EGFR-mediated matrix metalloproteinase-7 up-regulation promotes epithelial-mesenchymal transition via ERK1-AP1 axis during ovarian endometriosis progression.

Endometriosis, characterized by extrauterine development of endometrial glands and stroma, is associated with increased risk of ovarian cancer development. In the present study, we investigated the role of matrix metalloproteinase-7 (MMP-7) on epithelial-mesenchymal transition (EMT) during ovarian endometriosis ( N = 40) progression. We found that the expressions of EMT markers such as vimentin, slug, and N-cadherin were significantly elevated in late stages of ovarian endometriosis compared with those found in early stages. In addition, the activity and expression of ectopic MMP-7 were significantly higher in the late stages of endometriosis. In vitro studies revealed that increased expression of MMP-7 as well as epidermal growth factor (EGF), which was significantly elevated in severe stages of ovarian endometriosis, induced EMT in endocervical epithelial cells (End1/E6E7). Silencing the MMP-7 transcripts using small interfering RNA attenuated EMT responses, whereas treatment with recombinant active MMP-7 promoted EMT by cleaving E-cadherin. In addition, EGF receptor (EGFR) inhibitor treatments regressed endometriotic lesions and decreased MMP-7 activities in a mouse model of endometriosis. Chromatin immunoprecipitation assay identified EGFR-mediated ERK1 and activator protein 1 signaling for the transcriptional activation of MMP-7 in End1/E6E7 epithelial cells.-Chatterjee, K., Jana, S., DasMahapatra, P., Swarnakar, S. EGFR-mediated matrix metalloproteinase-7 up-regulation promotes epithelial-mesenchymal transition via ERK1-AP1 axis during ovarian endometriosis progression.

Determinants of Conception and Adverse Pregnancy Outcomes in Women with Endometriosis: A Longitudinal Study.

Endometriosis, affecting approximately 10% of reproductive-aged women globally, poses significant challenges, including chronic pelvic pain, dysmenorrhea, and infertility. In low- and middle-income countries like India, accessibility to affordable infertility care remains a concern. This multicenter prospective cohort study, conducted across six tertiary care hospitals in India from 2017 to 2022, aims to explore the natural progression of conception and pregnancy outcomes in women with endometriosis. Of the 257 participants, 19.1% conceived during the study, revealing significant geographic and income-based variations (p < 0.001, p = 0.01). Dysmenorrhea (p < 0.001) and dyspareunia (p=0.027) were correlated with conception, while no such associations were found with chronic pelvic pain or menstrual factors. Lesion type, number, and severity showed no conclusive link with conception. Natural conception occurred in 70% of cases, with an average post-surgery conception time of 282.1 days. Live birth rate was 85.7%, while complications included placenta previa (16.4%), preeclampsia (4.1%), and preterm births (4.1%). This study, one of the first in India on endometriosis-related fertility progression, emphasizes the need for comprehensive understanding and management of conception and pregnancy outcomes. Considering India's substantial endometriosis burden, the study recommends prioritizing larger multicenter investigations for a better understanding and effective strategies for infertility management.

Clinical characteristics and surgical management of endometriosis-associated infertility: A multicenter prospective cohort study.

OBJECTIVE: To study clinical, surgical characteristics and the relationship between endometriosis lesion types and conception rate after surgery in infertile women with endometriosis. METHODS: A prospective, multicenter cohort of 204 women (age 20-35 years) with endometriosis was followed up post-surgery between November 2017 and February 2020 at three tertiary-care hospitals. RESULTS: Based on the severity of endometriosis lesion type, deep infiltrating endometriosis (DIE) (81/204, 39.7%) was the most common lesion; followed by ovarian endometriosis (OMA) (64/204, 31.4%), and superficial peritoneal endometriosis (SUP) (59/204, 28.9%). Endometriosis patients had a single lesion type (94/204, 46.1%), two lesion types (77/204, 37.7%), or three lesion types (33/204, 16.2%) with significant differences between regions (P < 0.001). Around 40% (37/95) of obese women had SUP (P = 0.003) whereas 78% (14/18) of underweight women had DIE (P < 0.001). Significant differences in mean Endometriosis Fertility Index scores between endometriosis lesion types and patients with one, two, and three types of lesions were observed (P < 0.001). The majority (22/32, 68.8%) of the women conceived naturally after the surgery. Half (16/32; 50%) of the women with a single lesion type conceived after the surgery; of which most (13/16, 81.2%) had SUP, followed by OMA (2/16, 12.5%), and DIE (1/16, 6.3%). CONCLUSION: Women with SUP and only one type of endometriotic lesion were more likely to conceive post-surgery.

Protocol for a case-control study investigating the clinical phenotypes and genetic regulation of endometriosis in Indian women: the ECGRI study.

INTRODUCTION: Endometriosis is one of the common, gynaecological disorders associated with chronic pelvic pain and subfertility affecting ~10% of reproductive age women. The clinical presentation, etiopathogenesis of endometriosis subtypes and associated risk factors are largely unknown. Genome-Wide Association (GWA) Studies (GWAS) provide strong evidence for the role of genetic risk factors contributing to endometriosis. However, no studies have investigated the association of the GWAS-identified single-nucleotide polymorphism (SNPs) with endometriosis risk in the Indian population; therefore, one-sixth of the world's population is not represented in the global genome consortiums on endometriosis. The Endometriosis Clinical and Genetic Research in India (ECGRI) study aims to broaden our understanding of the clinical phenotypes and genetic risks associated with endometriosis. METHODS AND ANALYSIS: ECGRI is a large-scale, multisite, case-control study of 2000 endometriosis cases and 2000 hospital controls to be recruited over 4 years at 15 collaborating study sites across India covering representative Indian population from east,north-east, north, central, west and southern geographical zones of India. We will use the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project (WERF-EPHect) data collection instruments for capturing information on clinical, epidemiological, lifestyle, environmental and surgical factors. WERF-EPHect standard operating procedures will be followed for the collection, processing and storage of biological samples. The principal analyses will be for main outcome measures of the incidence of endometriosis, disease subtypes and disease severity determined from the clinical data. This will be followed by GWAS within and across ethnic groups. ETHICS AND DISSEMINATION: The study is approved by the Institutional Ethics Committee of Indian Council of Medical Research-National Institute for Research in Reproductive Health and all participating study sites. The study is also approved by the Health Ministry Screening Committee of the Government of India. The results from this study will be actively disseminated through discussions with endometriosis patient groups, conference presentations and published manuscripts.

Panel of Autoimmune Markers for Noninvasive Diagnosis of Minimal-Mild Endometriosis.

Endometriosis, characterized by the presence of endometrial-like tissue at extrauterine sites, is a common, chronic, estrogen-dependent, inflammatory condition associated with pelvic pain, subfertility, dysmenorrhea, and dyspareunia, affecting about 10% of reproductive-age women in any population. The diagnosis of endometriosis is usually delayed on an average by 8 to 11 years leading to significant consequences in terms of disease progression. The current study was aimed to validate enzyme-linked immunosorbent assay based on the epitopes of stomatin-like protein 2, tropomodulin 3 (TMOD3), and tropomyosin 3 (TPM3) for diagnosis of minimal-mild endometriosis (revised American Fertility Society Classification (rAFS) stage I-II) and to compare the performance with the reported markers: cancer antigen (CA) 125, CA19-9, α-enolase, Serine/threonine-protein kinase (PDIK1L), and syntaxin 5. This was a cross-sectional, multicenter study conducted during the year 2012 to 2015. Women with minimal-mild endometriosis (rAFS stage I-II [n = 133]) and healthy controls (n = 104) were screened for 11 novel autoimmune markers and reported markers α-enolase, PDIK1L, syntaxin 5, CA-125, and CA19-9. The sensitivity and diagnostic accuracy of serum antibodies against all the 11 epitopes were higher than that of CA-125, CA19-9, α-enolase, PDIK1L, and syntaxin 5 for diagnosis of rAFS stage I to II endometriosis. The sensitivity of 6 biomarkers (anti-TMOD3b-autoAb, anti-TMOD3c-autoAb, anti-TMOD3d-autoAb, anti-TPM3a-autoAb, anti-TPM3c-autoAb, and anti-TPM3d-autoAb) was higher at the specificity of ≥80% for diagnosis of rAFS stage I to II endometriosis as well as ultrasound-negative endometriosis. Further, logistic regression models of this panel of biomarkers showed increase in sensitivity, specificity, and diagnostic accuracy than individual biomarkers. The panel of 6 autoimmune biomarkers could be useful in setting up of noninvasive diagnostic test for detection of minimal-mild endometriosis.

Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis.

Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression.