Endometriosis is a chronic inflammatory disease for which there is currently no accurate screening test to identify or predict the probability of the disease in individuals. This can often lead to delays in diagnosis. Several systemic immune-inflammation indices are currently used as predictive or supportive markers for several inflammation-associated diseases. In this study, we investigated whether these immune-inflammation indices, such as systemic immune inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), and pan-immune inflammation value (PIV) could serve as predictive or supplementary markers for diagnosing endometriosis. A total of 434 women with confirmed endometriosis and 517 controls were included in this study. Data on peripheral blood tests, including total counts of white cells, neutrophils, monocytes, lymphocytes, and platelets, were collected, and systemic immune-inflammation indices were calculated. SII, SIRI, NLR, and PIV values were significantly higher in women diagnosed with endometriosis compared to controls. Using the cut-off values of 538 for SII, 0.814 for SIRI, 2.03 for NLR, and 210 for PIV, we achieved 76 % sensitivity and 70 % specificity. When the four indices were combined, the area under the ROC curve (AUC) was 0.796 (95 % CI: 0.766, 0.827), with 76 % sensitivity and 70 % specificity. In conclusion, while ultrasonography or MRI remains the gold standard for visualizing the lesions in diagnosing endometriosis, followed by laparoscopy and histologic verification, routine peripheral blood tests in combination with clinical symptoms, could provide additional clinical diagnostic value for endometriosis as a non-invasive and cost-effective test.

We wished to ascertain if there is an association between neutrophil extracellular traps and endometriosis (EMS). We collected the lesional tissues and normal endometrium of 30 patients suffering from endometriosis. Samples were also taken from healthy controls. Blood from the peripheral circulation was collected to isolate serum and neutrophils. A mouse model of endometriosis was also created. Expression of citrullinated histone and the myeloperoxidase level in tissue were measured by immunofluorescence staining and western blotting. The myeloperoxidase level in peripheral blood serum was measured by enzyme-linked immunosorbent assay. Staining (Trypan Blue) and flow cytometry were used to measure the apoptosis of neutrophils in peripheral blood. BALB/C mice were modeled by allotransplantation, and the experimental parameters noted above quantified. The myeloperoxidase content in the peripheral blood of patients with endometriosis was increased compared with that in healthy controls. Flow cytometry showed that the percent apoptosis of neutrophils in patients with endometriosis was lower than that in healthy controls. Expression of citrullinated histone was higher in the endometriosis group in humans and mice compared with respective controls according to immunofluorescence staining and western blotting. Our data suggest that a high concentration of neutrophil extracellular traps was observed in humans and mice suffering from endometriosis.

Released from trophoblast and other fetal cells, placental extracellular vesicles (EVs) reach the maternal peripheral blood and modulate immune responses. Increased EVs in plasma of preeclampsia (PE) patients indicate their involvement in the etiology of this condition. This study addresses the uptake of plasma EVs by peripheral blood mononuclear cells (PBMCs) and explores the underlying internalization mechanisms. Plasma EVs were isolated from women with normotensive pregnancy (EV) and those with PE (EV), and characterized by cryo-transmission electron microscopy, nanoparticle tracking analysis, Western blotting, flow cytometry, and micro bicinchoninic acid assay (micro-BCA). To investigate whether the origin of PBMCs affects uptake, samples from males, pregnant women, and non-pregnant women were included. Primary PBMCs and macrophages derived from the human leukemia monocytic cell line THP-1 were incubated with PKH-stained EVs, and uptake was assessed by flow cytometry and confocal microscopy. Key molecules involved in monocyte differentiation and macrophage function were evaluated in EV-treated cells using LEGENDplex™ assay and real-time polymerase chain reaction (RT-PCR). Independent of the PBMC source, EVs were mostly captured by monocytes and in a lower proportion by T lymphocytes. Capture of EV was higher than of EV in primary T lymphocytes, monocytes, and THP-1-derived macrophages. After inhibition by Wortmannin and Cytochalasin D, EV internalization by THP-1-derived macrophages was significantly inhibited but not completely abolished. No defined polarization profile of treated THP-1-derived macrophages could be identified. These findings provide evidence of EV modifications in PE, which enhance their uptake by monocytes and other immune cells, mainly through phagocytosis and endocytosis.

The reproductive tract, as a lumen connected to the outside world, its microbial community is influenced by various factors. The changes in its microbiome are closely related to women's health. The destruction of the micro ecological environment will lead to various infections, such as Bacterial vaginosis, sexually transmitted infections, adverse pregnancy outcomes, infertility and tumors. In recent years, with the continuous development and progress of molecular biology, research on reproductive tract microbiota has become a clinical hotspot. The reproductive tract microbiota is closely related to the occurrence and development of female reproductive tract diseases such as vaginitis, pelvic inflammation, PCOS, cervical lesions, and malignant tumors. This article reviews the research on the relationship between vaginal microbiota and female reproductive tract diseases, in order to provide theoretical basis for the prevention and treatment of female reproductive tract diseases.

Existing literature supports the association between atypical phospholipid antibodies - anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and adverse pregnancy outcomes. This study aimed to investigate the relationship between aPS/PT and premature rupture of membranes (PROM).

Recent studies have found Several lncRNAs were proved differential expression in diminished ovarian reserve (DOR) patients, however, the mechanism of DOR caused by lncRNAs is still largely unclear.

Gestational diabetes is marked impaired glucose tolerance, poses various adverse outcomes including increased BMI and obesity. These outcomes results from excess lipid accumulation which is marked by elevated triglycerides. In GDM, placenta exhibits altered lipid metabolism, including reduced fatty acid oxidation and increased triglyceride accumulation. These elevated triglycerides can also contribute to oxidative stress in GDM. SIRT7 plays an important role in regulating lipid metabolism and triglycerides levels. This study aimed to investigate the potential of miRNA to regulate the placental SIRT7 in GDM. PCR analysis reveals that SIRT7 expression along with oxidative stress markers elevated in GDM placenta. These elevated SIRT7 levels were positively correlated with BMI and triglycerides levels in GDM subjects. miR-125b-5p was identified to regulate SIRT7 mRNA using in-silico approaches. Expression levels of miR-125b-5p were found to be downregulated in GDM placenta and found to be negatively correlated with SIRT7 mRNA expression. To confirm the hypothesis BeWo cells were transfected with anti-miR-125b and miR-125b-mimic. Anti-miR overexpressed the SIRT7 expression where mimic dysregulated it. Additionally, overexpressing miR-125b-5p controlled the elevated SIRT7 caused by the exposure of high glucose in BeWo cells. Collectively this study indicated that miR-125b-5p may regulate lipid metabolism via SIRT7 contributing to GDM. These findings highlights the warrant of further research to develop the therapeutic approaches that target miR-125b-5p to reduce lipid accumulation and obesity in GDM.

Successful embryo implantation is contingent upon the intricate interaction between the endometrium and the blastocyst. Recurrent implantation failure (RIF) signifies the clinical challenge of failing pregnancy post-transfer of high-quality embryos, fresh or frozen, in at least three in vitro fertilization (IVF) cycles, often in women under 40 years. Recent studies identify impaired blastocyst maternal tissue communication among recurrent implantation failure causes. Despite successful embryo transfer in vitro fertilization cycles, endometrial factors persist in women with recurrent implantation failure history, underscoring implantation's complexity. The implantation window, during which the endometrium becomes receptive to the blastocyst, involves the expression of key molecules that facilitate the implantation process. When the literature was examined, it was observed that comparative immunohistochemical studies on key molecules such as α4β1 integrin, MUC-2 and PNAd, which are thought to play a critical role in the endometrium before and during implantation, were limited. In this study, we aimed to investigate, through immunohistochemical and histological analyses, the roles of adhesion molecules in the secretory phase endometrium of patients diagnosed with RIF.

In the eukaryotic system, exosomes are categorized as unique extracellular vesicles with dimensions ranging from 30 to 150 nm. These vesicles contain a variety of endogenous molecules, such as proteins, DNA, mRNA, microRNA, and circular RNA. They are essential for a wide range of metabolic events and have the potential to be used as therapeutic or diagnostic targets for a number of diseases, including ovarian diseases. By inducing changes in the surrounding environment, the donor exosomes transfer their contents to the receiving cells, so demonstrating the biological implications of major interactions between cells. Mesenchymal stem cells (MSCs) have produced exosomes have shown promise as a treatment for premature organ failure (POF or POI). Furthermore, exosomal transport has many complexities, and contributes to the pathophysiology of ovarian cancer by affecting cell growth, migration, metastastsis and etc. Owing to these facts, in this paper, we present the progress developed in the understanding of exosomes as a viable therapeutic avenue and indisputable prognostic targets in ovarian disorders.

Endometriosis and adenomyosis have common pathogenesis and close relationship, with multi-factors involved in related infertility and IVF failure. They lead to anatomical changes, ovarian reserve reduction, endocrine abnormalities, altered endometrial receptivity and immunological dysfunction. Collective evidence indicate that abnormal function of immune cells and secretion of cytokines are closely related to reproductive outcomes among the women. Some studies showed that increased secretion of tumor necrosis factor alpha (TNF-α) led a key role in pro-inflammatory response in women with endometriosis/adenomyosis.TNF-a is embrryotoxic and receptivity impairing. Therefore, immunotherapy is a targeted therapeutic strategy apart from routine treatment. TNF-α inhibitors such as etanercept and adalimumab were shown to reduce the embryotoxic and anti-inflammatory effects to increase IVF pregnancy rates in recurrent implantation failure or endometrioma patient. However, there's no evidence about the use of adalimumab for patients with endometriosis and/or adenomyosis undergoing Frozen embryo transfer(FET).

The endometrial and vaginal microbiota have co-evolved with the reproductive tract and play a key role in both health and disease. However, the difference between endometrial and vaginal microbiota, as well as their association with reproductive outcomes in women undergoing frozen embryo transfer, remains unclear. 120 women who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) and whole embryo freezing were enrolled. The vaginal and uterine microbiome were sequenced during the first frozen thawed embryo transfer. Based on whether or not they were pregnant after embryo transfer, women were assigned into two groups, and the microbiome of their reproductive tract was compared. The V3-V4 regions of the 16S rRNA gene were examined in the samples using the Next Generation Sequencing method. In the vagina, the non-pregnant group had higher bacterial species richness and diversity, with significantly lower Lactobacillus levels (91.66 % & 74.50 %) and higher Gardnerella levels (3.92 % & 12.12 %) than pregnant group (P < 0.05). In the uterine cavity, the diversity of uterine microbiome between pregnant group and non-pregnant group showed no significant differences. However, dramatic decrease in Lactobacillus (37.27 % & 33.45 %) and Pseudomonas (9.80 % & 4.08 %) were observed in the non-pregnant group (P < 0.05). There may be a correlation between the composition of female reproductive tract microbiome and the reproductive outcomes of patients with frozen-thawed embryo transfer. Lactobacillus-dominated microbiome in reproductive tract is more likely to be associated with higher clinical and ongoing pregnancy rate.

Immunological changes are believed to be a part of pre-eclampsia etiology. This study investigated the distribution of the specific peripheral B lymphocyte phenotypes in pre-eclampsia cases compared to uncomplicated pregnancies. The study cohort included 29 women with pre-eclampsia and 14 women with uncomplicated pregnancies. Blood samples were collected in the third trimester of primigravidae pregnancies, and immune cells were analyzed using flow cytometry. Cases with pre-eclampsia showed a significantly reduced expression of programmed cell death protein 1 (PD-1) on CD27CD24CD38 regulatory B cells compared with control pregnancies (p = 0.002; multivariate logistic regression: p = 0.009). Trends for a reduced PD-1 expression on regulatory CD27CD24 B cells and on live CD19 B cells were observed in cases of pre-eclampsia (p = 0.011 and p = 0.035; respectively). No significant differences between pre-eclampsia cases and controls in percentages of B cells, B1a cells, plasmablasts, naïve B cells, transitional/immature B cells, memory B cells, regulatory CD27CD24 B cells and regulatory CD27CD24CD38 B cells were observed. This is the first study to report reduced PD-1 expression on live B cells and regulatory B cells in pre-eclampsia. These results are in line with previous studies of peripheral regulatory T cells and decidual lymphocytes from pre-eclampsia patients. Reduced PD-1 expression on regulatory B cells in pre-eclampsia could indicate that a lack of immune suppression might play a role in the pathophysiology of pre-eclampsia.

Endometriosis (EMS) is a prevalent gynecological condition characterized by the presence of endometrial tissue outside the uterus, often leading to secondary dysmenorrhea (SD), chronic pelvic pain and infertility. This review explores the intricate connection between EMS- associated pain and SD, focusing on the pathophysiological mechanisms underlying dysmenorrhea in EMS. Key contributors to pain include inflammation, aberrant immune responses, neurogenic inflammation, peritoneal irritation, peripheral sensitization, central sensitization and cross-organ sensitization. Understanding the pain pathways in EMS highlights the complexity of symptom manifestation and underscores the necessity for a multidisciplinary approach to management. Clinical manifestations, including chronic pelvic pain, dyspareunia, infertility, gastrointestinal and bladder symptoms, fatigue and malaise, are discussed, emphasizing the diverse impact of EMS on women's health. Various treatment modalities, ranging from pharmacological interventions to surgical and complementary approaches, are outlined to provide comprehensive management strategies for EMS-related menstrual pain/SD. This review aims to enhance understanding and facilitate the effective management of EMS-associated SD, ultimately improving the quality of life for affected individuals.

Clinical effects of low-dose aspirin (LDA) on embryo implantation still remains controversial; therefore, we investigated the appropriate timing for starting LDA in frozen-thawed embryo transfer (ET) cycles. A cross-sectional study was conducted on 885 infertile women who underwent thrombophilia screening between 2020 and 2023. We recruited first frozen-thawed blastocyst transfer cycles in 553 consecutive women aged < 40 years. LDA was started on the day of ET from 2020 to 2021 in 79 women (day 0 group) and at 5 days after ET from 2021 to 2023 in 215 women (day 5 group). We also recruited 259 consecutive women who underwent first frozen-thawed blastocyst transfer without LDA treatment from 2020 to 2023 (control). We compared pregnancy outcomes after frozen-thawed ET between the three groups. In results, clinical pregnancy and livebirth rates after frozen-thawed ET in the day 0 group were significantly lower than those in the other two groups (clinical pregnancy rates: 57.5 %, 40.5 %, and 61.4 %, p = 0.005 and livebirth rates: 48.6 %, 34.2 %, and 54.0 %, p = 0.01 in the control, day 0, and day 5 groups, respectively). Multivariable logistic regression analysis showed that livebirth rate in the day 0 group was significantly lower than those in the other groups (odds ratio [OR]: 0.54, 95 % confidential interval [CI]: 0.31 -0.95); however, no significant difference in livebirth rates was found between the day 5 and control groups (OR: 1.13, 95 %CI: 0.70 -1.80). Starting LDA prior to implantation may decrease pregnancy and livebirth rates after frozen-thawed blastocyst transfer.

To further evaluate the effects of lymphocyte immunotherapy (LIT) for the treatment of RPL patients this study aimed to utilize this type of treatment in RPL patients with positive antinuclear antibodies (ANA) in comparison to ANA-negative RPL women. To this aim, 84 ANA-positive, 114 ANA negative, and 50 healthy pregnant women were recruited. To examine the frequency of cells before and after LIT, flowcytometry technique was employed. The levels of cytokines gene expression were also measured using real-time PCR. The ELISA technique was employed to assess the level of secreted cytokines in serum. Initial evaluation before LIT showed significantly lower NK cells and Th1/Th2 ratio in healthy pregnant women compared to both ANA-negative, and positive patients. Moreover, healthy pregnant women had significantly lower pro-inflammatory cytokine (IFN-γ) and higher anti-inflammatory cytokines (TGF-β and IL-4) compared to RPL patients. After LIT, NK cells frequency significantly decreased in both ANA-negative and -positive groups, however, reduced Th1/Th2 ratio was only significant in ANA-negative group. Significantly increased and decreased IL-4 and IFN-γ were only observed in ANA-negative patients. Furthermore, patients receiving routine treatment did not experience any remarkable changes in terms of cell frequency and cytokine levels. This study showed a significant improvement in pregnancy outcomes including increased pregnancy rate and live birth, and decreased miscarriages in both ANA-negative and positive RPL patients, which were notably higher in ANA-negative group.

Anti-phosphatidylserine/prothrombin antibodies (aPS/PT) are classified as non-criteria antiphospholipid antibodies (aPL), and are strongly associated with thrombosis and pregnancy complications linked to antiphospholipid syndrome (APS). This study aimed to investigate whether aPS/PT positivity is associated with adverse outcomes in vitro fertilization (IVF). The study included infertile women who tested positive aPS/PT and underwent IVF cycles, as well as infertile controls with pure tubal etiology. We compared the impact of aPS/PT on baseline and clinical characteristics, immune-related indicators, IVF laboratory metrics, and pregnancy outcomes. Women with aPS/PT exhibited lower numbers of retrieved oocytes, embryos, and both perfect and available embryos, as well as reduced rates of blastocyst formation. Furthermore, an imbalanced Th17/Treg ratio and significantly elevated serum IL-17A levels were observed in women with aPS/PT compared to controls. In conclusion, the presence of aPS/PT is associated with adverse IVF and pregnancy outcomes. Early screening for aPS/PT and appropriate consultation for couples undergoing IVF-ET should be considered. Additionally, specific immune and inflammatory mechanisms related to aPS/PT warrant further investigation.

Preeclampsia (PE) is a complex hypertensive disorder that occurs during pregnancy, with the immune system playing a key role. Although immune modulation is implicated in PE progression, the roles of specific immune cells and inflammatory mediators remain unclear.

Sporadic early miscarriages occur primarily due to embryonic aneuploidy. There is no evidence showing that stress is a direct cause of miscarriage. Yet, despite this, a national US survey and a Japanese survey found that many people mistakenly attributed miscarriage to the mental state or behavior of the women. Our present survey examined the risk factors and economic impact of resignation associated with miscarriage and pregnancy in Japan. The questionnaire to be completed consisted of 17 questions concerning individual characteristics and resignation from the workforce. Of the 1177 women, 392 left their employment and 785 continued working. At least 9 % of the women left their jobs because of miscarriage. The economic loss because of resignation due to miscarriage was found to be JPY 46,666,959,300 per year (USD 303,032,203). The number of children, exposure to in vitro fertilization and living with or near their father-in-law were independent risk factors for resignation. Significantly more women who left work in the first pregnancy due to miscarriage and infertility treatment remained unemployed. Thoughts that led to the conclusion that it is better to avoid working during pregnancy, that it is better not to do any work that places a heavy burden on the body, or that it is better not to work long or irregular hours during pregnancy were also independent risk factors for resignation. Significantly more women who lived with or near their mothers remained employed. Reproductive education is needed to prevent resignation following a miscarriage or during a pregnancy.

Clinical evidence increasingly suggests that traditional treatments for dysfunctional uterine bleeding (DUB) have limited success. In this study, blood samples from 10 DUB patients and 10 healthy controls were collected for transcriptome sequencing. Then, the differentially expressed genes (DEGs) were screened and crossed with the DUB-related module genes to obtain the target genes. These target genes were analyzed for functional enrichment. Further, the biomarkers were screened by protein-protein interaction (PPI) analysis and analyzed by the gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA). To explore the pathogenesis of DUB, immune microenvironment analyses were also performed. Potential drugs targeting these biomarkers were predicted for clinical treatment. The expression of these biomarkers was validated using quantitative real-time polymerase chain reaction (qRT-PCR). The results showed that, a total of 754 target genes were found to be related to cell proliferation and senescence. Five biomarkers-CENPE, KIF11, PIK3R1, SMC3, and SMC4-were identified, all of which were down-regulated in the DUB group, and most of these findings were confirmed by qRT-PCR. Notably, CENPE expression showed a negative association with activated NK cells and a positive association with resting NK cells. In addition, 44 potential drugs were predicted for DUB treatment. In conclusion, five DUB biomarkers were identified, enhancing understanding of gene regulation in DUB and providing a theoretical foundation for clinical diagnosis and treatment.

Proper regulation of intestinal permeability is essential for maintaining the integrity of the intestinal mucosal barrier. An abnormal increase in permeability can significantly contribute to the onset and progression of various diseases, including autoimmune disorders, metabolic conditions, allergies, and inflammatory bowel diseases. The potential connection between intestinal permeability and maternal health during pregnancy is increasingly recognized, yet a comprehensive review remains lacking. Pregnancy triggers a series of physiological structural adaptations and significant hormonal fluctuations that collectively contribute to an increase in intestinal permeability. Although an increase in intestinal permeability is typically a normal physiological response during pregnancy, an abnormal rise is associated with immune dysregulation, metabolic disorders, and various pregnancy-related complications, such as recurrent pregnancy loss, gestational diabetes mellitus, overweight and obesity during pregnancy, intrahepatic cholestasis of pregnancy, and preeclampsia. This paper discusses the components of the intestinal mucosal barrier, the concept of intestinal permeability and its measurement methods, and the mechanisms and physiological significance of increased intestinal permeability during pregnancy. It thoroughly explores the association between abnormal intestinal permeability during pregnancy and maternal diseases, aiming to provide evidence for the pathophysiology of disease development in pregnant women. Additionally, the paper examines intervention methods, such as gut microbiota modulation and nutritional interventions, to regulate intestinal permeability during pregnancy, improve immune and metabolic states, and offer feasible strategies for the prevention and adjuvant treatment of clinical pregnancy complications.

New paternity has been related to placenta-associated complications in pregnancy. We evaluated whether a lack of earlier pregnancies or deliveries with a current father are associated with the pregnancy, prenatal, and early neonatal outcomes after controlling for the most common maternal confounders in prospective birth cohort study. An online questionnaire was used to survey 4459 pregnant women from the Kuopio Birth Cohort in their third trimester. The topics included their history of paternity in current and earlier pregnancies. Data were combined with prenatal, perinatal, and early neonatal information. A multivariable logistic regression analysis was performed to compare the possible associations between selected pregnancy and early neonatal outcomes with respect to paternal change. Pregnant women with changed partners had higher rates of smoking during pregnancy and hypertension before pregnancy. In the adjusted analysis, primigravidas and nulliparous multigravidas with different father had the highest risks for preeclampsia (adjusted odds ratios (aORs) 4.46 and 2.69, respectively), low birth weight (aORs 3.15 and 2.25), and smallness for gestational age (aORs 2.23 and 2.16) compared to the parous controls. Nulliparous women who had earlier pregnancies with the current father had less preeclampsia or gestational hypertension, as well as low birth weight (aOR 0.42, 95 % confidence interval (CI) 0.21-0.82 and aOR 0.26, 95 % CI 0.08-0.87, respectively) compared to other nulliparas. Among parous women, most of the pregnancy, obstetric, and early neonatal outcomes were similar in the adjusted analysis, regardless of new changes in paternity.