Abstract STUDY QUESTION What is the role of iron in the pathophysiology of endometriosis? SUMMARY ANSWER Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory micro-environment, and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity, and malignant transformation. WHAT IS KNOWN ALREADY Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarize our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. STUDY DESIGN, SIZE, DURATION This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science, and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms (‘Iron’ and ‘Endometriosis’) and free-text search terms (‘Iron’, ‘Ferric’, ‘Ferrous’, ‘Endometriosis’, ‘Endometrioma’). PARTICIPANTS/MATERIALS, SETTING, METHODS This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle–Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions, and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity, and, possibly, malignant transformation. LIMITATIONS, REASONS FOR CAUTION A minority of the included studies were of objectively low quality with a high risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterize the included patients by known confounding variables, such as menstrual cycle phase, which may introduce bias to the findings. WIDER IMPLICATIONS OF THE FINDINGS Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localized hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. STUDY FUNDING/COMPETING INTEREST(S) J.W. and S.G.P. are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and an MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. REGISTRATION NUMBER A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818). 

The role of iron in the pathogenesis of endometriosis: a systematic review

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

After decades of research, we still face great challenges on endometriosis in terms of diagnosis and management. Serum CA125 has been used in the clinical practice in endometriosis, and many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels in endometriosis. In this article, relevant articles that addressed endometriosis associated with CA125 were searched for and retrieved from the databases PubMed, Embase and the Cochrane Library. Here we provide an in-depth literature review to depict CA125 dynamic expression in female reproductive tract and to highlight the practical value of CA125 in diagnosing endometriosis, distinguishing the severity of the disease, monitoring the effect of treatment and reflecting malignant transformation. So far, the development of a risk stratification system based on biomarker CA125 for endometriosis may help clinicians in making novel and more efficient strategies for the detection and treatment of endometriosis. In order to improve CA125 specificity and sensitivity, further research is needed to determine its diagnostic cut-off value. 

Research progress of CA125 in endometriosis: Teaching an old dog new tricks

One of the challenges in gene therapy is the transfer of the gene to the target cell. MicroRNAs (miRNAs) regulate gene expression after transcription by binding directly to the messenger and play a vital role in cell behaviors and the pathogenesis of some diseases. This study was aimed at developing poly (lactic-co-glycolic acid) (PLGA)- based nanoparticles (NPs) for gene delivery to endometriotic cyst stromal cells (ECSCs).In this experimental study, endometriosis cells were isolated from women with severe endometriosis (DIE) and digested by the enzymatic method (40 μg/ml DNAase I and 300 μg/ml collagenase type 3). PLGA-based NPs were synthesized and characterized. The size of sole PLGA NPs and PLGA/miRNA were 60 ± 4 nm and 70 ± 5.1 nm respectively. Poly lactic-co-glycolic-based NPs were used as vector carriers for miRNA 503 transfection in endometriosis cells. The cells were divided into the five groups of control and four doses (25, 50, 75, and 100 μm) of miRNA 503/PLGA at 12, 24, 48, and 72 hours. Viability and apoptosis were evaluated by the MTT assay and Annexin Kits. Data were analyzed by one-way analysis of variance.The results show that the size of PLGA/miRNA complex with dynamic light scattering (DLS) was 70 ± 5.1 nm and zeta potential values of the PLGA/PEI/miRNA complexes were 27.9 mV. Based on the MTT assay results, the optimal dose of miRNA 503/PLGA was 75 μm, at which the viability of ECSCs was 52.6% ± 1.2 (P≤0.001), and the optimal time was 48 hours. The apoptotic rates of ECSCs treated with PLGA/miRNA503 (34.75 ± 4.9%) were significantly higher than those of ECSCs treated with PLGA alone (3.35 ± 2.58%, P≤0.01).Cell death increased with increasing the concentration of miRNA; thus, it can be suggested as a treatment for endometriosis. 

Effect of PLGA Nanoparticle-Mediated Delivery of miRNA 503 on The Apoptosis of Ovarian Endometriosis Cells.

Malignant transformation of endometrioid heterotopias develops in 0.7-2.5 % of cases; 75 % of cases have an ovarian localisation and 25 % an extraovarian one. As it has been suggested that malignant endometriosis-associated neoplasia (MEAN) is developed in foci of atypical endometriosis. The review describes the mechanisms of carcinogenesis, the clinical and morphological features of the disease, and the principles of therapy. MEAN usually occur in younger women, are detected at stages I-II, and are mostly represented by clear cell and endometrioid carcinomas, but rare histological types have also been described. CTNNB1, PTEN, PIK3CA and ARID1A mutations are often detected in MEAN. The treatment of MEAN is not standardised, there are no prospective randomized trials assessing treatment. Patients with ovarian MEAN receive therapy similar to epithelial ovarian cancer. Patients with extraovarian localisation represent a subgroup that of patients that may require a personalised approach.

/pdf/malignant-endometriosis-associated-ovarian-and-extraovarian-39se6gq7.pdf

Malignant endometriosis-associated ovarian and extraovarian neoplasia (review of literature)

https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1002/ijgo.13585

Endometriosis and malignancy: The intriguing relationship

Response: Endometriosis and malignancy—The intriguing relationship

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Endometriosis and malignancy: The intriguing relationship

Response: Endometriosis and malignancy—The intriguing relationship