalence and the cause of neonatal uterine bleeding, also known as “genital crisis”? Is it associated with maternal lifestyle and obstetric history? Summary answer The prevalence of NUB has been estimated as 29% and it seems to be correlated to some aspects of the maternal lifestyle What is known already NUB is considered a physiological phenomenon characterized by a menstrual-like bleeding occurring during the first days of life in female newborns, with an estimated incidence of 3-5%. It seems to be related to the reduction of steroid hormones in the baby after the separation from the maternal placenta, although, actually, some theories hypothesize NUB as a consequence of the exposure to molecular disruptors during intrauterine life. However, data regarding NUB still remain uncertain. Interestingly, recent theories assume a correlation between NUB and endometriosis onset, considering it as a consequence of the retrograde menstruation of stem cells during the genital crisis Study design, size, duration This is a prospective cohort study performed in a population of 105 mothers-to-be who delivered their babies at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan between March 2022 and December 2022. Inclusion criteria were: gestation of a single female fetus, age between 18 and 42, being in healthy condition and undergoing a low-risk pregnancy. Women with endometriosis had also been included Participants/materials, setting, methods At the time of recruitment few days before delivery, patients were asked to fill a questionnaire regarding general clinical characteristics (BMI, smoking habits, diet). After two weeks from delivery, a follow up was performed asking them information about pregnancy outcomes (time to pregnancy, complications and type of delivery), a possible vaginal bleeding for the baby and its duration, the type of lactation (breastfeeding, formula or both) and clinical neonatal information. Main results and the role of chance NUB frequency was unexpectedly high. Twenty-nine percent of the babies experienced NUB with a duration of 3 days and insurgence 2 days post-partum. Among the variables analyzed, genital crisis resulted higher in newborns from women with significantly higher BMI compared to women with a lower BMI (BMI 23 vs 21.5 respectively, p&amp;lt;0.05). Smoking during pregnancy was associated with a higher incidence of newborns with NUB (20% vs 4% in controls; p &amp;lt; 0.05). According to the type of lactation, in newborns with genital crisis, 43% of them received maternal breastfeeding while the same type of feeding has been reported in 69% of controls (p&amp;lt;0.05). Lastly, soy consumption by the mothers was observed only in 41% of cases of genital crisis while among mothers whose newborns did not experience NUB, 58% declared presence of soy in their diet (p&amp;lt;0.05). Limitations, reasons for caution The population size is relatively small. Also, as prospective cohort study, loss of individuals at follow up and recall bias may occur Wider implications of the findings Collecting more information on the hormonal determinants of NUB could be useful for future studies on intrauterine life and reproductive disorders. If a link between NUB and endometriosis is confirmed, NUB might lead to the understanding of the onset of this pathological condition Trial registration number not applicable

The histopathological features of the surgical endometriosis model using systemic autoimmune disease-prone mice.

Endometriosis is a common gynecological disease that affects women of reproductive age in which the uterine endometrium grows outside the uterus. Origin of the ectopic endometrium is thought to be the retrograde endometrium through the oviducts. However, factors that determine the adherence and proliferation of the ectopic endometrium have not been revealed. Importantly, systemic autoimmune diseases are considered a key factor in the endometriosis onset. Herein, we established a surgical endometriosis rodent model using autoimmune disease-prone MRL/MpJ-Faslpr/lpr (MRL/lpr) and MRL/+ mice to provide basic evidence of the relationship between autoimmune disease and endometriosis. Endometriosis lesions were successfully induced in two regions after transplanting uterine tissues from donor mice into the peritoneal cavity of recipient mice: the peritoneum or adipose tissue around the transplantation point (proximal lesions) and the gastrosplenic ligament or intestinal mesentery far from the transplantation site (distal lesions). Distal lesions were observed only in MRL/lpr mice, whereas endometriosis lesions showed no genotype- or region-related differences in the histology and distribution of sex hormone receptors and T cells. In contrast, transplanted uterine tissues in donor MRL/lpr mice exhibited a large infiltration of T cells in the lamina propria. Splenomegaly was more common in recipient than that in donor MRL/lpr mice. These results suggest that the infiltration of endogenous T cells in the endometrium alters the growth features of ectopic endometrium, possibly affecting the severity of endometriosis in patients with systemic autoimmune diseases.

Pathogenesis Based Diagnosis and Treatment of Endometriosis.

Understanding the pathophysiology of endometriosis is changing our diagnosis and treatment. Endometriosis lesions are clones of specific cells, with variable characteristics as aromatase activity and progesterone resistance. Therefore the GE theory postulates GE incidents to start endometriosis, which thus is different from implanted endometrium. The subsequent growth in the specific environment of the peritoneal cavity is associated with angiogenesis, inflammation, immunologic changes and bleeding in the lesions causing fibrosis. Fibrosis will stop the growth and lesions look burnt out. The pain caused by endometriosis lesions is variable: some lesions are not painful while other lesions cause neuroinflammation at distance up to 28 mm. Diagnosis of endometriosis is made by laparoscopy, following an experience guided clinical decision, based on history, symptoms, clinical exam and imaging. Biochemical markers are not useful. For deep endometriosis, imaging is important before surgery, notwithstanding rather poor predictive values when confidence limits, the prevalence of the disease and the absence of stratification of lesions by size, localization and depth of infiltration, are considered. Surgery of endometriosis is based on recognition and excision. Since the surrounding fibrosis belongs to the body with limited infiltration by endometriosis, a rim of fibrosis can be left without safety margins. For deep endometriosis, this results in a conservative excision eventually with discoid excision or short bowel resections. For cystic ovarian endometriosis superficial destruction, if complete, should be sufficient. Understanding pathophysiology is important for the discussion of early intervention during adolescence. Considering neuroinflammation at distance, the indication to explore large somatic nerves should be reconsidered. Also, medical therapy of endometriosis has to be reconsidered since the variability of lesions results in a variable response, some lesions not requiring estrogens for growth and some being progesterone resistant. If the onset of endometriosis is driven by oxidative stress from retrograde menstruation and the peritoneal microbiome, medical therapy could prevent new lesions and becomes indicated after surgery.

The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain.

Endometriosis is a chronic, burdensome condition that is historically understudied. Consequently, there is a lack of understanding of the etiology of the disease and its associated symptoms, including infertility and chronic pelvic pain (CPP). Endometriosis development is influenced by estrogen metabolism and inflammation, which are modulated by several factors including the microbiome and the estrobolome (the collection of genes encoding estrogen-metabolizing enzymes in the gut microbiome). Therefore, there is increasing interest in understanding the role of microbiota in endometriosis etiology. To date, there is no cure for endometriosis and treatment options often are ineffective. This manuscript will review the potential relationship between the microbiome and endometriosis, infertility and CPP and highlight the available data on the microbiome in relation to endometriosis and its related symptoms. The overarching goal of this manuscript is to inform future microbiome research that will lead to a deeper understanding of the etiology of the disease and possible diagnostic modalities and treatments. The potential impact of the microbiome on estrogen regulation modulated by the estrobolome, as well as inflammation and other endometriosis-promoting mechanisms within the genital tract, will be reviewed. The methodological limitations of microbiome-related studies will be critically assessed to provide improved guidelines for future microbiome and clinical studies. PubMed databases were searched using the following keywords: endometriosis AND microbiome, infertility AND microbiome, pelvic pain AND microbiome, IVF (in-vitro fertilization) AND microbiome, endometriosis AND infertility. Clinical and preclinical animal trials that were eligible for review, and related to microbiome and endometriosis, infertility or CPP were included. All available manuscripts were published in 2002-2021. In total, 28 clinical and 6 animal studies were included in the review. In both human and animal studies, bacteria were enriched in endometriosis groups, although there was no clear consensus on specific microbiota compositions that were associated with endometriosis, and no studies included infertility or CPP with endometriosis. However, bacterial vaginosis-associated bacteria and Lactobacillus depletion in the cervicovaginal microbiome were associated with endometriosis and infertility in the majority (23/28) of studies. Interpretation of endometrial studies is limited owing to a variety of methodological factors, discussed in this review. In addition, metadata outlining antibiotic usage, age, race/ethnicity, menopausal status and timing of sample collection in relation to diagnosis of endometriosis was not consistently reported. Animal studies (6/6) support a bidirectional relationship between the gut microbiota and endometriosis onset and progression. There is evidence that a dysbiotic gut or genital microbiota is associated with multiple gynecologic conditions, with mounting data supporting an association between the microbiome and endometriosis and infertility. These microbiomes likely play a role in the gut-brain axis, which further supports a putative association with the spectrum of symptoms associated with endometriosis, including infertility and CPP. Collectively, this review highlights the demand for more rigorous and transparent methodology and controls, consistency across the field, and inclusion of key demographic and clinical characteristics of disease and comparison participants. Rigorous study designs will allow for a better understanding of the potential role of the microbiome in endometriosis etiology and the relationship to other disorders of the female reproductive tract.

From Environmental to Possible Occupational Exposure to Risk Factors: What Role Do They Play in the Etiology of Endometriosis?

Endometriosis is a gynecological disorder characterized by the presence of endometrial stroma and glands outside the uterine cavity. A systematic review of the literature was conducted to clarify, starting from environmental exposure data, whether possible occupational risk factors may correlate with the onset of the disease. The guidelines for reporting systematic reviews of the “PRISMA” statement were followed and two databases, Scopus and PubMed, were used. Of the 422 studies selected with specific keywords, 32 publications were eligible, 28 of which referred to chemical agents and 4 related to night work. Conflicting data emerged among these studies. Although some compounds seemed to be more involved than others in the onset of endometriosis. Association with exposure to organochlorine compounds is the most supported by the epidemiological data, while other pesticide exposure did not show any clear correlation. Likewise, the hypothesis of a correlation with perfluoroalkyls exposure is not currently supported by data. The involvement of metals as risk factors has not been confirmed, while the role of night work, in the case of long service, seems to play an etiological role. In order to clarify the potential occupational risk of endometriosis development, well-designed studies are needed to evaluate the potential association between chemical compounds and disease etiology.

The role of endometrial stem cells in the pathogenesis of endometriosis and their application to its early diagnosis†.

Focusing on endometrial stem cells (EnSCs) will contribute to clarifying the potential pathogenesis of endometriosis and provide support for the application of EnSCs as therapeutic and early diagnostic targets in endometriosis treatment.

Endometriosis and Microbiota: Is there a Relationship with the Perinatal Period?

The gut microbiota is a complex community of bacteria residing in the intestine. Animal models have demonstrated that several factors contribute to and can significantly alter the composition of the gut microbiota, including genetics; the mode of delivery at birth; the method of infant feeding; the use of medications, especially antibiotics; and the diet. The intestinal microflora provides a strong defense against intestinal pathogens and may be altered in inflammatory conditions that impact the gut, such as endometriosis. This research is in the form of a quantitative study aimed at discovering the relationship with development of the intestinal microbiome in the perinatal period and the impact of these microbiota on the local endometrial microenvironment as these mechanisms may influence gynecologic health outcomes and onset of endometriosis. We hypothesized that disease-specific changes of gut microbiota in patients with endometriosis may a provide new insights for psychological intervention, to improving the prognosis of endometriosis patients.

Interleukin-1/-33 Signaling Pathways as Therapeutic Targets for Endometriosis.

Endometriosis is an estrogen-dependent disease with symptoms of dysmenorrhea, chronic pain, and infertility that affects 6–10% of women of reproductive age. Medical or surgical therapy, such as administration of an anti-gonadotropin or ovarian cystectomy, provide effective pain relief. However, neither therapy can be used for patients wishing to become pregnant. Despite the high morbidity, the pathogenesis of endometriosis has not been well-elucidated. Several inflammatory cytokines are reported to participate in the onset of endometriosis. Here, we examined the role of interleukin (IL)-1/IL-33 signaling in the development of endometriosis using a mouse model of endometriosis. Endometriotic lesion volume was significantly reduced in Il33−/− and Il1r1−/− mice, and almost completely suppressed in Myd88−/− mice. Mice intraperitoneally administered with an antibody against IL-1 receptor 1 (IL-1R1) or IL-33 developed limited endometriotic lesions. Oral administration of an inhibitor against IL-1R-associated kinase 4 (IRAK4), a downstream signal molecule of MyD88, also suppressed lesion formation. Furthermore, even after the development of cystic lesions the IRAK4 inhibitor prevented the enlargement of lesions. These treatments all significantly reduced cellular proliferation, shown by decreased Ki-67 expression. These results reveal that IL-1/IL-1R1, IL-33/IL-33R and associated downstream signaling molecules are involved in the pathogenesis of endometriosis, and may provide novel therapeutic targets for endometriosis.

The levels of matrix metalloproteinase-9 and neutrophil gelatinase-associated lipocalin in different stages of endometriosis

This study was designed to explore matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) levels and MMP-9/NGAL ratio in women with and without endometriosis diagnosed surgically and/or histopathologically. The correlation between biomarkers and the severity of the disease is analysed. The revised American Fertility Society classification system was used to determine the severity of endometriosis. Serum MMP-9 and Ca125, urine NGAL levels were measured in all participants. Serum MMP-9 levels were significantly higher in the study group (n = 60) compared to controls (n = 31) (15.0 pg/mL (6.0–143.0) vs. 12.0 (4.0–18.0), respectively; p=.002). MMP-9 levels were significantly higher in severe endometriosis compared to mild endometriosis subgroups (p<.001). No significant difference was found between NGAL levels in study and control groups (p>.05). The diagnostic value of MMP-9 and NGAL is not superior than CA-125 for endometriosis. Nevertheless, MMP-9 might be a potential predictive marker for advanced stage of the disease.Impact StatementWhat is already known on this subject? The gold standard diagnostic test for diagnosis of endometriosis is laparoscopy combined with histopathological confirmation of eutopic endometrial glands and/or stroma. Both invasiveness and possible accompanying complications limit the preference regarding the surgical approach. Among non-invasive markers none has been accepted as gold standard neither for diagnosis nor for determining the severity of the disease. MMPs are extracellular endopeptidases, which have a significant role in degradation and remodelling of extracellular matrix for cellular migration and invasion. Among these, MMP-9 has been shown to be higher in eutopic/ectopic endometrial tissue in women with endometriosis and has been suggested to have a role in pathogenesis of endometriosis by promoting invasion of the endometriotic lesions. NGAL is an acute phase protein, which is involved in a variety of physiological and pathophysiological processes. The molecule has also been revealed to correlate with endometriosis pathophysiology through the epithelial–mesenchymal transition process which is the basis for the onset of endometriosis. But also, NGAL which composes a complex with MMP-9 (MMP-9 and NGAL complex), has been shown to protect MMP-9 from autodegradation in vitro which might be a contributing factor for endometriosis pathophysiology.What the results of this study add? MMP-9 cut-off level for prediction of severe endometriosis is a novel finding obtained from this study with acceptable sensitivity and specificity. On the other hand, NGAL seems to have no significant value either for diagnosis of for determining severity of the disease. After all, MMP-9 might be an easy use acceptable biomarker for endometriosis but further studies on larger populations are needed.What the implications are of these findings for clinical practice and/or further research? MMP might be a potential non-invasive predictive marker for advanced stage disease.

Associations between internal exposure levels of persistent organic pollutants in adipose tissue and deep infiltrating endometriosis with or without concurrent ovarian endometrioma

Endometriosis is a gynaecological disease characterized by the presence of ectopic endometrial tissue. Histologically, it appears as different sub-types, being peritoneal endometriosis, ovarian endometrioma (OvE) and deep infiltrating endometriosis (DIE), which are of major relevance due to their varying clinical presentations. A number of persistent organic pollutants (POPs) have been associated with the onset of endometriosis, yet the overall set of existing studies remains fairly divergent. In this preliminary case-control study we aimed to assess the potential associations between the internal exposure to POPs and the presence of DIE with or without concurrent OvE. Adipose tissue and serum samples were collected from surgically confirmed cases (n=55) and controls (n=44) enrolled during 2013 and 2015 in Pays de la Loire, France. Targeted pollutants (76 historical or more emerging POPs including dioxins, polychlorobiphenyls (PCB), polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), hexabromocyclododecanes (HBCDs) and organochlorine pesticides (OCPs) were quantified by chromatography coupled to mass spectrometry. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated from unconditional logistic regression adjusted for known confounding variables. The results showed significant associations between DIE and adipose tissue levels of 1.2.3.7.8 – PeCDD, OCDF, PCB 105, 114, 118 and 123, PBDE 183, PBB 153, and several OCPs including trans‑nonachlor, cis‑heptachlor epoxide, dieldrin, β-hexachlorocyclohexane and hexachlorobenzene. The largest associations were observed for OCDF followed by cis‑heptachlor epoxide, exhibiting adjusted ORs (95% CI) of 5.42 (2.73–12.85) and 5.36 (2.44–14.84) per 1-SD increase, respectively. The stratified analysis comparing both disease sub-types suggested that adipose tissue exposure markers may be more associated with DIE concurrent with OvE, however these results need to be confirmed in a larger population.

Important Initiative Roles of CD44 and Tenascin in Sampson's Theory of the Pathogenesis and Development of Endometriosis

Background Among several theories explaining the pathogenesis of endometriosis, Sampson's theory seems to be the most reliable and popular. However, this theory does have some problems. First, the onset of endometriosis is not as common as retrograde menstruation. Second, the surface of the peritoneum is capable of preventing the adhesion of foreign bodies such as endometrial cells. Regarding the first problem, several studies on immunosurveillance have been reported. The second problems has not yet been clarified, Therefore we investigated the problem in the present report. Methods Levels of CD44 and tenascin in both menstrual and peripheral blood were assayed in 19 healthy volunteer women in the first experiment. In the second experiment, the effects of tenascin on the activity of MMP-9 were investigated, because the invasive ability of endometriotic cells is known to be due to MMP activity. Results CD44 and tenascin concentrations were significantly higher in menstrual blood than in peripheral blood. Since CD44 is a specific hyaluronic acid receptor, CD44 in menstrual blood was demonstrated to be a specific matchmaker of adhesion between the endometrial cells and the peritoneal surface. Tenascin in menstrual blood and endometriotic cells up-regulated MMP activity and promoted the invasive action of endometriotic cells. Conclusion The present study clarified that adhesion of endometrial cells in menstrual blood on adhesion-preventive peritoneal surface was achieved by a mediator, CD44, in menstrual blood and that the ability of endometriotic cells to invade, induced by MMP, was achieved through up-regulation of MMP activity by the mediator tenascin.

Properties of the Mesenchymal Endometriotic Stem Cell in the Context of the Immune System and Analysis of its Role in Endometriosis

Recent studies of human mesenchymal stem cells (hMSCs) have revealed a number of properties that, if managed appropriately, may positively assist a large number of reparative or regenerative cellular processes. Their ability to produce factors and hormones coupled with their colony forming unit (CFU) potential renders these cells a valuable cellular bank for several therapies. The mesenchymal endometriotic stem cell (MESC) also exhibits part of these general properties but, in a paradoxical way, is implicated in the onset of endometriosis and thus infertility, a condition that torments millions of women worldwide. Although, there is no clear distinction about the regenerative or disease causing potential between a healthy and a non-physiological MESC, its postulated way of action leading to endometriosis involves its migration to and invasion of ectopic tissue. Such action may entail either the escapement of the MESC from the immunological function of surveillance or a regulatory-type masking, like a class-II negative state, that hides it from immunological interception. Since the acquired information on MESCs is sparse, this essay will briefly review papers and the small number of patents available in order to provide insight relevant to the understanding of this cell's contradictory behavior, whilst the immunological properties of MESCs will be used to formulate a potential theoretical basis on how to obstruct the initiation of endometriosis.

Melatonin protects against endometriosis via regulation of matrix metalloproteinase-3 and an apoptotic pathway

The role of matrix metalloproteinases (MMPs) in endometriosis, a gynecological disease of women, is unclear. The study investigated the activity of MMP-3 and its interplay with MMP-9 during the onset of endometriosis. Additionally, the importance of MMP-3 on the apoptotic pathway in endometriosis and effect of melatonin thereon were investigated. A Significant increase in the activity of MMP-3 with the severity of endometriosis in human was observed which was found similar in mice also. During the early phase of endometriosis, MMP-3 but not MMP-9 was increased and associated with the expression of transcription factor, c-Fos. Moreover, urokinase plasminogen activator and tissue inhibitor of metalloproteinase (TIMP)-3 were involved in MMP-3 regulation during endometriosis. Furthermore, MMP-3 activity that was parallel to c-Fos expression in endometriosis was reduced by melatonin pretreatment as characterized by diminished activator protein (AP)-1 DNA-binding activity. Because decreased apoptosis is an explanation for the perpetuation of endometriosis, we tested the role of melatonin on apoptotic pathway in preventing endometriosis. Significant regression of glandular epithelium was observed in melatonin-treated when compared to untreated mice. Melatonin treatment increased apoptotic cells in endometriotic zones. This was related to reduced Bcl-2 expression along with increased Bax expression and caspase-9 activation. In summary, early induction of MMP-3 was distinct from MMP-9 during endometriosis, which was regulated by c-Fos and TIMP-3. Melatonin suppressed MMP-3 activity and amplified apoptosis while regressing endometriosis through a caspase-3 mediated pathway. Thus, melatonin may be a therapeutic agent for resolving endometriosis.

Is the 30-item Endometriosis Health Profile (EHP-30) suitable as a self-report health status instrument for clinical trials?

This prospective study aimed to evaluate the suitability of the Endometriosis Health Profile-30 Questionnaire (EHP-30) as a self-report health status instrument. We compared our results with those from the U.K. and the U.S. and discovered relationships between the EHP-30 and patient characteristics. The results showed that the EHP 30 questionnaire is a user-friendly self-report tool suitable for use in endometriosis-related clinical research.