What's new in endo & adenomyosis research

The identification of the appendix often presents a diagnostic challenge due to its significant anatomical variability, compounded by the frequency with which appendiceal pathologies manifest as atypical clinical presentations that mimic diverse abdominal and pelvic conditions. Beyond acute appendicitis, a wide spectrum of inflammatory, infiltrative, and neoplastic processes can involve the appendix, necessitating the rigorous recognition of their distinct imaging signatures. This pictorial essay reviews the normal anatomy of the appendix, its positional variations, and the spectrum of diseases that may affect it, including acute appendicitis, endometriosis, epiploic appendagitis, appendiceal diverticulitis, mucocele, and primary tumors. While computed tomography (CT) remains the gold standard for primary diagnostic evaluation, magnetic resonance imaging (MRI) serves as a critical complementary modality in specific clinical scenarios, providing superior soft-tissue characterization and improving diagnostic confidence in challenging cases. Recognition of anatomical variants and the primary mimics of the appendix is essential for the accurate interpretation of abdominal imaging studies.

Endometriosis is a chronic gynecological disorder affecting up to 10% of women of reproductive age and is characterized by the presence of endometrial-like tissue outside the uterus. The condition is associated with chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility, and remains difficult to diagnose at early stages. Recent evidence suggests that endometriosis shares genetic and molecular pathways with other chronic pain and inflammatory disorders. Identifying reliable biomarkers is therefore essential to improve risk stratification and support earlier evaluation. Multiple domains have emerged as candidate markers for risk stratification, including genetic and epigenetic alterations, dysmenorrhea, migraine, autoimmune and endocrine disorders, and stress and early-life adversity. These factors have been associated with disease initiation, lesion development, and symptom severity. Understanding their interactions could support multimodal risk stratification approaches and guide preventive strategies. This narrative review highlights the multifactorial nature of endometriosis and synthesizes current evidence on emerging predictive markers. Although progress has been made, large prospective studies are still needed to validate these markers and facilitate the development of targeted interventions.

IMPORTANCE: Endometriosis, a chronic inflammatory condition affecting 10% of reproductive-aged individuals, remains underdiagnosed and poorly managed due to a limited understanding of its pathogenesis. Emerging evidence highlights the gut and reproductive tract microbiota as key modulators of estrogen metabolism, immune dysregulation, and inflammation, offering novel insights into disease mechanisms and therapeutic opportunities. OBJECTIVE: To synthesize current evidence on the mechanistic roles of microbiota in endometriosis pathogenesis, evaluate the diagnostic and therapeutic potential of microbial biomarkers and microbiota-targeted interventions, and identify priorities for translational research. EVIDENCE ACQUISITION: A systematic review of PubMed, Scopus, and Web of Science databases identified preclinical and clinical studies exploring microbiota-endometriosis interactions. The search strategy incorporated the terms "endometriosis" in combination with "microbiota," "reproductive tract," and "gut" to investigate microbial associations within gastrointestinal and reproductive systems in the context of the disease. RESULTS: Dysbiotic microbial profiles, characterized by reduced Lactobacillus and elevated Fannyhessea species, correlate with altered estrogen metabolism, pro-inflammatory cytokine production (eg, IL-6, TNF-α), and impaired immune surveillance in endometriosis. Preclinical studies demonstrate that probiotics and FMT attenuate lesion growth and inflammation in animal models, though human data remain limited. Noninvasive microbial signatures show promise for diagnostic applications, while causal validation in germ-free models and personalized microbiota-based therapies represent critical research gaps. CONCLUSIONS: The microbiota modulates endometriosis progression through hormonal, immune, and inflammatory pathways. Microbial biomarkers and therapies may improve diagnosis and treatment but require rigorous clinical validation. RELEVANCE: Advancing microbiota research could enable noninvasive diagnostics, precision therapies, and prevention strategies.

Subepithelial lesions (SELs) in the lower gastrointestinal tract are rare, and diagnosis and treatment of colorectal SELs are often challenging. Although endoscopic ultrasound-guided tissue acquisition (EUS-TA) is useful for minimally invasive histological diagnosis, few reports have described its use for right-sided colonic SELs because advancing an oblique-viewing echoendoscope into the right colon is difficult. A 30-year-old woman was referred to our hospital after colonoscopy revealed a protruding cecal lesion suggestive of an SEL. Contrast-enhanced computed tomography showed a 37-mm contrast-enhancing mass and an adjacent lesion, thought to be an enlarged lymph node, and gastrointestinal stromal tumor was suspected. A forward-viewing echoendoscope was inserted transanally and advanced successfully to the cecum in 4 min. EUS-TA of the cecal mass was performed using a 19-gauge fine-needle biopsy needle, and EUS-TA of the adjacent lesion was performed using a 25-gauge fine-needle biopsy needle. Histopathological and immunohistochemical examinations showed endometrial glands and stroma with positivity for estrogen receptor, progesterone receptor, and CD10, leading to a definitive diagnosis of endometriosis. This diagnosis enabled initial non-surgical management without immediate surgery.

Progesterone resistance in endometriosis reduces the efficacy of progestin. The non-classical progesterone receptor, progesterone receptor membrane component 1 (PGRMC1) may regulate progesterone signaling in the normal endometrium, but its expression and role in endometriosis remain unknown. We aimed to investigate PGRMC1 expression in endometriosis and its role in progesterone resistance. PGRMC1 expression in normal endometrium (NE), eutopic endometrium in patients with endometriosis (EE), and ovarian endometrioma (OE) was examined using immunohistochemistry. Cultured OE stromal cells (SCs) were subjected to PGRMC1 knockdown using siRNA and treated with AG205 (a PGRMC1 inhibitor) and RU486 (a PR inhibitor) under progesterone stimulation. Progesterone responsiveness was assessed by measuring IGFBP1 and PRL expression through real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). PGRMC1 expression in NESCs and EESCs was significantly lower in the secretory phase than in the proliferative phase (P < 0.01), with no similar changes observed in OE. Following siRNA-mediated PGRMC1 knockdown in OESCs, IGFBP1 and PRL expression was significantly upregulated (P < 0.05). Notably, treatment with siRNA and progestin induced significantly higher IGFBP1 and PRL expression than treatment with progestin alone (P < 0.05). AG205 induced similar effects on IGFBP1and PRL expression (P < 0.05), suggesting that suppression of PGRMC1 expression enhances progestin responsiveness in OESCs. However, AG205-induced IGFBP1 expression was abolished following treatment with RU486, suggesting that PGRMC1 acts through PR. In conclusion, suppressing PGRMC1, which is consistently expressed throughout the menstrual cycle in endometriotic lesions, may restore progesterone sensitivity and improve the efficacy of progestin-based therapies for endometriosis.

PURPOSE: To evaluate intraobserver and interobserver agreement in the interpretation of subtle MRI findings classified as minimal endometriosis, to assess the impact of the Kappa paradox in low-prevalence compartments, and to compare blinded rereads with the original prospective reports. MATERIALS AND METHODS: In this retrospective study, 100 pelvic MRI examinations (50 originally reported as minimal or incipient endometriosis and 50 originally reported as normal) were independently reviewed by three radiologists on two blinded occasions 4-8 weeks apart. Seven anatomical compartments were assessed. Agreement was measured with Cohen's Kappa, Fleiss' Kappa, PABAK, Gwet's AC1, and positive/negative agreement. Original reports were used as a clinical reference for descriptive comparison, and exact McNemar tests assessed directional asymmetry of discordance. RESULTS: Intraobserver agreement for any finding was fair (mean Kappa = 0.36, 95%CI 0.16-0.54; AC1 = 0.49), and interobserver agreement was also fair (Fleiss Kappa = 0.28; AC1 = 0.40). Agreement was consistently stronger for negative than for positive classifications. Ovarian findings showed the highest reproducibility, whereas very low-prevalence compartments showed a marked Kappa paradox. Multicategory analysis of uterosacral ligament laterality reduced agreement, mainly because unilateral-versus-bilateral disagreement remained frequent among positive cases. Comparison with original reports showed slight-to-moderate agreement (Kappa 0.18-0.46), with specificity (76-86%) consistently exceeding sensitivity (32-66%), indicating a more restricted threshold on blinded rereads, particularly for uterosacral ligament involvement. CONCLUSIONS: Agreement for subtle MRI findings interpreted as minimal endometriosis was only fair and clearly lower than that usually reported for deep endometriosis. Low-prevalence compartments were strongly affected by the Kappa paradox, and the low-to-moderate discordance with original reports, driven primarily by lower sensitivity on blinded rereads, supports the need for clearer operational criteria and more standardized interpretation.

The research by Chen et al. (2024) presents an innovative hypothesis linking creatine metabolism to ferroptosis resistance in endometriotic stromal cells via PrP suppression. While conceptually valuable, methodological aspects warrant reflection. A primary concern involves the supraphysiological creatine concentrations used, whose translational relevance is questionable without pharmacokinetic data confirming these levels in the peritoneal environment, particularly in light of available clinical metabolomics data suggesting differences in creatine levels in peritoneal fluid under physiological and pathological conditions. Furthermore, the proposed direct suppression of PrP ferrireductase activity would benefit from complementary biochemical validation using purified systems and affinity measurements to consolidate the molecular mechanism. Although human samples were included, the small cohort size and lack of control for confounding variables limit the specificity of interpretation, source attribution, and the external generalizability of the findings. Finally, future studies should target endogenous creatine synthesis or transport to clarify whether creatine is a causal driver of ferroptosis resistance or simply associated with the inflammatory microenvironment. Overall, Chen et al. provide an exciting contribution; these constructive considerations aim to support future refinements that will solidify the proposed model and its clinical significance.

(No abstract on file for this paper.)

The human microbiome, a dynamic endocrine organ, exerts profound systemic influence through the production of bioactive metabolites. While the microbiome-gut-brain axis is well-established, the direct conduit between the gut microbiota and the reproductive system, the Microbiome-Gut-Gonad Axis, remains an emerging paradigm. This review explored cutting-edge evidence to construct a comprehensive model of the Microbiome-Gut-Gonad axis, focusing on the mechanistic roles of specific microbial metabolites in both physiological reproductive function and the pathogenesis of endocrine disorders. We move beyond mere correlation to elucidate how gut-derived molecules, such as short-chain fatty acids (SCFAs), secondary bile acids, and indole derivatives, directly and indirectly modulate the hypothalamic-pituitary-gonadal (HPG) axis by modulating the production of neuropeptides and hormones (Gonadotropin-releasing hormone (GnRH)) that regulate reproductive functions and also steroidogenesis and gametogenesis. We examine novel mechanisms including: the epigenetic regulation of steroidogenic enzymes by butyrate; the modulation of enterohepatic circulation of estrogens by β-glucuronidase-producing bacteria; and the role of tryptophan metabolites as ligands for aryl hydrocarbon receptor (AhR) in ovarian and testicular function. Furthermore, we critically appraise the disruptive potential of dysbiosis-driven metabolite shifts in PCOS, endometriosis, and male infertility, highlighting microbial metabolite signatures as promising exploratory biomarkers that require standardized, multi-center clinical validation before diagnostic use. At present, these signatures should be considered candidate biomarkers only, because external validation cohorts, assay reproducibility, and clinically meaningful estimates of sensitivity, specificity, predictive values, and clinical utility have not yet been established. Therapeutically, we evaluate innovative interventions, including precision probiotics, postbiotics, and dietary strategies targeting specific bacterial guilds, but these approaches remain investigational because current human evidence is still limited and heterogeneous. Finally, by integrating microbial endocrinology into reproductive medicine, this review establishes a new framework for understanding the etiology of reproductive endocrine disorders and paves the way for microbiome-targeted therapeutic avenues. Importantly, the evidence base is tiered: mechanistic statements in this review are drawn primarily from in vitro and animal studies, human disease links are described separately as observational evidence, and interventional claims are limited to early clinical studies and randomized trial summaries.

Endometriosis rarely affects the abdominal wall and typically occurs following surgery, like uterine procedures or, more commonly, cesarean sections. There have been a few instances of endometriosis evolving into malignant clear cell carcinoma. Our goal was to examine all relevant cases documented in the literature and introduce a new case. In this article, we analyze reported occurrences of clear cell carcinoma in the abdominal wall and share the case of a 45-year-old woman with a mass on her front abdominal wall. An initial biopsy revealed clear cell carcinoma of the female genital tract. In our facility, she underwent extensive surgery involving the removal of the mass along with sections of the abdominal wall, uterus, fallopian tubes, ovaries, omentum, suspicious lymph nodes, and reconstruction of the abdominal wall using a double-sided mesh. She had a smooth recovery after the operation, but a month later, prior to commencing chemotherapy, she developed metastases in the liver and lungs. She was treated with systemic therapy and, after six months, displayed a positive response with some reduction in the disease. As of 15 months post-surgery, she is doing well under ongoing treatment. Clear cell carcinoma of the abdominal wall is an uncommon and aggressive cancer with a grim outlook. Physicians should be wary of the potential for malignancy in women with an abdominal wall mass and a history of gynecological surgeries, especially cesarean sections.

Postoperative recurrence remains a major obstacle to durable remission in patients with solid tumors, even after complete macroscopic resection. Growing evidence suggests that surgery creates a transient yet highly permissive biological window characterized by inflammatory signaling, coagulation activation, endothelial disruption, and systemic immune suppression. Together, these processes foster a protective niche that enables microscopic residual disease to evade immune surveillance and initiate metastatic outgrowth. Although modern adjuvant therapies have improved outcomes, their effectiveness is often limited by inadequate tumor-site specificity, systemic toxicity, poor immune cell trafficking, and tumor heterogeneity. Consequently, a critical unmet clinical need persists for biologically precise strategies capable of eliminating residual tumor cells at their point of vulnerability. Platelets, traditionally viewed as mediators of hemostasis, are now recognized as active regulators of tumor progression. By facilitating fibrin deposition, shielding circulating tumor cells from immune attack, and shaping inflammatory networks, platelets inadvertently support the survival of postoperative tumors. Paradoxically, these same wound-targeting properties create a compelling therapeutic opportunity: leveraging platelet-driven homing mechanisms to direct immunotherapy precisely to fibrin-rich surgical beds where recurrence often originates. In this review, we propose a platelet-guided CAR-T platform that leverages endogenous wound biology to create a precision immunotherapeutic delivery system. This strategy integrates platelet membrane cloaking or platelet-CAR-T conjugation with thrombin-responsive biomaterial depots to enhance local effector retention, amplify effector-to-target ratios, and prolong functional persistence. Programmable safety features, including affinity tuning, logic-gated activation, and inducible suicide switches, are used to reduce thrombo-inflammatory risk while preserving therapeutic efficacy. These mechanisms restrict activity to appropriate contexts and allow controlled shutdown in case of adverse events, improving overall safety. When coupled with minimal residual disease-guided patient selection using circulating biomarkers, this approach establishes a clinically actionable framework for perioperative intervention. Emerging preclinical evidence suggests that localized platelet-assisted delivery can reduce circulating tumor cell burden, enhance antigen presentation when combined with immune adjuvants, and suppress recurrence more effectively than systemic therapies. With rigorous safety validation, scalable manufacturing, and biomarker-enriched clinical trials, platelet-guided CAR-T therapy has the potential to transform the postoperative microenvironment from a sanctuary of tumor survival into a targeted domain for durable immune-mediated eradication.Clinical trial numberNot applicable.

Background: Endometriosis and lipedema are chronic female-predominant disorders characterized by persistent pain that is frequently disproportionate to anatomical lesion burden. Although traditionally interpreted within distinct lesion-centered frameworks, both conditions exhibit striking clinical and epidemiological parallels, including hormonally modulated symptom dynamics, overlap with central pain syndromes, weak correlation between structural disease severity and pain intensity, and symptom clustering during reproductive transitions such as puberty, pregnancy, and menopause. Methods: This study aims to synthesize clinical, molecular, neuroimmune, and endocrine evidence on the interrelationship between endometriosis and lipedema, and to propose a hypothesis-generating neuroimmune framework linking both conditions. This integrative narrative review conducted a non-systematic literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing on mechanisms related to chronic pain, mast cell biology, TRPV1 signaling, CGRP-mediated neurogenic inflammation, intracrine steroidogenesis, and peripheral and central sensitization. Results: The review identifies convergent biological characteristics between the two diseases, including mast cell activation, macrophage polarization, endothelial dysfunction, fibrosis, angiogenesis, intracrine estrogen metabolism, and persistent inflammatory signaling. In endometriosis, direct evidence demonstrates increased sensory innervation, nerve growth factor expression, TRPV1 sensitization, CGRP-positive fibers, and mast cell-nerve interactions. In lipedema, convergent upstream mechanisms, including mast cell infiltration, elevated histamine levels, adipose tissue inflammation, and local estrogen activation, support the plausibility of a functionally analogous neuroimmune organization, despite incomplete direct neural characterization. In this context, the mast cell-TRPV1-CGRP axis is proposed as a biologically plausible framework, directly supported in endometriosis and currently hypothetical in lipedema, connecting peripheral sensitization, neurogenic inflammation, hormonal chronodependence, and central nociceptive amplification. The model further conceptualizes pain crises as transient events of instability within a sensitized neuroimmune network and proposes mechanistic phenotypes that integrate gastrointestinal, inflammatory, central, and hormonal triggers. Conclusion: Endometriosis and lipedema may represent topographically distinct manifestations of a shared neuroimmune process operating within hormone-sensitive tissues. Although the evidentiary basis remains asymmetric, with stronger mechanistic support in endometriosis than in lipedema, this framework provides a biologically plausible and experimentally testable model integrating endocrine, immune, neural, and vascular contributors to chronic pain amplification. This perspective supports coordinated translational investigation across reproductive biology, endocrinology, and pain medicine and may contribute to future mechanism-based stratification and therapeutic development. This work is hypothesis-generating and is not intended to establish causality or to provide clinical recommendations; all proposed mechanistic and therapeutic inferences require prospective experimental validation.

OBJECTIVE: To evaluate central arterial stiffness, endothelial function, and circulating vascular biomarkers in women with ovarian endometriosis and to explore their associations compared with age-matched controls. METHODS: This cross-sectional observational study included women aged 18-40 years with Stage III-IV ovarian endometriosis (n = 20) and age-matched controls without endometriosis (n = 30). Of the 20 women with endometriosis, 18 were receiving Dienogest 2 mg/day at the time of assessment. Central arterial stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV) and aortic Augmentation Index standardized to 75 bpm (AIx@75) using the SphygmoCor® XCEL system. Endothelial function was evaluated by brachial artery flow-mediated dilatation (FMD). Circulating biomarkers including high-sensitivity C-reactive protein (hsCRP), E-selectin, and Endothelin-1 were measured using ELISA. Group comparisons were performed using unpaired t-tests or Mann-Whitney U-tests, and correlations were assessed using Pearson or Spearman analyses. RESULTS: Arterial stiffness parameters did not differ significantly between groups. cfPWV was comparable between women with endometriosis and controls (median [interquartile range] 6.6 [6.0-7.0] vs 6.4 [6.1-6.9] m/s; P = 0.749), as was AIx@75 (24.68% ± 8.71% vs 26.7% ± 12.72%; P = 0.547). However, endothelial function was significantly impaired in women with endometriosis, with lower FMD compared with controls (10.80% ± 3.47% vs 15.26% ± 2.59%; P < 0.001). hsCRP levels were significantly higher in women with endometriosis compared with controls (0.0318 [0.0114-0.0631] vs 0.0105 [0.0062-0.0224] mg/L; P = 0.009), whereas Endothelin-1 levels were significantly lower (15.6 [6.4-32.4] vs 30.6 [18.8-53.6] pg/mL; P = 0.045). E-selectin levels did not differ significantly between groups (P = 0.218). No significant correlations were observed between arterial stiffness indices and molecular markers. CONCLUSION: Women with ovarian endometriosis, the majority of whom were receiving Dienogest therapy, demonstrated impaired endothelial function and elevated systemic inflammation despite preserved central arterial stiffness. These findings support the concept of endometriosis as a systemic inflammatory condition associated with early functional vascular impairment.

A endometriose é uma doença inflamatória crônica estrogênio dependente caracterizada pela presença de tecido endometrial fora da cavidade uterina. O diagnóstico combina história clínica, exame físico e, em alguns casos, exames de imagem específicos, apesar de todas essas técnicas o diagnóstico ocorre tardiamente resultando num desfecho desfavorável pelas alterações inflamatórias progressivas. O tratamento tem como objetivo o controle álgico, embora haja demora no acesso ao diagnóstico, desvalorização das queixas, impacto financeiro e dificuldade de estabelecer diagnósticos diferenciais. OBJETIVO: Descrever as barreiras no diagnóstico e tratamento da endometriose. METODOLOGIA: Trata-se de uma revisão de escopo a partir da análise de artigos publicados entre 2020 e 2025, selecionados nas bases de dados SciELO, PubMed e LILACS através da combinação de descritores, cadastrados no DECs, combinados por meio dos operadores booleanos "and" e "or", em português e inglês, disponíveis gratuitamente, que abordaram de forma relevante as barreiras/limitações/desafios no diagnóstico e/ou tratamento da endometriose. O processo se deu a partir da pergunta norteadora "Quais as barreiras para o diagnóstico e tratamento da endometriose em regiões com recursos limitados?", após aplicar os critérios de inclusão e exclusão 17 artigos foram selecionados, os dados foram organizados no PRISMA-ScR e disponibilizados em tabelas/quadros. RESULTADOS: Por meio dos artigos incluídos nos resultados, observou-se que dentre as principais limitações e dificuldades encontradas estão o atraso no diagnóstico e a escolha de um tratamento adequado mediante as individualidades de cada paciente. A normalização dos sintomas, aspectos socioculturais e econômicos, a disponibilidade de exames de imagem também são fatores identificados como importantes. CONCLUSÃO: Observando sua característica inflamatória crônica e diferentes apresentações, a endometriose evidencia um alto nível de complexidade. Assim, estratégias que visem a educação em saúde tanto para pacientes quanto para profissionais, ampliação do acesso de exames diagnósticos e tratamento multidisciplinar devem ser o cerne do manejo para mulheres com endometriose.

Background/Objectives: Gastrointestinal (GI) symptoms, including abdominal pain, bloating, altered stool pattern, dyschezia, and nausea, are frequent in women with endometriosis and may persist despite conventional gynecological treatment. The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (low-FODMAP) diet is an established dietary intervention for irritable bowel syndrome. Its endometriosis-specific evidence base remains limited. This systematic review evaluated clinical evidence on the low-FODMAP diet or structured FODMAP restriction for GI symptoms in women with endometriosis. Methods: This systematic review was prospectively registered in PROSPERO (CRD420261388786) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. PubMed/MEDLINE, EBSCOhost, and BASE were searched from inception to 30 April 2026. Eligible reports were clinical studies investigating low-FODMAP diet or structured FODMAP restriction in women with confirmed, clinically diagnosed, imaging-based, or medically reported endometriosis and extractable GI or related clinical outcomes. Risk of bias was assessed with design-specific tools. Due to substantial heterogeneity across studies in design, comparators, and outcome measures, a narrative synthesis was performed. Results: Five clinical reports met the inclusion criteria: one randomized controlled crossover feeding trial, two prospective non-randomized studies, one retrospective audit of prospectively collected clinic data, and one case report. The randomized trial showed greater GI response during a 28-day low-FODMAP feeding period than during a nutritionally matched control diet. Prospective studies reported improvements in selected GI symptoms, constipation, pain, and quality-of-life domains, but interpretation was limited by non-randomized allocation, attrition, and mixed or pooled diet comparisons. The retrospective audit and case report supported clinical plausibility but were hypothesis-generating. Conclusions: The five available studies, though limited in number and design, indicate that a low-FODMAP diet can reduce GI symptoms in women with endometriosis, particularly those with abdominal pain, bloating, constipation, or IBS-like symptoms. Currently, the low-FODMAP diet should be viewed as a potentially useful, dietitian-guided GI symptom intervention for selected patients. Future trials should define responder profiles, assess long-term tolerability and nutritional safety, and determine the added value of reintroduction and personalization beyond short-term restriction.

Endometriosis is a gynecological disease affecting more than 190 million women of reproductive age worldwide, characterized by a complex molecular pathophysiology encompassing genetic, epigenetic, inflammatory, and immunological components. A fundamental methodological challenge in the study of endometriosis is the cellular heterogeneity of ectopic lesions: conventional analysis of bulk tissue specimens reflects averaged molecular profiles of mixed cell populations comprising glandular epithelium, stroma, fibrous and muscular tissue, and immune microenvironmental cells, substantially impeding the identification of cell-specific molecular alterations. This article presents an analysis of the capabilities of laser capture microdissection as a technology for the selective isolation of cell populations from heterogeneous tissues, enabling researchers to overcome this limitation. The methodological principles of the technology are described in detail, including critical parameters of biological material preparation, integration with downstream molecular analysis platforms, and the specificities of protocol standardization and validation across different tissue types. The broad applicability of laser capture microdissection in contemporary biomedical research is reviewed. Particular emphasis is placed on its application in endometriosis research specifically: data on transcriptomic profiling and differential gene expression analysis in the epithelial and stromal components of ectopic lesions are described; studies employing next-generation sequencing aimed at investigating somatic mutations, clonality, and mutational profiles of endometriotic cell populations are reviewed; and work in the field of multi-omics profiling across different disease forms is examined. The review also addresses existing methodological limitations of the technology and prospects for its further development, including integration with spatial transcriptomics, single-cell sequencing, and artificial intelligence-based approaches. Laser capture microdissection constitutes an instrument that opens fundamentally new avenues for investigating the molecular heterogeneity of endometriosis and establishing the foundation for the development of targeted, pathogenetically justified approaches to its diagnosis and treatment. This article also presents the authors’ own experience with the application of laser capture microdissection in endometriosis research. At the time of manuscript preparation, laser capture microdissection had been performed on 15 endometriotic lesion specimens obtained from patients with various forms of endometriosis, with separate isolation of epithelial and stromal components intended for subsequent molecular-genetic analysis.

Endo-Cycle© (Ендо-Цикл) — це глобальна інтегрована науково-клінічна доктрина та закрита операційна екосистема, що трансформує менеджмент ендометріозу у безперервний протокол довічного захисту соматичного та репродуктивного здоров'я жінки. Вона адаптується до індивідуальних вікових та репродуктивних змін, синтезуючи методи превентивного перехоплення хвороби, епігенетичного захисту гамет та прецизійної хірургії. / Endo-Cycle© is a global integrated scientific-clinical doctrine and closed operational ecosystem that transforms endometriosis management into a continuous protocol for the lifelong protection of a woman's somatic and reproductive health. Ендометріоз — це не локальна хвороба малого таза. Це хронічне, системне, нейроендокринне та імунологічне захворювання, що безперервно змінює біологічний вік жіночого організму (Endo-Age©). Традиційна фрагментована реактивна модель (хірургія + гормональна супресія) ігнорує каскадний патогенез та провокує прискорений Reproaging© і ятрогенне виснаження оваріального резерву. Endometriosis is not a localized pelvic disease. It is a chronic, systemic, neuroendocrine and immunological disorder that continuously alters the biological age of the female organism (Endo-Age©). The traditional fragmented reactive model ignores the cascade pathogenesis and provokes accelerated Reproaging© and iatrogenic ovarian reserve depletion. Українська: Методологічна доктрина «Ендо-цикл©» (V1.0) авторства Вікторії Гудзяк, доктора медичних наук, встановлює безперервну, замкнуту екосистему для довічного клінічного ведення ендометріозу. Відходячи від реактивних хірургічних моделей, вона запроваджує проактивну чотирифазну, що охоплює період від підліткового віку (Endo-Teen Pro-Reserve©) через активний репродуктивний вік (Fertile Endo-Age©) до тривалого збереження органів (Somatic Endo-Age©). Доктрина також кодифікує прецизійний хірургічний протокол Endo-Reserve©, який інтегрує холодний резервний гемостаз для досягнення ендосоматичного тазового мовчання©. Ukrainian: Методологічна доктрина «Endo-cycle©» (V1.0), розроблена д-ром Вікторією Гудзяк, запроваджує безперервну екосистему для довічного клінічного управління ендометріозом. Відмовляючись від реактивних хірургічних моделей, вона впроваджує проактивну чотирифазну структуру: від підліткового віку (Endo-Teen Pro-Reserve©) та активного репродуктивного періоду (Fertile Endo-Age©) до тривалого збереження органів (Somatic Endo-Age©). Доктрина також кодифікує протокол прецизійної операції Endo-Reserve© з інтеграцією гемостазу холодних матриць для досягнення ендо-соматичної тазової тиші.

BACKGROUND: Endometriosis is sustained by ectopic endometrial implants that remain proliferative and vascularized, making endocrine modulation a cornerstone of therapy. Estetrol (E4) an endogenous estrogen produced during pregnancy, with selective tissue activity, may modulate progesterone (P4) outputs in ectopic tissue and potentially shift lesion biology toward growth restraint without reinforcing vascular support. OBJECTIVE: To test whether E4 modifies P4 effects on lesion proliferation, apoptosis-related signaling, and angiogenic/endothelial activation in vivo. METHODS: Hormonally intact female mice bearing allografted endometriotic lesions received vehicle, E4 (3 mg/day), P4 (4.25 mg/day), or E4 + P4 once daily for 14 days. Lesions and eutopic endometrium were assessed by immunohistochemistry (Ki-67, cleaved caspase-3, BAX, VEGF, PECAM-1/CD31, Cyclin D1) with epithelial/stromal quantification, and endothelial angiogenic behavior was evaluated using a tube-formation assay. RESULTS: Lesions exhibited higher proliferative activity than eutopic endometrium. P4 reduced lesion proliferation, and the E4 + P4 combination produced the strongest growth restraint. Apoptosis-related markers increased under endocrine treatments, with the combined regimen showing robust activation. Notably, P4 enhanced angiogenesis-related readouts (VEGF and PECAM/CD31), whereas E4 + P4 prevented these increases and reduced endothelial tube formation, consistent with attenuated endothelial activation under the combined regimen. CONCLUSIONS: The E4-P4 combination supports a "balanced" endocrine profile-robust growth restraint without concurrent endothelial activation-thereby decoupling proliferation restraint from angiogenic activation.

Bowel involvement is a severe manifestation of deep endometriosis that affects approximately 8-12% of women with endometriosis. Bowel endometriosis is most commonly localised in the rectosigmoid colon and frequently coexists with other pelvic lesions. The pathogenesis of bowel endometriosis is multifactorial, involving hormonal, inflammatory, immune, genetic, and anatomical factors. Clinical presentation ranges from asymptomatic disease to severe gastrointestinal and pelvic symptoms, which can mimic other digestive disorders such as irritable bowel syndrome and inflammatory bowel disease. Diagnostic delays frequently exceed 7-10 years. Transvaginal ultrasound and MRI are the main non-invasive tools for the diagnosis and preoperative assessment of rectosigmoid endometriosis. First-line medical therapy with combined oral contraceptives or progestogens might provide symptom control but is not curative, whereas surgery is reserved for bowel obstruction or severe or refractory symptoms, with surgical approach tailored to disease characteristics and patient needs. Fertility outcomes remain uncertain, and the complexity of long-term management, including the rare risk of malignant transformation, supports the need for multidisciplinary follow-up.

(No abstract on file for this paper.)

Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet sex-specific risk factors are usually not included in conventional predictive models. Specifically, heart failure (HF) in women may be influenced by sex-specific hormones and pathologies that need to be addressed to improve prevention and treatment. This expert consensus statement aims to provide a comprehensive roadmap for HF prevention and management across specific conditions affecting women during their life-course. Each section focuses on the impact of a specific female condition on CVD and how to prevent and manage HF in specific settings: 1. Pregnancy with a specific focus on how to deal with hypertensive disorders in the acute and chronic setting and how to prevent and treat Peripartum Cardiomyopathy (PPCM); 2. Gynecological conditions predisposing to HF, such as Polycystic Ovary Syndrome (PCOS), endometriosis, and the menopausal transition. Emphasis is placed on chronic inflammation, metabolic dysfunction, and the "window of opportunity" for Menopausal Hormone Therapy (MHT); 3. Cardio-Oncology: mitigating Cancer Therapy-Related Cardiac Dysfunction (CTRCD) in breast and gynecological cancers, focusing on female-specific cardiotoxicity profiles, the importance of subclinical detection of cardiac dysfunction and the implementation of cardioprotective strategies (ACE-inhibitors, Beta-blockers, SGLT2 inhibitors) during cardiotoxic treatments. Lifestyle interventions such as the DASH diet and exercise-based rehabilitation are highlighted as essential for maintaining cardiac reserve.

BACKGROUND: The prognostic significance of adenomyosis in endometrial cancer (EC) remains controversial. Although several studies have suggested an association between adenomyosis and favorable tumor characteristics or improved survival outcomes, it remains unclear whether this relationship persists after adjustment for established clinicopathologic prognostic factors. AIM: To investigate the impact of coexisting adenomyosis on clinicopathologic characteristics and survival outcomes in patients with endometrioid-type endometrial cancer. METHODS: This retrospective cohort study included 527 consecutive patients with histologically confirmed endometrioid-type endometrial cancer who underwent primary surgical treatment between January 2010 and May 2025 at a tertiary gynecologic oncology center. Patients were categorized according to the presence or absence of adenomyosis identified in hysterectomy specimens. Clinicopathologic characteristics were compared between groups. Disease-free survival (DFS) and overall survival (OS) were evaluated using the Kaplan-Meier method and Cox proportional hazards regression analyses. RESULTS: Adenomyosis was identified in 154 patients (29.2%). No significant differences were observed between patients with and without adenomyosis regarding age, tumor grade, FIGO stage, myometrial invasion, lymphovascular space invasion (LVSI), lymph node metastasis, or adjuvant treatment (all p > 0.05). Kaplan-Meier analysis demonstrated no significant differences in either DFS or OS according to adenomyosis status (log-rank p = 0.626 and p = 0.697, respectively). In multivariable analysis, LVSI remained the only independent predictor of poorer DFS (HR 2.15, 95% CI 1.02-4.53, p = 0.044), whereas older age (HR 1.08, 95% CI 1.06-1.12, p < 0.001), grade 3 histology (HR 2.11, 95% CI 1.26-3.54, p = 0.005), advanced FIGO stage (HR 1.92, 95% CI 1.18-2.93, p = 0.003), and positive peritoneal cytology (HR 4.47, 95% CI 1.20-16.64, p = 0.026) were independently associated with poorer OS. Adenomyosis was not identified as an independent prognostic factor for either DFS or OS. CONCLUSION: In this cohort of patients with endometrioid-type endometrial cancer, coexisting adenomyosis was not independently associated with distinct clinicopathologic features, disease-free survival, or overall survival. Established clinicopathologic factors remained the primary determinants of oncologic outcomes.

BACKGROUND: Early-life exposures may influence long-term reproductive health, but comprehensive population-based evidence remains limited. This study aimed to evaluate the associations between six early-life factors (long-term/recurrent antibiotic use [LRAU], birth weight, multiple birth, breastfeeding, age at menarche and maternal smoking around birth) and the risk of six major non-neoplastic gynecological diseases in adulthood. METHODS: This large observational association study used data from 272,706 women derived from the UK Biobank, a population-based cohort resource. Six gynecological disorders-uterine fibroids (UF), polycystic ovary syndrome (PCOS), endometriosis, genital prolapse, female infertility, and premenstrual syndrome (PMS)-were identified from hospital inpatient records, first occurrence records, and self-reports. Multivariable logistic regression was used as the primary analysis to estimate adjusted odds ratios (aORs), with Cox models as supplementary analyses. The primary adjusted model included age at recruitment, ethnicity, educational attainment, Townsend deprivation index, and smoking status. A Bonferroni-adjusted significance threshold of P < 0.0014 was applied. RESULTS: Among 272,706 women, the prevalence of the six non-neoplastic gynecological diseases ranged from 0.07% for PMS to 8.51% for UF. After Bonferroni correction, LRAU during early life was associated with higher odds of UF, PCOS, endometriosis, genital prolapse, and PMS. Earlier menarche was associated with higher odds of UF, PCOS, endometriosis, and genital prolapse. Maternal smoking around birth was associated with endometriosis, genital prolapse, and PMS. Not being breastfed as a baby was associated with endometriosis and PMS. Birth weight was associated with genital prolapse. Findings were generally consistent across Cox models and sensitivity analyses, although PMS estimates should be interpreted cautiously because of limited cases. CONCLUSIONS: These findings suggest associations between selected early-life factors and adult non-neoplastic gynecological diseases. Some exposures are potentially modifiable, whereas others are non-modifiable. Together, these factors may help identify individuals at higher risk and inform future studies on risk stratification, but their potential preventive implications require further causal validation.

(No abstract on file for this paper.)

No direct evidence for the management of vaginal endometriosis was identified. Current understanding draws upon broader endometriosis management strategies, where a combination of surgical and pharmacological interventions, such as using LNG-IUS post-surgery, shows potential to manage symptoms and reduce recurrence, although additional targeted research is needed.

Endometriosis is a chronic inflammatory and fibrotic condition in 1 in 10 women characterized by the abnormal growth of endometrial tissue outside of the uterus. Endometriotic tissues attach to the peritoneal mesothelium lining the pelvic cavity to establish harmful lesions and implants in ectopic sites, leading to pelvic pain, infertility, and reduced quality of life. Dysregulated behaviors such as cell migration, invasion, proliferation, and immune escape drive lesion formation. The endometriotic microenvironment contributing to these cell behaviors is complex, with notable components including high local levels of estradiol (E2), a potent estrogen molecule, fibrotic extracellular matrix stiffening, inflammatory markers, and diverse cellular interactions. However, dynamic cellular processes in endometriosis are still not well understood. Moreover, the field is understudied and would benefit from more accessible, diverse, and physiologically relevant in vitro models. This dissertation investigates how hormonal and mechanical microenvironmental cues regulate dynamic cellular processes during endometriosis progression using accessible in vitro models. Our first focus is on hormonal signaling, as E2 has been widely implicated in endometriosis pathogenesis. Whether commonly used cell culture models faithfully capture E2-driven migratory phenotypes, and how hormonal cues interact with the physical properties of the microenvironment, remain open questions. This work first examines the effects of E2 on actin organization, morphodynamic flexibility, and migratory behavior in an endometriotic epithelial cell line (12Z), with the goal of validating its hormone responsiveness. Unexpectedly, E2 sensitivity was found to be context-dependent, motivating a broader investigation into additional microenvironmental regulators of cell behavior. Our subsequent studies focus on the role of mechanical tissue stiffening during fibrosis, using polyacrylamide gels to model healthy and pathological matrices. We demonstrate that substrate stiffness regulates epithelial motility, cytoskeletal organization, and collective migration. We then develop an in vitro model of endometriotic implantation into the mesothelium and show that endometriotic spheroids preferentially disrupt mesothelial barriers on glass, while fibrotic stiffness produces graded effects. By characterizing hormone responses and integrating mechanobiology into co-culture in vitro systems, this dissertation advances our understanding of early lesion establishment. This work also informs future in vitro model design and provides tools for more physiologically informed endometriosis research.

Background: The surgical management of chronic pelvic pain (CPP), particularly in endometriosis, often focuses on lesion excision or nerve decompression. However, persistent pain frequently occurs despite “anatomical perfection,” suggesting central nervous system involvement. Neuropelveology faces a “surgical paradox” when dealing with central sensitization (CS), where peripheral interventions fail to address a systemic nociplastic state. Methods: This systematic review followed PRISMA guidelines and was registered in PROSPERO (CRD420261335008). A search across PubMed, Embase, and Cochrane (2010–2026) identified 71 relevant studies involving over 12,000 participants. Results: CS prevalence in the endometriosis population ranges from 11.3% to 58.2%, rising to 74.8% in specialized tertiary referral centers. The Central Sensitization Inventory (CSI) is a robust predictor of surgical failure; every one-point increase in preoperative CSI raises the risk of persistent pain (OR 1.02, p = 0.02). Objective markers, such as the collapse of Conditioned Pain Modulation (CPM), confirm that “high-sensitizers” (CSI ≥ 40) suffer from a systemic “software” failure of pain inhibition. Conclusions: We propose a paradigm shift in neuropelveology. In patients with high CSI scores (≥40), functional neuromodulation—specifically the LION procedure—should be prioritized over traditional nerve decompression to address the nociplastic nature of the pain.

Personal health tracking technologies are commonly designed around cisnormative and binary assumptions, limiting their usefulness and safety for transgender and gender-diverse (TGD) individuals. This paper investigates how TGD people with endometriosis engage with existing health-tracking tools and the barriers they encounter in doing so. We report findings from an online questionnaire (n=34) exploring lived experiences, self-tracking practices, and perceptions of exclusion. Our results highlight a set of design tensions in current tools, including privacy and disclosure concerns, gendered designs, reductionist symptom models, and an emotional burden associated with tracking. We argue for more inclusive, gender-affirming approaches to self-tracking and present this work as a provocation for researchers and designers to rethink how identity and embodied experiences are encoded in self-tracking technologies.

OBJECTIVE: The aim of this study was to characterize recurrence patterns, identify clinicopathologic prognostic factors associated with overall survival and disease-free survival, and determine the independent prognostic significance of adenomyosis in surgically treated endometrial carcinoma. METHODS: This retrospective single-center cohort included 868 patients who underwent primary surgical treatment for histopathologically confirmed endometrial carcinoma. Clinicopathologic characteristics, recurrence patterns, treatment modalities, and survival outcomes were analysed. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Multivariable Cox regression models included age at diagnosis, FIGO stage, histologic type, and adenomyosis. Additional endometrioid-only subgroup and surgery-period sensitivity analyses were performed. RESULTS: During follow-up, recurrence occurred in 211 patients (24.3%). Recurrence was significantly more frequent in non-endometrioid tumors and increased progressively with advancing FIGO stage and tumor grade (all p < 0.001). In multivariable analysis, increasing age, advanced FIGO stage, and non-endometrioid histology were independently associated with poorer OS. Age and FIGO stage also independently predicted DFS. Adenomyosis was associated with lower unadjusted recurrence rates; however, after adjustment, it was not independently associated with OS and showed only a borderline association with DFS. Similar recurrence patterns were observed in the endometrioid-only subgroup, and surgery-period sensitivity analysis demonstrated consistent prognostic associations across different treatment eras. CONCLUSION: FIGO stage, age, and histologic type remain the major determinants of survival in endometrial carcinoma. While adenomyosis was associated with more favorable unadjusted outcomes, its independent prognostic value appears limited after accounting for established clinicopathologic factors. These findings support the continued importance of classical risk factors and highlight the need for future studies integrating molecular classification to better define the prognostic role of adenomyosis.

Abstract Background Endometriosis, defined by the abnormal growth of endometrial-like tissue outside the uterus, impacts 6–10% of women of reproductive age and is a significant contributor to infertility. The Estrogen Receptor 1 ( ESR1 ) gene is integral to estrogen-dependent signalling pathways, and variations in this gene have been associated with an increased susceptibility to endometriosis. Methods This study investigated the relationship between two polymorphisms in the ESR1 gene (rs9340799 and rs2234693) and infertility associated with endometriosis in South Indian women. The research involved three groups: infertile women diagnosed with endometriosis, infertile women without the condition, and fertile women serving as controls. Genotyping was performed using PCR, and statistical analyses assessed genotype distributions. Additionally, in silico analyses were conducted using GeneMANIA and STRING to examine ESR1 -related gene–gene and protein–protein interaction networks. Results Among the 163 subjects studied, no significant association was observed between either ESR1 SNP and infertility related to endometriosis across all genetic models. In silico analysis revealed that ESR1 participates in biologically meaningful networks, interacting with multiple genes and proteins involved in hormonal signalling, transcriptional regulation, and reproductive functions, supporting its functional relevance in endometriosis pathways. Conclusion Although ESR1 variants rs9340799 and rs2234693 were not statistically associated with endometriosis-related infertility in this population, bioinformatics analyses underscored ESR1 's role in regulatory networks related to estrogen signalling. These findings warrant further large-scale and functional studies integrating both genetic association and molecular pathway data to better understand ESR1 's contribution to endometriosis.

Recent studies have highlighted the crucial role of mechanical properties in the ovarian microenvironment for ovarian function. However, the mechanisms that cause ovarian matrix stiffening during aging remain incompletely understood. Here we utilized atomic force microscopy (AFM) to demonstrate that human ovarian matrix stiffness increases with aging and in pathophysiological conditions, such as chemotherapy-induced premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS) and ovarian endometriosis. By integrating proteomic analysis of human ovarian tissue with transcriptomic profiling of human ovarian fibroblasts, we identified that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix (ECM), thereby increasing ovarian matrix stiffness. Genetic deletion of Il11ra1 in mice mitigated the increase in ovarian matrix stiffness and the decline in ovarian function associated with aging, chemotherapy-induced POI and PCOS. Single-nuclei RNA sequencing (snRNA-seq) revealed that blocking Il11ra1 reduces the proportion of activated fibroblasts. Furthermore, administration of siIl11 nanoparticles to aged mice and rats enhanced fertility and reduced ovarian matrix stiffness. Together, these findings highlight the pro-inflammatory factor IL-11 in regulating ovarian matrix stiffness. We propose that anti-IL-11 therapy represents a promising translational strategy for delaying ovarian aging.

(No abstract on file for this paper.)

Background: Endometriosis is a chronic gynecological disorder associated with pelvic pain, infertility, metabolic disturbances, and impaired quality of life. Lifestyle factors such as diet, physical activity, obesity, and stress have been implicated in the progression and severity of endometriosis. Lifestyle modification may offer a cost-effective adjunctive approach in improving both metabolic and reproductive outcomes in affected women. Aim: To evaluate the effect of lifestyle modifications on metabolic and reproductive outcomes among women with endometriosis. Materials and Methods: This prospective interventional study was conducted among 50 women aged 18-40 years diagnosed with endometriosis at a tertiary care center. Participants underwent a structured six-month lifestyle modification program including dietary counseling, physical activity, weight management, stress reduction, and behavioral counseling. Baseline and post-intervention assessments included anthropometric measurements, fasting blood glucose, lipid profile, insulin resistance, menstrual characteristics, pain severity using Visual Analogue Scale (VAS), and quality of life using Endometriosis Health Profile-30 (EHP-30). Statistical analysis was performed using paired ttest and chi-square test, with p<0.05 considered statistically significant. Results: Significant reductions were observed in body weight, body mass index, waist circumference, fasting blood glucose, triglyceride levels, and HOMA-IR scores following intervention (p<0.05). Reproductive outcomes also improved significantly, including menstrual regularity, ovulatory cycles, dysmenorrhea, dyspareunia, and chronic pelvic pain. Mean dysmenorrhea VAS score decreased from 7.8±1.2tan4.3±1.5 (p<0.001). Quality of life scores improved significantly after lifestyle modification. Conclusion: Lifestyle modification significantly improved metabolic health, reproductive outcomes, symptom severity, and quality of life among women with endometriosis. Incorporating structured lifestyle interventions may serve as an effective adjunct in endometriosis management.

(No abstract on file for this paper.)

Endometriosis is a chronic inflammatory disease characterised by ectopic endometrial tissue, progressive fibrosis and chronic pain, with a pathogenesis that goes beyond oestrogen dependence. The central question this review seeks to answer is: are steroidal alkaloids - nitrogenous plant-derived steroids with a unique structure - a mechanistically sensible, non-hormonal alternative that can simultaneously target the inflammatory, fibrotic and epigenetic drivers of endometriotic lesion persistence, while preserving fertility and avoiding systemic hormonal suppression? A growing body of evidence points to non-hormonal molecular networks including immune dysregulation, angiogenesis, and resistance to apoptosis as drivers of lesion persistence [1]. These molecular disturbances are associated with treatment resistance and limit the long-term efficacy of hormone-based therapies. This review synthesises recent mechanistic advances that describe the non-hormonal signalling pathways that maintain endometriotic lesions, with a specific emphasis on NF-κB-mediated sterile inflammation, inflammasome activation, PI3K/Akt/mTOR-dependent survival signalling, Hedgehog-driven fibrosis and epigenetic repression of progesterone receptor expression. Steroidal alkaloids are critically reviewed as multitarget modulators suppressing inflammatory signalling, inhibiting invasive and fibrotic remodelling, and restoring apoptotic sensitivity in this pathophysiological context, without direct systemic oestrogen deprivation. Structural determinants of steroidal alkaloid activity, including glycosylation status, nitrogen topology and configuration of the steroidal scaffold, are discussed in the context of pathway selectivity, pharmacokinetics and toxicity. Preclinical in vitro and in vivo evidence is critically reviewed in the context of key translational limitations such as bioavailability constraints, narrow therapeutic index and teratogenic risk from developmental pathway inhibition. This review highlights steroidal alkaloids as a mechanistically rational, non-hormonal approach to target lesion persistence and fibrosis in endometriosis, integrating molecular, pharmacological and structural insights, and outlines the major hurdles that must be overcome for clinical translation. The main objective of this review is to address a specific unanswered question: can steroidal alkaloids with their multitarget pharmacology offer a biologically coherent, non-hormonal strategy for the treatment of endometriosis that goes beyond oestrogen deprivation to target the molecular machinery of lesion survival, fibrosis and immune dysregulation. This question is addressed by reviewing the nonhormonal signalling networks that support ectopic lesions, the structural and pharmacokinetic properties of steroidal alkaloids that are relevant to these pathways, and the translational challenges that need to be addressed for clinical translation.

Background: Adenomyosis is commonly associated with dysmenorrhea and heavy menstrual bleeding. Although the levonorgestrel-releasing intrauterine system (Mirena, LNG-IUS) is recommended as a first-line conservative treatment, device displacement or expulsion remains a major limitation, especially in patients with enlarged uteri or deep uterine cavities. Objectives: To evaluate the clinical efficacy and safety of the Indomethacin-GyneFix IUD (GyneFix IUD) combined with LNG-IUS in patients with adenomyosis and to assess whether uterine cavity depth influences device stability. Methods: In this single-center prospective randomized controlled trial, 270 patients with adenomyosis were randomly assigned in a 1:1:1 ratio to the GyneFix IUD + LNG-IUS group, the ring IUD + LNG-IUS group, or the LNG-IUS-alone group (90 patients each). The primary endpoint was the rate of device displacement/expulsion at 6 months. Secondary endpoints included changes in visual analogue scale (VAS) scores, pictorial blood loss assessment chart (PBAC) scores, uterine volume, hemoglobin (Hb), serum CA125, adverse events and patient acceptance. Subgroup analysis was performed according to uterine cavity depth (?9cm vs. >9 cm). Results: At 6 months, the displacement/expulsion rate was significantly lower in the GyneFix IUD + LNG-IUS group (2.22%) than in the ring IUD + LNG-IUS group (10.00%) and the LNG-IUS-alone group (18.89%) (?2=13.468, P0.05). Adverse event rates were comparable among groups (all P>0.05). Patient willingness to choose the same treatment again (95.12%) and willingness to recommend it (90.24%) were significantly higher in the GyneFix IUD + LNG-IUS group. In patients with uterine cavity depth >9 cm, the stability advantage of this strategy was more pronounced. Conclusion: GyneFix IUD combined with LNG-IUS significantly reduces device displacement/expulsion in adenomyosis, particularly in patients with deeper uterine cavities, while maintaining comparable symptom relief and safety. It may represent a more stable and acceptable long-term conservative treatment option.

Purpose: Adolescent endometriosis (EMs) imposes substantial physical and psychological burdens on young female patients, and adaptive coping strategies are vital for their health management. This study aimed to explore the latent classes of parental rearing patterns and coping styles among adolescent females with endometriosis, and examine the interrelationships between parental rearing, psychological resilience and coping styles. The findings intend to provide theoretical evidence and practical references for mental health intervention and public health services targeting this vulnerable group. Methods: This cross-sectional study consecutively recruited participants from 2024 to 2026 at a tertiary Class A hospital in Shenyang. A total of 168 adolescents aged 12– 20 years were enrolled via convenience sampling. Parental Rearing Patterns Scale, the Resilience Scale, and the Coping Styles Scale were used to collect relevant data. Latent class analysis (LCA) was adopted to classify parental rearing patterns and coping styles. Independent samples t-test, one-way ANOVA and bias-corrected Bootstrap mediation analysis (5,000 resamples) were further performed for statistical testing. Results: LCA identified two parenting subtypes (31.5% positive-empowering, 68.5% high-pressure restrictive) and three coping subtypes (58.9% active problem-solving, 28.0% passive-avoidant, 13.1% social support-seeking). Psychological resilience differed significantly across parenting patterns and coping styles (P< 0.05). Mediation analysis revealed that high-pressure restrictive parenting was negatively associated with psychological resilience, and resilience was correlated with coping styles (P< 0.05). The indirect effect was 0.295 (P< 0.05), and the direct effect was non-significant. As this was a cross-sectional study, the findings only indicate statistical indirect associations rather than causal mediation. Conclusion: Different parenting styles and coping patterns lead to varied psychological and clinical outcomes. Positive-empowering parenting and active coping facilitate patients’ psychological adjustment and disease management. By contrast, high-pressure restrictive parenting, avoidant coping and low willingness to seek help tend to trigger negative emotions, reduce treatment adherence and delay intervention. Parenting styles affect coping behaviors partly through psychological resilience. Targeted improvement of psychological resilience can effectively enhance patients’ ability to cope with the disease. Keywords: adolescent endometriosis, parental rearing patterns, psychological resilience, coping styles, mediation effect

(No abstract on file for this paper.)

Актуальность: Эндометриоз встречается примерно у 10% женщин репродуктивного возраста и является одной из основных причин хронической тазовой боли и бесплодия. Диагностическая задержка достигает 7-10 лет, что определяет потребность в точных неинвазивных методах визуализации. Цель исследования – оценить диагностическую точность трансвагинального ультразвукового исследования и магнитно-резонансной томографии при выявлении эндометриоза у женщин репродуктивного возраста. Материалы и методы: Системный поиск проведен в PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science (до 31 января 2025 г.) согласно PRISMA-DTA 2018; качественные исследования оценивались по QUADAS-2. Включены оригинальные диагностические работы с привлечением женщин 18-49 лет с подозрением на эндометриоз; индексный тест – трансвагинальное ультразвуковое исследование (ТВУЗИ) по протоколу International Deep Endometriosis Analysis (IDEA) или магнитно-резонансная томография (МРТ) по протоколам Европейского общества урогенитальной радиологии (ESUR); референтный стандарт – лапароскопия с гистологической верификацией. Результаты: Включено 40 исследований (28 – ТВУЗИ, 12 – МРТ; 17 – прямые сравнительные). Чувствительность/специфичность для эндометрия: ТВУЗИ – 0,94/0,96, МРТ – 0,95/0,97; для глубокого инфильтративного эндометриоза (ГИЭ) ректосигмоидной области: 0,85/0,92 и 0,83/0,95 соответственно. При наступлении ректовагинальной перегородки чувствительность МРТ (0,74 против 0,51 у ТВУЗИ выше) при прогрессивной специфичности. Прямое внутрикортное сравнение не выявило статистически значимых показателей между методами ректосигмоидного ГИЭ (р=0,86; р=0,50). Заключение: Экспертное ТВУЗИ по протоколу IDEA и МРТ по протоколу ESUR являются последовательными диагностическими тестами для выявления эндометриомы и ректосигмоидного ГИЭ; являются взаимодополняющими методами первой линии. МРТ имеет преимущество при последней ректовагинальной перегородке и мультикомпартментальном процессе. С учётом классификации Американской и Глобальной коллегии специалистов по эндометриозу (AGCES), показывающей разделительную оценку генитального и экстрагенитального компонента заболевания, стандартизированная визуализация имеет ключевое значение в стратификации клинических форм. Для Казахстана приоритетной стороной остается перспективная проверка методов визуализации на локальной территории.

Additional file 1: Supplementary figures and tables.

Clear cell gynaecological cancers (CCGC) are rare, biologically distinct and often chemo-resistant with poor prognosis in advanced stages. Endometriosis is a well-recognised precursor, yet its impact on CCGC behaviour is unclear. We performed a retrospective dual-centre analysis to evaluate real-world outcomes.

Abstract Background Pro-EGCG has shown therapeutic promise for endometriosis, yet its immunoregulatory mechanisms remain unclear. Myeloid-derived suppressor cells (MDSCs) are key drivers of disease progression. This study investigates whether Pro-EGCG alleviates endometriosis by modulating MDSC-mediated immune and stromal dysregulation. Methods The therapeutic effects of Pro-EGCG were evaluated in an experimental endometriosis mouse model by assessing lesion burden, histology, and MDSC dynamics. The functional necessity of monocytic MDSCs (M-MDSCs) was validated via adoptive transfer. Clinical relevance was assessed in peripheral blood and lesions from women with or without endometriosis via flow cytometry and multiplex immunofluorescence staining. Furthermore, the direct effects of Pro-EGCG on human PBMC-derived M-MDSCs were examined in vitro, including their immunosuppressive function and their ability to promote fibrosis in a co-culture system with human endometriotic stromal cells. Results In the mouse model, Pro-EGCG treatment significantly reduced lesion weight, volume, and fibrosis, accompanied by consistent M-MDSC reduction systemically and locally. Lesion-infiltrating M-MDSCs, rather than polymorphonuclear MDSCs (PMN-MDSCs), positively correlated with disease severity. Adoptive transfer of M-MDSCs reversed Pro-EGCG’s therapeutic effects. In clinical samples, data confirmed a significant expansion of M-MDSCs in patients with endometriosis compared to controls. In vitro, Pro-EGCG compromised human M-MDSC survival and impaired their suppressive capacity by inhibiting ROS, Arg-1, and NO production. Furthermore, M-MDSC-induced stromal cell proliferation and fibrotic gene expression were abolished by Pro-EGCG preconditioning. Conclusion Pro-EGCG hinders endometriosis progression by inhibiting M-MDSC accumulation, immunosuppressive functions, and pro-endometriotic activities. These findings position Pro-EGCG as a potential immunotherapy for endometriosis and other M-MDSC-driven inflammatory disorders.

(No abstract on file for this paper.)

Background: While endometriosis has a high prevalence among women during their reproductive years, appendiceal endometriosis is an uncommon clinical condition that affects women, and it is mostly presented as acute appendicitis, and or similar to several other gynecological disorders.​Case Presentation: A thirty-four years old female presented with symptoms of a one-day of acute right lower quadrant (RLQ) pain as well as a chronic history of abdominal pain and chronic recurrent pelvic pain. The physical and clinical assessment referred for laboratory, the findings suggested acute appendicitis, then admitted to Baghdad teaching hospital for Laparoscopic appendectomy, and the specimen was sent for histopathological examination, where it revealed endometrial glands and stroma embedded in the muscularis propria of the appendix.​Conclusion: Although rare, appendiceal endometriosis should be considered in the differential diagnosis of RLQ pain in reproductive-age women. This case indicates the necessity of routine histopathological examination of all appendectomy specimens to ensure accurate diagnosis and appropriate follow-up.

OBJECTIVES: To update the 2021 International Society for Gynecologic Endoscopy (ISGE) recommendations for structured reporting of dynamic ultrasound findings in patients with suspected or known endometriosis, integrating recent technical and methodological advances and contemporary diagnostic evidence. Study design A multidisciplinary ISGE working group (sonologists, surgeons, radiologists, methodologists) performed a focused, non-systematic literature review (January 2015-September 2025), prioritizing prospective multicentre diagnostic accuracy studies, high-quality cohorts, systematic reviews and intersociety consensus statements. Draft items were derived from validated frameworks (International Deep Endometriosis Analysis, Morphological Uterus Sonographic Assessment, International Endometrial Tumor Analysis, International Ovarian Tumor Analysis) and the #Enzian classification, refined by a writing subgroup and scored iteratively using Delphi rounds. Evidence quality and recommendation strength were graded using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: When performed by experienced operators, dynamic ultrasound shows high specificity and generally high sensitivity for ovarian endometriomas, many forms of deep endometriosis, and adenomyosis; sensitivity is more variable, particularly for parametrial involvement and small superficial peritoneal lesions. Structured, compartment-based reporting improved completeness and may increase concordance with intraoperative mapping compared with unstructured reports. The 2026 ISGE update expands the 2021 template with standardized superficial peritoneal descriptors, lateral compartment subdivision (parametrium, pelvic sidewall, pelvic nerve assessment) and detailed quantitative pelvic metrics. Optional advanced fields capture items supported by lower-quality or emerging evidence. Implementation recommendations include targeted training, Picture Archiving and Communication System integration, and staged adoption. CONCLUSIONS: The 2026 ISGE structured ultrasound report provides a practical, surgically actionable template. Prospective multicentre validation and standardized training are priorities.

(No abstract on file for this paper.)

BACKGROUND: Endometriosis is a chronic inflammatory disorder that affects 5-15% of women of reproductive age. It is characterized by severe symptoms, including dysmenorrhea and non-cyclic pelvic pain, which can substantially impair quality of life. Although diet is a major modifiable risk factor for many chronic diseases, its potential role in endometriosis has received limited attention. This study aimed to investigate the association between Dietary Acid Load (DAL) and the odds of endometriosis among Iranian women. METHODS: This hospital-based case-control study was conducted in Tehran, Iran, between February to September 2021. Participants included women diagnosed with endometriosis and healthy controls, all of whom were evaluated by a gynecologist who was blinded to the study object. Dietary intake was assessed using a validated 168-item food frequency questionnaire (FFQ). DAL was estimated using Two indices: Potential Renal Acid Load (PRAL) and Net Endogenous Acid Production (NEAP). Logistic regression models were used to investigate the association between DAL and odds of endometriosis. RESULTS: A total of 105 women with endometriosis and 208 healthy controls were included in the study. The results showed that each one-unit increase in PRAL and NEAP was associated with an 8%, and 4% increase in the odds of endometriosis, respectively. CONCLUSION: Higher DAL was associated with increased odd of endometriosis. These findings suggest that reducing the consumption of acid-producing foods may help lower the risk of endometriosis. Further prospective studies are warranted to confirm these findings and clarify the underlying mechanisms.

Dysmenorrhea is one of the most frequent gynecological complaints among adolescents and women of reproductive age. It is often normalized as a routine part of menstruation, yet recurrent menstrual pain may substantially reduce educational participation, work productivity, sleep quality, mental well-being, and social functioning. This article provides an IMRAD-based analytical review of dysmenorrhea with emphasis on clinical phenotypes, prostaglandin-centered pathogenesis, differential diagnosis, contemporary treatment strategies, real-world evidence, artificial intelligence, pharmacovigilance, and implementation perspectives for Uzbekistan. Evidence was synthesized from PubMed-indexed reviews, Cochrane evidence, WHO menstrual health materials, ACOG and ESHRE guidance, and regulatory sources from FDA and EMA on real-world evidence and AI-enabled health technologies. The review highlights that primary dysmenorrhea is mainly driven by increased endometrial production of prostaglandin F2α and prostaglandin E2, which induce myometrial hypercontractility, vasoconstriction, ischemia, and pain. Secondary dysmenorrhea requires active evaluation for endometriosis, adenomyosis, fibroids, pelvic inflammatory disease, and structural anomalies. NSAIDs, hormonal therapy, heat therapy, exercise, patient education, and timely referral form the core of modern management. The article argues that modern dysmenorrhea care should combine pathophysiological reasoning with real-world evidence, patient-reported outcomes, pharmacovigilance, and ethically governed artificial intelligence. Such an approach is especially important for health systems developing electronic prescriptions, registries, and digital clinical decision support. For Uzbekistan, structured menstrual health documentation may create a foundation for safer analgesic use, earlier detection of secondary dysmenorrhea, and locally relevant research.

Ovarian endometrioma is a form of endometriosis that often presents a diagnostic challenge due to its ability to mimic ovarian malignancy both clinically and biochemically. Markedly elevated CA-125 levels may further raise suspicion of malignancy, potentially leading to overdiagnosis and overtreatment. We report the case of a 39-year-old woman with a recurrent ovarian mass presenting with progressive dysmenorrhea, abdominal enlargement, and menstrual irregularities. Examination revealed a large abdominal mass with a significantly elevated CA-125 level of 1,500 U/mL. Ultrasonography demonstrated a cystic lesion with a characteristic “ground glass appearance” without solid components, suggestive of endometrioma. However, intraoperative findings of extensive adhesions raised strong suspicion of malignancy. Frozen section analysis suggested a benign lesion consistent with endometrioma, which was subsequently confirmed by final histopathological examination. The patient subsequently underwent total hysterectomy and unilateral salpingo-oophorectomy, followed by postoperative GnRH agonist therapy. This case highlights that ovarian endometrioma can closely mimic ovarian malignancy, particularly in the presence of markedly elevated CA-125 levels. Histopathological examination remains the gold standard for definitive diagnosis. A comprehensive and individualized approach is essential to avoid unnecessary aggressive management and to optimize patient outcomes. AbstrakEndometrioma ovarium merupakan salah satu bentuk endometriosis yang sering menimbulkan tantangan diagnostik karena dapat menyerupai keganasan ovarium, baik secara klinis maupun biokimiawi. Peningkatan kadar CA-125 yang sangat tinggi sering kali memperkuat kecurigaan terhadap keganasan sehingga berpotensi menyebabkan overdiagnosis dan overtreatment. Dilaporkan kasus seorang wanita berusia 39 tahun dengan massa ovarium rekuren yang disertai keluhan dismenore progresif, pembesaran abdomen, dan gangguan menstruasi. Pemeriksaan menunjukkan massa abdomen berukuran besar dengan kadar CA-125 mencapai 1.500 U/mL. Ultrasonografi memperlihatkan lesi kistik dengan gambaran khas ground glass appearance tanpa komponen solid yang mengarah pada diagnosis endometrioma. Namun, temuan intraoperatif berupa adhesi luas menimbulkan kecurigaan kuat terhadap keganasan ovarium. Pemeriksaan frozen section menunjukkan lesi jinak yang konsisten dengan endometrioma dan selanjutnya dikonfirmasi melalui pemeriksaan histopatologi definitif tanpa ditemukan tanda keganasan. Pasien menjalani histerektomi total dan salpingo-ooforektomi unilateral, diikuti terapi agonis GnRH pascaoperasi. Kasus ini menunjukkan bahwa endometrioma ovarium dapat menyerupai keganasan ovarium, terutama pada kondisi dengan kadar CA-125 yang sangat tinggi. Pemeriksaan histopatologi tetap merupakan standar emas dalam menegakkan diagnosis definitif. Pendekatan diagnostik yang komprehensif dan individual diperlukan untuk menghindari tindakan yang tidak perlu serta mengoptimalkan luaran pasien.

(No abstract on file for this paper.)

Primary dysmenorrhea is a recurrent menstrual pain syndrome occurring in the absence of identifiable pelvic pathology. Its most accepted pathophysiological model centers on increased endometrial production of prostaglandin F2α and prostaglandin E2 during menstruation. These mediators intensify uterine contractions, increase intrauterine pressure, reduce uterine blood flow, induce ischemia, and sensitize pain pathways. This article reviews the biological role of prostaglandins, the clinical rationale for NSAID therapy, timing and safety considerations, real-world effectiveness, pharmacovigilance, artificial intelligence, and personalized treatment strategies. The evidence synthesis shows that anti-inflammatory therapy is pathogenetically justified when primary dysmenorrhea is prostaglandin-dominant. However, treatment success depends on early initiation, correct dosing, patient education, safety screening, and reassessment when response is inadequate. Real-world data and AI-based analytics may help identify patients with poor response, detect adverse drug reaction signals, and improve clinical decision support. The article also discusses how Uzbekistan’s developing e-prescription and digital health systems may support safer NSAID use and national evidence generation. A central conclusion is that NSAID therapy should not be evaluated only as a drug effect, but as a complete clinical strategy that includes diagnosis, timing, adherence, contraindication screening, follow-up, and referral criteria. When this strategy is implemented correctly, prostaglandin inhibition remains a rational first-line approach. When it fails, clinicians should consider secondary dysmenorrhea, central sensitization, inadequate exposure, or non-prostaglandin mechanisms rather than repeating empirical analgesic escalation.

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Background & Objective: Laparoscopic and histological evaluation is the most reliable method for confirming the presence of endometriosis; nevertheless, imaging methods may provide useful information. In this study, the diagnostic value of imaging findings for the diagnosis of endometriosis was compared with that of pathology.Materials & Methods: This cross-sectional study was conducted in Khorramabad, Lorestan, Iran. The imaging results of 118 patients with symptoms of endometriosis who had undergone ultrasound, Computed Tomography (CT) scan, and Magnetic Resonance Imaging (MRI), and who had a positive result suggestive of endometriosis in at least one of the three modalities, were compared with their pathology reports. Additionally, information such as the history of cesarean section, delivery, laparoscopic procedures, marital status, and type of lesion was collected and analyzed.Results: In this study, the sensitivity of ultrasound for the diagnosis of endometriosis was 93.2%. The sensitivity of MRI for the diagnosis of endometriosis was 98.3%. CT scan had the lowest sensitivity among these three modalities, at 65.8%.Conclusion: Based on the results of this study, ultrasound and MRI have a remarkable ability to diagnose endometriosis with the least number of false negatives due to their high sensitivity. Given their limited sensitivity and high radiation exposure, the use of CT scans for diagnosing endometriosis in the abdominal and pelvic cavities is not practical.

BACKGROUND: Aspartame, a widely used artificial sweetener, has been implicated in multiple toxicities. However, its potential reproductive toxicity mechanisms remain unclear. This study aimed to investigate the underlying relationship between aspartame exposure and endometriosis pathogenesis. METHODS: Following the toxicity analysis of aspartame, we compiled its toxicity targets and simultaneously retrieved endometriosis-related genes. By intersecting these two gene lists, we identified the aspartame-induced endometriosis genes and enriched their biological functions and pathways. Subsequently, we established core targets by PPI network and topological analysis alongside machine learning algorithms and detected expression patterns of these hub genes in bulk and single-cell datasets. Finally, molecular docking and dynamics simulations were conducted to assess the interaction stability between aspartame and core targets, followed by in vitro and in vivo validation, and virtual gene knockout technology to elucidate the underlying molecular mechanisms. RESULTS: Firstly, we identified a total of 124 targets for aspartame and 3344 genes related to endometriosis. And we constructed an aspartame-endometriosis-genes regulatory network comprising 40 intersecting targets, among which five significantly differentially expressed targets were searched: ACE, DPP4, MME, IL1B, and PTGS2, and projected these genes onto a single-cell dataset to reveal their distribution patterns. Molecular docking and dynamics simulations identified PTGS2 as the core target exhibiting the most stable interaction with aspartame. Cellular and mice experimental validation further demonstrated that aspartame exposure promoted endometriosis progression by modulating oxidative stress and mitochondrial dysfunction, while PTGS2 knockdown and pharmacological inhibition partially reversed these aspartame-induced cellular phenotypes. Additionally, virtual gene knockout analysis suggested that PTGS2 perturbation disrupted immune-related gene networks, implicating altered intercellular communication and immune homeostasis in aspartame-associated endometriosis. CONCLUSION: Taken together, our study firstly established association between aspartame exposure and endometriosis pathogenesis, identified PTGS2 as a key target gene mediated by aspartame in endometriosis, proposed its underlying mechanisms of action, and analyzed the clinical value and significance.

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STUDY QUESTION: Are there distinct symptom clusters in women with endometriosis and adenomyosis, and how do these clusters predict quality of life? SUMMARY ANSWER: Latent class analyses of 22 438 women with endometriosis identified four symptom phenotypes, including high pain-gastrointestinal and psychological-neurological clusters; adenomyosis cases were concentrated in high‑pain classes without a minimal‑symptom group, and high‑burden phenotypes had poorer quality of life. WHAT IS KNOWN ALREADY: Endometriosis and adenomyosis are heterogeneous conditions with diagnostic delays of 4-11 years. The classification based on surgical findings and imaging fails to capture the complex, systemic symptom combinations that affect patients' quality of life (QoL). STUDY DESIGN, SIZE, DURATION: Large-scale cross-sectional cohort study using data from the United States-based All of Us Research Program (Controlled Tier v8; May 2018-October 2023). PARTICIPANTS/MATERIALS, SETTING, METHODS: The dataset included 22 438 women with electronic health records (EHR) and/or self-reported endometriosis. Four Latent Class Analyses (LCA) were performed on different patient groups: (i) the full endometriosis cohort (n = 22 438); (ii) an age-corrected subset restricted to premenopausal women (aged 18-45; n = 5542) to minimize menopausal confounding; and two subgroups derived from the age-corrected cohort to test whether concomitant adenomyosis defines distinct symptomatic phenotypes: (iii) clinically confirmed endometriosis without adenomyosis (n = 1797) and (iv) adenomyosis with endometriosis (n = 643). LCA was performed using 19 self-reported and EHR-derived symptoms and comorbidities (e.g. chronic pelvic pain, migraine, depression, gastrointestinal symptoms) to identify patient subgroups. Multinomial logistic regression assessed sociodemographic (age, BMI, deprivation index) and clinical predictors (hormonal contraceptive use, surgical history) of class membership. The association between latent classes and QoL outcomes was evaluated using data from the 'Overall Health' and 'Health Care Access and Utilization' surveys. Data are available via the All of Us Researcher Workbench (https://workbench.allofus.org). MAIN RESULTS AND THE ROLE OF CHANCE: Latent class analysis of clinically confirmed endometriosis identified four distinct symptom phenotypes, most notably a severe 'High Pain & Gastrointestinal with Mood Symptoms' (High) cluster and a unique 'Predominantly Psychological/Neurological' cluster that challenges traditional gynecological-focused diagnostic frameworks. Patients with adenomyosis exhibited a distinct profile with two high-pain symptom classes and the absence of a fully asymptomatic group, indicating a higher overall disease burden. Membership in the High class was significantly associated with lower general health scores, reduced social satisfaction, and increased barriers to healthcare access. LIMITATIONS, REASONS FOR CAUTION: The All of Us is a United States-based research program, and the findings should be replicated in other independent cohorts to confirm generalizability across other geographical regions. The cross-sectional design limits causal inference regarding QoL outcomes. Also, the analyses rely on a mix of diagnostic approaches, including surgical and non-surgical clinical and self-reported diagnoses, which is both a strength and a limitation. The 'Minimal Symptom Burden' class may reflect under-documentation of symptoms in clinical records rather than a true lack of symptoms, and the High class may reflect to patients who have higher multimorbidity, hence have more hospital visits. WIDER IMPLICATIONS OF THE FINDINGS: These results support a shift toward personalized, interdisciplinary management of endometriosis that addresses mental health and gastrointestinal symptoms alongside pelvic pain. The identification of a 'Predominantly Psychological/Neurological' cluster suggests that young women presenting with non-classical symptoms (anxiety, migraine, depression) could be screened for endometriosis to reduce diagnostic delays and improve life-course potential. FUNDING: D.K. was supported by a 'Ramón y Cajal' fellowship from the Spanish Ministry of Science and Innovation (RYC2024-050099-I). O.G. was supported by a postdoctoral award from the Amy P Goldman Foundation. DISCLOSURES: I.F. is the co-founder and co-owner of Sur180 Therapeutics, which is developing a novel treatment for endometriosis, and the Chief Scientific Officer of Nura Health, which is developing a non-invasive diagnostic solution for the disease. I.F. has received ARPA-H grant no. ARPA-H-ICHUB-24-101-1035 as Principal Investigator, consulting fees from Nura Health and Sur180 Therapeutics, and stock and share options in both companies. I.F. is also the inventor on patents for 'Compositions and methods for treating endometriosis' (US10695341 and US10729693) and serves as an unpaid Board Member of the World Endometriosis Society and the Fundación Puertorriqueña de Pacientes con Endometriosis (ENDOPR). H.S.T. received speaker fees from Gedeon Richter, a grant from AbbVie through Yale University, consulting fees from Regeneron, and is a co-inventor on Yale's endometriosis biomarkers and treatments (including US11993816B2, US10982282B2, and US12286629B2). He also serves on the boards of the Environmental Health Trust and Environment and Human Health. TRIAL REGISTRATION NUMBER: N/A.

Introduction. Endometriosis affects 10-20% of reproductive-age women. Emerging evidence links the gut microbiota to endometriosis pathogenesis, but observational studies are limited by confounding, reverse causation and uncertainty about whether reported microbial signals represent reproducible aetiological associations.Hypothesis/Gap Statement. Whether genetically predicted gut microbial genera are associated with endometriosis risk remains unclear, and available observational evidence does not establish robust causal effects after accounting for multiple testing.Aim. This study aimed to explore potential Mendelian randomization (MR)-based associations between genetically predicted gut microbiota composition and endometriosis using a two-sample MR framework.Methodology. Genome-wide association study (GWAS) summary statistics for 119 bacterial genera (MiBioGen consortium: n=18,340) and endometriosis (FinnGen: 8,288 cases, 68,969 controls) were used. Single nucleotide polymorphisms (SNPs) associated with each genus (P<5×10⁻⁵) were selected as instrumental variables after linkage disequilibrium clumping and weak instrument exclusion. The primary method was inverse-variance weighting (IVW), supplemented by four complementary methods. Benjamini-Hochberg false discovery rate (FDR) correction was applied across all 119 genera.Results. Seven genera showed nominally significant IVW associations with endometriosis (P<0.05): Lactococcus, Olsenella, Senegalimassilia, Ruminococcaceae UCG-002, Holdemania, Eubacterium ruminantium group and Anaerotruncus. Olsenella, Ruminococcaceae UCG-002 and Anaerotruncus were directionally associated with increased risk, whereas the remaining four were directionally associated with reduced risk. However, none survived FDR correction (all FDR-adjusted P=0.731). No significant heterogeneity or horizontal pleiotropy was detected.Conclusion. These findings provide exploratory and suggestive MR evidence for potential associations between specific gut microbial genera and endometriosis, rather than definitive causal evidence. As no associations survived multiple testing correction, these results should be interpreted as hypothesis-generating and require replication in larger, ancestry-matched cohorts.

OBJECTIVES: Endometriosis presents a multitude of challenges for individuals. Current treatment of the disease is based on pharmacotherapy that aims to relieve pain, improves future fertility, potentially slows disease progression and lessen the likelihood of recurrence. The present review outlines recent reports on the importance of Gonadotropin-Releasing Hormone antagonists/antagonists and a new prospective as a significant second- line treatment option. MATERIAL AND METHODS: A review of the literature from the last 5 years was conducted. The search included the following medical subject: "endometriosis", "GnRh agonists", "GnRh antagonists", "pharmacotherapy".The articles published in English were included. Publications without full text access and duplicates were rejected. RESULTS: Current researches no longer focuse exclusively on finding new GnRH agonists/antagonists, but rather on maximizing their usage, in favour of the latter ones . Multiple active substances are now being combined into one tablet, which makes it easier for patients to take their medication and improves their adherence to treatment recommendations. 24 months monotherapy of linzagolix did not indicate any clinically relevant impact on overall bone condition in comparison to placebo group. Relugolix combination therapy maintained bone mass density over two years while effectively alleviating pain symptoms. CONCLUSIONS: Despite being effective, all of treatments may have additional negative effects. The best approach to pharmacotherapy depends on the individual patient's needs and circumstances. Taking into consideretion potential effects, an appropriate dose or a combination of the above options should be performed. The treatment options of Relugolix and Linzagolix are both promising and well-tolerated. Further researches should focuse on long-term bone health monitoring strategies and its safety profile.

Aripiprazole, a third-generation atypical antipsychotic drug, crosses the placental barrier, yet its developmental skeletal effects remain unexplored. This study aimed to evaluate impact of prenatal aripiprazole exposure, administered at three different doses, on the ossification of axial skeleton in 20-day old rat fetuses. Forty pregnant Sprague-Dawley rats were assigned to four groups: control and three aripiprazole treated-groups receiving 3 mg/kg (low dose aripiprazole), 6 mg/kg (high dose aripiprazole), and 12 mg/kg (double high dose aripiprazole [DHDA]) daily from gestational days 6-19. Fetuses were delivered on gestation day 20, weighed, and processed for skeletal evaluation using Alizarin Red staining. Ossification of craniofacial bones, hyoid bone, vertebral centra and arches, sternum, and ribs were assessed and categorized as complete, delayed, or absent. A total of 151 fetuses were analyzed. Aripiprazole exposure induced a dose dependent reduction in fetal weight and in the number of completely ossified skeletal centers. Craniofacial bones, particularly parietal, interparietal, supraoccipital, and presphenoid, were the most affected. Significant impairments were observed in vertebral centra and arches across cervical, thoracic, lumbar, sacral, and coccygeal regions, with the DHDA group exhibiting the greatest deficits. Sternebrae ossification showed marked reduction, whereas rib ossification remained unaffected. A strong positive correlation was found between fetal weight and total number of complete ossification centers across all groups. Prenatal exposure to aripiprazole leads to dose dependent fetal growth restriction and delayed ossification of axial skeleton in rat fetuses. Future investigations should focus on the molecular mechanisms and consequences related to prenatal impacts of aripiprazole.