Female Reproductive Diseases Research Articles

The cGAS-STING pathway and female reproductive system diseases.

The cGAS-STING pathway has become a crucial role in the detection of cytosolic DNA and the initiation of immune responses. The cGAS-STING pathway not only mediates protective immune defense against various DNA-containing pathogens but also detects tumor-derived DNA to generate intrinsic anti-tumor immunity. However, abnormal activation of the cGAS-STING pathway by self-DNA can also lead to autoimmune diseases and inflammatory disorders. This article reviews the mechanisms and functions of the cGAS-STING pathway, as well as the latest research progress in female reproductive-related diseases. We focus on the regulatory mechanisms and roles of this pathway in common female reproductive disorders, discuss the clinical potential of the cGAS-STING pathway as biomarkers and therapeutic agents for female reproductive diseases, as well as the research controversies, technical issues, and biological knowledge gaps that need to be resolved. Furthermore, we provide new ideas for the treatment and prevention of these diseases.

The role of RAD51 regulators and variants in primary ovarian insufficiency, endometriosis,and polycystic ovary syndrome.

The study of RAD51 regulators in female reproductive diseases has novel biomarker potential and implications for therapeutic advancement. Regulators of RAD51 play important roles in maintaining genome integrity and variations in these genes have been identified in female reproductive diseases including primary ovarian insufficiency (POI), endometriosis, and polycystic ovary syndrome (PCOS). RAD51 modulators change RAD51 activity in homologous recombination, replication stress, and template switching pathways. However, molecular implications of these proteins in primary ovarian insufficiency, endometriosis, and polycystic ovary syndrome have been understudied. For each reproductive disease, we provide its definition, current diagnostic and therapeutic treatment strategies, and associated genetic variations. Variants were discovered in RAD51, and regulators including DMC1, RAD51B, SWS1, SPIDR, XRCC2and BRCA2 linked with POI. Endometriosis is associated with variants in XRCC3, BRCA1and CSB genes. Variants in BRCA1 were associated with PCOS.Our analysis identifiednovel biomarkers for POI (DMC1 and RAD51B) and PCOS (BRCA1). Further biochemical and cellular analyses of RAD51 regulator functions in reproductive disorders will advance our understanding of the pathogenesis of these diseases.

Biomarkers and diagnostic significance of non-coding RNAs in extracellular vesicles of pathologic pregnancy.

Intercellular communication is an important mechanism for the development and maintenance of normal biological processes in all organs, including the female reproductive system. Extracellular vesicles, as important carriers of intercellular communication, contain a variety of biologically active molecules, such as mRNAs, miRNAs, lncRNAs, and circRNAs, which are involved in cell-to-cell exchanges as well as in many physiological and pathological processes in the body. Compared with biomarkers found in tissues or body fluids, extracellular vesicles show better stability due to the presence of their envelope membrane which prevents the degradation of the RNA message in their vesicles. Therefore, the genomic and proteomic information contained in extracellular vesicles can serve as important markers and potential therapeutic targets for female reproductive system-related diseases or placental function. Moreover, changes in the expression of non-coding RNAs (mainly miRNAs, lncRNAs, and circRNAs) in maternal extracellular vesicles can accurately and promptly reflect the progress of female reproductive system diseases. The aim of this review is to collect information on different types of non-coding RNAs with key molecular carriers in female pathologic pregnancies (preeclampsia and recurrent spontaneous abortion), so as to explore the relevant molecular mechanisms in female pathologic pregnancies and provide a theoretical basis for clinical research on the pathogenesis and therapeutic approaches of reproductive system diseases. The current state of the art of exosome isolation and extraction is also summarized.

Causality between neuroticism personality clusters and female reproductive diseases in European population: a two-sample bidirectional mendelian randomization study

BackgroundThe causality between neuroticism, a personality trait characterized by the tendency to experience negative emotions, and female reproductive diseases remains unclear. To provide evidence for the development of effective screening and prevention strategies, this study employed Mendelian randomization (MR) to investigate the causality between neuroticism clusters and female reproductive diseases.MethodsInstrumental variables were obtained from large-scale genome-wide association studies of populations of European descent involving three neuroticism clusters (depressed affect, worry, sensitivity to environmental stress, and adversity [SESA]) in the Complex Trait Genetics database and six female reproductive diseases (infertility, polycystic ovary syndrome [PCOS], spontaneous abortion, recurrent spontaneous abortion, endometriosis, and uterine fibroids) in the FinnGen database. The bidirectional two-sample MR analysis was conducted using the inverse variance-weighted, weighted median, and MR-Egger methods, whereas the sensitivity analysis was conducted using the Cochran’s Q-test, MR-Egger intercept, and leave-one-out analysis.ResultsIn the forward analysis, genetically predicted depressed affect and worry components of neuroticism significantly increased the risk of infertility (depressed affect: odds ratio [OR] = 1.399, 95% confidence interval [CI]: 1.054–1.856, p = 0.020; worry: OR = 1.587, 95% CI: 1.229–2.049, p = 0.000) and endometriosis (depressed affect: OR = 1.611, 95% CI: 1.234–2.102, p = 0.000; worry: OR = 1.812, 95% CI: 1.405–2.338, p = 0.000). Genetically predicted SESA component of neuroticism increased only the risk of endometriosis (OR = 1.524, 95% CI: 1.104–2.103, p = 0.010). In the reverse analysis, genetically predicted PCOS was causally associated with an increased risk of the worry component of neuroticism (Beta = 0.009, 95% CI: 0.003–0.016, p = 0.003).ConclusionsThe MR study showed that the three neuroticism personality clusters had definite causal effects on at least one specific female reproductive disease. Moreover, PCOS may increase the risk of the worry component of neuroticism. This finding suggests the need to screen for specific female reproductive diseases in populations with high neuroticism and assess the psychological status of patients with PCOS.

Per- and Polyfluoroalkyl Substances (PFASs) and Their Potential Effects on Female Reproductive Diseases.

Per- and polyfluoroalkyl substances (PFASs) are a class of anthropogenic organic compounds widely present in the natural and human living environments. These emerging persistent pollutants can enter the human body through multiple channels, posing risks to human health. In particular, exposure to PFASs in women may cause a series of reproductive health hazards and infertility. Based on a review of the existing literature, this study preliminarily summarizes the effects of PFAS exposure on the occurrence and development of female reproductive endocrine diseases, such as polycystic ovary syndrome (PCOS), endometriosis, primary ovarian insufficiency (POI), and diminished ovarian reserve (DOR). Furthermore, we outline the relevant mechanisms through which PFASs interfere with the physiological function of the female ovary and finally highlight the role played by nutrients in reducing the reproductive health hazards caused by PFASs. It is worth noting that the physiological mechanisms of PFASs in the above diseases are still unclear. Therefore, it is necessary to further study the molecular mechanisms of PFASs in female reproductive diseases and the role of nutrients in this process.

Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis

BackgroundThe relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis.MethodsInstruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction.ResultsOur univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880–1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970–1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350–1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983–1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671–1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919–1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644–1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137–1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results.ConclusionThe results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future.

Deciphering the role of female reproductive tract microbiome in reproductive health: a review.

Relevant studies increasingly indicate that female reproductive health is confronted with substantial challenges. Emerging research has revealed that the microbiome interacts with the anatomy, histology, and immunity of the female reproductive tract, which are the cornerstone of maintaining female reproductive health and preventing adverse pregnancy outcomes. Currently, the precise mechanisms underlying their interaction and impact on physiological functions of the reproductive tract remain elusive, constituting a prominent area of investigation within the field of female reproductive tract microecology. From this new perspective, we explore the mechanisms of interactions between the microbiome and the anatomy, histology, and immunity of the female reproductive tract, factors that affect the composition of the microbiome in the female reproductive tract, as well as personalized medicine approaches in managing female reproductive tract health based on the microbiome. This study highlights the pivotal role of the female reproductive tract microbiome in maintaining reproductive health and influencing the occurrence of reproductive tract diseases. These findings support the exploration of innovative approaches for the prevention, monitoring and treatment of female reproductive tract diseases based on the microbiome.

Knockdown of DNMT1 Induces SLCO3A1 to Promote Follicular Growth by Enhancing the Proliferation of Granulosa Cells in Mammals.

In female mammals, the proliferation and apoptosis of granulosa cells (GCs) have been shown to determine the fate of follicles. DNA methyltransferases (DNMTs) and SLCO3A1 have been reported to be involved in the survival of GCs and follicular growth. However, the molecular mechanisms enabling DNMTs to regulate the expression of SLCO3A1 to participate in follicular growth are unclear. In this study, we found that the knockdown of DNMT1 enhanced the mRNA and protein levels of SLCO3A1 by regulating the chromatin accessibility probably. Moreover, SLCO3A1 upregulated the mRNA and protein levels of MCL1, PCNA, and STAR to promote the proliferation of GCs and facilitated cell cycle progression by increasing the mRNA and protein levels of CCNE1, CDK2, and CCND1, but it decreased apoptosis by downregulating the mRNA and protein levels of CASP3 and CASP8. Moreover, SLCO3A1 promoted the growth of porcine follicles and development of mice follicles. In conclusion, the knockdown of DNMT1 upregulated the mRNA and protein levels of SLCO3A1, thereby promoting the proliferation of GCs to facilitate the growth and development of ovarian follicles, and these results provide new insights into investigations of female reproductive diseases.

Potential Causal Association between Plasma Metabolites, Immunophenotypes, and Female Reproductive Disorders: A Two-Sample Mendelian Randomization Analysis.

While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished. Instrumental variables for 486 circulating metabolites (N = 7824) and 731 immunophenotypes (N = 3757) were derived from a genome-wide association study (GWAS) meta-analysis. FinnGen contributed data on 14 female reproductive disorders. A bidirectional two-sample Mendelian randomization study was performed to determine the relationships between exposures and outcomes. The robustness of results, potential heterogeneity, and horizontal pleiotropy were examined through sensitivity analysis. High levels of mannose were found to be causally associated with increased risks of gestational diabetes (GDM) (OR [95% CI], 6.02 [2.85-12.73], p = 2.55 × 10-6). A genetically predicted elevation in the relative count of circulating CD28-CD25++CD8+ T cells was causally related to increased female infertility risk (OR [95% CI], 1.26 [1.14-1.40], p = 1.07 × 10-5), whereas a high absolute count of NKT cells reduced the risk of ectopic pregnancy (OR [95% CI], 0.87 [0.82-0.93], p = 5.94 × 10-6). These results remained consistent in sensitivity analyses. Our study supports mannose as a promising GDM biomarker and intervention target by integrating metabolomics and genomics.

Bisphenol A triggers apoptosis in mouse pre-antral follicle granulosa cells via oxidative stress

BackgroundBisphenol A (BPA), an endocrine disrupting chemical with weak estrogenic and anti-androgenic activity, is widely present in various environmental media and organisms. It has certain reproductive toxicity and can cause a variety of female reproductive system diseases. Although BPA-stimulated apoptosis of granulosa cells has been widely elaborated, the effect of BPA on mouse pre-antral follicle granulosa cells (mpGCs) has not been well elucidated.ResultsIn this study, the results of live-dead cell staining showed that high concentrations of BPA severely impaired mpGCs growth viability and affected the cell cycle transition of mpGCs. We confirmed that BPA promotes the production of reactive oxygen species (ROS) and facilitates oxidative stress in mpGCs. In addition, immunofluorescence, transmission electron microscopy, and flow cytometry experiments demonstrated that BPA treatment for mpGCs resulted in apoptotic features, such as rounding, cytoplasmic crinkling, and mitochondrial damage. This was accompanied by a large production of ROS and apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus. RNA-seq data showed that several apoptosis-related pathways were enriched in the high concentration BPA-treated group compared with the normal group, such as the p53 pathway, MAPK pathway, etc.ConclusionsThese results suggest that cells undergo oxidative stress effects and apoptosis after BPA treatment for mpGCs, which affects normal follicle development. The potential mechanism of BPA-induced female reproductive toxicity was elucidated, while providing a research basis for the prevention and treatment of female reproductive diseases.

Modern Subtype Classification and Outlier Detection Using the Attention Embedder to Transform Ovarian Cancer Diagnosis.

Ovarian cancer, a deadly female reproductive system disease, is a significant challenge in medical research due to its notorious lethality. Addressing ovarian cancer in the current medical landscape has become more complex than ever. This research explores the complex field of Ovarian Cancer Subtype Classification and the crucial task of Outlier Detection, driven by a progressive automated system, as the need to fight this unforgiving illness becomes critical. This study primarily uses a unique dataset painstakingly selected from 20 esteemed medical institutes. The dataset includes a wide range of images, such as tissue microarray (TMA) images at 40× magnification and whole-slide images (WSI) at 20× magnification. The research is fully committed to identifying abnormalities within this complex environment, going beyond the classification of subtypes of ovarian cancer. We proposed a new Attention Embedder, a state-of-the-art model with effective results in ovarian cancer subtype classification and outlier detection. Using images magnified WSI, the model demonstrated an astonishing 96.42% training accuracy and 95.10% validation accuracy. Similarly, with images magnified via a TMA, the model performed well, obtaining a validation accuracy of 94.90% and a training accuracy of 93.45%. Our fine-tuned hyperparameter testing resulted in exceptional performance on independent images. At 20× magnification, we achieved an accuracy of 93.56%. Even at 40× magnification, our testing accuracy remained high, at 91.37%. This study highlights how machine learning can revolutionize the medical field's ability to classify ovarian cancer subtypes and identify outliers, giving doctors a valuable tool to lessen the severe effects of the disease. Adopting this novel method is likely to improve the practice of medicine and give people living with ovarian cancer worldwide hope.

Structural basis of the subcortical maternal complex and its implications in reproductive disorders.

The subcortical maternal complex (SCMC) plays a crucial role in early embryonic development. Malfunction of SCMC leads to reproductive diseases in women. However, the molecular function and assembly basis for SCMC remain elusive. Here we reconstituted mouse SCMC and solved the structure at atomic resolution using single-particle cryo-electron microscopy. The core complex of SCMC was formed by MATER, TLE6 and FLOPED, and MATER embraced TLE6 and FLOPED via its NACHT and LRR domains. Two core complexes further dimerize through interactions between two LRR domains of MATERs in vitro. FILIA integrates into SCMC by interacting with the carboxyl-terminal region of FLOPED. Zygotes from mice with Floped C-terminus truncation showed delayed development and resembled the phenotype of zygotes from Filia knockout mice. More importantly, the assembly of mouse SCMC was affected by corresponding clinical variants associated with female reproductive diseases and corresponded with a prediction based on the mouse SCMC structure. Our study paves the way for further investigations on SCMC functions during mammalian preimplantation embryonic development and reveals underlying causes of female reproductive diseases related to SCMC mutations, providing a new strategy for the diagnosis of female reproductive disorders.

Microorganism-derived extracellular vesicles: emerging contributors to female reproductive health.

Extracellular vesicles (EVs) are cell-derived nanoparticles that carry small molecules, nucleic acids, and proteins long distances in the body facilitating cell-cell communication. Microorganism-derived EVs mediate communication between parent cells and host cells, with recent evidence supporting their role in biofilm formation, horizontal gene transfer, and suppression of the host immune system. As lipid-bound bacterial byproducts, EVs demonstrate improved cellular uptake and distribution in vivo compared to cell-free nucleic acids, proteins, or small molecules, allowing these biological nanoparticles to recapitulate the effects of parent cells and contribute to a range of human health outcomes. Here, we focus on how EVs derived from vaginal microorganisms contribute to gynecologic and obstetric outcomes. As the composition of the vaginal microbiome significantly impacts women's health, we discuss bacterial EVs from both healthy and dysbiotic vaginal microbiota. We also examine recent work done to evaluate the role of EVs from common vaginal bacterial, fungal, and parasitic pathogens in pathogenesis of female reproductive tract disease. We highlight evidence for the role of EVs in women's health, gaps in current knowledge, and opportunities for future work. Finally, we discuss how leveraging the innate interactions between microorganisms and mammalian cells may establish EVs as a novel therapeutic modality for gynecologic and obstetric indications.

The Emerging Role of MicroRNAs in Female Reproductive Diseases

Female infertility represents a significant global medical concern, attributable to a spectrum of disorders affecting the reproductive system, which encompasses premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), Asherman syndrome (AS), endometriosis, preeclampsia, ovarian cancer, and endometrial cancer. It exerts a pervasive impact on women's reproductive well-being on a global scale. Recent years have witnessed a mounting body of evidence, drawing from investigations employing murine models and human clinical data, which elucidates the dysfunction of microRNAs (miRNAs) in various reproductive pathologies. This dysfunction, it appears, plays a pivotal role in the context of female gametogenesis and fertility. Nonetheless, the precise mechanistic links between miRNA dysfunction and the pathogenesis of these disorders remain, in many cases, inadequately understood. This comprehensive review endeavors to shed light on recent advancements in research pertaining to the regulatory functions of miRNAs in the etiology of diverse reproductive disorders that culminate in infertility. Furthermore, it addresses the potential utility of miRNAs as diagnostic biomarkers and therapeutic targets for these conditions. The paper also examines the existing limitations and challenges inherent to the clinical application of miRNAs in this context.

Causal association between lipid-lowering drugs and female reproductive endocrine diseases: a drug-targeted Mendelian randomization study.

The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs. In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility. PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea. The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.

The mechanisms crosstalk and therapeutic opportunities between ferroptosis and ovary diseases.

Ferroptosis, a form of regulated cell death, was first defined in 2012. Ferroptosis mainly involves iron-driven lipid peroxidation damage of cells. This process is regulated by iron homeostasis, redox balance, lipid metabolism, glutathione metabolism, and various disease signaling pathways. Iron is one of the key mineral elements that regulate the physiological function of women and the development of ovarian tumors. Occurrence of Ferroptosis has some hidden dangers and advantages in ovary diseases. Some scholars have shown that ferroptosis of ovarian granulosa cells (GC) promotes the development of ovarian dysfunction and polycystic ovary syndrome (PCOS). Interestingly, drug-resistant ovarian cancer cells are very sensitive to ferroptosis, suggesting that pharmacological positive and negative regulation of ferroptosis has great potential in the treatment of benign ovarian diseases and ovarian cancer. This article aimed to assess how ferroptosis occurs and the factors controlling ferroptosis. Moreover, we summarize how ferroptosis can be used to predict, diagnose and target treatment ovary disease. Meanwhile, we also evaluated the different phenomena of Ferroptosis in ovarian diseases. It aims to provide new directions for the research and prevention of female reproductive diseases.

Efficacy of Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Animal Model of Female Reproductive Diseases: A Meta-Analysis.

Female reproductive disorders, such as premature ovarian insufficiency (POI), intrauterine adhesion (IUA) or thin endometrium, and polycystic ovary syndrome (PCOS), are the main factors affecting fertility. Mesenchymal stem cells derived-extracellular vesicles (MSC-EVs) have gained traction as a new potential treatment and were widely studied in these diseases. However, their impact is still not fully clear. A systematic search of PubMed, Web of Science, EMBASE, the Chinese National Knowledge of Infrastructure, and WanFang online databases was performed up to September 27th, 2022, and the studies of MSC-EVs-based therapy on the animal models of female reproductive diseases were included. The primary outcomes were anti-Müllerian hormone (AMH) in POI and endometrial thickness in IUA, respectively. 28 studies (POI, N = 15; IUA, N = 13) were included. For POI, MSC-EVs improved AMH at 2weeks (SMD 3.40, 95% CI 2.02 to 4.77) and 4weeks (SMD 5.39, 95% CI 3.43 to 7.36) compared with placebo, and no difference was found when compared with MSCs in AMH (SMD -2.03, 95% CI -4.25 to 0.18). For IUA, MSC-EVs treatment could increase the endometrial thickness at 2weeks (WMD 132.36, 95% CI 118.99 to 145.74), but no improvement was found at 4weeks (WMD 166.18, 95% CI -21.44 to 353.79). The combination of MSC-EVs with hyaluronic acid or collagen had a better effect on the endometrial thickness (WMD 105.31, 95% CI 85.49 to 125.13) and glands (WMD 8.74, 95% CI 1.34 to 16.15) than MSC-EVs alone. The medium dose of EVs may allow for great benefits in both POI and IUA. MSC-EVs treatment could improve the functional and structural outcomes in female reproductive disorders. The combination of MSC-EVs with HA or collagen may enhance the effect. These findings can accelerate the translation of MSC-EVs treatment to human clinical trials.

Circulating Inflammatory Cytokines and Female Reproductive Diseases: A Mendelian Randomization Analysis.

Extensive studies have provided considerable evidence suggesting the role of inflammation in the development of female reproductive diseases. However, causality has not been established. To explore whether genetically determined circulating levels of cytokines are causally associated with female reproductive diseases and discover potential novel drug targets for these diseases. Instrumental variables (IVs) for 47 circulating cytokines were obtained from a genome-wide association study (GWAS) meta-analysis of 31 112 European individuals. Protein quantitative trait loci and expression quantitative trait loci close to genes served as our IVs. Summary data of 9 female reproductive diseases were mainly derived from GWAS meta-analysis of the UK biobank and FinnGen. We elevated the association using the Wald ratio or inverse variance-weighted Mendelian randomization (MR) with subsequent assessments for MR assumptions in several sensitivity and colocalization analyses. We consider a false discovery rate <0.05 as statistical significance in MR analyses. Replication studies were conducted for further validation, and phenome-wide association studies were designed to explore potential side effects. Our results indicated that high levels of macrophage colony-stimulating factor (MCSF), growth-regulated oncogene-alpha (GROα), and soluble intercellular adhesion molecule-1 were associated with increased risks of endometriosis, female infertility, and pre-eclampsia, respectively. High platelet-derived growth factor-BB (PDGF-BB) levels that reduced the risk of ovarian aging were also supported. Replication analysis supported the relationship between GROα and female infertility, and between MCSF and endometriosis. We identified 4 correlated pairs that implied potential protein drug targets. Notably, we preferred highlighting the value of PDGF-BB as a drug target for ovarian aging, and MCSF as a drug target for endometriosis.

Comparison of the effect of levonorgestrel-intrauterine system with or without oral megestrol acetate on fertility-preserving treatment in patients with atypical endometrial hyperplasia: A prospective, open-label, randomized controlled phase II study

ObjectiveTo compare the effects of levonorgestrel-intrauterine system (LNG-IUS) with or without oral megestrol acetate (MA) versus MA alone on fertility-preserving treatment in patients with atypical endometrial hyperplasia (AEH). MethodsThis was a single-center phase II study with an open-label, randomized, controlled trial conducted between July 2017 and June 2020 at the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. A total of 180 patients (18–45 years) with primary AEH were randomly assigned (1:1:1) to the MA (N = 60), LNG-IUS (N = 60), or MA + LNG-IUS (N = 60) groups, in which the patients received MA (160 mg orally daily), LNG-IUS, or MA + LNG-IUS (MA 160 mg orally daily plus LNG-IUS), respectively. The primary endpoint was complete response (CR) rate at 16 weeks of treatment. The secondary endpoints were CR rate at 32 weeks of treatment, adverse events, and recurrence and pregnancy rates. All analyses were conducted in a modified intention to treat (ITT) population who underwent randomization and in whom treatment was initiated. ResultsThe Kaplan-Meier estimate of 16-week CR rates (with 95% confidence interval) were 19.2% (9.0–29.4%) in the MA group, 35.0% (22.8–47.2%) in the LNG-IUS group, and 29.4% (17.2–41.6%) in the MA + LNG-IUS groups. Side effects such as weight gain, increased nocturnal urine, night sweat, insomnia and edema face seemed to occur less frequently in LNG-IUS group compared with MA group. No difference was found among groups regarding second endpoints. ConclusionsLNG-IUS or LNG-IUS plus MA did not show significant therapeutic benefit compared with MA alone. Further studies including sufficient sample-size are needed to validate these findings due to the underpowered design of this trial. FundingThis study was supported by the National Key Research and Development Program of China (Grant No 2019YFC1005200 and 2019YFC1005204), Shanghai Medical Centre of Key Programs for Female Reproductive Diseases (Grant No. 2017ZZ010616), Shanghai sailing program (Grant No. 19YF1404200), and Shen Kang clinical project (SHDC22021219).Trial registrationClinicalTrials.govNCT03241888. https://www.clinicaltrials.gov/ct2/show/NCT03241888?term=NCT03241888&draw=2&rank=1

The Application of Nanoparticle-Based Imaging and Phototherapy for Female Reproductive Organs Diseases.

Various female reproductive disorders affect millions of women worldwide and bring many troubles to women's daily life. Let alone, gynecological cancer (such as ovarian cancer and cervical cancer) is a severe threat to most women's lives. Endometriosis, pelvic inflammatory disease, and other chronic diseases-induced pain have significantly harmed women's physical and mental health. Despite recent advances in the female reproductive field, the existing challenges are still enormous such as personalization of disease, difficulty in diagnosing early cancers, antibiotic resistance in infectious diseases, etc. To confront such challenges, nanoparticle-based imaging tools and phototherapies that offer minimally invasive detection and treatment of reproductive tract-associated pathologies are indispensable and innovative. Of late, several clinical trials have also been conducted using nanoparticles for the early detection of female reproductive tract infections and cancers, targeted drug delivery, and cellular therapeutics. However, these nanoparticle trials are still nascent due to the body's delicate and complex female reproductive system. The present review comprehensively focuses on emerging nanoparticle-based imaging and phototherapies applications, which hold enormous promise for improved early diagnosis and effective treatments of various female reproductive organ diseases.