Engineered extracellular vesicles in female reproductive and pregnancy-related disorders.

Lifestyle, nutrition, and metabolic status are central to maintaining women’s reproductive health. With the rising prevalence of infertility, the need for effective strategies to preserve and enhance women’s reproductive well-being has become increasingly urgent. Quercetin, a plant-derived polyphenol, has attracted growing interest for its potential to support reproductive health, regulate the hormonal balance, and improve fertility. This narrative review examines Quercetin’s role in women’s reproductive health and delineates its possible mechanisms of action in female reproductive system disorders, including polycystic ovary syndrome, recurrent miscarriage, and cervical, ovarian, and endometrial cancer (EC). By highlighting the biological pathways through which quercetin may exert its effects, this article underscores the need for further research and clinical trials to validate its therapeutic potential and its applications as a bioactive compound in foods aimed at enhancing women’s reproductive health.

Recurrent spontaneous abortion (RSA) is defined as two or more consecutive miscarriages generally occured in the same gestation period. It affects about 1%-5% of females at childbearing ages. Except for multiple causes for RSA been identified, such as chromosome abnormalities, maternal genital malformation, endocrine dysfunction, reproductive tract infections, thrombophilia, according to the American College of Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetricians and Gynecologists (RCOG), there are still 80% of risk factors related to immunology. Recently, RSA has been classified into two categories: autoimmune and alloimmune. Some autoantibodies may lead to pregnancy loss by targeting at vascular endothelial cells, trophoblastic cells and preimplantation embryos while alloimmune RSA may associate with the imbalance of immune interactions at the maternal-fetal interface. This article reviewed the two types of RSA respectively on the basis of immunological pathogenesis. Key words: Recurrent spontaneous abortion (RSA); Immune factors; Etiology; Diagnose

Reproductive disorders, including preeclampsia (PE), endometriosis, premature ovarian failure (POF), and polycystic ovary syndrome (PCOS), present substantial challenges to women's reproductive health. Exosomes (EXOs) are cell-derived vesicles containing molecules that influence target cells' gene expression and cellular behavior. Among their cargo, microRNAs (miRNAs)-short, non-coding RNAs typically 19-25 nucleotides in length-play a crucial role in post-transcriptional gene regulation and have been extensively studied for their therapeutic potential. miRNAs are considered therapeutic targets because they regulate key cellular pathways such as proliferation, apoptosis, angiogenesis, and tissue repair. This review examines the role of exosomal miRNAs from sources such as mesenchymal stem cells (MSCs), plasma, and amniotic fluid in female reproductive disorders, including PE, POF, PCOS, and endometriosis. We discuss their biological origins, mechanisms of miRNA sorting and packaging, and their therapeutic applications in modulating disease progression. By categorizing miRNAs according to their beneficial or detrimental effects in specific conditions, we aim to simplify the understanding of their roles in female infertility.

Female reproductive disorders present significant challenges worldwide. Transfer RNA-derived small RNAs (tsRNAs), a structurally diverse class of non-coding RNAs mainly comprising tRNA halves (tiRNAs) and tRNA-derived fragments (tRFs), have emerged as key regulators in human health and disease. This review outlines the biogenesis and functions of tsRNAs and summarizes their mechanistic involvement and clinical implications across a range of reproductive pathologies. In pregnancy-related complications, such as embryo implantation failure and recurrent spontaneous abortion, aberrant tsRNA profiles perturb trophoblast behavior, endometrial decidualization, and maternal-fetal crosstalk, thereby compromising placental development and pregnancy outcome. In benign gynecological conditions including premature ovarian failure and endometriosis, dysregulated tsRNAs disrupt granulosa cell survival, promote stromal proliferation, and reshape inflammatory signaling, ultimately altering follicular development and uterine homeostasis. As our understanding of tsRNA-mediated pathways deepens, these molecules offer promising potential as diagnostic biomarkers and therapeutic targets for precision medicine in female reproductive disorders.

Balanced vaginal microbiota and, as a continuum, cervical canal microbiota help prevent reproductive disorders, including recurrent miscarriage (RM). In a significant proportion of couples with RM, routine diagnostic workup cannot find any manageable cause, leading to a requirement for new diagnostic tools. In the present study, we determined the quantitative composition of the microbiota of the vagina and cervical canal, assessed by real-time polymerase chain reaction, in women with RM. It also evaluated their derangements related to the pathogenesis of RM, and thus the suitability of this test as a diagnostic tool for managing RM. Vaginal and cervical canal specimens of 25 women with RM and 25 healthy volunteers were collected. The test results revealed information about the total vaginal bacterial biomass by measuring the abundance of Lactobacillus spp.; other bacteria; and pathogens, including Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma (urealyticum + parvum), and Candida spp. Overall, the findings of this study implied the abundance of Lactobacillus spp. decreased in women with RM with an increase in the abundance of other microorganisms in accordance with the reduction in the abundance of Lactobacillus spp. due to aerobic vaginitis and bacterial vaginosis. Vaginal and cervical canal microbiota need to be considered during the diagnostic workup of women with RM. IMPACT STATEMENT What is already known on this subject? Recurrent miscarriage (RM) is a well-known reproductive disorder. Its diagnostic workup is not successful in determining the underlying problem in many cases. Hence, novel diagnostic tools based on real-time polymerase chain reaction (PCR) are needed for evaluating reproductive microbiota, which are considerably reliable, to satisfy the expectations of women with RM. What do the results of this study add? Overall, the decrease in the abundance of Lactobacillus spp. was found to be related to RM, and the patterns of the presence of other microorganisms were in accordance with the reduction in the abundance of Lactobacillus spp. These findings suggested an important role of vaginal and cervical canal microbiota in the pathogenesis of RM. What are the implications of these findings for clinical practice and/or further research? Additional research is warranted to elucidate the functional impact of altered components of the microbiota of vaginal and cervical canals on the physiology of the local cervical canal and its participation in the microbiota of the endometrial cavity, especially regarding unsuccessful pregnancies as a result of the disturbed physiology of the local endometrial microenvironment. However, possible applications of real-time PCR-based tests for the screening of subclinical infections in clinical practice require the performance of further investigations in patients with RM.

Currently the significant part of reproductive disorders such as refractory pregnancy loss (RPL), infertility, unsuccessful in vitro fertilization (IVF) are thought to be connected with different genetic factors. One of the main hereditary risk factors for obstetrical pathology development is the presence of polymorph alleles in several genes of folic acid cycle. The present study is dedicated to investigation of the effect of folic acid cycle polymorph variants MTHFR C677 T, MTR A2756G and MTRR A66G on the RPL development and unsuccessful IVF. The samples of peripheral blood of 138 women were tested and showed a statistically significant increase of pathologic genetic alleles of MTRR A66G and MTHFR C677T frequency in two groups of patients with reproductive disorders, i.e. RPL and IVF, versus the control group. Also the advantage of simultaneous analysis of three folic cycle genetic polymorphisms at once in women with reproductive function disorder was demonstrated in comparison with the analysis of isolated polymorphism MTHFR C677T. The combination of polymorph alleles has a significant influence on the pathology development and by many times increases the risk of RPL development and unsuccessful IVF.

Research on the role of homocysteine (Hcy) in female reproductive disorders has provided new insights for enhancing female fertility and improving clinical pregnancy outcomes. However, further studies are needed to fully elucidate the complex mechanisms involved and optimize therapeutic strategies, to develop more effective interventions for women with reproductive health conditions. This narrative review systematically synthesizes evidence from clinical and mechanistic studies published over the past 15 years. We critically appraise study limitations, distinguish between observational associations and causal evidence, and contextualize heterogeneity in study populations and diagnostic thresholds. Numerous epidemiological and clinical studies have reported a consistent association between Hcy dysregulation and adverse reproductive outcomes across the female lifespan. Elevated Hcy is implicated in the pathophysiology of polycystic ovary syndrome (PCOS), diminished ovarian reserve (DOR), reproductive aging, unexplained infertility (UI), endometriosis, and adverse pregnancy outcomes, and is linked to poor outcomes in assisted reproductive technology (ART). A growing body of evidence indicates that optimizing Hcy levels via dietary, lifestyle, and targeted nutritional interventions may improve reproductive outcomes. Close clinical monitoring is essential for any pharmacological intervention to ensure safety and efficacy. This review provides a comprehensive synthesis of the role of Hcy in female reproductive disorders and the therapeutic potential of Hcy-targeted interventions, serving as a reference for improving female fertility and clinical pregnancy outcomes. Large-scale, multicenter randomized controlled trials are required to further validate the efficacy of Hcy-lowering therapies in improving live birth and long-term maternal and neonatal outcomes. Continued research in this field will enable the development of targeted, personalized prevention and treatment strategies for women with reproductive disorders.

Ultrasound and intrauterine adhesions: a novel structured approach to diagnosis and management.

BackgroundHuman reproductive disorders consist of frequently occurring dysfunctions including a broad range of phenotypes affecting fertility and women’s health during pregnancy. Several female-related diseases have been associated with hypofertility/infertility phenotypes, such as recurrent pregnancy loss (RPL). Other occurring diseases may be life-threatening for the mother and foetus, such as preeclampsia (PE) and intra-uterine growth restriction (IUGR). FOXD1 was defined as a major molecule involved in embryo implantation in mice and humans by regulating endometrial/placental genes. FOXD1 mutations in human species have been functionally linked to RPL’s origin.MethodsFOXD1 gene mutation screening, in 158 patients affected by PE, IUGR, RPL and repeated implantation failure (RIF), by direct sequencing and bioinformatics analysis. Plasmid constructs including FOXD1 mutations were used to perform in vitro gene reporter assays.ResultsNine non-synonymous sequence variants were identified. Functional experiments revealed that p.His267Tyr and p.Arg57del led to disturbances of promoter transcriptional activity (C3 and PlGF genes). The FOXD1 p.Ala356Gly and p.Ile364Met deleterious mutations (previously found in RPL patients) have been identified in the present work in women suffering PE and IUGR.ConclusionsOur results argue in favour of FOXD1 mutations’ central role in RPL, RIF, IUGR and PE pathogenesis via C3 and PlGF regulation and they describe, for the first time, a functional link between FOXD1 and implantation/placental diseases. FOXD1 could therefore be used in clinical environments as a molecular biomarker for these diseases in the near future.KeywordsRecurrent pregnancy loss, Preeclampsia, Intra-uterine growth restriction, FOXD1

Therapeutic importance of Zishen Yutai Pill on the female reproductive health: A review

Objective:Female reproductive disorders (FRDs) are common health conditions that may present with significant symptoms. Diet and environment are potential areas for FRD interventions. We utilized a knowledge graph (KG) method to predict factors associated with common FRDs (e.g., endometriosis, ovarian cyst, and uterine fibroids).Materials and Methods:We harmonized survey data from the Personalized Environment and Genes Study on internal and external environmental exposures and health conditions with biomedical ontology content. We merged the harmonized data and ontologies with supplemental nutrient and agricultural chemical data to create a KG. We analyzed the KG by embedding edges and applying a random forest for edge prediction to identify variables potentially associated with FRDs. We also conducted logistic regression analysis for comparison.Results:Across 9765 PEGS respondents, the KG analysis resulted in 8535 significant predicted links between FRDs and chemicals, phenotypes, and diseases. Amongst these links, 32 were exact matches when compared with the logistic regression results, including comorbidities, medications, foods, and occupational exposures.Discussion:Mechanistic underpinnings of predicted links documented in the literature may support some of our findings. Our KG methods are useful for predicting possible associations in large, survey-based datasets with added information on directionality and magnitude of effect from logistic regression. These results should not be construed as causal, but can support hypothesis generation.Conclusion:This investigation enabled the generation of hypotheses on a variety of potential links between FRDs and exposures. Future investigations should prospectively evaluate the variables hypothesized to impact FRDs.

Aim. Celiac disease (CD) is a multifactorial pathology with high genetic predisposition, and is associated with reproductive health disorders in women. The purpose of the study was to investigate the presence of HLA-DQ2.5 (HLA-DQA1 * 05:01 HLA-DQB1 * 02) and HLA-DQ8 (HLA-DQB1 *03:02) genotypes of predisposition to CD in women with recurrent pregnancy loss. Methods. PCR-SSP (polymerase chain reaction with sequence-specific primers). Results. The increased risk of recurrent pregnancy loss in women is associated with DQ2.5 - the pre-disposition genotype for CD (c2=4.35, P<0,05). Calculation of odds ratio (OR) showed more than 4-fold increase in recurrent pregnancy loss risk in women with HLA-DQ2.5 genotype. Conclusions. The study of HLA markers of celiac disease in women with reproductive loss is important for the purpose of preconceptional prevention of recurrent pregnancy loss. Keywords: celiac disease, recurrent pregnancy loss, HLA markers.

Aim. Fertility disorders are one of the most common problems of reproductive medicine. Chromosomal abnormalities play a crucial role in reproductive failure. The main purpose of our study was to determine the types and frequency of chromosomal aberrations in couples with history of infertility. Methods. Karyotyping was performed in 652 couples with reproductive failure between 2004 and 2022, including 203 couples with primary infertility (PI), 240 couples with recurrent pregnancy loss (RPL) and 209 – with sporadic pregnancy loss (SPL). Results. Numerical and structural karyotype abnormalities were detected in 37 (2.84 %) of 1304 individuals with infertility, most frequently in group with PI – 3.4 % and RPL – 3.3 %. Chromosomal abnormalities were detected in 3.1 % woman and 2.6 % men. The most common cytogenetic abnormalities (26 cases of 37; 2 %) are translocations, reciprocal – 18 cases (1.4 %) and Robertsonian – 8 cases (0.6 %). Numerical and structural gonosomal abnormalities were detected in 9 individuals (0.7 %), supernumerary marker chromosome – in 2 (0.14 %). Conclusions. Karyotype abnormalities are most common in individuals with PI and RPL and a occur with the same frequency among women and men. Numerical gonosomal abnormalities were detected only as mosaic form.

Assessment of reproductive disorders and birth defects in communities near hazardous chemical sites. II. Female reproductive disorders

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) signalling pathway regulates cell metabolism, inflammation and the immune response. This signalling pathway is essential for maintaining reproductive homeostasis and influencing steroidogenesis, implantation, and embryonic development. The central sensor, AMPK, regulates cell function in response to metabolic stress. The dysregulation of AMPK signalling has been implicated in several female reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis, infertility, and reproductive ageing. This review provides an overview of the role of AMPK in reproductive function and disorders, as well as potential therapeutic targets to restore balance in this signalling pathway. It discusses AMPK signalling in folliculogenesis, oocyte maturation, pregnancy maintenance, pre-eclampsia (PE) pathogenesis, PCOS, preterm birth, endometriosis, dysmenorrhoea and other disorders related to female reproduction. A deeper understanding of AMPK signalling in these contexts could provide new insights for the development of therapeutic interventions for reproductive health.