The Role of Nanomedicine in Benign Gynecologic Disorders.

Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.

The uterine secretome initiates growth of gynecologic tissues in ectopic locations.

Endosalpingiosis (ES) and endometriosis (EM) refer to the growth of tubal and endometrial epithelium respectively, outside of their site of origin. We hypothesize that uterine secretome factors drive ectopic growth. To test this, we developed a mouse model of ES and EM using tdTomato (tdT) transgenic fluorescent mice as donors. To block implantation factors, progesterone knockout (PKO) tdT mice were created. Fluorescent lesions were present after oviduct implantation with and without WT endometrium. Implantation was increased (p<0.05) when tdt oviductal tissue was implanted with endometrium compared to oviductal tissue alone. Implantation was reduced (p<0.0005) in animals implanted with minced tdT oviductal tissue with PKO tdT endometrium compared to WT endometrium. Finally, oviductal tissues was incubated with and without a known implantation factor, leukemia inhibitory factor (LIF) prior to and during implantation. LIF promoted lesion implantation. In conclusion, endometrial derived implantation factors, such as LIF, are necessary to initiate ectopic tissue growth. We have developed an animal model of ectopic growth of gynecologic tissues in a WT mouse which will potentially allow for development of new prevention and treatment modalities.

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis.

BACKGROUND: Endometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear. METHODS: We employed multi-omics approaches on two cohorts of endometriosis patients with 39 samples. GO terms and KEGG pathways enrichment analyses were used to investigate the functional changes involved in endometriosis. Pearson's correlation coefficient analysis was conducted to explore the relationship between global proteome and ubiquitylome in endometriosis. The protein expression levels of ubiquitin-, fibrosis-related proteins, and E3 ubiquitin-protein ligase TRIM33 were validated via Western blot. Transfecting human endometrial stroma cells (hESCs) with TRIM33 small interfering RNA (siRNA) in vitro to explore how TRIM33 affects fibrosis-related proteins. RESULTS: Integration of proteomics and transcriptomics showed genes with concurrent change of both mRNA and protein level which involved in ECM production in ectopic endometria. Ubiquitylomics distinguished 1647 and 1698 ubiquitinated lysine sites in the ectopic (EC) group compared to the normal (NC) and eutopic (EU) groups, respectively. Further multi-omics integration highlighted the essential role of ubiquitination in key fibrosis regulators in endometriosis. Correlation analysis between proteome and ubiquitylome showed correlation coefficients of 0.32 and 0.36 for ubiquitinated fibrosis proteins in EC/NC and EC/EU groups, respectively, indicating positive regulation of fibrosis-related protein expression by ubiquitination in ectopic lesions. We identified ubiquitination in 41 pivotal proteins within the fibrosis-related pathway of endometriosis. Finally, the elevated expression of TGFBR1/α-SMA/FAP/FN1/Collagen1 proteins in EC tissues were validated across independent samples. More importantly, we demonstrated that both the mRNA and protein levels of TRIM33 were reduced in endometriotic tissues. Knockdown of TRIM33 promoted TGFBR1/p-SMAD2/α-SMA/FN1 protein expressions in hESCs but did not significantly affect Collagen1/FAP levels, suggesting its inhibitory effect on fibrosis in vitro. CONCLUSIONS: This study, employing multi-omics approaches, provides novel insights into endometriosis ubiquitination profiles and reveals aberrant expression of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, emphasizing their critical involvement in fibrosis pathogenesis and potential therapeutic targets.

Extracellular vesicles in endometriosis: role and potential.

Endometriosis is a chronic inflammatory gynecological disease, which profoundly jeopardizes women's quality of life and places a significant medical burden on society. The pathogenesis of endometriosis remains unclear, posing major clinical challenges in diagnosis and treatment. There is an urgent demand for the development of innovative non-invasive diagnostic techniques and the identification of therapeutic targets. Extracellular vesicles, recognized for transporting a diverse array of signaling molecules, have garnered extensive attention as a novel mode of intercellular communication. A burgeoning body of research indicates that extracellular vesicles play a pivotal role in the pathogenesis of endometriosis, which may provide possibility and prospect for both diagnosis and treatment. In light of this context, this article focuses on the involvement of extracellular vesicles in the pathogenesis of endometriosis, which deliver information among endometrial stromal cells, macrophages, mesenchymal stem cells, and other cells, and explores their potential applications in the diagnosis and treatment, conducing to the emergence of new strategies for clinical diagnosis and treatment.

Dissecting the shared genetic architecture between endometriosis and polycystic ovary syndrome.

Background: Previous study suggested evidence for coexistence and similarities between endometriosis and polycystic ovary syndrome (PCOS), but it is unclear regarding the shared genetic architecture and causality underlying the phenotypic similarities observed for endometriosis and PCOS. Methods: By leveraging summary statistics from public genome-wide association studies regarding endometriosis (European-based: N=470,866) and PCOS (European-based: N=210,870), we explored the genetic correlation that shared between endometriosis and PCOS using linkage disequilibrium score regression. Shared risk SNPs were derived using PLACO (Pleiotropic analysis under composite null hypothesis) and FUMA (Functional Mapping and Annotation of Genetic Associations). The potential causal association between endometriosis and PCOS was investigated using two-sample Mendelian randomization (MR). Linkage disequilibrium score for the specific expression of genes analysis (LDSC-SEG) were performed for tissue enrichment analysis. The expression profiles of the risk gene in tissues were further examined. Results: A positive genetic association was observed between endometriosis and PCOS. 12 significant pleiotropic loci shared between endometriosis and PCOS were identified. Genetic associations between endometriosis and PCOS were particularly enriched in uterus, endometrium and fallopian tube. Two-sample MR analysis further indicated a potential causative effect of endometriosis on PCOS, and vice versa. Microarray and RNA-seq verified the expressions of SYNE1 and DNM3 were significantly altered in the endometrium of patients with endometriosis or PCOS compared to those of control subjects. Conclusion: Our study indicates the genetic correlation and shared risk genes between PCOS and endometriosis. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics.

Long-term therapy with dienogest or other oral cyclic estrogen-progestogen can reduce the need for ovarian endometrioma surgery.

BACKGROUND: Almost 10% of women in reproductive age are diagnosed with ovarian endometriomas and can experience symptoms and infertility disorders. Ovarian endometriomas can be treated with medical or surgical therapy. OBJECTIVE: To assess whether long-term therapy with dienogest or oral cyclic estrogen-progestogens is effective in reducing the size of ovarian endometriomas, alleviating associated symptoms, and reducing the requirement for surgery. DESIGN: Prospective non-interventional cohort study. METHODS: We enrolled childbearing women diagnosed with ovarian endometriomas. We collected demographic, clinical, and surgical data, including the evaluation of ovarian endometrioma-associated symptoms and pain using the visual analog scale. We grouped the women according to treatment regimen into dienogest, estrogen-progestogens, and no-treatment. Patient's assessment was performed at baseline and after 12 months evaluating the largest ovarian endometrioma diameter (in millimeters) and the associated symptoms. Furthermore, we analyzed the impact of hormonal treatment in a sub-group of women fulfilling at baseline the criteria for a first-line surgical approach (ovarian endometrioma > 30 mm with visual analog scale > 8 or ovarian endometrioma > 40 mm before assisted reproductive treatments or any ovarian endometrioma(s) > 60 mm). RESULTS: We enrolled 142 patients: 62, 38, and 42 in dienogest, estrogen-progestogens, and no-treatment groups, respectively. No significant differences were found regarding baseline characteristics. After 12 months, the mean largest ovarian endometrioma diameter increased in the no-treatment group (31.1 versus 33.8; p < 0.01), while a significant reduction was registered in the dienogest (35.1 versus 25.8; p < 0.01) and estrogen-progestogens (28.4 versus 16.7; p < 0.01) groups; no significant difference in ovarian endometrioma diameter reduction between these two latter groups was noted (p = 0.18). Ovarian endometrioma-associated symptoms and pain improved in dienogest and estrogen-progestogens groups, with a significantly greater effect for dienogest than for estrogen-progestogens for dysmenorrhea (74% versus 59%; p < 0.01). In the sub-group of women eligible for first-line surgery at baseline, long-term treatment with dienogest and estrogen-progestogens reduced surgical eligibility by 30%. CONCLUSIONS: Decreased mean largest ovarian endometriomas'diameter after 12 months and reduction of the need for surgical treatment by 30% were observed in dienogest and estrogen-progestogens groups. Long-term treatment with dienogest had a greater effect in alleviating dysmenorrhea and pain.

[Rules of acupoint selection and pattern-acupoint relationship in treatment with acupuncture and moxibustion for endometriosis based on complex network analysis technology].

OBJECTIVE: To explore the rules of acupoint selection and pattern-acupoint relationship in treatment with acupuncture and moxibustion for endometriosis (EMs) based on complex network analysis technology. METHODS: The articles for clinical trial of EMs treated with acupuncture and moxibustion were searched from CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase and Cochrane Library from the inception of the databases to December 14, 2022. Using Microsoft Excel 2019 software, the database was established to collect the use frequency of acupoint, meridian tropism, location and pattern-acupoint relationship. SPSS Modeler 18.0 Apriori algorithm was adopted to conduct the association rule analysis, Cytoscape3.7.2 software was used to plot the complex co-occurrence network map; and SPSS Statistics 26.0 was adopted to perform hierarchical cluster analysis on high-frequency acupoints and a tree diagram was drawn. RESULTS: A total of 163 articles were included, and 167 core acupoint prescriptions and 74 pattern-associated acupoint prescriptions were extracted, involving 92 acupoints, with a cumulative frequency of 1 223 times. The top five acupoints with the highest use frequency were Guanyuan (CV 4), Sanyinjiao (SP 6), Zhongji (CV 3), Zigong (EX-CA 1) and Qihai (CV 6). The selected acupoints were mostly distributed in the chest, abdomen and lower limbs; and the involved meridians included the conception vessel, the spleen meridian of foot-taiyin and the stomach meridian of foot-yangming. The acupoint compatibility of high frequency referred to Guanyuan (CV 4) - Sanyinjiao (SP 6), Guanyuan (CV 4) - Zhongji (CV 3), and Guanyuan (CV 4) - Zigong (EX-CA 1). The close association was presented among Guanyuan (CV 4), Sanyinjiao (SP 6), Qihai (CV 6) and Zhongji (CV 3), which had the strongest connection with the other acupoints; among the top 25 acupoints with the highest use frequency, 5 acupoint prescriptions with high frequency were obtained by the cluster analysis. Guanyuan (CV 4), Qihai (CV 6), Sanyinjiao (SP 6), Zigong (EX-CA 1) and Zhongji (CV 3) were selected for cold and blood stagnation; Guanyuan (CV 4), Sanyinjiao (SP 6), Zhongji (CV 3), Dahe (KI 12) and Taixi (KI 3) for kidney deficiency and blood stagnation; Zhongji (CV 3), Guanyuan (CV 4), Sanyinjiao (SP 6), Xuehai (SP 10) and Diji (SP 8) for qi and blood stagnation; Qihai (CV 6), Guanyuan (CV 4), Zusanli (ST 36), Xuehai (SP 10), and Zigong (EX-CA 1) for qi deficiency and blood stagnation; Sanyinjiao (SP 6), Fenglong (ST 40), Zhongliao (BL 33), Ciliao (BL 32) and Xialiao (BL 34) for interaction of phlegm and stasis; and Daheng (SP 15), Guanyuan (CV 4), Zhongji (CV 3), Qihai (CV 6) and Zhongwan (CV 12) for retention of damp and heat. CONCLUSION: The core acupoints are Guanyuan (CV 4), Sanyinjiao (SP 6), Zhongji (CV 3), Qihai (CV 6) and Zigong (EX-CA 1) in treatment of endometriosis with acupuncture and moxibustion. Six patterns/syndromes are involved in clinical practice. In terms of the properties, functions and indications, the supplementary acupoints are selected on the basis of the core acupoints for different patterns/sydnromes of the disease.

[A case of small intestinal endometriosis with bowel obstruction and perforation].

A 47-year-old woman was referred to our hospital with recurring lower abdominal pain persisting for more than 2 weeks. Imaging modalities showed small bowel obstruction caused by a mass lesion in the terminal ileum. Despite undergoing fasting, rehydration, and decompression through an ileus tube, her symptoms persisted. Furthermore, the condition deteriorated on day 4, with the onset of her menstrual period. An emergency surgery was conducted on the 7th day after hospitalization. Surgical observations indicated severe stenosis around the ileocecal valve and ileal perforation approximately 40cm from the oral stricture. As a result, ileocecal resection was performed. Pathological examination revealed endometrial tissue infiltration through the mucosal lamina propria to the ileal subserosa. Thus, the patient was identified with intestinal endometriosis of the ileocecum. Endometriosis of the small bowel is an uncommon condition that eventually causes intractable bowel obstruction. Although preoperative diagnosis is considered challenging, intestinal endometriosis should be included in the differential diagnosis in cases of bowel obstruction in women of childbearing age.

Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1ß-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

FEMaLe: The use of machine learning for early diagnosis of endometriosis based on patient self-reported data-Study protocol of a multicenter trial.

INTRODUCTION: Endometriosis is a chronic disease that affects up to 190 million women and those assigned female at birth and remains unresolved mainly in terms of etiology and optimal therapy. It is defined by the presence of endometrium-like tissue outside the uterine cavity and is commonly associated with chronic pelvic pain, infertility, and decreased quality of life. Despite the availability of various screening methods (e.g., biomarkers, genomic analysis, imaging techniques) intended to replace the need for invasive surgery, the time to diagnosis remains in the range of 4 to 11 years. AIMS: This study aims to create a large prospective data bank using the Lucy mobile health application (Lucy app) and analyze patient profiles and structured clinical data. In addition, we will investigate the association of removed or restricted dietary components with quality of life, pain, and central pain sensitization. METHODS: A baseline and a longitudinal questionnaire in the Lucy app collects real-world, self-reported information on symptoms of endometriosis, socio-demographics, mental and physical health, economic factors, nutritional, and other lifestyle factors. 5,000 women with confirmed endometriosis and 5,000 women without diagnosed endometriosis in a control group will be enrolled and followed up for one year. With this information, any connections between recorded symptoms and endometriosis will be analyzed using machine learning. CONCLUSIONS: We aim to develop a phenotypic description of women with endometriosis by linking the collected data with existing registry-based information on endometriosis diagnosis, healthcare utilization, and big data approach. This may help to achieve earlier detection of endometriosis with pelvic pain and significantly reduce the current diagnostic delay. Additionally, we may identify dietary components that worsen the quality of life and pain in women with endometriosis, upon which we can create real-world data-based nutritional recommendations.

Identification of a rare copy number polymorphic gain at 3q12.2 with candidate genes for familial endometriosis.

Endometriosis is a complex disease that affects 10-15% of women of reproductive age. Familial studies show that relatives of affected patients have a higher risk of developing the disease, implicating a genetic role for this disorder. Little is known about the impact of germline genomic copy number variant (CNV) polymorphisms on the heredity of the disease. In this study, we describe a rare CNV identified in two sisters with familial endometriosis, which contain genes that may increase the susceptibility and progression of this disease. We investigated the presence of CNVs from the endometrium and blood of the sisters with endometriosis and normal endometrium of five women as controls without the disease using array-CGH through the Agilent 2x400K platform. We excluded common CNVs that were present in the database of genomic variation. We identified, in both sisters, a rare CNV gain affecting 113kb at band 3q12.2 involving two candidate genes: ADGRG7 and TFG. The CNV gain was validated by qPCR. ADGRG7 is located at 3q12.2 and encodes a G protein-coupled receptor influencing the NF-kappaß pathway. TFG participates in chromosomal translocations associated with hematologic tumor and soft tissue sarcomas, and is also involved in the NF-kappa B pathway. The CNV gain in this family provides a new candidate genetic marker for future familial endometriosis studies. Additional longitudinal studies of affected families must confirm any associations between this rare CNV gain and genes involved in the NF-kappaß pathway in predisposition to endometriosis.

Nodular image in the appendix observed on ultrasound: endometriosis or neuroendocrine neoplasia?

Objective: To evaluate the association between clinical and imaging with surgical and pathological findings in patients with suspected neuroendocrine tumor of appendix and/or appendix endometriosis. Methods: Retrospective descriptive study conducted at the Teaching and Research Institute of Hospital Israelita Albert Einstein, in which medical records and databases of patients with suspected neuroendocrine tumor of appendix and/or endometriosis of appendix were analyzed by imaging. Results: Twenty-eight patients were included, all of which had some type of appendix alteration on the ultrasound examination. The pathological outcome of the appendix found 25 (89.3%) lesions compatible with endometriosis and three (10.7%) neuroendocrine tumors. The clinical findings of imaging and surgery were compared with the result of pathological anatomy by means of relative frequency. Conclusion: It was possible to observe a higher prevalence of appendix endometriosis when the patient presented more intense pain symptoms. The image observed on ultrasound obtained a high positive predictive value for appendicular endometriosis.

Effects of herbal compounds on various aspects of endometriosis treatment: a systematic review.

OBJECTIVE: Endometriosis means the presence of tissue similar to normal endometrium outside the uterus. Although surgical, hormonal, and analgesic treatment relieves symptoms and improves fertility, it is associated with side effects and a high recurrence rate. Alternative medicines like medicinal plants have been used for the treatment of chronic diseases. Given the global importance of endometriosis as a chronic disease affecting over 15% of all women in their fertile period, this systematic review aimed to give a comprehensive view of research on medicinal plants. MATERIALS AND METHODS: Comprehensive searches were performed on three databases, including PubMed/MEDLINE, Web of Science Core Collection (Indexes = SCI-EXPANDED, SSCI, A, and HCI Timespan), and Scopus, to identify papers published until June 2023. Keywords, such as "Endometriosis" and "Herbal Medicine", were used to search. A manual search of valid journals followed by a manual search of the references of the retrieved full-text articles was performed. All retrieved articles were imported into a database into Endnote X9. Articles that did not meet the inclusion criteria were excluded from the study, and the full texts of all the articles that met the inclusion criteria were assessed. Studies that evaluated the effects of herbal compounds on various aspects of endometriosis treatment were included in the review. RESULTS: In total, 11 studies were included in the present study. The evidence showed that in addition to safety, drugs available alongside treatments could play an effective role in improving the symptoms associated with endometriosis. In this study, the positive results of using Chinese treatments were reported in aspects such as fertility rate, pain, endometriosis recurrence rate, quality of life, sexual function, CA-125 level, and menopause symptoms. CONCLUSIONS: A wide range of preclinical and clinical studies evaluated the effectiveness and safety of medicinal plants in the treatment of endometriosis symptoms. Thus, alternative treatments for endometriosis with no or low side effects should be included in the holistic treatment of endometriosis upfront. However, there is still a need for well-designed trials to investigate standard interventions and specific and safe doses of herbal medicines.

Vitamin D and reproductive disorders: a comprehensive review with a focus on endometriosis.

Vitamin D is a fat-soluble steroid hormone that was initially known only for regulating calcium and phosphorus levels and maintaining bone health. However, it was later discovered that many organs express vitamin D metabolizing enzymes and have a ligand for vitamin D, which regulates the expression of an extensive assortment of genes. As a result, vitamin D is indispensable for the proper function of organs, and its deficiency is believed to be a critical factor in symptoms and disorders such as cardiovascular diseases, autoimmune diseases, and cancers. The significance of vitamin D in reproductive tissues was recognized later, and studies have revealed its crucial role in male and female fertility, as well as proper reproductive function during pregnancy. Vitamin D deficiency has been identified as a risk factor for infertility, gonadal cancers, pregnancy complications, polycystic ovary syndrome, and endometriosis. However, data investigating the association between vitamin D levels and reproductive disorders, including endometriosis, have encountered inconsistencies. Therefore, the present study aims to review existing research on the effect of vitamin D on proper reproductive function, and the role of deficiency in reproductive diseases and specifically focuses on endometriosis.

Exploring the feasibility of indocyanine green fluorescence for intraoperative ureteral visualisation in robotic transvaginal natural orifice transluminal endoscopy surgery during endometriosis resection.

BACKGROUND: To assess the feasibility of use of indocyanine green (ICG) in identifying and minimising urinary tract injury during surgical resection of endometriosis through robotic transvaginal natural orifice transluminal endoscopy surgery (RvNOTES). METHODS: We conducted a retrospective case series in two academic tertiary care hospitals. We examined 53 patients who underwent RvNOTES hysterectomy with planned endometriosis resection. RESULTS: The study involved 53 patients undergoing RvNOTES with ICG fluorescence for endometriosis resection. Mean patient age was 37.98 ± 6.65 years. Operative time averaged 181.32 ± 53.94 min, with estimated blood loss at 45.57 ± 33.62 mL. Postoperative stay averaged 0.23 ± 0.47 days. No ICG-related complications occurred. CONCLUSION: No complications occurred with ICG fluorescence in RvNOTES. It appears to be a safe option for ureteral localisation and preservation. ICG fluorescence is widely used in diverse medical specialities for identifying ureters during complex surgeries. Larger studies are needed to firmly establish its advantages in intraoperative ureteral visualisation during RvNOTES for deep infiltrative endometriosis.

Transgender and gender diverse people with endometriosis: A perspective on affirming gynaecological care.

Transgender and gender diverse people presumed female at birth experience gynaecological conditions, such as chronic pelvic pain at elevated rates, estimated to impact between 51% and 72% of this population, compared to rates of up to 26.6% in cisgender women. The negative impact of these conditions is likely amplified due to limited access to safe and affirming healthcare. Despite this high prevalence rate, there is limited research investigating the prevalence, presentation or management options for trans and gender diverse people with endometriosis. Cisgender women with endometriosis report barriers to accessing care, with lengthy times to diagnosis and limited treatment options available. However, barriers for trans and gender diverse individuals are enhanced by physician bias and lack of education in gender-affirming care. This is reflected in stories of discrimination and denial of basic healthcare. A healthcare environment built on the presumption that gynaecological patients are women, others trans and gender diverse patients, which can result in avoidance of needed medical care. A lack of knowledge of gender-affirming care alongside healthcare provider bias highlights a need for gender-affirming care and bias reduction training in undergraduate healthcare provider curricula. Research to date assessing current curriculum in Australia and Aotearoa (New Zealand) shows limited inclusion of lesbian, gay, bisexual, trans, queer, intersex, asexual and other related identities content as a whole with gender-affirming care being among the least-frequently addressed topics. This review will detail barriers to accessing gender-affirming healthcare specific to gynaecology, interweaving the experiences of a non-binary individual seeking access to gender-affirming endometriosis care.

Transgender and gender diverse people with endometriosis: a perspective on affirming gynaecological careTransgender and gender diverse people have limited access to safe and affirming healthcare. Barriers to accessing care are particularly prominent for those presumed female at birth attempting to access gynaecological care for conditions, such as endometriosis or chronic pelvic pain (CPP). A key barrier to safe and affirming healthcare for this population is a lack of inclusion of trans and gender diverse health in healthcare provider curriculum. The dearth of healthcare providers knowledgeable in gender-affirming care results in healthcare discrimination and poorer health outcomes for trans and gender diverse people.

Heme metabolism and HO-1 in the pathogenesis and potential intervention of endometriosis.

Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase-1 (HO-1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO-1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti-inflammatory, and anti-proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Robotic assisted versus laparoscopic surgery for deep endometriosis: a meta-analysis of current evidence.

Endometriosis is a benign inflammatory onco-mimetic disease affecting 10-15% of women in the world. When it is refractory to medical treatments, surgery may be required. Usually, laparoscopy is the preferred approach, but robotic surgery has gained popularity in the last 15 years. This study aims to evaluate the safety and efficacy of robotic-assisted laparoscopic surgery (RAS) versus conventional laparoscopic surgery (LPS) in the treatment of endometriosis. This study adheres to PRISMA guidelines and is registered with PROSPERO. Studies reporting perioperative data comparing RAS and LPS surgery in patients with endometriosis querying PubMed, Google Scholar and ClinicalTrials.gov were included in the analysis. The Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS-2) was used for the quality assessment of the selected articles. Fourteen studies were identified, including 2709 patients with endometriosis stage I-IV for the meta-analysis. There were no significant differences between RAS and LPS in terms of intraoperative and postoperative complications, conversion rate and estimated blood loss. However, patients in the RAS group have a longer operative time (p < 0.0001) and longer hospital stay (p = 0.020) than those in the laparoscopic group. Robotic surgery is not inferior to laparoscopy in patients with endometriosis in terms of surgical outcomes; however, RAS requires longer operative times and longer hospital stay. The benefits of robotic surgery should be sought in the easiest potential integration of robotic platforms with new technologies. Prospective studies comparing laparoscopy to the new robotic systems are desirable for greater robustness of scientific evidence.

IGF2BP3 promotes glutamine metabolism of endometriosis by interacting with UCA1 to enhances the mRNA stability of GLS1.

BACKGROUND: Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) has been implicated in numerous inflammatory and cancerous conditions. However, its precise molecular mechanisms in endometriosis (EMs) remains unclear. The aim of this study is to examine the influence of IGF2BP3 on the occurrence and progression of EMs and to elucidate its underlying molecular mechanism. METHODS: Efects of IGF2BP3 on endometriosis were confrmed in vitro and in vivo. Based on bioinformatics analysis, RNA immunoprecipitation (RIP), RNA pull-down assays and Fluorescent in situ hybridization (FISH) were used to show the association between IGF2BP3 and UCA1. Single-cell spatial transcriptomics analysis shows the expression distribution of glutaminase 1 (GLS1) mRNA in EMs. Study the effect on glutamine metabolism after ectopic endometriotic stromal cells (eESCs) were transfected with Sh-IGF2BP3 and Sh-UCA1 lentivirus. RESULTS: Immunohistochemical staining have revealed that IGF2BP3 was upregulated in ectopic endometriotic lesions (EC) compared to normal endometrial tissues (EN). The proliferation and migration ability of eESCs were greatly reduced by downregulating IGF2BP3. Additionally, IGF2BP3 has been observed to interact with urothelial carcinoma associated 1 (UCA1), leading to increased stability of GLS1 mRNA and subsequently enhancing glutamine metabolism. Results also demonstrated that IGF2BP3 directly interacts with the 3' UTR region of GLS1 mRNA, influencing its expression and stability. Furthermore, UCA1 was able to bind with c-MYC protein, stabilizing c-MYC mRNA and consequently enhancing GLS1 expression through transcriptional promotion. CONCLUSION: These discoveries underscored the critical involvement of IGF2BP3 in the elevation and stability of GLS1 mRNA in the context of glutamine metabolism by interacting with UCA1 in EMs. The implications of our study extended to the identification of possible therapeutic targets for individuals with EMs.