Yoneda et al. recently reported distinct inflammatory, microbiological, and clinical characteristics between cervical-type and vaginal-type visible fetal membranes in cervical insufficiency. We discuss the potential influence of operative management, particularly emergency cervical cerclage, on interpretation of the reported outcome differences. We suggest that anatomical classification, biological severity, and operative feasibility should be considered complementary dimensions when evaluating visible fetal membranes in cervical insufficiency.

Antinuclear antibodies (ANA) are biomarkers of immune dysregulation whose reproductive significance depends on the clinical setting and antibody profile. This narrative review synthesizes clinical and experimental evidence on ANA in infertility, assisted reproductive technology (ART), recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), endometriosis and pregnancy complications. Follicular-fluid studies and experimental models implicate oocyte maturation, embryo development, trophoblast function and placental immune regulation, providing biological plausibility without establishing ANA-mediated causation in human reproductive failure. Clinical studies show enrichment of ANA in infertility and RPL populations, whereas subsequent pregnancy prognosis, ART outcomes and perinatal associations vary with population, assay, titer and endpoint. We distinguish isolated ANA positivity from specific ANA-associated autoantibodies and established autoimmune disease because these findings carry different clinical implications. Disease-directed treatment for systemic lupus erythematosus or antiphospholipid syndrome is considered separately from empirical treatment in ANA-positive infertility patients. Some intervention studies report improved early reproductive outcomes, but current evidence does not support routine corticosteroids, hydroxychloroquine, aspirin or heparin solely on the basis of ANA positivity. ANA positivity is therefore best interpreted as a context-dependent marker that may guide targeted assessment rather than an independent therapeutic target. Prospective studies linking defined antibody profiles to tissue mechanisms, reproductive outcomes and treatment response are needed to establish clinically useful applications.

Missed abortion (MA) is a complex pregnancy complication with multifactorial etiologies, including embryonic chromosomal anomalies and maternal endocrine disorders. Among these, immune dysregulation at the maternal-fetal interface has been recognized as a critical contributing factor. Secreted protein acidic and rich in cysteine (SPARC) is implicated in macrophage polarization and trophoblast function, but its role in MA-associated immune imbalance remains unclear. Decidual tissues were collected from 7 to 10 week MA patients and gestational age-matched healthy controls who underwent induced abortions. SPARC expression and macrophage phenotypes were assessed by Western blot and multiplex immunofluorescence staining for SPARC, CD68, CD86, and CD206. In vitro, THP-1 monocytes were differentiated into macrophages by PMA, which were then exposed to the conditioned media collected from SPARC-knockdown or control HTR8/SVneo trophoblasts. Cell viability, migration and apoptosis of HTR8/SVneo cells were evaluated under indirect co-culture with macrophages, with or without TNF-α neutralizing antibody. SPARC expression was significantly reduced in MA decidua, and its expression negatively correlated with the proportion of M1 macrophages, while positively correlated with M2 macrophages. SPARC knockdown in trophoblasts promoted macrophages M1 polarization, elevated TNF-α, and impaired macrophage-induced trophoblast viability, invasion, and survival. TNF-α neutralization partially rescued these effects. Mechanistically, SPARC promoted M2 polarization via the AKT/SP1 pathway, and its knockdown suppressed Akt phosphorylation and SP1 expression. Reduced SPARC in MA decidua drives M1 macrophage dominance and TNF-α-mediated trophoblast dysfunction through AKT/SP1 signaling, highlighting SPARC as a potential therapeutic target for MA.

Anticentromere antibodies (ACAs) impair chromosome segregation of oocytes and embryos, contributing to repeated in vitro fertilization failure. We evaluated whether ex vivo γ-globulin supplementation of oocyte culture medium could improve reproductive outcomes without systemic administration of high-dose intravenous immunoglobulin. This prospective study enrolled women aged 30-46 years with infertility and ACA titres ≥ 1:640 undergoing intracytoplasmic sperm injection. In Phase I, 40 oocytes underwent parallel dose-ranging at 0%, 1.0%, 1.5%, and 2.0% γ-globulin. No concentration met the prespecified criterion for an unacceptable reduction in fertilization with ≥ 1 pronucleus, and 2.0% was selected for Phase II. The γ-globulin-treated cohort (n = 16) was compared with historical controls (n = 28) and age-matched ACA-negative controls. In the primary oocyte-based analysis, normal fertilization rates were similar between treatment and historical control groups, whereas treatment was associated with higher good-quality blastocyst (9.6% vs. 4.2%; risk ratio [RR], 2.28; 95% confidence interval [CI], 1.05-4.93) and live birth rates (4.0% vs. 0.4%; RR, 11.40; 95% CI, 1.35-96.58). A patient-based analysis similarly showed a higher cumulative live birth rate than in historical controls (31.3% vs. 3.6%; P = 0.018). A supplementary age-adjusted mixed-effects analysis accounting for clustering within patients and retrievals yielded a consistent but imprecise association with higher odds of live birth (adjusted OR, 12.02; 95% CI, 1.38-104.45; P = 0.024). Several oocyte-based developmental outcomes remained lower than in ACA-negative controls. These findings provide preliminary proof of concept, with potential benefit observed in isolated oocytes without immune cells. Further studies are required.

Preeclampsia (PE) is a severe pregnancy-related condition characterized by high blood pressure and, in some cases, proteinuria and multiorgan dysfunction, with high risk of mother and newborn mortality. Women affected by PE often experience an exacerbated inflammatory response, with elevated levels of pro-inflammatory cytokines detected both systemically and locally in the placenta. Echinacea angustifolia and Zingiber officinale are natural compounds with well-documented anti-inflammatory and analgesic properties. Due to their minimal adverse effects for mother and fetus, they are often used during pregnancy; however, limited information is available regarding their impact on placental cells. An in vitro approach was employed using qPCR and whole-cell ELISA to study the anti-inflammatory effects of the combination of Echinacea and Ginger (ECHI + GIN) on endothelial cell lines (HUVECs) and a monocytic cell line (THP-1). The findings were further validated in primary endothelial cells isolated from preeclamptic decidual tissues (DECs-PE). We did not observe a synergistic effect between the two compounds, particularly in endothelial cells. While these compounds influenced THP-1, these effects were markedly attenuated by the cultivation in gravid serum. ECHI + GIN treatment downregulated the chronic inflammatory response, acting on the expression of CCL2/MCP-1 and VCAM1, which are involved in macrophage recruitment.

Gestational diabetes mellitus (GDM) is related to multiple negative pregnancy outcomes such as miscarriage, pre-eclampsia and so on. Cell senescence was considered potential mechanism of GDM. However, the role and mechanism of high glucose and cellular senescence in trophoblast cells are largely unknown. Here, we observed cell senescence and expression of glucose transporter 3 (GLUT3) were up-regulated in GDM placenta. In vitro study confirmed the migration and invasion abilities were impaired in H2O2-induced senescent choriocarcinoma JEG3 cells. Additionally, high glucose triggered senescent phenotype, impaired migration and invasion of senescent JEG3 cells. The expression of GLUT3 was increased in senescent JEG3 cells, and overexpression of GLUT3 induced cell senescence, suggesting a feedback loop between cell senescence and up-regulation of GLUT3. Overexpression of GLUT3 enhanced glucose uptake and lactate accumulation, and decreased migration and invasion of JEG3 cells, mechanically, these processes were dependent on IGFBP4. These data suggest that GLUT3/high glucose induces migration and invasion dysfunction of trophoblast cells, possibly contributing to placental dysfunction of GDM.

Successful pregnancy requires precise regulation of the maternal-fetal immune microenvironment, where maternal immune tolerance toward the semi-allogeneic fetus must be balanced with effective antimicrobial defense. Interferons (IFNs), a family of pleiotropic immunoregulatory cytokines, are central to this process. Produced by endometrial cells, decidual stromal cells, trophoblasts, and decidual immune cells, IFNs establish a highly coordinated signaling network that regulates endometrial receptivity, decidualization, trophoblast differentiation and invasion, spiral artery remodeling, and immune homeostasis. Unlike canonical systemic interferon responses, IFN activity at the maternal-fetal interface is precisely controlled in a cell type-, spatial-, and temporal-specific manner, thereby limiting excessive inflammation while preserving host defense. Disruption of this tightly regulated network is increasingly recognized as a key driver of pregnancy complications, including preeclampsia (PE), recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), preterm birth, and fetal growth restriction. In this Review, we summarize the cellular sources, spatiotemporal regulation, molecular mechanisms, and physiological functions of IFNs at the maternal-fetal interface, and discuss how aberrant IFN signaling contributes to adverse pregnancy outcomes. We further highlight emerging opportunities for biomarker development and targeted immunomodulatory therapies, providing a conceptual framework for translating mechanistic insights into precision reproductive medicine.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. Heat shock 70 kDa protein 1B (HSPA1B) is critical for stress response and inflammation, but its role in PCOS remains unknown. To validate HSPA1B as a key pathogenic gene in PCOS and investigate its regulatory mechanisms. Two PCOS datasets (GSE155489, granulosa cells; GSE54250, whole blood) were analyzed for differentially expressed genes. HSPA1B diagnostic value was assessed by ROC curve. Dihydrotestosterone (DHT)-induced KGN cell and dehydroepiandrosterone (DHEA)-induced mouse PCOS models were established. siRNA/adenoviral silencing, overexpression, methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), luciferase assay, actinomycin D chase, MTT, flow cytometry, ELISA, and Western blot were used to evaluate HSPA1B effects on granulosa cell function and dissect the YY1-NSUN7-m[5]C-HSPA1B axis. HSPA1B was identified as a core DEG, upregulated in patient blood and DHT-induced KGN cells (AUC = 0.9273). Silencing HSPA1B reversed DHT-induced injury: restored viability, reduced IL-6/IL-1β, decreased apoptosis, stabilized mitochondrial potential, reduced ROS, and inhibited M1 macrophage polarization (all P < 0.05). In vivo, HSPA1B silencing ameliorated ovarian pathology, corrected sex hormones (restored estradiol [E2], decreased testosterone [T]), and alleviated inflammation (all P < 0.01). Mechanistically, NSUN7 bound HSPA1B mRNA 3' UTR, enhancing stability via m[5]C methylation; Yin Yang 1 (YY1) activated NOP2/Sun RNA methyltransferase 7 (NSUN7) transcription by promoter binding. Rescue experiments established the YY1-NSUN7-m[5]C-HSPA1B axis. This study revealed the YY1-NSUN7- m[5]C -HSPA1B epigenetic axis in PCOS pathogenesis, providing a foundation for HSPA1B-targeted therapy.

Unexplained recurrent pregnancy loss affects many fertile couples who want to conceive. Possibly, the maternal immune system is involved in the underlying mechanism of such unexplained cases and immune-suppressing corticosteroids can be used to modulate this system and improve pregnancy outcome. As a high quality, sufficiently powered randomized controlled trials in the unselected unexplained RPL population is currently lacking, the PREMI (Prednisolone administration in patients with unexplained REcurrent Miscarriages) trial was designed. Here, we discuss the rationale for the administration of prednisolone, including its potential mechanisms, safety, administration protocol and study population.

Ovarian cancer is one of the most lethal gynecological malignancies with poor prognosis due to high drug resistance and low tumor susceptibility. This study investigated the cytotoxic effects of four sterols of fungal origin, ergosterol (ES), cholesterol (CS), β-sitosterol (βS), and lanosterol (LS) on human ovarian cancer SKOV3 cells, revealing that they exert their effects by correlating with autophagy and ferroptosis‑related signaling, and analyzed the structure-activity relationship. SKOV3 tumor cells were treated with four types of sterols for 24 h. Cell viability, cell cycle, apoptosis, mitochondrial membrane potential, and the expression of proteins associated with autophagy and ferroptosis were assessed, and the correlation between their structure and antitumor activity was analyzed. All four sterols inhibited SKOV3 cell proliferation in a dose-dependent manner, with the IC50 values ranked as LS (28.32 μg/mL) < CS (32.07 μg/mL) < βS (73.53 μg/mL) < ES (78.67 μg/mL). The four sterols significantly suppressed cell migration, induced G0/G1 phase arrest and apoptosis, reduced mitochondrial membrane potential, and caused mitochondrial structural damage. Meanwhile, they markedly up-regulated the expression of LC3II/LC3I and P53, and down-regulated the expression of SLC7A11 and GPX4. The number of conjugated double bonds in sterols was negatively correlated with IC50, cell viability and migration rate, and positively correlated with apoptosis rate and key protein expression, the substituents at C24, C28 and C29 of the side chain also enhanced the cytotoxicity. These findings indicate that fungal sterols are associated with correlated regulation of the autophagy-ferroptosis network and P53 activation in SKOV3 cells, providing a theoretical basis for anti-ovarian cancer drug development.

Antisperm antibodies (ASA) have been implicated in reproductive failure in cows. Present study investigated 58 crossbred cows, of which 38 (normal-cows, NC, n = 16; repeat-breeder-cows, RBC, n = 22) were used for ASA analyses and fertility evaluation, while subsequent bacteriological component included additional 20 cows. ASA levels were assessed from maiden to conceptional-estrus using mixed-antiglobulin reaction (MAR-IgG and MAR-IgA) tests and ELISA, and candidate spermatozoal-bacterial protein pairs were assessed for sequence and three-dimensional structural similarity. MAR-IgG and MAR-IgA levels were significantly lower during conceptional-estrus than during maiden-estrus in both NC and RBC cows, whereas differences between NC and RBC at same estrus stage were less pronounced, indicating that ASA levels were closely associated with conception status than with fertility classification. Receiver operating characteristic analysis based on cow-level measurements showed that MAR-IgG and MAR-IgA discriminated conceptional from non-conceptional status, with area under the curve values of 0.799 and 0.806, respectively. Head-bound spermatozoa represented predominant antibody binding, suggesting that sperm head antigens constitute major ASA targets. Bacillus spp., Escherichia coli and Staphylococcus spp. were predominant bacterial isolates recovered from the genital tract. Sequence and structural analyses of previously identified cross-reactive sperm and bacterial proteins revealed substantial peptide-level similarity and structural-overlap, and structural-superimposition produced low root mean square deviation values, indicating close structural similarity between sperm and bacterial proteins. Collectively, these findings indicate that lower ASA levels are associated with successful conception and support molecular mimicry between genital bacterial and sperm proteins as a plausible mechanism contributing to reproductive immunoinfertility in cows.

Immunocontraceptive vaccines have emerged as a promising, non-invasive strategy for regulating fertility in wildlife, domestic animals, and humans, particularly in species such as elephants where conventional population control methods are often impractical or ethically challenging. These vaccines act by eliciting immune responses against critical reproductive targets, thereby disrupting gametogenesis, fertilization, or endocrine regulation. The major categories include gonadotropin-releasing hormone (GnRH)-based vaccines, zona pellucida (ZP)-based vaccines, and gamete-specific antigen vaccines. Anti-GnRH vaccines induce neutralizing antibodies that suppress the hypothalamic-pituitary-gonadal axis by inhibiting luteinizing hormone and follicle-stimulating hormone secretion, ultimately blocking steroidogenesis and gamete production. In contrast, ZP-based vaccines target oocyte surface glycoproteins, preventing sperm binding and fertilization. Emerging molecular targets, including sperm-egg interaction proteins such as IZUMO1 and JUNO, offer enhanced specificity. These vaccines predominantly stimulate humoral immune responses, with antigen-specific antibody production playing a central role, although cell-mediated immunity may contribute to sustained effects. In elephants, vaccines such as porcine zona pellucida (PZP) and GnRH-based formulations (e.g., GonaCon) have shown variable success in inducing reversible infertility, though challenges remain regarding booster requirements, duration of efficacy, and potential side effects. Advances in scientific technologies, particularly peptide engineering and viral-vector platforms, have contributed significantly to the development of immunocontraceptive vaccines by enhancing antigen specificity, immunogenicity, and overall vaccine performance. However, variability in immune responses, species-specific efficacy, and ethical considerations continue to limit widespread application. This review aims to help understanding the molecular and immunological mechanisms are essential for optimizing safe, effective, and sustainable fertility control strategies.