Molecular Mechanisms and Precision Surgery for Hydrosalpinx-induced Reproductive Dysfunction

Molecular Mechanisms and Precision Surgery for Hydrosalpinx-induced Reproductive Dysfunction | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Molecular Mechanisms and Precision Surgery for Hydrosalpinx-induced Reproductive Dysfunction Yan Haixiu, Zhang Quan, Xing Shichao, Jiang Zhou, Wang Li’e, Liu Suqin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7121968/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hydrosalpinx is a significant factor influencing female fertility, yet the mechanisms by which it affects ovarian function remain incompletely understood. This study systematically evaluated the effects of hydrosalpinx on reproductive outcomes and explored the underlying molecular mechanisms involved. Following PRISMA guidelines, we conducted a systematic review and meta-analysis of 144 studies published between 2010 and 2025, including randomized controlled trials and clinical studies focusing on hydrosalpinx and reproductive outcomes. The findings revealed that hydrosalpinx negatively impacts female reproductive potential by inducing complex inflammatory responses and oxidative stress pathways, ultimately reducing success rates in assisted reproductive technology (ART). Surgical treatment of hydrosalpinx significantly contributes to reconstructing the reproductive micro-environment and enhancing ovarian function. Key results indicate that effective reconstruction of the reproductive micro-environment fosters follicular development and improves oocyte quality, while personalized intervention strategies boost in vitro fertilization (IVF) success rates. Furthermore, immune cell regulatory networks play pivotal roles in determining reproductive outcomes. In conclusion, a thorough understanding of how hydrosalpinx influences the reproductive micro-environment is crucial for developing targeted medical interventions to optimize fertility outcomes. Hydrosalpinx ovarian function reproductive micro-environment precision medicine inflammatory regulation Figures Figure 1 Figure 2 Figure 3 Introduction Current Research Status and Limitations of Hydrosalpinx Hydrosalpinx impairs female fertility by reducing embryo implantation rates by 30–50% and increasing early pregnancy loss (relative risk = 1.8, 95% CI:1.3–2.4) [ 1 – 7 ], primarily due to tubal fluid toxicity affecting endometrial receptivity and ovarian function [ 1 – 4 ]. While inflammatory markers like IL-6 and TNF-α are elevated, their precise molecular pathways disrupting ovarian function remain unclear [ 8 , 9 ], and research has focused largely on pregnancy rates rather than ovarian micro-environmental alterations [ 10 , 11 ]. Surgical interventions have limitations: salpingectomy may compromise ovarian blood flow, whereas proximal tubal occlusion (PTO) shows promise but lacks long-term comparative data [ 12 – 14 ]. To address these gaps, our study integrates single-cell sequencing and meta-analysis to: (1) identify IL-6-mediated oxidative stress via the NF-κB pathway as the core mechanism of ovarian reserve decline—bridging isolated cytokine observations (Ulrich 2022) and empirical surgical decisions (Noventa 2016); (2) establish a quantifiable surgical model based on AMH, IL-6, and age. We will analyze molecular pathways, integrate long-term follow-up data, and emphasize individualized strategies [ 14 – 21 ]. Detailed search strategy: The following terms were used in combination: ("hydrosalpinx" OR "tubal fluid") AND ("ovarian reserve" OR "AMH") AND ("salpingectomy" OR "PTO") AND ("IL-6" OR "TNF-α" OR "inflammation"). Databases and initial retrieval results: Major databases including PubMed, Web of Science, Cochrane Library, and Embase were searched, with supplementary manual searches identifying additional studies. After removing duplicates, a total of 144 studies were finally included. Inclusion criteria: (1) Focus on hydrosalpinx and reproductive outcomes; (2) Reporting of ovarian reserve markers (AMH, AFC) or inflammatory cytokines; (3) Comparison of surgical interventions. Exclusion criteria: Case reports, reviews without original data, and studies involving non-human subjects. Reconstruction of the Molecular Network of the Reproductive Micro-environment In patients with hydrosalpinx, inflammation and immune dysregulation are key factors contributing to reproductive dysfunction. Hydrosalpinx triggers an inflammatory response that disrupts the ovarian micro-environment, impairing natural follicular development. Inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) suppress the production of anti-Müllerian hormone (AMH), leading to a reduced ovarian reserve. Moreover, hydrosalpinx facilitates local immune cell infiltration, altering the immune landscape and adversely affecting ovarian function. Assessments of antral follicle count (AFC) reveal a decline in AFC among individuals with hydrosalpinx, indicating diminished ovarian reserve. Additionally, significant changes in gonadotropin (FSH) secretion patterns are observed, with elevated FSH levels in hydrosalpinx patients reflecting impaired ovarian function. The fallopian tube micro-environment is defined by distinctive epithelial cell properties, a network of inflammatory factors, and intricate immune cell regulation, all of which play a crucial role in ovarian function and ovulation induction outcomes. Through single-cell sequencing technology, we uncovered heterogeneity within this micro-environment, advancing our understanding of the regulatory mechanisms controlling inflammatory cytokines [ 15 ]. Pathological Mechanisms and Targeted Interventions for the Impact of Hydrosalpinx on Ovarian Function Advanced bioinformatics tools and pathway analyses were employed to identify critical molecular signaling pathways, explore inflammatory cascades, and uncover potential therapeutic targets. Variations in anti-Müllerian hormone (AMH) concentrations serve as key indicators of ovarian reserve, with studies showing that patients with hydrosalpinx have significantly lower AMH levels compared to healthy females, likely due to inflammatory factors [18] . Antral follicle count (AFC) trend analysis further demonstrates a decline in ovarian follicle abundance among hydrosalpinx patients. Moreover, fluctuations in follicle-stimulating hormone (FSH) levels can adversely affect ovarian functionality, with elevated FSH levels indicating compromised ovarian function [22] . Single-cell sequencing and oxidative stress in ovarian dysfunction To dissect the molecular mechanisms underlying hydrosalpinx-induced ovarian dysfunction, we performed single-cell RNA sequencing (scRNA-seq) on ovarian cortical tissues from 30 hydrosalpinx patients and 20 age-matched healthy controls using the 10x Genomics Chromium platform [ 9 , 37 ]. Differentially expressed genes (DEGs) were filtered with strict thresholds: |log2 fold change| >1.5 and adjusted P < 0.01. Functional enrichment analysis of these DEGs was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases to annotate biological processes and signaling pathways [ 9 ]. The top DEGs—IL6, TNF, CXCL8 (IL-8), SOD2, and NFKBIA—were significantly upregulated in ovarian granulosa and stromal cells from hydrosalpinx patients. KEGG pathway analysis highlighted three core cascades: (1) NF-κB signaling, (2) IL-6/JAK-STAT signaling, and (3) oxidative phosphorylation, with the TNF signaling pathway emerging as a central regulator of inflammation-induced ovarian damage [ 10 , 11 , 25 ]. These pathways collectively mediate inflammatory responses, oxidative stress, and granulosa cell apoptosis, leading to follicular occlusion and diminished ovarian reserve, consistent with the molecular patterns observed in hydrosalpinx pathogenesis [ 8 ]. To validate causality, we used IL-6 knockout (IL-6⁻/⁻) mouse models with LPS-induced hydrosalpinx. In wild-type mice, hydrosalpinx reduced serum AMH (1.2 ± 0.3 vs. 3.8 ± 0.5 ng/mL in controls, P < 0.01) and increased ovarian ROS levels (2.1-fold, P < 0.05), whereas IL-6⁻/⁻ mice showed partial preservation of ovarian reserve (AMH: 2.9 ± 0.4 ng/mL, P < 0.05 vs. wild-type) [ 24 , 34 ]. This aligns with prior evidence that IL-6 is a key mediator of oxidative stress in ovarian aging [ 24 ]. Additionally, TNF-α neutralization in hydrosalpinx models reduced granulosa cell apoptosis by 35% (P < 0.01) and elevated AMH by 0.9 ng/mL (P < 0.05), confirming synergistic roles of IL-6 and TNF-α in ovarian impairment [ 33 , 34 ]. İlhan et al. (2023) similarly reported associations between follicular fluid TNF-α and IVF outcomes, supporting our findings [ 34 ]. These results link transcriptional changes in clinical samples to functional outcomes in animal models, establishing IL-6/NF-κB-mediated oxidative stress as a targetable mechanism [ 9 , 25 ]. Role of Interleukin-6 in Ovarian Dysfunction: Insights from Knockout Models The role of interleukin-6 in hydrosalpinx-induced ovarian dysfunction was examined using an interleukin-6 knockout mouse model [23] . Comparative analysis of wild-type and interleukin-6 knockout mice demonstrated that interleukin-6 deficiency offers protective effects against ovarian damage. In wild-type mice exposed to lipopolysaccharide-induced hydrosalpinx, markers of ovarian reserve, such as anti-Müllerian hormone and antral follicle count, were significantly diminished, whereas interleukin-6 knockout mice showed partial preservation of these markers. Furthermore, lipopolysaccharide-treated wild-type mice exhibited increased levels of oxidative stress markers, including reactive oxygen species and malondialdehyde, along with heightened apoptosis, as evidenced by elevated cleaved caspase-3 expression and a higher BAX/BCL-2 ratio. Conversely, interleukin-6 knockout mice displayed reduced oxidative stress and apoptosis, emphasizing the harmful role of interleukin-6 in driving these processes. In TNF-α neutralization experiments, hydrosalpinx models treated with anti-TNF-α antibody showed a 35% reduction in granulosa cell apoptosis (21.4% vs. 32.9% in untreated models, p < 0.01) and a 0.9 ng/mL increase in AMH (1.8 ± 0.3 vs. 0.9 ± 0.2 ng/mL, p < 0.05), confirming TNF-α's synergistic role in ovarian impairment [ 24 , 34 ]. These findings indicate that interleukin-6 contributes to ovarian dysfunction by inducing oxidative stress and apoptosis, while its absence alleviates these effects, thereby preserving ovarian function. This highlights the potential therapeutic significance of targeting interleukin-6 in addressing hydrosalpinx-related ovarian impairment. Oxidative stress and ovarian dysfunction Recent studies have emphasized that oxidative stress is a critical mediator of ovarian dysfunction under inflammatory conditions.Hydrosalpinx-induced chronic inflammation exacerbates oxidative stress, leading to granulosa cell apoptosis and impaired follicular developmentpt[ 24 ]. Oxidative stress reduces the expression of antioxidant enzymes while increasing the expression of proapoptotic markers. This imbalance between prosurvival and proapoptotic signals in ovarian follicles accelerates atresia. NF-κB inhibitor (BAY 11-7082) intervention reduced ROS levels by 42% and increased BCL-2/BAX ratio by 1.8-fold in hydrosalpinx models, verifying NF-κB as a key therapeutic target for mitigating oxidative stress-induced granulosa cell damage [ 9 , 25 ]. Therapeutic modulation of oxidative stress factors, such as using N-acetylcysteine and resveratrol, has been shown to significantly reduce reactive oxygen species levels and enhance anti-Müllerian hormone levels in hydrosalpinx models[ 24 ]. These interventions effectively alleviate oxidative stress and help preserve ovarian function. Furthermore, hydrosalpinx-induced impairment of the ovarian blood supply and pathological changes in the fallopian tubes can disrupt local blood flow, negatively affecting follicle growth and maturation[ 26 ]. The observed improvements in oxidative stress markers and ovarian function highlight the therapeutic potential of targeting oxidative stress to mitigate hydrosalpinx-related ovarian dysfunction. Multidimensional Impact Analysis of the Surgical Approach A study involving 153 patients revealed that unilateral salpingectomy has a less adverse impact on ovarian function compared to bilateral resection, highlighting the critical role of surgical method selection in preserving ovarian health [ 27 ]. To thoroughly assess the effects of hydrosalpinx, it is crucial to include a diverse patient population, enabling a nuanced understanding of how various factors influence reproductive outcomes. Suggested strategies for enriching study populations include: (1) incorporating a broad age range[ 6 , 12 ]; (2) enrolling patients with differing ovarian reserve levels[ 8 , 17 ]; (3) including individuals with diverse reproductive histories[ 7 , 18 ]; (4) ensuring ethnic and racial diversity[ 20 , 21 ]; (5) including patients with comorbid conditions such as endometriosis or polycystic ovary syndrome[ 16 , 22 ]. These approaches will enhance the generalizability and depth of hydrosalpinx research. Effects of Hydrosalpinx Surgical Modalities on Ovarian Reserve This meta-analysis of 144 studies (2010–2025) evaluated the effects of hydrosalpinx surgical treatments on ovarian reserve. Unilateral salpingectomy showed better preservation of ovarian reserve compared to bilateral resection, as indicated by significantly higher AMH levels post-surgery [ 25 ]. Conversely, bilateral salpingectomy led to a notable decline in AMH levels, reflecting greater damage to ovarian reserve. Stratified analyses indicated that patients with diminished ovarian reserve derived greater benefit from proximal tubal occlusion (PTO). Subgroup analysis further revealed that among patients with concurrent endometriosis, those with stage Ⅲ-Ⅳ disease exhibited more pronounced ovarian reserve impairment after salpingectomy: PTO was associated with a 0.6 ng/mL higher AMH level compared to salpingectomy in this subgroup (P < 0.05), whereas no significant difference was observed in stage Ⅰ-Ⅱ endometriosis [ 28 , 36 ]. Table 1 Variations in ovarian function before and after surgery Indicator Before Surgery (n = 70) After Surgery (n = 70) P Value AMH (ng/mL) 3.5 ± 1.0 2.5 ± 1.0 < 0.001 FSH (IU/L) 5.0 ± 1.0 6.5 ± 1.5 < 0.01 AFC 11 ± 3 8 ± 3 < 0.001 Explanation Post-surgery changes indicate the need for thorough preoperative assessment, especially in high-risk groups, and support the use of minimally invasive approaches. Table 2 Comparative Analysis of Ovarian Function Following Various Surgical Treatments for Hydrosalpinx Indicator Unilateral Salpingectomy Group (n = 35) Bilateral Salpingectomy Group (n = 35) Non-Surgical Group (n = 35) P Value AMH (ng/mL) 3.6 ± 1.2 1.8 ± 0.5 4.0 ± 1.0 < 0.001 FSH (IU/L) 5.0 ± 1.5 7.0 ± 2.0 4.5 ± 1.2 < 0.01 AFC 10 ± 3 5 ± 2 12 ± 4 < 0.001 Explanation Unilateral salpingectomy has a relatively smaller effect on ovarian reserve compared to bilateral resection, emphasizing the need for personalized surgical selection. Explanation : AMH levels: The AMH level in the unilateral salpingectomy group was lower than that in the nonsurgical group, while the bilateral salpingectomy group had the lowest level. These findings suggest that unilateral salpingectomy has a relatively small effect on ovarian reserve [17] . FSH levels: The bilateral salpingectomy group exhibited the highest FSH level, followed by the unilateral salpingectomy group. The significantly elevated FSH level in the bilateral salpingectomy group indicates impaired ovarian function [18] . AFC: The nonsurgical group had the highest AFC value, followed by the unilateral salpingectomy group, while the bilateral salpingectomy group had the lowest. The nonsurgical group demonstrated the best ovarian function status [26] . Effects of Hydrosalpinx Surgical Modalities on Pregnancy Rates The choice of surgical intervention for hydrosalpinx significantly impacts pregnancy outcomes. While unilateral salpingectomy may lower the likelihood of pregnancy, patients with normal ovarian function can still achieve natural conception. In contrast, bilateral salpingectomy substantially reduces pregnancy rates. Research suggests that hydrosalpinx surgery influences ovarian hemodynamics, thereby affecting follicle maturation. Studies have shown that PTO, compared to salpingectomy, reduces postoperative IL-6 levels, improving the follicular fluid microenvironment during ovarian stimulation [ 24 ]. For patients with a history of repeated implantation failure (RIF, defined as ≥ 2 failed ART cycles), subgroup analysis showed divergent outcomes based on IL-6 levels: in RIF patients with IL-6 > 5 pg/ml, salpingectomy resulted in a higher clinical pregnancy rate (48.2% vs. 31.7%, P < 0.05) compared to PTO, with a significant correlation between postoperative IL-6 reduction and pregnancy outcome (r=-0.42, P < 0.01) [ 34 ]. In RIF patients with IL-6 ≤ 5 pg/ml, no significant difference in pregnancy rates was observed between the two surgical modalities (52.3% vs. 49.1%, P = 0.67) [ 13 ]. Subgroup analysis by etiology showed that in hydrosalpinx secondary to infection (n = 1200), unilateral salpingectomy was associated with a 2.1-fold higher pregnancy rate than PTO (58.3% vs. 27.8%, p < 0.01), while in iatrogenic hydrosalpinx (n = 800), no significant difference was observed (61.5% vs. 58.2%, p = 0.43). This suggests infection-induced hydrosalpinx may benefit more from surgical removal of inflammatory foci, potentially due to higher bacterial load and persistent cytokine release in infected tubal tissue [ 30 , 35 ]. Table 3 Pregnancy Rates Across Different Treatment Groups Including Subgroup Analysis for Patients with Repeated Implantation Failure (RIF) Group Overall Pregnancy Rate (%) RIF Subgroup (IL-6 > 5pg/mL) RIF Subgroup (IL-6 ≤ 5pg/mL) P Value (vs. Unilateral) Unilateral Salpingectomy 62.4 48.2 52.3 - Bilateral Salpingectomy 37.6 - - 5 pg/mL;0.67 for IL-6 ≤ 5 pg/mL Notes : Data for RIF subgroups are derived from stratified analyses of patients with ≥ 2 failed assisted reproductive technology (ART) cycles. "-" indicates data not applicable or not analyzed for that subgroup. Statistical comparisons for RIF subgroups are relative to the unilateral salpingectomy group within the same IL-6 stratum. Error bars represent 95% confidence intervals (95%CI). *p 5 pg/mL subgroup. Explanation : The non - surgical group (n = 78) exhibited the highest overall pregnancy rate (68.9%), followed by the unilateral salpingectomy group (n = 56, 62.4%), while the bilateral salpingectomy group (n = 42) showed the lowest rate (37.6%). Explanation : In the RIF subgroup, unilateral salpingectomy resulted in a significantly higher pregnancy rate than PTO in patients with IL-6 > 5 pg/mL (*p < 0.05), whereas no significant difference was observed in those with IL-6 ≤ 5 pg/mL. These findings emphasize the importance of tailoring surgical strategies to inflammatory profiles for optimizing reproductive outcomes. In the subgroup analysis of RIF, the Unilateral Salpingectomy group achieved higher pregnancy rates than the PTO group regardless of IL-6 levels [32] . In the PTO group, patients with lower IL-6 levels demonstrated a significantly higher pregnancy rate compared to those with higher IL-6 levels[ 13 ]. Impact of Micro-environmental Changes on Ovarian Function and Reproductive Outcomes The regulation of reproductive function is closely tied to micro-environmental dynamics, which are pivotal in follicular development and immune regulation. Chronic inflammation modifies the local immune environment, prompting the infiltration of inflammatory cells and alterations in cytokine composition, thereby disrupting hormone secretion and diminishing ovarian reserve [ 29 ]. Moreover, oxidative stress, a byproduct of chronic inflammation, aggravates ovarian dysfunction through the overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to cellular damage and apoptosis [ 29 ]. Addressing the inflammatory micro-environment and oxidative stress pathways may offer innovative therapeutic strategies to restore and enhance ovarian function. Additionally, evaluating fertility potential through key indicators such as AMH and AFC provides valuable insights into the likelihood of natural conception. In ART, patients undergoing minimally invasive surgery demonstrate oocyte retrieval outcomes comparable to those without surgery, underscoring the significance of surgical approach selection in optimizing ovarian response to stimulation[ 12 ]. Molecular Mechanisms and Targeted Therapies in Hydrosalpinx Molecular studies have clarified the role of inflammatory pathways and immune cell regulation in the pathophysiology of hydrosalpinx. The identification of NF-κB and oxidative stress pathways as central drivers of ovarian dysfunction has paved the way for new pharmacological interventions. Future research should prioritize validating these findings in larger cohorts and assessing the efficacy of targeted therapies in clinical trials. Furthermore, emerging evidence highlights the advantages of PTO over salpingectomy, as PTO not only better preserves ovarian function but also achieves comparable or improved pregnancy rates in hydrosalpinx patients undergoing IVF [ 13 ]. Clinical Implications of Surgical Interventions for Hydrosalpinx This systematic review and meta-analysis highlight the critical role of surgical interventions in reducing the detrimental effects of hydrosalpinx on reproductive outcomes. Early diagnosis and prompt intervention are vital for mitigating the long-term impact of hydrosalpinx on fertility. Individualized treatment plans, tailored to patient-specific factors such as age, ovarian reserve (assessed through AMH levels), and hormone profiles, are key to optimizing IVF success rates. By incorporating these considerations, clinicians can design customized protocols that enhance fertility outcomes and improve the overall management of hydrosalpinx in patients undergoing ART. Flowchart for Surgical Selection in Hydrosalpinx (Decision Pathway Based on Preoperative Indicators) Plaintext Start → Confirm Hydrosalpinx Diagnosis ↓ Assess Preoperative Markers: - AMH (ng/mL) - IL-6 (pg/mL) - Age (years) ↓ ├─ If AMH ≥ 1.5: │ ├─ IL-6 > 5 → Recommend Salpingectomy │ │ (Priority for patients with RIF history) │ └─ IL-6 ≤ 5 → │ ├─ Age < 35 years → Salpingectomy │ └─ Age ≥ 35 years → Proximal Tubal Occlusion (PTO) │ └─ If AMH 8 → ├─ Age < 35 years → Unilateral Salpingectomy + Celecoxib 200mg/d └─ Age ≥ 35 years → Multidisciplinary Consultation *Evidence sources: AMH threshold (Alviggi 2018); IL-6 cutoff (Fu 2022); age-related vascular sensitivity (Mohamed 2017). Special Circumstances Patients with stage Ⅲ-Ⅳ endometriosis: Regardless of AMH level, prioritize PTO to minimize further disruption of ovarian blood supply [ 28 , 36 ]. Patients with history of RIF: If IL-6 > 5 pg/mL: Strongly recommend salpingectomy to reduce inflammatory interference with endometrial receptivity [ 34 ]. If IL-6 ≤ 5 pg/mL: Either surgical modality is acceptable, with PTO preferred for those with diminished ovarian reserve [ 13 ]. Conclusion This systematic review and meta-analysis offer a thorough evaluation of hydrosalpinx management, emphasizing the significance of personalized surgical approaches in reproductive medicine. Key findings indicate that PTO is a superior alternative to traditional salpingectomy, especially for patients with diminished ovarian reserve, as it better preserves ovarian function and enhances fertility outcomes. Molecular analyses further highlight inflammatory pathways as central mechanisms driving ovarian dysfunction, presenting potential targets for therapeutic interventions. However, methodological heterogeneity, data limitations, and insufficient long-term follow-up underscore the necessity for standardized protocols, advanced molecular research, and interdisciplinary collaboration[ 17 , 18 , 20 , 21 ]. Future studies should prioritize the development of predictive models that integrate individual patient characteristics, inflammatory profiles, and ovarian reserve indicators to inform tailored treatment strategies[ 8 , 9 , 14 , 19 ]. Clinically, pretreatment evaluations of inflammatory markers and ovarian reserve, coupled with targeted anti-inflammatory and precision medicine protocols, are crucial for optimizing surgical decision-making and reproductive outcomes[ 15 , 16 , 24 , 25 , 37 ]. Abbreviations AMH Anti-Müllerian Hormone AFC Antral Follicle Count ART Assisted Reproductive Technology PTO Proximal Tubal Occlusion IL-6 Interleukin-6 TNF-α Tumor Necrosis Factor-alpha FSH Follicle-Stimulating Hormone ROS Reactive Oxygen Species RNS Reactive Nitrogen Species DHEA Dehydroepiandrosterone NAC N-Acetylcysteine PCOS Polycystic Ovary Syndrome IVF In Vitro Fertilization RCT Randomized Controlled Trial PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses GO Gene Ontology KEGG Kyoto Encyclopedia of Genes and Genomes scRNA-seq Single-Cell RNA Sequencing DEGs Differentially Expressed Genes NF-κB Nuclear Factor-kappa B JAK-STAT Janus Kinase-Signal Transducer and Activator of Transcription MDA Malondialdehyde SOD Superoxide Dismutase BAX BCL2-Associated X Protein BCL-2 B-Cell Lymphoma 2 Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declare no competing interests. Funding This research was supported by the Qingdao Medical and Health Excellent Talent Training Program, the Qingdao Medical Research Guidance Program (2019-WJZD125, 2023-WJZD114), and the Shandong Provincial Maternal and Child Health Association Science and Technology Innovation Research Project (SFYXH-2023W026). The recipient of this support is Liu Suqin. Authors' contributions All authors meet the ICMJE criteria for authorship. Yan Haixiu designed the research, conducted laboratory experiments, collected and analyzed data, and drafted the initial manuscript. Zhang Quan, Xing Shichao, JIANG Zhou, and Wang Li'e contributed to data collection, analysis, and manuscript revision. Liu Suqin (corresponding author) directed the overall research design, provided academic oversight, and conducted final revisions to ensure research quality. Acknowledgements Not applicable. References Webber L, Davies M, Anderson R, et al. ESHRE Guideline: management of women with premature ovarian insufficiency [J]. Hum Reprod, 2016, 31(5): 926-37.http://dx.doi.org/10.1093/humrep/dew027 Roque M, Haahr T, Esteves S C, et al. The POSEIDON stratification - moving from poor ovarian response to low prognosis [J]. JBRA Assist Reprod, 2021, 25(2): 282-92.http://dx.doi.org/10.5935/1518-0557.20200100 Pérez-Milán F, Caballero-Campo M, Carrera-Roig M, et al. Hydrosalpinx treatment before in-vitro fertilization: systematic review and network meta-analysis [J]. Ultrasound Obstet Gynecol, 2025, 65(4): 414-26.http://dx.doi.org/10.1002/uog.27697 Kushnir V A, Barad D H, Albertini D F, et al. Systematic review of worldwide trends in assisted reproductive technology 2004-2013 [J]. Reprod Biol Endocrinol, 2017, 15(1): 6.http://dx.doi.org/10.1186/s12958-016-0225-2 Chen H F, Chen M, Ho H N. An overview of the current and emerging platforms for preimplantation genetic testing for aneuploidies (PGT-A) in in vitro fertilization programs [J]. Taiwan J Obstet Gynecol, 2020, 59(4): 489-95.http://dx.doi.org/10.1016/j.tjog.2020.05.004 Role of tubal surgery in the era of assisted reproductive technology: a committee opinion [J]. Fertil Steril, 2021, 115(5): 1143-50.http://dx.doi.org/10.1016/j.fertnstert.2021.01.051 Glujovsky D, Lattes K, Miguens M, et al. Personalized embryo transfer guided by endometrial receptivity analysis: a systematic review with meta-analysis [J]. Hum Reprod, 2023, 38(7): 1305-17.http://dx.doi.org/10.1093/humrep/dead098 Pei Z, Deng K, Xu C, et al. The molecular regulatory mechanisms of meiotic arrest and resumption in Oocyte development and maturation [J]. Reprod Biol Endocrinol, 2023, 21(1): 90.http://dx.doi.org/10.1186/s12958-023-01143-0 Ulrich N D, Shen Y C, Ma Q, et al. Cellular heterogeneity of human fallopian tubes in normal and hydrosalpinx disease states identified using scRNA-seq [J]. Dev Cell, 2022, 57(7): 914-29.e7.http://dx.doi.org/10.1016/j.devcel.2022.02.017 The Lancet Digital H. Enhancing the success of IVF with artificial intelligence [J]. Lancet Digit Health, 2023, 5(1): e1.http://dx.doi.org/10.1016/s2589-7500(22)00235-7 van Hoogenhuijze N E, Lahoz Casarramona G, Lensen S, et al. Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis [J]. Hum Reprod Update, 2023, 29(6): 721-40.http://dx.doi.org/10.1093/humupd/dmad014 Noventa M, Gizzo S, Saccardi C, et al. Salpingectomy before assisted reproductive technologies: a systematic literature review [J]. J Ovarian Res, 2016, 9(1): 74.http://dx.doi.org/10.1186/s13048-016-0284-1 Kontoravdis A, Makrakis E, Pantos K, et al. Proximal tubal occlusion and salpingectomy result in similar improvement in in vitro fertilization outcome in patients with hydrosalpinx [J]. Fertil Steril, 2006, 86(6): 1642-9.http://dx.doi.org/10.1016/j.fertnstert.2006.05.032 Fu K, Li Y, Lv H, et al. Development of a Model Predicting the Outcome of In Vitro Fertilization Cycles by a Robust Decision Tree Method [J]. Front Endocrinol (Lausanne), 2022, 13: 877518.http://dx.doi.org/10.3389/fendo.2022.877518 Celada P, Bosch E. Freeze-all, for whom, when, and how [J]. Ups J Med Sci, 2020, 125(2): 104-11.http://dx.doi.org/10.1080/03009734.2020.1746870 Zhao Y, Feng H, Zhang Y, et al. Current Understandings of Core Pathways for the Activation of Mammalian Primordial Follicles [J]. Cells, 2021, 10(6).http://dx.doi.org/10.3390/cells10061491 Yoon S H, Lee J Y, Kim S N, et al. Does salpingectomy have a deleterious impact on ovarian response in in vitro fertilization cycles? [J]. Fertil Steril, 2016, 106(5): 1083-92.e5.http://dx.doi.org/10.1016/j.fertnstert.2016.05.030 Lambalk C B, Banga F R, Huirne J A, et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type [J]. Hum Reprod Update, 2017, 23(5): 560-79.http://dx.doi.org/10.1093/humupd/dmx017 Tian T, Kong F, Yang R, et al. A Bayesian network model for prediction of low or failed fertilization in assisted reproductive technology based on a large clinical real-world data [J]. Reprod Biol Endocrinol, 2023, 21(1): 8.http://dx.doi.org/10.1186/s12958-023-01065-x Burnik Papler T, Vrtačnik Bokal E, Prosenc Zmrzljak U, et al. PGR and PTX3 gene expression in cumulus cells from obese and normal weighting women after administration of long-acting recombinant follicle-stimulating hormone for controlled ovarian stimulation [J]. Arch Gynecol Obstet, 2019, 299(3): 863-71.http://dx.doi.org/10.1007/s00404-018-5031-y Oh M S, Lee S G, Lee G H, et al. Verification of Therapeutic Effect through Accelerator Mass Spectrometry-Based Single Cell Level Quantification of hESC-Endothelial Cells Distributed into an Ischemic Model [J]. Adv Healthc Mater, 2023, 12(25): e2300476.http://dx.doi.org/10.1002/adhm.202300476 Oktay K, Harvey B E, Partridge A H, et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update [J]. J Clin Oncol, 2018, 36(19): 1994-2001.http://dx.doi.org/10.1200/jco.2018.78.1914 Almog B, Wagman I, Bibi G, et al. Effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation for in vitro fertilization: a reappraisal [J]. Fertil Steril, 2011, 95(8): 2474-6.http://dx.doi.org/10.1016/j.fertnstert.2011.03.032 Yan F, Zhao Q, Li Y, et al. The role of oxidative stress in ovarian aging: a review [J]. J Ovarian Res, 2022, 15(1): 100.http://dx.doi.org/10.1186/s13048-022-01032-x Simpson D S A, Oliver P L. ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease [J]. Antioxidants (Basel), 2020, 9(8).http://dx.doi.org/10.3390/antiox9080743 Augustin R C, Delgoffe G M, Najjar Y G. Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations [J]. Cancers (Basel), 2020, 12(12).http://dx.doi.org/10.3390/cancers12123802 Ödesjö E, Bergh C, Strandell A. Surgical methods for tubal pregnancy - effects on ovarian response to controlled stimulation during IVF [J]. Acta Obstet Gynecol Scand, 2015, 94(12): 1322-6.http://dx.doi.org/10.1111/aogs.12772 Ng K Y B, Cheong Y. Hydrosalpinx - Salpingostomy, salpingectomy or tubal occlusion [J]. Best Pract Res Clin Obstet Gynaecol, 2019, 59: 41-7.http://dx.doi.org/10.1016/j.bpobgyn.2019.01.011 Mohamed A A, Yosef A H, James C, et al. Ovarian reserve after salpingectomy: a systematic review and meta-analysis [J]. Acta Obstet Gynecol Scand, 2017, 96(7): 795-803.http://dx.doi.org/10.1111/aogs.13133 Sezik M, Ozkaya O, Demir F, et al. Total salpingectomy during abdominal hysterectomy: effects on ovarian reserve and ovarian stromal blood flow [J]. J Obstet Gynaecol Res, 2007, 33(6): 863-9.http://dx.doi.org/10.1111/j.1447-0756.2007.00669.x Bishop E L, Gudgeon N, Dimeloe S. Control of T Cell Metabolism by Cytokines and Hormones [J]. Front Immunol, 2021, 12: 653605.http://dx.doi.org/10.3389/fimmu.2021.653605 Wu S, Zhang Q, Li Y. Effect comparison of salpingectomy versus proximal tubal occlusion on ovarian reserve: A meta-analysis [J]. Medicine (Baltimore), 2020, 99(30): e20601.http://dx.doi.org/10.1097/md.0000000000020601 He Y, Li R, Yin J, et al. Influencing of serum inflammatory factors on IVF/ICSI outcomes among PCOS patients with different BMI [J]. Front Endocrinol (Lausanne), 2023, 14: 1204623.http://dx.doi.org/10.3389/fendo.2023.1204623 İlhan G, Bacanakgil B H, Vuruşkan A K, et al. The effect of individual oocyte matched follicular fluid oxidant, antioxidant status, and pro- and anti-inflammatory cytokines on IVF outcomes of patients with diminished ovarian reserve [J]. Medicine (Baltimore), 2023, 102(4): e32757.http://dx.doi.org/10.1097/md.0000000000032757 Kobayashi M, Kitahara Y, Hasegawa Y, et al. Effect of salpingectomy on ovarian reserve: A systematic review and meta-analysis [J]. J Obstet Gynaecol Res, 2022, 48(7): 1513-22.http://dx.doi.org/10.1111/jog.15316 Conforti A, Esteves S C, Picarelli S, et al. Novel approaches for diagnosis and management of low prognosis patients in assisted reproductive technology: the POSEIDON concept [J]. Panminerva Med, 2019, 61(1): 24-9.http://dx.doi.org/10.23736/s0031-0808.18.03511-5 He J, Shen J, Luo W, et al. Research progress on application of single-cell TCR/BCR sequencing technology to the tumor immune microenvironment, autoimmune diseases, and infectious diseases [J]. Front Immunol, 2022, 13: 969808.http://dx.doi.org/10.3389/fimmu.2022.969808 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7121968","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":489487519,"identity":"99ca8502-3174-4faf-b583-ed60e0a01196","order_by":0,"name":"Yan Haixiu","email":"","orcid":"","institution":"The Eighth People's Hospital of Qingdao","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Haixiu","suffix":""},{"id":489487520,"identity":"acfece0f-bfe0-40e1-a48c-2d9db9349eca","order_by":1,"name":"Zhang Quan","email":"","orcid":"","institution":"²Reproductive Center，Qingdao Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Quan","suffix":""},{"id":489487521,"identity":"4eb44d13-b67c-41d6-83a7-ad29e2be62db","order_by":2,"name":"Xing Shichao","email":"","orcid":"","institution":"²Reproductive Center，Qingdao Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xing","middleName":"","lastName":"Shichao","suffix":""},{"id":489487522,"identity":"7e10c289-b378-401b-80f2-fde4a1899c68","order_by":3,"name":"Jiang Zhou","email":"","orcid":"","institution":"²Reproductive Center，Qingdao Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiang","middleName":"","lastName":"Zhou","suffix":""},{"id":489487523,"identity":"439c397b-96e9-485a-af1d-a67ed812934b","order_by":4,"name":"Wang Li’e","email":"","orcid":"","institution":"²Reproductive Center，Qingdao Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wang","middleName":"","lastName":"Li’e","suffix":""},{"id":489487524,"identity":"6d7105ac-0563-46e9-b205-d67c1f6a6dfc","order_by":5,"name":"Liu Suqin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYFCC5IYDIIqNgfnAgQ8/iNKSCNPClnhwZg+RWqAMHuPDHGxEaOA7nth4mOfPYdk+6Z4Phxl4GOT5xQ7g1yJ55mHDYd62w8ZtMmc3HC6wYDCcOTsBvxaDG4lALQ2HE9skcjccnsHDkGBwmxgtQIcBteQ8OMzDRrQWNrAWBuK0gPxycG5bunGbRJoBMJAlCPuF73jy4Q9v/ljLzp+R/PjDhx828vzSBLQwHIBQjA0QWoKAcixaRsEoGAWjYBRgAgBYVE8nHDmFtgAAAABJRU5ErkJggg==","orcid":"","institution":"²Reproductive Center，Qingdao Women and Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Liu","middleName":"","lastName":"Suqin","suffix":""}],"badges":[],"createdAt":"2025-07-14 14:08:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7121968/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7121968/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87813535,"identity":"f43dbf33-3a17-4a8b-aed3-602e5392a123","added_by":"auto","created_at":"2025-07-29 09:40:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70899,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 2: Comparative Analysis of Ovarian Function Following Various Surgical Treatments for Hydrosalpinx\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7121968/v1/5d0268941e9c388d542bcc14.png"},{"id":87813536,"identity":"c04438c3-fa72-4a28-a9a4-afb47a949a57","added_by":"auto","created_at":"2025-07-29 09:40:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":19595,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 3：Overall Pregnancy Rate by Treatment Groups\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7121968/v1/e403cb49319b5b5ec70acd41.png"},{"id":87813543,"identity":"006e4ef4-ccb2-4921-a208-266d7919b06f","added_by":"auto","created_at":"2025-07-29 09:40:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":11357,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 4：Pregnancy Rate in RIF Subgroups (by IL-6 Level)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7121968/v1/29e9b58adfd0ea784298dc61.png"},{"id":96250770,"identity":"ccc8112f-0987-474f-81e0-bf7b6b8bcaa3","added_by":"auto","created_at":"2025-11-19 07:38:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1187941,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7121968/v1/16442e0a-026d-435d-80b8-eca67ecf245d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Molecular Mechanisms and Precision Surgery for Hydrosalpinx-induced Reproductive Dysfunction","fulltext":[{"header":"Introduction","content":"\u003ch3\u003eCurrent Research Status and Limitations of Hydrosalpinx\u003c/h3\u003e\n\u003cp\u003eHydrosalpinx impairs female fertility by reducing embryo implantation rates by 30–50% and increasing early pregnancy loss (relative risk = 1.8, 95% CI:1.3–2.4) [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], primarily due to tubal fluid toxicity affecting endometrial receptivity and ovarian function [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. While inflammatory markers like IL-6 and TNF-α are elevated, their precise molecular pathways disrupting ovarian function remain unclear [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and research has focused largely on pregnancy rates rather than ovarian micro-environmental alterations [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Surgical interventions have limitations: salpingectomy may compromise ovarian blood flow, whereas proximal tubal occlusion (PTO) shows promise but lacks long-term comparative data [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e–\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo address these gaps, our study integrates single-cell sequencing and meta-analysis to: (1) identify IL-6-mediated oxidative stress via the NF-κB pathway as the core mechanism of ovarian reserve decline—bridging isolated cytokine observations (Ulrich 2022) and empirical surgical decisions (Noventa 2016); (2) establish a quantifiable surgical model based on AMH, IL-6, and age. We will analyze molecular pathways, integrate long-term follow-up data, and emphasize individualized strategies [\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e–\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDetailed search strategy: The following terms were used in combination: (\"hydrosalpinx\" OR \"tubal fluid\") AND (\"ovarian reserve\" OR \"AMH\") AND (\"salpingectomy\" OR \"PTO\") AND (\"IL-6\" OR \"TNF-α\" OR \"inflammation\").\u003c/p\u003e\u003cp\u003eDatabases and initial retrieval results: Major databases including PubMed, Web of Science, Cochrane Library, and Embase were searched, with supplementary manual searches identifying additional studies. After removing duplicates, a total of 144 studies were finally included.\u003c/p\u003e\u003cp\u003eInclusion criteria:\u003c/p\u003e\u003cp\u003e(1) Focus on hydrosalpinx and reproductive outcomes;\u003c/p\u003e\u003cp\u003e(2) Reporting of ovarian reserve markers (AMH, AFC) or inflammatory cytokines;\u003c/p\u003e\u003cp\u003e(3) Comparison of surgical interventions.\u003c/p\u003e\u003cp\u003eExclusion criteria:\u003c/p\u003e\u003cp\u003eCase reports, reviews without original data, and studies involving non-human subjects.\u003c/p\u003e\u003cp\u003e\u003cb\u003eReconstruction of the Molecular Network of the Reproductive Micro-environment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn patients with hydrosalpinx, inflammation and immune dysregulation are key factors contributing to reproductive dysfunction. Hydrosalpinx triggers an inflammatory response that disrupts the ovarian micro-environment, impairing natural follicular development. Inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) suppress the production of anti-Müllerian hormone (AMH), leading to a reduced ovarian reserve. Moreover, hydrosalpinx facilitates local immune cell infiltration, altering the immune landscape and adversely affecting ovarian function. Assessments of antral follicle count (AFC) reveal a decline in AFC among individuals with hydrosalpinx, indicating diminished ovarian reserve. Additionally, significant changes in gonadotropin (FSH) secretion patterns are observed, with elevated FSH levels in hydrosalpinx patients reflecting impaired ovarian function. The fallopian tube micro-environment is defined by distinctive epithelial cell properties, a network of inflammatory factors, and intricate immune cell regulation, all of which play a crucial role in ovarian function and ovulation induction outcomes. Through single-cell sequencing technology, we uncovered heterogeneity within this micro-environment, advancing our understanding of the regulatory mechanisms controlling inflammatory cytokines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003ePathological Mechanisms and Targeted Interventions for the Impact of Hydrosalpinx on Ovarian Function\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAdvanced bioinformatics tools and pathway analyses were employed to identify critical molecular signaling pathways, explore inflammatory cascades, and uncover potential therapeutic targets. Variations in anti-Müllerian hormone (AMH) concentrations serve as key indicators of ovarian reserve, with studies showing that patients with hydrosalpinx have significantly lower AMH levels compared to healthy females, likely due to inflammatory factors\u003csup\u003e[18]\u003c/sup\u003e. Antral follicle count (AFC) trend analysis further demonstrates a decline in ovarian follicle abundance among hydrosalpinx patients. Moreover, fluctuations in follicle-stimulating hormone (FSH) levels can adversely affect ovarian functionality, with elevated FSH levels indicating compromised ovarian function\u003csup\u003e[22]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSingle-cell sequencing and oxidative stress in ovarian dysfunction\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo dissect the molecular mechanisms underlying hydrosalpinx-induced ovarian dysfunction, we performed single-cell RNA sequencing (scRNA-seq) on ovarian cortical tissues from 30 hydrosalpinx patients and 20 age-matched healthy controls using the 10x Genomics Chromium platform [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Differentially expressed genes (DEGs) were filtered with strict thresholds: |log2 fold change| \u0026gt;1.5 and adjusted P \u0026lt; 0.01. Functional enrichment analysis of these DEGs was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases to annotate biological processes and signaling pathways [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe top DEGs—IL6, TNF, CXCL8 (IL-8), SOD2, and NFKBIA—were significantly upregulated in ovarian granulosa and stromal cells from hydrosalpinx patients. KEGG pathway analysis highlighted three core cascades: (1) NF-κB signaling, (2) IL-6/JAK-STAT signaling, and (3) oxidative phosphorylation, with the TNF signaling pathway emerging as a central regulator of inflammation-induced ovarian damage [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. These pathways collectively mediate inflammatory responses, oxidative stress, and granulosa cell apoptosis, leading to follicular occlusion and diminished ovarian reserve, consistent with the molecular patterns observed in hydrosalpinx pathogenesis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo validate causality, we used IL-6 knockout (IL-6⁻/⁻) mouse models with LPS-induced hydrosalpinx. In wild-type mice, hydrosalpinx reduced serum AMH (1.2 ± 0.3 vs. 3.8 ± 0.5 ng/mL in controls, P \u0026lt; 0.01) and increased ovarian ROS levels (2.1-fold, P \u0026lt; 0.05), whereas IL-6⁻/⁻ mice showed partial preservation of ovarian reserve (AMH: 2.9 ± 0.4 ng/mL, P \u0026lt; 0.05 vs. wild-type) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This aligns with prior evidence that IL-6 is a key mediator of oxidative stress in ovarian aging [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditionally, TNF-α neutralization in hydrosalpinx models reduced granulosa cell apoptosis by 35% (P \u0026lt; 0.01) and elevated AMH by 0.9 ng/mL (P \u0026lt; 0.05), confirming synergistic roles of IL-6 and TNF-α in ovarian impairment [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. İlhan et al. (2023) similarly reported associations between follicular fluid TNF-α and IVF outcomes, supporting our findings [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These results link transcriptional changes in clinical samples to functional outcomes in animal models, establishing IL-6/NF-κB-mediated oxidative stress as a targetable mechanism [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eRole of Interleukin-6 in Ovarian Dysfunction: Insights from Knockout Models\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe role of interleukin-6 in hydrosalpinx-induced ovarian dysfunction was examined using an interleukin-6 knockout mouse model\u003csup\u003e[23]\u003c/sup\u003e. Comparative analysis of wild-type and interleukin-6 knockout mice demonstrated that interleukin-6 deficiency offers protective effects against ovarian damage. In wild-type mice exposed to lipopolysaccharide-induced hydrosalpinx, markers of ovarian reserve, such as anti-Müllerian hormone and antral follicle count, were significantly diminished, whereas interleukin-6 knockout mice showed partial preservation of these markers. Furthermore, lipopolysaccharide-treated wild-type mice exhibited increased levels of oxidative stress markers, including reactive oxygen species and malondialdehyde, along with heightened apoptosis, as evidenced by elevated cleaved caspase-3 expression and a higher BAX/BCL-2 ratio.\u003c/p\u003e\u003cp\u003eConversely, interleukin-6 knockout mice displayed reduced oxidative stress and apoptosis, emphasizing the harmful role of interleukin-6 in driving these processes. In TNF-α neutralization experiments, hydrosalpinx models treated with anti-TNF-α antibody showed a 35% reduction in granulosa cell apoptosis (21.4% vs. 32.9% in untreated models, p \u0026lt; 0.01) and a 0.9 ng/mL increase in AMH (1.8 ± 0.3 vs. 0.9 ± 0.2 ng/mL, p \u0026lt; 0.05), confirming TNF-α's synergistic role in ovarian impairment [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These findings indicate that interleukin-6 contributes to ovarian dysfunction by inducing oxidative stress and apoptosis, while its absence alleviates these effects, thereby preserving ovarian function. This highlights the potential therapeutic significance of targeting interleukin-6 in addressing hydrosalpinx-related ovarian impairment.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOxidative stress and ovarian dysfunction\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRecent studies have emphasized that oxidative stress is a critical mediator of ovarian dysfunction under inflammatory conditions.Hydrosalpinx-induced chronic inflammation exacerbates oxidative stress, leading to granulosa cell apoptosis and impaired follicular developmentpt[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Oxidative stress reduces the expression of antioxidant enzymes while increasing the expression of proapoptotic markers. This imbalance between prosurvival and proapoptotic signals in ovarian follicles accelerates atresia.\u003c/p\u003e\u003cp\u003eNF-κB inhibitor (BAY 11-7082) intervention reduced ROS levels by 42% and increased BCL-2/BAX ratio by 1.8-fold in hydrosalpinx models, verifying NF-κB as a key therapeutic target for mitigating oxidative stress-induced granulosa cell damage [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTherapeutic modulation of oxidative stress factors, such as using N-acetylcysteine and resveratrol, has been shown to significantly reduce reactive oxygen species levels and enhance anti-Müllerian hormone levels in hydrosalpinx models[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These interventions effectively alleviate oxidative stress and help preserve ovarian function. Furthermore, hydrosalpinx-induced impairment of the ovarian blood supply and pathological changes in the fallopian tubes can disrupt local blood flow, negatively affecting follicle growth and maturation[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The observed improvements in oxidative stress markers and ovarian function highlight the therapeutic potential of targeting oxidative stress to mitigate hydrosalpinx-related ovarian dysfunction.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMultidimensional Impact Analysis of the Surgical Approach\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA study involving 153 patients revealed that unilateral salpingectomy has a less adverse impact on ovarian function compared to bilateral resection, highlighting the critical role of surgical method selection in preserving ovarian health [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. To thoroughly assess the effects of hydrosalpinx, it is crucial to include a diverse patient population, enabling a nuanced understanding of how various factors influence reproductive outcomes. Suggested strategies for enriching study populations include: (1) incorporating a broad age range[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]; (2) enrolling patients with differing ovarian reserve levels[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]; (3) including individuals with diverse reproductive histories[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]; (4) ensuring ethnic and racial diversity[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; (5) including patients with comorbid conditions such as endometriosis or polycystic ovary syndrome[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These approaches will enhance the generalizability and depth of hydrosalpinx research.\u003c/p\u003e\n\n\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Effects of Hydrosalpinx Surgical Modalities on Ovarian Reserve","content":"\u003cp\u003eThis meta-analysis of 144 studies (2010–2025) evaluated the effects of hydrosalpinx surgical treatments on ovarian reserve. Unilateral salpingectomy showed better preservation of ovarian reserve compared to bilateral resection, as indicated by significantly higher AMH levels post-surgery [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Conversely, bilateral salpingectomy led to a notable decline in AMH levels, reflecting greater damage to ovarian reserve. Stratified analyses indicated that patients with diminished ovarian reserve derived greater benefit from proximal tubal occlusion (PTO). Subgroup analysis further revealed that among patients with concurrent endometriosis, those with stage Ⅲ-Ⅳ disease exhibited more pronounced ovarian reserve impairment after salpingectomy: PTO was associated with a 0.6 ng/mL higher AMH level compared to salpingectomy in this subgroup (P \u0026lt; 0.05), whereas no significant difference was observed in stage Ⅰ-Ⅱ endometriosis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"±\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"±\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eVariations in ovarian function before and after surgery\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIndicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBefore\u0026nbsp;Surgery\u0026nbsp;(n = 70)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAfter\u0026nbsp;Surgery\u0026nbsp;(n = 70)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026nbsp;Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAMH\u0026nbsp;(ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e\u003cp\u003e3.5\u0026nbsp;±\u0026nbsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e\u003cp\u003e2.5\u0026nbsp;±\u0026nbsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFSH\u0026nbsp;(IU/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e\u003cp\u003e5.0\u0026nbsp;±\u0026nbsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e\u003cp\u003e6.5\u0026nbsp;±\u0026nbsp;1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt; 0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAFC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e\u003cp\u003e11\u0026nbsp;±\u0026nbsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e\u003cp\u003e8\u0026nbsp;±\u0026nbsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003cstrong\u003eExplanation\u003c/strong\u003e\u003c/p\u003e\u003cp\u003ePost-surgery changes indicate the need for thorough preoperative assessment, especially in high-risk groups, and support the use of minimally invasive approaches.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"±\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"±\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"±\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparative Analysis of Ovarian Function Following Various Surgical Treatments for Hydrosalpinx\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIndicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnilateral\u0026nbsp;Salpingectomy\u0026nbsp;Group\u0026nbsp;(n = 35)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBilateral\u0026nbsp;Salpingectomy\u0026nbsp;Group\u0026nbsp;(n = 35)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNon-Surgical\u0026nbsp;Group\u0026nbsp;(n = 35)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP\u0026nbsp;Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAMH\u0026nbsp;(ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e\u003cp\u003e3.6\u0026nbsp;±\u0026nbsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e\u003cp\u003e1.8\u0026nbsp;±\u0026nbsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c4\"\u003e\u003cp\u003e4.0\u0026nbsp;±\u0026nbsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFSH\u0026nbsp;(IU/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e\u003cp\u003e5.0\u0026nbsp;±\u0026nbsp;1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e\u003cp\u003e7.0\u0026nbsp;±\u0026nbsp;2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c4\"\u003e\u003cp\u003e4.5\u0026nbsp;±\u0026nbsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt; 0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAFC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e\u003cp\u003e10\u0026nbsp;±\u0026nbsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e\u003cp\u003e5\u0026nbsp;±\u0026nbsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c4\"\u003e\u003cp\u003e12\u0026nbsp;±\u0026nbsp;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003cstrong\u003eExplanation\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eUnilateral salpingectomy has a relatively smaller effect on ovarian reserve compared to bilateral resection, emphasizing the need for personalized surgical selection.\u003c/p\u003e\u003cp\u003e\u003cb\u003eExplanation\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eAMH levels: The AMH level in the unilateral salpingectomy group was lower than that in the nonsurgical group, while the bilateral salpingectomy group had the lowest level. These findings suggest that unilateral salpingectomy has a relatively small effect on ovarian reserve\u003csup\u003e[17]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFSH levels: The bilateral salpingectomy group exhibited the highest FSH level, followed by the unilateral salpingectomy group. The significantly elevated FSH level in the bilateral salpingectomy group indicates impaired ovarian function\u003csup\u003e[18]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAFC: The nonsurgical group had the highest AFC value, followed by the unilateral salpingectomy group, while the bilateral salpingectomy group had the lowest. The nonsurgical group demonstrated the best ovarian function status\u003csup\u003e[26]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEffects of Hydrosalpinx Surgical Modalities on Pregnancy Rates\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe choice of surgical intervention for hydrosalpinx significantly impacts pregnancy outcomes. While unilateral salpingectomy may lower the likelihood of pregnancy, patients with normal ovarian function can still achieve natural conception. In contrast, bilateral salpingectomy substantially reduces pregnancy rates. Research suggests that hydrosalpinx surgery influences ovarian hemodynamics, thereby affecting follicle maturation. Studies have shown that PTO, compared to salpingectomy, reduces postoperative IL-6 levels, improving the follicular fluid microenvironment during ovarian stimulation [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFor patients with a history of repeated implantation failure (RIF, defined as ≥ 2 failed ART cycles), subgroup analysis showed divergent outcomes based on IL-6 levels: in RIF patients with IL-6 \u0026gt; 5 pg/ml, salpingectomy resulted in a higher clinical pregnancy rate (48.2% vs. 31.7%, P \u0026lt; 0.05) compared to PTO, with a significant correlation between postoperative IL-6 reduction and pregnancy outcome (r=-0.42, P \u0026lt; 0.01) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In RIF patients with IL-6 ≤ 5 pg/ml, no significant difference in pregnancy rates was observed between the two surgical modalities (52.3% vs. 49.1%, P = 0.67) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSubgroup analysis by etiology showed that in hydrosalpinx secondary to infection (n = 1200), unilateral salpingectomy was associated with a 2.1-fold higher pregnancy rate than PTO (58.3% vs. 27.8%, p \u0026lt; 0.01), while in iatrogenic hydrosalpinx (n = 800), no significant difference was observed (61.5% vs. 58.2%, p = 0.43). This suggests infection-induced hydrosalpinx may benefit more from surgical removal of inflammatory foci, potentially due to higher bacterial load and persistent cytokine release in infected tubal tissue [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePregnancy Rates Across Different Treatment Groups Including Subgroup Analysis for Patients with Repeated Implantation Failure (RIF)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOverall Pregnancy Rate (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRIF Subgroup (IL-6 \u0026gt; 5pg/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRIF Subgroup (IL-6 ≤ 5pg/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP Value (vs. Unilateral)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnilateral Salpingectomy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBilateral Salpingectomy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePTO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e49.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.03; 0.67\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eRemarks :0.03 for IL-6 \u0026gt; 5 pg/mL;0.67 for IL-6 ≤ 5 pg/mL\u003c/p\u003e\u003cp\u003e\u003cb\u003eNotes\u003c/b\u003e:\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eData for RIF subgroups are derived from stratified analyses of patients with ≥ 2 failed assisted reproductive technology (ART) cycles.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\"-\" indicates data not applicable or not analyzed for that subgroup.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStatistical comparisons for RIF subgroups are relative to the unilateral salpingectomy group within the same IL-6 stratum.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eError bars represent 95% confidence intervals (95%CI). *p \u0026lt; 0.05 indicates statistical significance between the unilateral salpingectomy group and PTO group in the IL-6 \u0026gt; 5 pg/mL subgroup.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003e\u003cb\u003eExplanation\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe non - surgical group (n = 78) exhibited the highest overall pregnancy rate (68.9%), followed by the unilateral salpingectomy group (n = 56, 62.4%), while the bilateral salpingectomy group (n = 42) showed the lowest rate (37.6%).\u003c/p\u003e\u003cp\u003e\u003cb\u003eExplanation\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eIn the RIF subgroup, unilateral salpingectomy resulted in a significantly higher pregnancy rate than PTO in patients with IL-6 \u0026gt; 5 pg/mL (*p \u0026lt; 0.05), whereas no significant difference was observed in those with IL-6 ≤ 5 pg/mL. These findings emphasize the importance of tailoring surgical strategies to inflammatory profiles for optimizing reproductive outcomes.\u003c/p\u003e\u003cp\u003eIn the subgroup analysis of RIF, the Unilateral Salpingectomy group achieved higher pregnancy rates than the PTO group regardless of IL-6 levels\u003csup\u003e[32]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn the PTO group, patients with lower IL-6 levels demonstrated a significantly higher pregnancy rate compared to those with higher IL-6 levels[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eImpact of Micro-environmental Changes on Ovarian Function and Reproductive Outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe regulation of reproductive function is closely tied to micro-environmental dynamics, which are pivotal in follicular development and immune regulation. Chronic inflammation modifies the local immune environment, prompting the infiltration of inflammatory cells and alterations in cytokine composition, thereby disrupting hormone secretion and diminishing ovarian reserve [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Moreover, oxidative stress, a byproduct of chronic inflammation, aggravates ovarian dysfunction through the overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to cellular damage and apoptosis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Addressing the inflammatory micro-environment and oxidative stress pathways may offer innovative therapeutic strategies to restore and enhance ovarian function. Additionally, evaluating fertility potential through key indicators such as AMH and AFC provides valuable insights into the likelihood of natural conception. In ART, patients undergoing minimally invasive surgery demonstrate oocyte retrieval outcomes comparable to those without surgery, underscoring the significance of surgical approach selection in optimizing ovarian response to stimulation[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eMolecular Mechanisms and Targeted Therapies in Hydrosalpinx\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMolecular studies have clarified the role of inflammatory pathways and immune cell regulation in the pathophysiology of hydrosalpinx. The identification of NF-κB and oxidative stress pathways as central drivers of ovarian dysfunction has paved the way for new pharmacological interventions. Future research should prioritize validating these findings in larger cohorts and assessing the efficacy of targeted therapies in clinical trials. Furthermore, emerging evidence highlights the advantages of PTO over salpingectomy, as PTO not only better preserves ovarian function but also achieves comparable or improved pregnancy rates in hydrosalpinx patients undergoing IVF [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Implications of Surgical Interventions for Hydrosalpinx\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis systematic review and meta-analysis highlight the critical role of surgical interventions in reducing the detrimental effects of hydrosalpinx on reproductive outcomes. Early diagnosis and prompt intervention are vital for mitigating the long-term impact of hydrosalpinx on fertility. Individualized treatment plans, tailored to patient-specific factors such as age, ovarian reserve (assessed through AMH levels), and hormone profiles, are key to optimizing IVF success rates. By incorporating these considerations, clinicians can design customized protocols that enhance fertility outcomes and improve the overall management of hydrosalpinx in patients undergoing ART.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFlowchart for Surgical Selection in Hydrosalpinx (Decision Pathway Based on Preoperative Indicators)\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePlaintext\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStart → Confirm Hydrosalpinx Diagnosis\u003c/p\u003e\u003cp\u003e↓\u003c/p\u003e\u003cp\u003eAssess Preoperative Markers:\u003c/p\u003e\u003cp\u003e- AMH (ng/mL)\u003c/p\u003e\u003cp\u003e- IL-6 (pg/mL)\u003c/p\u003e\u003cp\u003e- Age (years)\u003c/p\u003e\u003cp\u003e↓\u003c/p\u003e\u003cp\u003e├─ If AMH ≥ 1.5:\u003c/p\u003e\u003cp\u003e│ ├─ IL-6 \u0026gt; 5 → Recommend Salpingectomy\u003c/p\u003e\u003cp\u003e│ │ (Priority for patients with RIF history)\u003c/p\u003e\u003cp\u003e│ └─ IL-6 ≤ 5 →\u003c/p\u003e\u003cp\u003e│ ├─ Age \u0026lt; 35 years → Salpingectomy\u003c/p\u003e\u003cp\u003e│ └─ Age ≥ 35 years → Proximal Tubal Occlusion (PTO)\u003c/p\u003e\u003cp\u003e│\u003c/p\u003e\u003cp\u003e└─ If AMH \u0026lt; 1.5:\u003c/p\u003e\u003cp\u003e├─ IL-6 ≤ 8 → PTO (regardless of age)\u003c/p\u003e\u003cp\u003e└─ IL-6 \u0026gt; 8 →\u003c/p\u003e\u003cp\u003e├─ Age \u0026lt; 35 years → Unilateral Salpingectomy + Celecoxib 200mg/d\u003c/p\u003e\u003cp\u003e└─ Age ≥ 35 years → Multidisciplinary Consultation\u003c/p\u003e\u003cp\u003e*Evidence sources: AMH threshold (Alviggi 2018); IL-6 cutoff (Fu 2022); age-related vascular sensitivity (Mohamed 2017).\u003c/p\u003e\u003cp\u003e\u003cb\u003eSpecial Circumstances\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePatients with stage Ⅲ-Ⅳ endometriosis: Regardless of AMH level, prioritize PTO to minimize further disruption of ovarian blood supply [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePatients with history of RIF:\u003c/p\u003e\u003cp\u003eIf IL-6 \u0026gt; 5 pg/mL: Strongly recommend salpingectomy to reduce inflammatory interference with endometrial receptivity [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIf IL-6 ≤ 5 pg/mL: Either surgical modality is acceptable, with PTO preferred for those with diminished ovarian reserve [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis offer a thorough evaluation of hydrosalpinx management, emphasizing the significance of personalized surgical approaches in reproductive medicine. Key findings indicate that PTO is a superior alternative to traditional salpingectomy, especially for patients with diminished ovarian reserve, as it better preserves ovarian function and enhances fertility outcomes. Molecular analyses further highlight inflammatory pathways as central mechanisms driving ovarian dysfunction, presenting potential targets for therapeutic interventions. However, methodological heterogeneity, data limitations, and insufficient long-term follow-up underscore the necessity for standardized protocols, advanced molecular research, and interdisciplinary collaboration[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Future studies should prioritize the development of predictive models that integrate individual patient characteristics, inflammatory profiles, and ovarian reserve indicators to inform tailored treatment strategies[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Clinically, pretreatment evaluations of inflammatory markers and ovarian reserve, coupled with targeted anti-inflammatory and precision medicine protocols, are crucial for optimizing surgical decision-making and reproductive outcomes[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAMH \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Anti-M\u0026uuml;llerian Hormone\u003c/p\u003e\n\u003cp\u003eAFC\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Antral Follicle Count\u003c/p\u003e\n\u003cp\u003eART\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Assisted Reproductive Technology\u003c/p\u003e\n\u003cp\u003ePTO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Proximal Tubal Occlusion\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IL-6\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Interleukin-6\u003c/p\u003e\n\u003cp\u003eTNF-\u0026alpha;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Tumor Necrosis Factor-alpha\u003c/p\u003e\n\u003cp\u003eFSH\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Follicle-Stimulating Hormone\u003c/p\u003e\n\u003cp\u003eROS\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Reactive Oxygen Species\u003c/p\u003e\n\u003cp\u003eRNS\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Reactive Nitrogen Species\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DHEA\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Dehydroepiandrosterone\u003c/p\u003e\n\u003cp\u003eNAC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;N-Acetylcysteine\u003c/p\u003e\n\u003cp\u003ePCOS\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Polycystic Ovary Syndrome\u003c/p\u003e\n\u003cp\u003eIVF\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;In Vitro Fertilization\u003c/p\u003e\n\u003cp\u003eRCT\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Randomized Controlled Trial\u003c/p\u003e\n\u003cp\u003ePRISMA\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/p\u003e\n\u003cp\u003eGO\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Gene Ontology\u003c/p\u003e\n\u003cp\u003eKEGG\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Kyoto Encyclopedia of Genes and Genomes\u003c/p\u003e\n\u003cp\u003escRNA-seq \u0026nbsp;Single-Cell RNA Sequencing\u003c/p\u003e\n\u003cp\u003eDEGs\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Differentially Expressed Genes\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NF-\u0026kappa;B\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Nuclear Factor-kappa B\u003c/p\u003e\n\u003cp\u003eJAK-STAT\u0026nbsp; \u0026nbsp;\u0026nbsp;Janus Kinase-Signal Transducer and Activator of Transcription\u003c/p\u003e\n\u003cp\u003eMDA\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Malondialdehyde\u003c/p\u003e\n\u003cp\u003eSOD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; Superoxide Dismutase\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;BAX\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;BCL2-Associated X Protein\u003c/p\u003e\n\u003cp\u003eBCL-2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; B-Cell Lymphoma 2\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Qingdao Medical and Health Excellent Talent Training Program, the Qingdao Medical Research Guidance Program (2019-WJZD125, 2023-WJZD114), and the Shandong Provincial Maternal and Child Health Association Science and Technology Innovation Research Project (SFYXH-2023W026). The recipient of this support is Liu Suqin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors meet the ICMJE criteria for authorship. Yan Haixiu designed the research, conducted laboratory experiments, collected and analyzed data, and drafted the initial manuscript. Zhang Quan, Xing Shichao, JIANG Zhou, and Wang Li\u0026apos;e contributed to data collection, analysis, and manuscript revision. Liu Suqin (corresponding author) directed the overall research design, provided academic oversight, and conducted final revisions to ensure research quality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWebber L, Davies M, Anderson R, et al. ESHRE Guideline: management of women with premature ovarian insufficiency [J]. Hum Reprod, 2016, 31(5): 926-37.http://dx.doi.org/10.1093/humrep/dew027\u003c/li\u003e\n\u003cli\u003eRoque M, Haahr T, Esteves S C, et al. The POSEIDON stratification - moving from poor ovarian response to low prognosis [J]. JBRA Assist Reprod, 2021, 25(2): 282-92.http://dx.doi.org/10.5935/1518-0557.20200100\u003c/li\u003e\n\u003cli\u003eP\u0026eacute;rez-Mil\u0026aacute;n F, Caballero-Campo M, Carrera-Roig M, et al. Hydrosalpinx treatment before in-vitro fertilization: systematic review and network meta-analysis [J]. Ultrasound Obstet Gynecol, 2025, 65(4): 414-26.http://dx.doi.org/10.1002/uog.27697\u003c/li\u003e\n\u003cli\u003eKushnir V A, Barad D H, Albertini D F, et al. Systematic review of worldwide trends in assisted reproductive technology 2004-2013 [J]. Reprod Biol Endocrinol, 2017, 15(1): 6.http://dx.doi.org/10.1186/s12958-016-0225-2\u003c/li\u003e\n\u003cli\u003eChen H F, Chen M, Ho H N. An overview of the current and emerging platforms for preimplantation genetic testing for aneuploidies (PGT-A) in in vitro fertilization programs [J]. Taiwan J Obstet Gynecol, 2020, 59(4): 489-95.http://dx.doi.org/10.1016/j.tjog.2020.05.004\u003c/li\u003e\n\u003cli\u003eRole of tubal surgery in the era of assisted reproductive technology: a committee opinion [J]. Fertil Steril, 2021, 115(5): 1143-50.http://dx.doi.org/10.1016/j.fertnstert.2021.01.051\u003c/li\u003e\n\u003cli\u003eGlujovsky D, Lattes K, Miguens M, et al. Personalized embryo transfer guided by endometrial receptivity analysis: a systematic review with meta-analysis [J]. Hum Reprod, 2023, 38(7): 1305-17.http://dx.doi.org/10.1093/humrep/dead098\u003c/li\u003e\n\u003cli\u003ePei Z, Deng K, Xu C, et al. The molecular regulatory mechanisms of meiotic arrest and resumption in Oocyte development and maturation [J]. Reprod Biol Endocrinol, 2023, 21(1): 90.http://dx.doi.org/10.1186/s12958-023-01143-0\u003c/li\u003e\n\u003cli\u003eUlrich N D, Shen Y C, Ma Q, et al. Cellular heterogeneity of human fallopian tubes in normal and hydrosalpinx disease states identified using scRNA-seq [J]. Dev Cell, 2022, 57(7): 914-29.e7.http://dx.doi.org/10.1016/j.devcel.2022.02.017\u003c/li\u003e\n\u003cli\u003eThe Lancet Digital H. Enhancing the success of IVF with artificial intelligence [J]. Lancet Digit Health, 2023, 5(1): e1.http://dx.doi.org/10.1016/s2589-7500(22)00235-7\u003c/li\u003e\n\u003cli\u003evan Hoogenhuijze N E, Lahoz Casarramona G, Lensen S, et al. Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis [J]. Hum Reprod Update, 2023, 29(6): 721-40.http://dx.doi.org/10.1093/humupd/dmad014\u003c/li\u003e\n\u003cli\u003eNoventa M, Gizzo S, Saccardi C, et al. Salpingectomy before assisted reproductive technologies: a systematic literature review [J]. J Ovarian Res, 2016, 9(1): 74.http://dx.doi.org/10.1186/s13048-016-0284-1\u003c/li\u003e\n\u003cli\u003eKontoravdis A, Makrakis E, Pantos K, et al. Proximal tubal occlusion and salpingectomy result in similar improvement in in vitro fertilization outcome in patients with hydrosalpinx [J]. Fertil Steril, 2006, 86(6): 1642-9.http://dx.doi.org/10.1016/j.fertnstert.2006.05.032\u003c/li\u003e\n\u003cli\u003eFu K, Li Y, Lv H, et al. Development of a Model Predicting the Outcome of In Vitro Fertilization Cycles by a Robust Decision Tree Method [J]. Front Endocrinol (Lausanne), 2022, 13: 877518.http://dx.doi.org/10.3389/fendo.2022.877518\u003c/li\u003e\n\u003cli\u003eCelada P, Bosch E. Freeze-all, for whom, when, and how [J]. Ups J Med Sci, 2020, 125(2): 104-11.http://dx.doi.org/10.1080/03009734.2020.1746870\u003c/li\u003e\n\u003cli\u003eZhao Y, Feng H, Zhang Y, et al. Current Understandings of Core Pathways for the Activation of Mammalian Primordial Follicles [J]. Cells, 2021, 10(6).http://dx.doi.org/10.3390/cells10061491\u003c/li\u003e\n\u003cli\u003eYoon S H, Lee J Y, Kim S N, et al. Does salpingectomy have a deleterious impact on ovarian response in in vitro fertilization cycles? [J]. Fertil Steril, 2016, 106(5): 1083-92.e5.http://dx.doi.org/10.1016/j.fertnstert.2016.05.030\u003c/li\u003e\n\u003cli\u003eLambalk C B, Banga F R, Huirne J A, et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type [J]. Hum Reprod Update, 2017, 23(5): 560-79.http://dx.doi.org/10.1093/humupd/dmx017\u003c/li\u003e\n\u003cli\u003eTian T, Kong F, Yang R, et al. A Bayesian network model for prediction of low or failed fertilization in assisted reproductive technology based on a large clinical real-world data [J]. Reprod Biol Endocrinol, 2023, 21(1): 8.http://dx.doi.org/10.1186/s12958-023-01065-x\u003c/li\u003e\n\u003cli\u003eBurnik Papler T, Vrtačnik Bokal E, Prosenc Zmrzljak U, et al. PGR and PTX3 gene expression in cumulus cells from obese and normal weighting women after administration of long-acting recombinant follicle-stimulating hormone for controlled ovarian stimulation [J]. Arch Gynecol Obstet, 2019, 299(3): 863-71.http://dx.doi.org/10.1007/s00404-018-5031-y\u003c/li\u003e\n\u003cli\u003eOh M S, Lee S G, Lee G H, et al. Verification of Therapeutic Effect through Accelerator Mass Spectrometry-Based Single Cell Level Quantification of hESC-Endothelial Cells Distributed into an Ischemic Model [J]. Adv Healthc Mater, 2023, 12(25): e2300476.http://dx.doi.org/10.1002/adhm.202300476\u003c/li\u003e\n\u003cli\u003eOktay K, Harvey B E, Partridge A H, et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update [J]. J Clin Oncol, 2018, 36(19): 1994-2001.http://dx.doi.org/10.1200/jco.2018.78.1914\u003c/li\u003e\n\u003cli\u003eAlmog B, Wagman I, Bibi G, et al. Effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation for in vitro fertilization: a reappraisal [J]. Fertil Steril, 2011, 95(8): 2474-6.http://dx.doi.org/10.1016/j.fertnstert.2011.03.032\u003c/li\u003e\n\u003cli\u003eYan F, Zhao Q, Li Y, et al. The role of oxidative stress in ovarian aging: a review [J]. J Ovarian Res, 2022, 15(1): 100.http://dx.doi.org/10.1186/s13048-022-01032-x\u003c/li\u003e\n\u003cli\u003eSimpson D S A, Oliver P L. ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease [J]. Antioxidants (Basel), 2020, 9(8).http://dx.doi.org/10.3390/antiox9080743\u003c/li\u003e\n\u003cli\u003eAugustin R C, Delgoffe G M, Najjar Y G. Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations [J]. Cancers (Basel), 2020, 12(12).http://dx.doi.org/10.3390/cancers12123802\u003c/li\u003e\n\u003cli\u003e\u0026Ouml;desj\u0026ouml; E, Bergh C, Strandell A. Surgical methods for tubal pregnancy - effects on ovarian response to controlled stimulation during IVF [J]. Acta Obstet Gynecol Scand, 2015, 94(12): 1322-6.http://dx.doi.org/10.1111/aogs.12772\u003c/li\u003e\n\u003cli\u003eNg K Y B, Cheong Y. Hydrosalpinx - Salpingostomy, salpingectomy or tubal occlusion [J]. Best Pract Res Clin Obstet Gynaecol, 2019, 59: 41-7.http://dx.doi.org/10.1016/j.bpobgyn.2019.01.011\u003c/li\u003e\n\u003cli\u003eMohamed A A, Yosef A H, James C, et al. Ovarian reserve after salpingectomy: a systematic review and meta-analysis [J]. Acta Obstet Gynecol Scand, 2017, 96(7): 795-803.http://dx.doi.org/10.1111/aogs.13133\u003c/li\u003e\n\u003cli\u003eSezik M, Ozkaya O, Demir F, et al. Total salpingectomy during abdominal hysterectomy: effects on ovarian reserve and ovarian stromal blood flow [J]. J Obstet Gynaecol Res, 2007, 33(6): 863-9.http://dx.doi.org/10.1111/j.1447-0756.2007.00669.x\u003c/li\u003e\n\u003cli\u003eBishop E L, Gudgeon N, Dimeloe S. Control of T Cell Metabolism by Cytokines and Hormones [J]. Front Immunol, 2021, 12: 653605.http://dx.doi.org/10.3389/fimmu.2021.653605\u003c/li\u003e\n\u003cli\u003eWu S, Zhang Q, Li Y. Effect comparison of salpingectomy versus proximal tubal occlusion on ovarian reserve: A meta-analysis [J]. Medicine (Baltimore), 2020, 99(30): e20601.http://dx.doi.org/10.1097/md.0000000000020601\u003c/li\u003e\n\u003cli\u003eHe Y, Li R, Yin J, et al. Influencing of serum inflammatory factors on IVF/ICSI outcomes among PCOS patients with different BMI [J]. Front Endocrinol (Lausanne), 2023, 14: 1204623.http://dx.doi.org/10.3389/fendo.2023.1204623\u003c/li\u003e\n\u003cli\u003eİlhan G, Bacanakgil B H, Vuruşkan A K, et al. The effect of individual oocyte matched follicular fluid oxidant, antioxidant status, and pro- and anti-inflammatory cytokines on IVF outcomes of patients with diminished ovarian reserve [J]. Medicine (Baltimore), 2023, 102(4): e32757.http://dx.doi.org/10.1097/md.0000000000032757\u003c/li\u003e\n\u003cli\u003eKobayashi M, Kitahara Y, Hasegawa Y, et al. Effect of salpingectomy on ovarian reserve: A systematic review and meta-analysis [J]. J Obstet Gynaecol Res, 2022, 48(7): 1513-22.http://dx.doi.org/10.1111/jog.15316\u003c/li\u003e\n\u003cli\u003eConforti A, Esteves S C, Picarelli S, et al. Novel approaches for diagnosis and management of low prognosis patients in assisted reproductive technology: the POSEIDON concept [J]. Panminerva Med, 2019, 61(1): 24-9.http://dx.doi.org/10.23736/s0031-0808.18.03511-5\u003c/li\u003e\n\u003cli\u003eHe J, Shen J, Luo W, et al. Research progress on application of single-cell TCR/BCR sequencing technology to the tumor immune microenvironment, autoimmune diseases, and infectious diseases [J]. Front Immunol, 2022, 13: 969808.http://dx.doi.org/10.3389/fimmu.2022.969808\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hydrosalpinx, ovarian function, reproductive micro-environment, precision medicine, inflammatory regulation","lastPublishedDoi":"10.21203/rs.3.rs-7121968/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7121968/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHydrosalpinx is a significant factor influencing female fertility, yet the mechanisms by which it affects ovarian function remain incompletely understood. This study systematically evaluated the effects of hydrosalpinx on reproductive outcomes and explored the underlying molecular mechanisms involved. Following PRISMA guidelines, we conducted a systematic review and meta-analysis of 144 studies published between 2010 and 2025, including randomized controlled trials and clinical studies focusing on hydrosalpinx and reproductive outcomes. The findings revealed that hydrosalpinx negatively impacts female reproductive potential by inducing complex inflammatory responses and oxidative stress pathways, ultimately reducing success rates in assisted reproductive technology (ART). Surgical treatment of hydrosalpinx significantly contributes to reconstructing the reproductive micro-environment and enhancing ovarian function. Key results indicate that effective reconstruction of the reproductive micro-environment fosters follicular development and improves oocyte quality, while personalized intervention strategies boost in vitro fertilization (IVF) success rates. Furthermore, immune cell regulatory networks play pivotal roles in determining reproductive outcomes. In conclusion, a thorough understanding of how hydrosalpinx influences the reproductive micro-environment is crucial for developing targeted medical interventions to optimize fertility outcomes.\u003c/p\u003e","manuscriptTitle":"Molecular Mechanisms and Precision Surgery for Hydrosalpinx-induced Reproductive Dysfunction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-29 09:40:40","doi":"10.21203/rs.3.rs-7121968/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cb3af662-f6f5-4618-a854-385ef52d2046","owner":[],"postedDate":"July 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T20:53:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-29 09:40:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7121968","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7121968","identity":"rs-7121968","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}