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Abstract Background Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. Objective This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. Findings Among the pro‐inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL‐β), IL‐6, and tumor necrosis factor α (TNF‐α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre‐existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia‐inducible factor 1α (HIF‐1α), transforming growth factor β1 (TGF‐β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non‐psychoactive member of cannabinoids which has well‐known and notable anti‐inflammatory and antiangiogenic properties. This agent has been shown to decrease IL‐1β, IL‐6, TNF‐α, VEGF, TGFβ, and MMPs in different animal models of diseases. Conclusion It seems that CBD could be a possible treatment for endometriosis due to its anti‐inflammatory and antiangiogenic activity, however, further studies are needed.

Key Clinical Message Endometriosis may contribute to Mullerian adenosarcoma development but makes diagnosis challenging given similar symptoms. Survival benefit has not been definitively shown for chemotherapy, hormonal therapy, or radiotherapy, consolidating surgery as the mainstay treatment. Local excision may be a treatment option for patients with confined tumors wishing to preserve their fertility.

Abstract Endometriosis is a common gynaecological condition, with a long diagnostic delay. Surgery is required to confirm a diagnosis, highlighting the need for a non‐invasive biomarker. Extracellular vesicles (EVs) may have a role in endometriosis pathogenesis, yet there is limited EV biomarker literature available. This study aimed to investigate the feasibility of isolating cervico‐vaginal fluid EVs sampled using cervical brushes and vaginal swabs and to compare these methods. After providing informed consent, patients undergoing surgery for suspected endometriosis had cervical brush and vaginal swab samples collected under general anaesthetic. Isolated EVs were characterised through negative stain transmission electron microscopy (TEM), Western blotting (TSG101, CD63, Calnexin, ApoB, Albumin), tunable resistive pulse sensing (TRPS), microBCA assays and RT‐qPCR of miRNAs. PCR was performed on samples prior to EV isolation to assess bacteria present in samples. Cervical brush and vaginal swab EVs were intact vesicles with limited co‐isolated contaminants. Cervical brushes had higher concentrations of particles compared to match vaginal swabs, although both samples had low concentrations. Protein and miRNA yield were similar between matched samples. PCR demonstrated only a small amount DNA within samples was bacterial (>0.5%). Cervico‐vaginal fluids EVs were successfully isolated from cervical brushes and vaginal swabs, demonstrating a new method of sampling reproductive EVs. EV yield from both sample types was low. Similar protein and miRNA levels suggest either sampling method may be suitable for biomarker studies.

Abstract Endometriosis (EMS) is a prevalent gynecological condition lacking reliable diagnostic biomarkers. This prospective study aimed to analyze the potential of serum heat shock transcription factor 1 (HSF1) as a diagnostic marker for EMS. Clinical features of 92 EMS patients and 52 controls were recorded, revealing significant differences in dysmenorrhea, dyspareunia, pelvic pain, nulliparity, and CA125 levels. Serum HSF1 was upregulated in EMS patients, with higher levels in American Society for Reproductive Medicine (ASRM) III/IV than ASRM I/II. Receiver operating characteristic curve analysis demonstrated good diagnostic function for serum HSF1 (AUC: 0.857, sensitivity: 91.30%, specificity: 63.46%). Serum HSF1, dysmenorrhea, dyspareunia, and nulliparity were independent risk factors for EMS, while dysmenorrhea and serum HSF1 were independent risk factors for EMS severity. Additionally, the GSE25628 dataset was downloaded from the GEO database for differential analysis of gene expression. The HSF1 downstream target genes PTGES3, HSP90AA1, and HSPB1 showed significant differential expression in EMS, suggesting their involvement in the regulatory mechanism of HSF1 in EMS.

Key Clinical Message Although endometriosis is a common condition, both extrapelvic endometriosis and endometriosis associated malignancy (EAM) are rare. We describe the first reported case of a patient with Müllerian‐type carcinosarcoma arising in gastric endometriosis.

Abstract Background and Aims Endometriosis is a common reason for infertility and poor outcomes of assisted reproductive technology (ART). Inflammation is involved in the pathogenesis of this disease. The presence of microorganisms in women with endometriosis may increase levels of inflammatory markers. The purpose of this study is to determine the relationship between the presence of bacteria in the follicular fluid with the inflammatory markers of the complete blood count (CBC) and the outcomes of in vitro fertilization (IVF) in women with endometriosis. Methods This case–control study was conducted on 74 patients undergoing IVF, referred to Al‐Zahra Hospital in Rasht (Iran) in 2021. The patients were divided into two case groups including 37 women with endometrioma and the control group, including 37 infertile women with a male factor and normal ultrasound. In total, 74 follicular fluids were collected from the case and control groups and were cultured in the laboratory. The relationship between culture results with IVF outcomes and the levels of CBC inflammatory markers including the number of white blood cells (WBCs), lymphocytes, neutrophils, neutrophil‐to‐lymphocyte ratio (NLR), lymphocyte‐to‐monocyte ratio (LMR), and platelet‐to‐lymphocyte ratio (PLR), erythrocyte sedimentation rate (ESR), and c‐reactive protein (CRP) was analyzed. Results There was no significant statistical difference between the frequency of bacteria present in the follicular fluid (p = 0.861), the mean rate of fertilization (p = 0.363), the frequency of CRP (p = 0.999), and the mean WBCs, lymphocytes, neutrophils, NLR, LMR, and PLR in the two groups. There was a significant statistical difference between the mean number of oocytes of metaphase II (p = 0.034) and the mean ESR (p = 0.018) in the two groups. Conclusions It seems necessary to evaluate follicular fluid as a biological substance that is considered an optimal factor for predicting oocyte quality, fertilization rate, embryo quality, and the success rate of ART.

Abstract Defective decidualization of endometrial stromal cells (ESCs) in endometriosis (EM) patients leads to inadequate endometrial receptivity and EM‐associated infertility. Hypoxia is an inevitable pathological process of EM and participates in deficient decidualization of the eutopic secretory endometrium. Enhancer of zeste homology 2 (EZH2) is a methyltransferase which catalyses H3K27Me3, leading to decreased expression levels of target genes. Although EZH2 expression is low under normal decidualization, it is abundantly increased in the eutopic secretory endometrium of EM and is induced by hypoxia. Chromatin immunoprecipitation‐PCR results revealed that decidua marker IGFBP1 is a direct target of EZH2, partially explaining the increased levels of histone methylation modification in defected decidualization of EM. To mechanism controlling this, we examined the effects of hypoxia on EZH2 and decidualization. EZH2 mRNA showed decreased m6A modification and increased expression levels under hypoxia and decidualization combined treatment. Increased EZH2 expression was due to the increased expression of m6A demethylase ALKBH5 and decreased expression of the m6A reader protein YTHDF2. YTHDF2 directly bind to the m6A modification site of EZH2 to promote EZH2 mRNA degradation in ESCs. Moreover, selective Ezh2 depletion in mouse ESCs increased endometrial receptivity and improved mouse fertility by up‐regulating decidua marker IGFBP1 expression. This is the first report showing that YTHDF2 can act as a m6A reader to promote decidualization by decreasing the stability of EZH2 mRNA and further increasing the expression of IGFBP1 in ESCs. Taken together, our findings highlight the critical role of EZH2/H3K27Me3 in decidualization and reveal a novel epigenetic mechanism by which hypoxia can suppress EM decidualization by decreasing the m6A modification of EZH2 mRNA.

Abstract Transcription factor 21 (TCF21) and estrogen receptor beta (ERβ, encoded by ESR2) are highly expressed in endometriotic stromal cells (ESCs) and contribute to the pathogenesis of endometriosis. However, the exploration of TCF21 and ERβ expression regulation at the molecular level remains limited. Here, by using bioinformatics analysis and experimental verification, we identified PES1, also known as Pescadillo, as a negative regulator in the development of endometriosis that downregulates TCF21 and ERβ expression in ESCs. PES1 overexpression regulated critical biological processes involved in endometriosis development, such as invasion and apoptosis. A coimmunoprecipitation assay showed that PES1 could form a complex with Forkhead box M1 (FOXM1). Further analyses elucidated that siPES1 in ectopic lesions decreased the stability of FOXM1 protein and reduced the binding activities of FOXM1 to TCF21 and ESR2 promoters, thus weakening the transcriptional inhibition of TCF21 and ERβ by FOXM1. Moreover, in an endometriosis mouse model, overexpressing PES1 effectively reduced the growth of ectopic lesions and suppressed TCF21 and ERβ expression, which suggests a promising therapeutic strategy for endometriosis. Collectively, our results indicate that the loss of PES1 in ectopic lesions contributes to endometriosis progression by upregulating ERβ and TCF21 expression through heterodimer formation with FOXM1. Moreover, targeting PES1 could serve as a treatment method for endometriosis.

Abstract Aims As a chronic inflammatory disease, endometriosis (EMS) is often associated with pain affecting different aspects of women's lives. Up to now, a wide variety of interventions have been implemented to alleviate pain in patients with this condition, including pharmacological, surgical, and rarely non‐pharmacological ones. Against this background, this review aimed to investigate pain‐focused psychological interventions among EMS women. Methods A systematic review of the articles published in this field was conducted through a comprehensive search on the databases of Scopus, PubMed, MEDLINE, Web of Science, ScienceDirect, the Cochrane Library, PsycINFO, Google Scholar, and Scientific Information Database (SID). The quality of studies was then assessed by the Jadad Scale. Results In total, 10 articles were entered into this systematic review. The findings further revealed that the pain‐focused psychological interventions in patients with EMS were cognitive‐behavioral therapy (CBT) (n = 2), mindfulness therapy (n = 4), yoga (n = 2), psychoeducation (n = 1), and progressive muscle relaxation (PMR) training (n = 1). Besides, the findings established that all the given interventions had improved and reduced pain in women living with this condition. Moreover, five articles were of good quality based on the Jadad Scale. Conclusion The study results demonstrated that all the listed psychological interventions had affected pain relief and improvement in women suffering from EMS. Considering the limited number of studies in this field and the fact that there were only five articles endowed with good quality, more high‐quality studies could provide stronger evidence to support the implementation of the mentioned interventions influencing pain in patients.

Abstract The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow‐up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re‐operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02–2.11) and non‐Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow‐up. Re‐operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer‐driver mutations may inform a future molecular classification of endometriosis.

Abstract Background This study explores sex‐specific differences in pain localization using pain drawings in female patients with endometriosis. Traditional human body outlines (HBOs) used for pain drawings are often viewed as male, making accurate pain assessment difficult. The study aims to compare pain localization and extent between patients presented with sexless and female HBOs. Methods A total of 49 female patients with endometriosis completed questionnaires and pain drawings (n = 24 and n = 26 with individually designed sexless and female HBOs, respectively). The Ruzika similarity index was used to investigate potential differences in pain drawings between sexless and female HBOs. Hypothesis testing was applied to compare the number of pixels marked in the pain extents and to investigate the suitability of the presented body outline. Results Sex of HBOs used in pain drawings had no effect on pain area, and no statistically significant differences were found in pain localization or area between female and sexless outlines. Most, but not all participants found the body outlines suitable. Conclusions The findings suggest that differences in the resulting areas marked in the pain drawings were negligible and the preferences for sexless pain drawings were not significant, so that a sexless body outline for pain drawings could be a good choice, especially when a study does not focus on one specific sex.

Abstract Endometriosis (EM) is one of the leading gynecological disorders, and associated with excessive functioning of endometrial stromal cells (ESCs). The current study was conducted to determine the expression and role of methyltransferase‐like 3 (METTL3) in the proliferation, invasion, and migration of ESCs in EM. The documented expression levels of METTL3, microRNA (miR)‐21‐5p, and WNT inhibitory factor 1 (WIF1) in eutopic (Eut) and ectopic (Ect) endometrial tissues and ESCs were determined by a combination of real‐time quantitative polymerase chain reaction and Western blot assay. After transfection with pcDNA3.1‐METTL3, miR‐21‐5p mimic, and WIF1 small interfering RNA, cell counting kit‐8, colony formation, and Transwell assays were performed in the Ect ESCs (Ect‐ESCs). Subsequently, the binding of miR‐21‐5p to METTL3 was analyzed, along with quantification of the N6‐methyladenosine (m6A) level, the enrichments of METTL3 and m6A on WIF1, and the mRNA stability of WIF1. In our findings, METTL3 was downregulated in the EM tissues and cells. METTL3 overexpression intrinsically reduced the proliferation, invasion, and migration of Ect‐ESCs. miR‐21‐5p inhibited the METTL3 expression while METTL3 enhanced the mRNA stability and expression of WIF1 via m6A modification. Additionally, a negative correlation of METTL3 was identified with miR‐21‐5p along with a positive correlation with the WIF1 mRNA in EM tissues. The miR‐21‐5p overexpression or WIF1 downregulation enhanced the proliferation, invasion, and migration of Ect‐ESCs. Collectively, miR‐21‐5p inhibited the METTL3‐mediated m6A modification and mRNA stability of WIF1, thereby facilitating the proliferation, invasion, and migration of Ect‐ESCs.

Abstract Endometriosis is a common, estrogen‐dependent chronic gynecological disease that endangers the reproductive system and systemic metabolism of patients. We aimed to investigate the differences in metabolic profiles in the follicular fluid between infertile patients with endometriosis and controls. A total of 25 infertile patients with endometriosis and 25 infertile controls who were similar in age, BMI, fertilization method and ovulation induction treatment were recruited in this study. Metabolomics analysis of follicular fluid was performed by two methods of high‐performance liquid chromatography tandem mass spectrometry. There were 36 upregulated and 17 downregulated metabolites in the follicular fluid of patients in the endometriosis group. KEGG pathway analysis revealed that these metabolites were enriched in phenylalanine, tyrosine and tryptophan biosynthesis, aminoacyl‐tRNA biosynthesis, phenylalanine metabolism and pyrimidine metabolism pathways. A biomarker panel consisting of 20 metabolites was constructed by random forest, with an accuracy of 0.946 and an AUC of 0.988. This study characterizes differences in follicular fluid metabolites and associated pathway profiles in infertile patients with endometriosis. These findings can provide a better comprehensive understanding of the disease and a new direction for the study of oocyte quality, as well as potential metabolic markers for the prognosis of endometriosis.

Background Certain symptoms associated with infertility are associated with cardiovascular disease, including menstrual cycle irregularity, early menopause, and obesity; however, few studies have investigated the association between infertility and cardiovascular disease risk. Methods and Results Participants in the NHSII (Nurses' Health Study II) who reported infertility (12 months of trying to conceive without success, including women who subsequently conceived) or who were gravid, with no infertility were followed from 1989 until 2017 for development of incident, physician‐diagnosed coronary heart disease (CHD) (myocardial infarction, coronary artery bypass grafting, angioplasty, stent) and stroke. Time‐varying Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs and were adjusted a priori for potential confounding variables. Among 103 729 participants, 27.6% reported having ever experienced infertility. Compared with gravid women who had not reported infertility, women with a history of infertility had greater risk of CHD (HR, 1.13 [95% CI, 1.01–1.26]) but not stroke (HR, 0.91 [95% CI, 0.77–1.07]). The association between history of infertility and CHD was strongest among women who reported infertility at an earlier age (HR for infertility first reported at ≤25 years, 1.26 [95% CI, 1.09–1.46]; HR at 26–30 years, 1.08 [95% CI, 0.93–1.25]; HR at >30 years, 0.91 [95% CI, 0.70–1.19]). When we investigated specific infertility diagnoses, elevated risk of CHD was observed among women whose infertility was attributed to an ovulatory disorder (HR, 1.28 [95% CI, 1.05–1.55]) or endometriosis (HR, 1.42 [95% CI, 1.09–1.85]). Conclusions Women with infertility may be at an increased risk of CHD. Risk differed by age at first infertility diagnosis and was restricted to ovulatory‐ and endometriosis‐related infertility.

Abstract Purpose To screen Zn2+‐dependent histone deacetylase (HDAC) 1‐11 in endometriotic cells and then evaluated the HDACs identified from the screening in ovarian endometrioma (OE) and deep endometriotic (DE) lesions, and to evaluate the therapeutic potential of HDAC8 inhibition in mice. Methods Quantification of gene and protein expression levels of HDAC1‐11 in endometriotic cells stimulated by TGF‐β1, and immunohistochemistry analysis of Class I HDACs and HDAC6 in OE/DE lesion samples. The therapeutic potential of HDAC8 inhibition was evaluated by a mouse model of deep endometriosis. Results The screening identified Class I HDACs and HDAC6 as targets of interest. Immunohistochemistry analysis found a significant elevation in HDAC8 immunostaining in both OE and DE lesions, which was corroborated by gene and protein expression quantification. For other Class I HDACs and HDAC6, their lesional expression was more subtle and nuanced. HDAC1 and HDAC6 staining was significantly elevated in DE lesions while HDAC2 and HDAC3 staining was reduced in DE lesions. Treatment of mice with induced deep endometriosis with an HDAC8 inhibitor resulted in significantly longer hotplate latency, a reduction of lesion weight by nearly two‐thirds, and significantly reduced lesional fibrosis. Conclusions These findings highlight the progression‐dependent nature of specific HDAC aberrations in endometriosis, and demonstrate, for the first titme, the therapeutic potential of suppressing HDAC8.

Abstract Purpose This study aimed to investigate whether serum leucine‐rich α2‐glycoprotein (LRG) is a useful diagnostic biomarker for endometriosis, including the evaluation of treatment efficacy and exploration of LRG production in endometriotic lesions. Methods Forty‐three women with endometriomas were compared to 22 women with benign ovarian cysts and 30 women who underwent assisted reproduction as controls. Changes in serum LRG levels were assessed before and after surgery, and during dienogest treatment. LRG expression in endometriotic tissue samples was evaluated using immunoblotting. Results Serum LRG levels in the endometrioma group (80.0 ± 36.3 μg/mL) were significantly higher than those in the benign ovarian cyst (65.1 ± 27.0 μg/mL, p = 0.0265) and control (57.8 ± 22.3 μg/mL, p = 0.0028) groups. Serum LRG levels after endometrioma surgery were significantly lower than preoperative levels (p = 0.0484). Serum LRG levels consistently decreased during dienogest treatment. LRG expression levels were significantly higher in endometriotic tissues than in the normal endometrium. Conclusion Serum LRG, possibly derived from local and systemic origins, could be used as a potential biomarker for the diagnosis and treatment of endometriosis.

Abstract Purpose This study aimed to explore whether umbilical cord‐derived mesenchymal stem cells (UC‐MSCs) could be used as a therapeutic resource for endometriosis. Methods Of seven cynomolgus monkeys with endometriosis, five were administered UC‐MSCs (intervention group) and two were administered saline (control group). First, intravenous US‐MSC treatment was administered for three months. Second, weekly intravenous US‐MSC administration combined with monthly intraperitoneal US‐MSC administration was conducted for 3 months. Finally, weekly intraperitoneal US‐MSC administration was conducted for 3 months. The dose of UC‐MSCs was set to 2 × 106 cells/kg for all administration routes. Laparoscopic findings and serum cancer antigen 125 (CA125) levels were also evaluated. The Revised American Society for Reproductive Medicine classification was used for laparoscopic evaluation. Results Laparoscopic findings showed exacerbation of endometriosis after intraperitoneal UC‐MSC administration, although no changes were observed in the control group. Intravenous UC‐MSC administration decreased the level of CA125 in all monkeys; however, the difference was not significant. Intraperitoneal UC‐MSC administration significantly exacerbated endometriosis compared with intravenous administration (p = 0.02). Conclusions This study revealed that intraperitoneal UC‐MSC administration exacerbates endometriosis in a nonhuman primate model of the disease.

Abstract Purpose The aim of this study was to evaluate the dynamic change in staining of Class I HDACs and Hdac6 in lesions harvested serially from different time points in mice with induced endometriosis. In addition, the effect of Hdac8 activation as well as Hdac8 and Hdac6 inhibition on lesional progression and fibrogenesis was evaluated. Methods Immunohistochemistry analysis of Class I HDACs and Hdac6 in serially harvested lesion samples in mouse. Hdac8 activation, as well as Hdac6/8 inhibition, was evaluated in mice with induced endometriosis. Results We found a progressive increase in lesional staining of Hdac1, Hdac8, and Hdac6 and gradual decrease in Hdac2 staining and consistently reduced staining of Hdac3 during the course of lesional progression. The stromal Hdac8 staining correlated most prominently with all markers of lesional fibrosis. Hdac8 activation significantly accelerated the progression and fibrogenesis of endometriotic lesions. In contrast, specific inhibition of Hdac8 or Hdac6, especially of Hdac8, significantly hindered lesional progression and fibrogenesis. Conclusions Hdac8 is progressively and aberrantly overexpressed as endometriotic lesions progress. This, along with the documented HDAC1 upregulation in endometriosis and the overwhelming evidence for the therapeutic potentials of HDACIs, calls for further and in‐depth investigation of epigenetic aberrations of endometriosis in general and of HDACs in particular.

Abstract Background and Aims Cytokine profiles of peripheral blood and other bodily fluids provide diagnostic indicators for assessing inflammatory processes. Menstrual effluent may provide a noninvasive source of biological material for monitoring cytokine levels in blood and in endometrial tissues. This pilot study investigated the potential of measuring cytokines in menstrual effluent, and compared the cytokine profiles of menstrual versus peripheral blood. Methods Seven healthy donors (aged ≥18 and ≤45 years) collected menstrual effluent on day 2 of menses. Matched peripheral blood samples were collected by venous blood draw on the same day. Levels of 62 cytokines were measured in all samples by 62‐plex Luminex assay. Results Peripheral blood and menstrual effluent cytokine profiles were tenuously correlated (r2 = 0.26, p 0.05) for 53/62 cytokines in menstrual effluent versus peripheral blood. Levels of TGF‐β (r2 = 0.87, p = 0.002) and CCL7 (r2 = 0.63, p = 0.033) were significantly positively correlated between matched menstrual and peripheral blood samples. Conclusion In this group of study participants, the cytokine profile of menstrual effluent was quantitatively distinct from peripheral blood, and also characterized by higher levels of inflammatory signaling. This pattern of comparative menstrual blood cytokine profiles points to a need for further studies to evaluate the relationship between peripheral and menstrual blood cytokines in broader populations including both healthy and diseased states.

Abstract Aim The study aimed to identify the relationships between metabolic syndrome indicators and BMI in women with endometriosis. Design A retrospective observational study design was utilized to analyse secondary data from a longitudinal dataset. Methods A total of 281,810 women diagnosed with endometriosis and aged 15 through 49 were drawn from the National Health Insurance Service‐National Health Screening Cohort data of the Republic of Korea from the year 2009 to 2016. Body mass index (BMI) and five indicators of metabolic syndrome were extracted. Descriptive statistics, Cochran–Mantel–Haenszel test, chi‐square test and Cochran‐Armitage test were used. Results Yearly changes in abnormal waist circumference, elevated fasting blood sugar and abnormally low levels of high‐density lipoprotein cholesterol were statistically significant. The risk groups of these indicators all showed statistically significant differences according to BMI. The proportions of women with abnormal findings for all indicators significantly increased as BMI increased.

Abstract A hallmark of endometriosis – a chronic debilitating condition whose causes are poorly understood – is neuronal innervation of lesions. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with endometriosis but also contribute to a pro‐growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. The diverse array of contributions that neurons play in endometriosis indicate that it should be considered as a nerve‐centric disease. This review is focused on the emerging field of exoneural biology and how it applies to the field of endometriosis, in particular the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the mechanisms of neuronal contribution to endometriosis, as well as their interactions with accompanying stromal and immune cells, will unearth novel disease‐relevant pathways and targets, providing additional, more selective therapeutic horizons.

Abstract Omphalolith is a rare and underdiagnosed entity due to the accumulation of sebum and keratin in the umbilicus. It usually occurs in the elderly with deep and narrow umbilicus. Early recognition of omphalolith is important to prevent complications, unnecessary investigations, and anxiety. We report herein two new cases of omphalolith.

Introduction: There is considerable variation in the types of symptoms experienced by people living with endometriosis, and it is unclear which symptoms impact people the most. This study aimed to identify the specific symptoms that are "most impactful" to people living with the condition., Material and Methods: Two sequential online surveys were conducted. Women aged over 18 years with a diagnosis of endometriosis were eligible to participate. Participants first provided a free-text list of all the endometriosis symptoms they experienced (Survey 1, Australian only). Responses were condensed into a shorter list by grouping symptom types and selecting the top 20 most common and most impactful. Survey 2 (international) participants reviewed the list and selected all that they had experienced in the last 3 months, nominated one as their single "most impactful symptom", and rated its impact on one of five randomized scale types., Results: Survey 1 and Survey 2 had 195 and 983 responses, respectively. The mean age of respondents was 30.8 ± 7.9 years. There were 275 separate symptom descriptions from Survey 1, which were condensed into 104 groups, of which 25 met criteria for inclusion in Survey 2. The most commonly experienced symptoms were abdominal pain (93% of respondents), bloating (92%), and fatigue (90%), and the symptoms nominated as causing the most impact were pelvic pain (20%), abdominal pain (15%), and cramps (7%). Nearly everyone (99.7%) in Survey 2 reported experiencing at least one pain symptom. The symptoms that generated the highest impact scores were infertility (99.8/100), irregular menstrual cycles (95.3/100), and constipation (92/100). The average impact score was 87.5/100., Conclusions: There was substantial variation in the symptom selected as causing the most impact, and the level of impact was high. A focus on measuring the "most impactful symptom" in future research may enable us to better capture and measure the true symptom experience., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: There is a gap in knowledge regarding development of endometriosis and adenomyosis lesions visible at transvaginal ultrasound. The objectives were to evaluate if women with symptoms suggestive of endometriosis or adenomyosis but normal ultrasound examination develop endometriosis or adenomyosis lesions visible at ultrasound over time and if alterations of symptoms over time are associated with ultrasound findings at follow-up., Material and Methods: This was a prospective cohort study of 100 symptomatic women with normal initial ultrasound examination during 2014-2017 who underwent follow-up ultrasound examination in 2022. Symptoms suggestive of endometriosis were assessed using visual analog scale at both examinations and minimal clinically important difference of 10 mm was considered as a significant alteration. An examiner with expertise in advanced ultrasound examination of endometriosis performed transvaginal ultrasound examinations in accordance with the consensus protocol by the International Deep Endometriosis Analysis group., Results: At follow-up ultrasound examination of 100 women, 13 (13% [95% CI 7.1-21.2]) had visible endometriosis or adenomyosis lesions, 8 (8% [95% CI 3.5-15.2]) had endometriosis lesions, and 6 (6% [95% CI 2.2-12.6]) had adenomyosis. At follow-up, women with endometriosis or adenomyosis lesions reported lower intensity of dysmenorrhea and chronic pelvic pain compared to women without lesions (48 mm [IQR 16-79] vs. 73 mm [IQR 46-85] and 45 mm [IQR 26-57] vs. 57 mm [IQR 36-75], p = 0.087 and p = 0.026, respectively). None of the women with endometriosis or adenomyosis lesions reported increased intensity of dysmenorrhea at follow-up, compared to 32/86 women (37%) without lesions (p = 0.008). Increased intensity of chronic pelvic pain tended to be less common in women with lesions compared to those without (3/13 [23%] vs. 35/86 [41%], p = 0.223)., Conclusions: Our findings suggest that in symptomatic women, endometriosis and adenomyosis lesions visible at ultrasound may develop over time. However, majority of women remain having normal ultrasound examinations despite symptoms. Exacerbation of dysmenorrhea or chronic pelvic pain during follow-up was not associated with the development of endometriosis or adenomyosis lesions visible at ultrasound, suggesting that even women with less severe symptoms might benefit from a follow-up ultrasound when indicated., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: "Improvement in the most bothersome symptom" was recently selected as a core outcome for endometriosis intervention trials. This study aimed to explore the applicability of the construct of "symptom bother" in representing the lived experiences of people with endometriosis., Material and Methods: Semi-structured interviews were conducted to understand the meaning of "symptom bother" and related constructs. Eighteen interviews were conducted: 14 among people with a surgical diagnosis of endometriosis who were recruited from the community, and four with people who were recruited from a private gynecology clinic who had either a confirmed diagnosis or a high suspicion of the disease. All interviews were audio recorded, transcribed verbatim, and analyzed thematically., Results: Three primary themes were identified: (1) endometriosis symptoms and priorities vary with time and context, (2) endometriosis symptoms impair normal daily functioning, (3) endometriosis symptoms are more than just a "bother." The concept of "bother" to describe endometriosis symptoms did not resonate with most participants. Whilst "bother" was familiar language, it did not encompass the broader implications of living with endometriosis. Participants felt "bother" implied emotional distress, lacking a full understanding of the consequences of the disease. Instead, "symptom impact" was endorsed, allowing participants to quantify and objectively assess their symptoms, free from negative connotations., Conclusions: This was the first qualitative study to explore "symptom bother" among people living with endometriosis. Instead of "bother," "impact" was widely endorsed as a suitable construct. This term more appropriately captured the broad ways in which endometriosis symptoms impair daily functioning., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder affecting salivary and lacrimal glands, while endometriosis involves uterine-like tissue growth outside the uterus, causing pelvic pain and infertility. Investigating their intricate relationship using real-world data is crucial due to limited research on their connection., Material and Methods: This population-based cohort study included patients with endometriosis and controls without endometriosis. Propensity score matching was used to balance baseline differences in demographic and clinic characteristics between the two groups. Cox proportional hazards model were used to estimate the effect of endometriosis on the risk of new-onset pSS over time. A symmetrical cohort study, including patients with pSS and propensity score-matched controls without pSS, was conducted to investigate the effect of pSS on the risk of endometriosis over time. To elaborate on the mechanisms linking endometriosis and pSS, Ingenuity Pathway Analysis was performed to identify activated pathways in eutopic endometrium from patients with endometriosis and parotid tissues from patients with pSS., Results: A total of 15 947 patients with endometriosis and 15 947 propensity score-matched controls without endometriosis were included. Patients with endometriosis presented a significantly greater risk of pSS compared to non-endometriosis controls (adjusted hazard ratio, aHR = 1.57, 95% CI = 1.29-1.91, p < 0.001). In the symmetrical cohort study, which included 4906 pSS patients and 4,906 propensity score-matched controls without pSS, patients with pSS were found to be at a significantly higher risk of endometriosis compared to non-pSS controls (aHR = 1.51, 95% CI = 1.12-2.04, p = 0.012). Ingenuity Pathway Analysis showed that the underlying cellular mechanisms involved autoimmune-related pathways, including activation of dendritic cell maturation, and chronic inflammatory pathways, including the fibrosis signaling pathway., Conclusions: These findings support a bidirectional association between endometriosis and pSS, which may be driven by dendritic cell maturation and fibrosis signaling pathways., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Endometriosis is a gynecologic condition often described as the "chameleon of gynecology" because of its elusive symptoms. The World Health Organization acknowledges its severe impact on quality of life due to pain, fatigue, depression, and infertility. There is limited literature on the prevalence of endometriosis, knowledge of which is essential for effective prevention, treatment strategies, and funding. We aim to structure and present the published data on endometriosis prevalence, synthesizing the discrepancy between health insurance and clinical data. PubMed, Cochrane CENTRAL, and LIVIVO were researched for peer-reviewed articles published between January 2000 and July 2023 on women of reproductive age. Health insurance companies argue that few women (~1%) are affected by endometriosis. Interestingly, the prevalence of clinical data studies (6.8%), population-based surveys/self-reported studies (6.6%), and symptomatic patient data (21%) revealed a different picture. Based on the data gathered, a multi-layered prevalence model has been proposed to illustrate the large discrepancy in the prevalence numbers, leading to the disease being underestimated and underfunded. This variability may be influenced by the heterogeneity in designs and the analyzed data, and clinical complexity. In summary, this narrative review reveals that the prevalence of endometriosis is higher than health insurance and other stakeholders might have previously assumed., (© 2024 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objective: To investigate the anogenital distance from the upper verge of the anus to the posterior fourchette (AGD AF ), FASL, and BCL2 combination as a reliable and non-invasive tool for the diagnosis of endometriosis., Methods: This study included 100 women with endometriosis and 50 women without endometriosis as the control group. All cases underwent history taking, body mass index (BMI) measurement, AGD measurement, and FASL and BCL2 immunohistochemical staining of the eutopic endometrial tissue., Results: This study included 150 women divided into endometriosis and control groups. Endometriosis cases significantly had shorter AGD AF , 22.9 ± 2.6 mm, compared with the control group, 27.3 ± 3.5 mm (P < 0.001). Lower FASL and higher BCL2 expression were associated with endometriosis (P < 0.001). The combined measurement of AGD AF (cut-off point 24.55 mm) with FASL and BCL2 was associated with endometriosis (P < 0.001). The combined diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of AGD AF , FASL, and BCL2 were 83%, 78%, 87.3%, and 69.6%, respectively. The area under the curve was greater for AGD AF , FASL, and BCL2 in combination than for individual measurements., Conclusion: Combining short AGD AF with high BCL2 and low FASL is a highly sensitive, non-invasive diagnostic tool for endometriosis., (© 2024 International Federation of Gynecology and Obstetrics.)

Abstract Long noncoding RNAs are a group of more than 200 nt, nonprotein coding RNAs, some of which are dysregulated in many pathophysiological processes including endometriosis. This study aims to clarify the roles of dysregulated growth arrest‐specific 5 (GAS5) in patients with endometriosis, and unveil the underlying mechanisms. We obtained endometrium samples from 37 patients with endometriosis and 23 controls without endometriosis. Primary endometrial stromal cells (ESCs) and endothelial cells were separated from the endometrium. Levels of GAS5 were quantified using quantitative real‐time polymerase chain reaction, and levels of p27, cleaved caspase‐3, cleaved poly (ADP‐Ribose) polymerase 1, vascular endothelial growth factor A, tissue inhibitor of metalloproteinases 3 (TIMP3), and trypsin‐modified soy protein 10 were assessed by immunoblotting. Cell viability was examined using MTT assays, and the cell cycle and apoptosis were analyzed by flow cytometry. Endothelial cell tube formation capacity was assayed in vitro. GAS5 and p27 levels were found lower in the endometrium samples from patients with endometriosis. Primary ESCs from patients with endometriosis had increased viability, reduced apoptosis, and a relatively uncontrolled cell cycle. Gain‐ and loss‐of‐function studies confirmed that GAS5 regulated p27 expression in ESCs. Furthermore, GAS5 level was relatively low in primary endothelial cells from patients with endometriosis and GAS5 acted as an angiogenesis inhibitor by regulating the miR‐181c‐TIMP3 axis. Thus, lower GAS5 level in endometrium might be related to endometriosis by regulating cell proliferation, apoptosis, cell cycle, and angiogenesis.

Abstract Purpose The authors compared assisted reproductive technique (ART) outcomes and the recurrence rate of endometrioma in the infertile patients undergoing sclerotherapy vs laparoscopic ovarian cystectomy. Methods In this prospective cross‐sectional study, a total of 101 infertile patients, with unilateral endometriomas, were divided into two groups. The first group (n = 57) underwent ART after 1 year of unsuccessful spontaneous pregnancy after laparoscopic ovarian cystectomy; the second group (n = 44) had ethanol sclerotherapy (EST) at the time of oocyte retrieval. The authors measured the number of oocytes, clinical pregnancy rate (CPR), live birth rate (LBR), complication, and recurrence of endometriomas as the primary and secondary outcomes. Results The two groups had no significant differences in baseline characteristics and ovarian stimulation markers and also total number of oocytes. 42.1% and 34.1% of the patients (n = 24 and 15) had clinical pregnancy, and 38.6% and 29.5% (n = 22 and 13) had live birth following ART cycles in the surgery group and sclerotherapy group (P = .41, 0.34). The recurrence rates were 14.0% and 34.1% in the surgery and sclerotherapy groups (P = .017, X2 = 5.67). Conclusions Ethanol sclerotherapy can be a good alternative to surgery concerning the treatment of endometrioma; however, the recurrence of the disease in this group is significantly higher.

Abstract Purpose To assess the efficacy and safety of dydrogesterone in Japanese women with ovarian endometrioma in a real‐world setting. Methods The post‐marketing study involved 15 sites in Japan. Dydrogesterone 10 mg twice daily orally was administered for 21 days (day 5‐25 of each menstrual cycle) for 4 cycles. The primary outcome measure was the change in ovarian endometrioma volume from baseline. Secondary outcome measures included total dysmenorrhea score (0 = absent to 3 = severe), severity of dysmenorrhea pain [0‐10cm visual analog scale (VAS)], serum carbohydrate antigen 125 (CA‐125) levels, and safety. Results The study group comprised women with an endometrioma aged 20 to 49 (47.4% cases aged ≥40 years). Endometrioma volume was reduced in 50% (26/52), unchanged in 25% (13/52), and increased in 25% (13/52) of women from baseline to the end of cycle 5; three‐quarters of patients thus had either reduced or unchanged ovarian endometrioma volume. Dydrogesterone significantly reduced total dysmenorrhea scores and severity of dysmenorrhea pain VAS during treatment compared with baseline. CA‐125 levels were not significantly changed during the study. The incidence of adverse events and adverse drug reactions in 59 subjects was 13.6% and 11.9%. Conclusions Dydrogesterone prevented an increase in endometrioma size in many women, and it also significantly improved total dysmenorrhea scores and severity of dysmenorrhea pain, and was well tolerated. The ClinicalTrials.gov identifier of the study was NCT02921763.

Abstract Evolutionary and comparative approaches can yield novel insights into human adaptation and disease. Endometriosis and polycystic ovary syndrome (PCOS) each affect up to 10% of women and significantly reduce the health, fertility, and quality of life of those affected. PCOS and endometriosis have yet to be considered as related to one another, although both conditions involve alterations to prenatal testosterone levels and atypical functioning of the hypothalamic–pituitary–gonadal (HPG) axis. Here, we propose and evaluate the novel hypothesis that endometriosis and PCOS represent extreme and diametric (opposite) outcomes of variation in HPG axis development and activity, with endometriosis mediated in notable part by low prenatal and postnatal testosterone, while PCOS is mediated by high prenatal testosterone. This diametric disorder hypothesis predicts that, for characteristics shaped by the HPG axis, including hormonal profiles, reproductive physiology, life‐history traits, and body morphology, women with PCOS and women with endometriosis will manifest opposite phenotypes. To evaluate these predictions, we review and synthesize existing evidence from developmental biology, endocrinology, physiology, life history, and epidemiology. The hypothesis of diametric phenotypes between endometriosis and PCOS is strongly supported across these diverse fields of research. Furthermore, the contrasts between endometriosis and PCOS in humans parallel differences among nonhuman animals in effects of low versus high prenatal testosterone on female reproductive traits. These findings suggest that PCOS and endometriosis represent maladaptive extremes of both female life‐history variation and expression of sexually dimorphic female reproductive traits. The diametric disorder hypothesis for endometriosis and PCOS provides novel, unifying, proximate, and evolutionary explanations for endometriosis risk, synthesizes diverse lines of research concerning the two most common female reproductive disorders, and generates future avenues of research for improving the quality of life and health of women.

Abstract Aim Considering the wide impact of endometriosis on various aspects of health, this study aimed to explore the impact of endometriosis on Iranian women's lives. Design The present study used a qualitative approach and conventional content analysis. Methods Twenty patients suffering from endometriosis referring to Imam Khomeini Hospital in Tehran took part in this study. The sampling was done purposefully until data saturation. After deep semi‐structured interviews, the content analysis of the interviews was done according to the steps proposed by Zhang and Wildemuth. Results The mean age of the participants was 34.53 (SD: 5.81) years (range: 23–43) with duration of illness of 6.30 ± 5.86 years. Their educational level varied from high school to university, and most of them were employed. Analysis of the data from participants' experiences led to the formation of 5 categories under the titles "Physical suffering, instability of marital life, mental disorder, disruption in social life and self‐care" and 11 subcategories. Conclusion The findings of the present study showed that endometriosis can adversely affect women's lives including physical, sexual, psychological and social problems. Although in some cases patients adopt different strategies for self‐care, the need for more support is felt.

Abstract Background Endometriosis is a common gynecological condition in which stromal or glandular epithelium is implanted in extrauterine locations. Endometriosis causes detrimental effects on the granulosa cells, and phthalate interferes with the biological and reproductive function of endometrial cells at a molecular level. Methods This article retrospectively reviewed the studies on phthalate exposure and its relationship with endometriosis. A literature search was performed for scientific articles using the keywords “phthalate and endometriosis,” “endometriosis and granulosa cells,” “phthalate and granulosa cells,” and “phthalates and endometrial cells.” Results Endometriosis can affect cytokine production, steroidogenesis, cell cycle progression, expression of estrogen receptor‐α (ER‐α)/progesterone receptor (PR), and cause endoplasmic reticulum stress, senescence, apoptosis, autophagy, and oxidative stress in the granulosa cells. Mono‐n‐butyl phthalate (MnBP) alters the expression of cytokines, cell cycle‐associated genes, ovarian stimulation, steroidogenesis, and progesterone production. Several in vitro studies have demonstrated that phthalate caused inflammation, invasion, change in cytokines, increased oxidative stress, viability, resistance to hydrogen peroxide, and proliferation of endometrial cells. Conclusion This might provide new insights about the impact of phthalate on the pathogenesis of endometriosis and its consequences on the ovarian function.

Ovarian clear cell carcinoma (OCCC) reportedly develops from endometriosis. However, the molecular mechanism underlying its malignant progression to OCCC remains elusive. This study aimed to identify an essential gene in the malignant transformation of endometriosis to OCCC. We performed RNA sequencing in formalin‐fixed, paraffin‐embedded (FFPE) tissues of endometriosis (n = 9), atypical endometriosis (AtyEm) (n = 18), adjacent endometriosis to OCCC (AdjEm) (n = 7), and OCCC (n = 17). We found that tetraspanin 1 (TSPAN1) mRNA level was significantly increased by 2.4‐ (DESeq2) and 3.4‐fold (edgeR) in AtyEm and by 80.7‐ (DESeq2) and 101‐fold (edgeR) in OCCC relative to endometriosis. We confirmed that TSPAN1 protein level was similarly overexpressed in OCCC tissues and cell lines. In immortalized endometriosis cell lines, TSPAN1 overexpression enhanced cell growth and invasion. Mechanistically, TSPAN1 triggered AMP‐activated protein kinase (AMPK) activity, promoting endometriosis and cell growth. Upregulated levels of TSPAN1 are considered an early event in the development of high‐risk endometriosis that could progress to ovarian cancer. Our study suggests the potential of TSPAN1 as a screening candidate for high‐risk endometriosis.

Abstract Aim To identify Endometriosis Nurse Specialists' roles and responsibilities in accredited Endocentres, how these align with the Royal College of Nursing Skills Framework and potential for development to improve patient care. Design Cross‐sectional national survey. Methods Data were collected from an online survey distributed to all 66 Endometriosis Nurse Specialists working across 58 UK‐based Endometriosis registered centres. The response rate was 58% (N = 38). Data from closed questions were analysed using descriptive statistics, and free text responses were collated and analysed thematically. Results Unlike Nurse Specialists in other fields of practice, most Endometriosis Nurse Specialists (N = 33, 87%) had another nursing role. The median hours worked per week as an endometriosis nurse was only 13.5 hr. Most respondents (N = 35, 92%) spent all or most of their allocated hours collecting and inputting endometriosis data, whilst over a third (N = 13, 34%) were not undertaking any autonomous, nurse‐led patient consultations.

Abstract Severe adhesions between the bladder and uterus necessitated an atypical incision in the cesarean section of a woman with endometriosis. This could not be predicted with pre‐surgery MRI. No methods in the literature are able to predict adhesions with true certainty; it is therefore still difficult to diagnose intra‐abdominal adhesions.

Abstract Endometriosis in an estrogen‐dependent disease that is characterized by the presence of endometrial tissue outside the uterine cavity leading to pain and infertility in many affected women. Highly efficient treatment options which create a hypo‐estrogenic environment can cause side effects such as hot flushes and bone mass loss that are not favorable for premenopausal women. Previous work has demonstrated that increased local or systemic prolactin seems to be involved in the pathogenesis of endometriosis. Here we examined two prolactin receptor (PRLR) blocking antibodies in a murine endometriosis interna model which relies on the induction of systemic hyperprolactinemia in female SHN mice. The severity of the disease is determined by the degree of endometrial invasion into the myometrium. In this model, endometriosis was inhibited by clinical gold standards such as progestins and anti‐estrogenic approaches. PRLR blockade completely inhibited endometriosis in this mouse model to the same extent as the anti‐estrogen faslodex or the GnRH antagonist cetrorelix. In contrast to cetrorelix and faslodex, the PRLR antibodies did not decrease relative uterine weights and were thus devoid of anti‐estrogenic effects. We therefore hypothesize that PRLR antibodies may present a novel and highly efficient treatment option for endometriosis with a good safety and tolerability profile. Clinical studies are on the way to test this hypothesis.

Abstract Endometriosis constitutes a benign condition, occurring in 10%–12% of menstruating women. Bowel involvement is estimated to occur in 5%–12% with the rectosigmoid region involved in up to 90% of these cases. We present the case of a 45‐year‐old Caucasian female patient with rectosigmoid endometriosis.

Abstract Background Endometriosis is an estrogen‐dependent disease and causes pelvic pain and infertility. The limits of current pharmacotherapy in women who desire to become pregnant prompt the development of various targeted molecules for more effective treatment. A review article focused on the unique aspect of cellular metabolic reprogramming of endometriotic cells has been reported. The cellular metabolic pathways are reprogrammed to adapt to a variety of environmental stresses (e.g., nutrient starvation or glucose deprivation, hypoxic stress, excessive reactive oxygen species generation, and other environmental factors). This review aims to summarize macrophage polarization and metabolic reprogramming in endometriosis. Methods A literature search was performed between January 2000 and March 2022 in the PubMed and Google Scholar databases using a combination of specific terms. Results Macrophage cellular metabolism has a marked influence on its phenotype and function. Preclinical studies showed that metabolic conversion toward glycolysis or oxidative phosphorylation drives macrophage polarization to M1 or M2 phenotype, respectively. Such cellular metabolic rewiring can offer new therapeutic opportunities. Conclusion A better understanding of metabolic reprogramming biology in endometriosis‐associated macrophages is essential in considering novel therapeutic approach for endometriosis. However, there are currently no detailed studies on therapeutic strategies targeting the cellular metabolic properties of endometriosis‐associated macrophages.

Abstract Purpose To investigate the relationship between the microbiome of the female genital tract and endometriosis. Methods This prospective cohort study included 36 women who underwent laparoscopic surgery for ovarian tumor from July 2019 to April 2020. Of them, 18 had endometriosis, and 18 did not have endometriosis. Vaginal secretions, endometrial fluid, peritoneal fluid, and ovarian cystic fluid were collected during surgery. Next‐generation sequencing of bacterial 16S rRNA was performed to characterize the microbiome. Results Specific microbiomes were not detected in either peritoneal fluid or ovarian cystic fluid regardless of the presence or absence of endometriosis and the type of cyst. When the cutoff value of infectious bacterial abundance in the vagina was set as 64.3%, there were many cases more than a cutoff value in the endometriosis group significantly (p = 0.01). When the cutoff value of infectious bacterial abundance in the endometrium was set as 18.6%, there were many cases more than a cutoff level in the endometriosis cases significantly (p = 0.02). Conclusion Peritoneal fluid and ovarian cystic fluid are almost sterile, although dysbiosis may occur in the vaginal and endometrial microbiome in women with endometriosis.

Abstract Purpose We investigated the change, if any, in prostaglandin E2 (PGE2) signaling in endometriotic lesions of different developmental stages in mouse. In addition, we evaluated the effect of treatment of mice with induced deep endometriosis (DE) with inhibitors of PGE2 receptor subtypes EP2 and EP4 and metformin. Methods Three mouse experimentations were conducted. In Experiment 1, female Balb/C mice were induced with endometriosis or DE and were serially sacrificed after induction. Experiments 2 and 3 evaluated the effect of treatment with EP2 and EP4 inhibitors and metformin, respectively, in mice with induced DE. Immunohistochemistry analysis of COX‐2, EP2, and EP4, along with the extent of lesional fibrosis, was evaluated. Results The immunostaining of COX‐2, EP2, and EP4 turned from activation to a stall as lesions progressed. Treatment with EP2/EP4 inhibitors in DE mice exacerbated endometriosis‐associated hyperalgesia and promoted fibrogenesis in lesions even though it suppressed the PGE2 signaling dose‐dependently. In contrast, treatment with metformin resulted in increased PGE2 signaling, concomitant with improved hyperalgesia, and retarded lesional fibrogenesis. Conclusions The PGE2 signaling diminishes as endometriotic lesions progress. Treatment with EP2/EP4 inhibitors in DE mice exacerbates endometriosis, but metformin appears to be promising seemingly through the induction of the PGE2 signaling.

Abstract Background Reproductive‐age women occasionally face the pathological condition of adenomyosis, which is often concurrent with endometriosis. It is believed that endometriosis and adenomyosis increases the risk of obstetric complications. Although new insights into the mechanism of obstetric complications due to endometriosis are emerging, there is little information on the etiology of adverse pregnancy outcomes in pregnant women with adenomyosis. Methods We performed a literature review focusing on the pathophysiological pathways of obstetric complications in women with adenomyosis using currently available basic and clinical studies. We used the internet search engines PubMed and Google Scholar to search for studies published between January 2000 and June 2021. We carefully read pertinent sections within each document to ensure relevancy. Main findings The prevalence of adverse pregnancy outcomes in women with adenomyosis is increased after adjusting for conceiving by assisted reproductive technology. Thus, adenomyosis emerges as a relevant factor associated with several obstetric complications such as preterm birth, preterm premature rupture of membranes, placental abruption, small for gestational age/fetal growth restriction, and preeclampsia. Conclusion It is plausible that the impact of adenomyosis on pregnancy outcomes is not always the same; rather it is dependent on the degree of uterine involvement and subtypes.

Abstract Purpose To explore the histopathological findings of cesarean scar defect (CSD) and the immunological component in women with cesarean scar syndrome (CSS). Methods This retrospective study was conducted in a university hospital and a public hospital. A total of 63 patients with secondary infertility due to CSS who underwent laparoscopic resection of the CSD lesion were enrolled (CSS group), and 21 patients who underwent hysterectomy with a history of cesarean section were enrolled as control (non‐CSS group). We compared the differences in histopathological findings of CSD lesions by hematoxylin and eosin staining and immunohistochemistry for CD3, CD20, CD56, CD68, CD138, myeloperoxidase, and tryptase between the two groups. Results The frequency of presence of endometrium on the CSD surface was significantly lower (p = 0.0023) and that of adenomyosis was significantly higher (p = 0.0195) in the CSS group than in the non‐CSS group. The number of CD3‐, CD20‐, CD68‐, and tryptase‐positive cells was significantly lower in the CSS group than in the non‐CSS group; however, the number of CD138‐positive cells was significantly higher in the CSS group (p = 0.0042). Conclusions This study suggested that the absence of endometrium, presence of adenomyosis, and chronic inflammation in CSD contributes to secondary infertility due to CSS.

Abstract Purpose While the prevailing view holds that the prostaglandin E2 (PGE2) signaling plays a vital role in endometriosis, PGE2 also is known to be anti‐fibrotic. We investigated the immunostaining of COX‐2, EP2, and EP4, along with fibrotic content in ovarian endometrioma (OE) and deep endometriosis (DE) lesions, and in OE lesions from adolescent and adult patients. In addition, we evaluated the effect of substrate stiffness on the expression of COX‐2, EP2, and EP4 in endometrial stromal cells. Methods Immunohistochemistry analysis of COX‐2, EP2, and EP4, along with the quantification of lesional fibrosis, was conducted for OE and DE lesion samples and also OE lesion samples from adolescent and adult patients. The effect of substrate rigidity on fibroblast‐to‐myofibroblast transdifferentiation (FMT) and the expression of COX‐2, EP2, and EP4, with or without TGF‐β1 stimulation, were investigated. Results The immunostaining of COX‐2, EP2, and EP4 was substantially reduced in endometriotic lesions as lesions became more fibrotic. Both TGF‐β1 stimulation and stiff substrates induced FMT and reduced the expression of COX‐2, EP2, and EP4. Conclusions Since fibrosis is a common feature of endometriosis, our results thus cast doubts on the use of therapeutics that suppresses the PGE2 signaling pathway, either by inhibiting COX‐2 or EP2/EP4.

Abstract Purpose It is unknown whether surgery for endometriosis or recurrence of endometriosis affects obstetric outcomes. Methods A total of 208 pregnant women with a history of endometriosis were analyzed. Patients who had endometriomas >3 cm and no history of laparoscopic surgery for endometriosis were defined as non‐surgery group (n = 60), while those who had a history of surgery for endometriosis (n = 148) were defined as surgery group. We investigated the obstetric outcomes in 208 patients according to with or without postoperative recurrence of endometriosis and the time from surgery to pregnancy. Results Among 177 cases of on‐going pregnancy, in surgery group, there were lower prevalence of placenta previa compared with non‐surgery group (8.5% vs. 23.4%; p = 0.020). Subgroup analysis revealed a decreased prevalence of placenta previa in postoperative non‐recurrence group (6.0%: p = 0.007) compared with non‐surgery (23.4%) and postoperative recurrence group (28.6%). Placenta previa was more prevalent in the patients who got pregnant more than 2 years after surgery (20.0%) than the patients who got pregnant within 2 years (2.4%: p = 0.002). Multivariate analysis revealed that the surgery was associated with a reduction in placenta previa (OR: 0.32, 95% CI [0.11–0.90]; p = 0.032). Conclusions Pregnancy within two years after laparoscopic surgery for endometriosis may reduce placenta previa.

Introduction: There is a growing body of literature concerning endometriosis patients' perspectives on the healthcare system and endometriosis care in New Zealand. However, there is little research available on the perspectives of general practitioners (GPs) internationally, and none currently in New Zealand. The purpose of this study is to address New Zealand GPs' understanding of and approach to endometriosis diagnosis, referrals, management and guidelines., Methods and Materials: An online, anonymous survey was shared with 869 GP clinics and completed by 185 New Zealand-based GPs regarding their awareness and application of the inaugural 2020 'Diagnosis and Management of Endometriosis in New Zealand' guidelines, their perception of their endometriosis knowledge, the diagnostic value they assign to symptoms, the treatments they recommend and the reasons they refer patients to specialist gynaecologists. Differences between groups were conducted using Chi-squared tests, and text answers were assessed thematically using inductive, semantic coding., Results: All 185 GPs had gynaecology consults, and 73% had gynaecology consults every week. Despite 65% being aware of the 2020 guidelines, only 35% overall had read them. Only 52% of GPs considered themselves to know enough about endometriosis for their routine practice. The most common treatment to be considered first line was intrauterine contraceptive devices (IUDs; 96%), whereas the most common alternative treatment recommended was exercise (69%). The most common reason for referral to specialist care was the failure of all attempted treatments (84%)., Conclusions: Many of the study's results align with current New Zealand and international endometriosis guidelines, particularly the prioritisation of progestin-only therapies, the reduced emphasis on surgical treatment as the first line and the low rates of alternative treatment recommendations. This study also highlights the need to improve awareness of inappropriate GP recommendations, including long-term treatment with prescription-only pain relief such as codeine and pregnancy for symptomatic relief., Patient or Public Contribution: Two of the authors involved in the design and conduct of the study, data interpretation and manuscript preparation have sought care for endometriosis., Trial Registration: NA., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Abstract Background It has been well established that endometriosis is an estrogen‐dependent disease. Although the exact pathogenesis of the disease is still unclear, it is known to be characterized by estrogen‐dependent growth and maintenance of the ectopic endometrium and increased local estrogen production. Methods The authors reviewed studies on local estrogen production and estrogen activities mediated by estrogen receptors in endometriotic tissues. Main findings Aberrant expression of several enzymes in local endometriotic lesions contributed to the production and metabolism of estrogens. Aromatase was one of the key therapeutic targets for the regulation of local estrogen formation. Our findings suggest that PGC‐1a, a transcriptional coactivator‐modulating steroid hormone, regulates aromatase expression and activity. Estrogen activities mediated by different types of estrogen receptors abnormally elevated in local tissues could also be involved in the development of endometriosis. The authors demonstrated that the isoflavone aglycone, a partial agonist of the estrogen receptor, suppressed the formation of endometriotic lesions. Conclusions Local estrogen production and estrogen activity mediated by estrogen receptors are important potential therapeutic targets for endometriosis.