Combination antiretroviral therapy (cART) has improved human immunodeficiency virus (HIV) management, but long-term use is associated with reproductive dysfunction. This study investigated TLD (Tenofovir, Lamivudine and Dolutegravir)-based cART effects on ovarian function using animal models and exploratory clinical investigations in women living with HIV. In the animal study, female Wistar rats were randomized into control, TLD-based cART (22 mg/kg), and dolutegravir alone (2.5 mg/kg) groups, administered orally for 28 days. Estrous cycle, histology, oxidative stress, reproductive hormones, and ova count were assessed. Both TLD-based cART and dolutegravir significantly prolonged diestrus (p = 0.0083 and p = 0.0007, respectively) and reduced metestrus (p = 0.0057 and p = 0.0083, respectively). Treated groups showed significantly reduced ova counts (p = 0.0002 and 0.0003, respectively). Histology revealed structural alterations of the ovary, including atretic follicles, distorted stroma, and sparse theca cells. Additionally, treated groups showed increased malondialdehyde (p = 0.0421) and decreased glutathione (p = 0.0046) and catalase activities (p = 0.0411), indicating oxidative stress. Serum follicle-stimulating and luteinizing hormones were significantly reduced in both treated groups (FSH: p < 0.0001 and p = 0.0002; LH: p < 0.0001 and p = 0.0108, respectively). In the clinical investigation, serum anti-Müllerian hormone (AMH) levels were evaluated in HIV-positive women (n = 20) receiving TLD-based cART. Ten participants (50%) had AMH in low/very low categories ( < 1.0 ng/mL), while 11 (55%) had AMH below the normal reference range ( < 1.5 ng/mL). Menstrual interval and dysmenorrhea showed no significant changes. These preliminary findings suggest Dolutegravir and TLD-based cART may negatively affect female reproductive function by altering ovarian structure, hormonal balance, and ovarian reserve, potentially predisposing women living with HIV to fertility complications.

Polycystic ovary syndrome (PCOS) is a complicated, endocrine-endemic disorder with a prevalence rate of 8-13% in reproductive-age women in the world, which manifests through insulin resistance, hyperandrogenism, and reproductive dysfunction. Despite its high global prevalence, existing therapeutic interventions focus predominantly on symptom management rather than targeting the heterogeneous and multifactorial pathophysiology of the syndrome. Intestinal barrier integrity is destroyed by dysbiosis of the gut microbiota and induces endotoxemia and chronic low-grade inflammation through signalling pathways, such as LPS-TLR4-NF-kB signalling, which contribute to increased insulin resistance and androgen excess. These mechanistic pathways we dissect include changes in short-chain fatty acids (SCFAs), bile acid metabolism, involvement of FXR and TGR5 receptors, neuroendocrine regulation of the gut-brain axis, and microbial metabolites (tryptophan and agmatine), which altogether alter metabolic and reproductive abnormalities in PCOS. The preclinical evidence in the area of fecal microbiota transplantation proves the causal component of microbiota imbalance in the phenotype of PCOS. Dietary interventions that have been reviewed are fiber and resistant starch modulation, probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and pharmacotherapies like metformin, which also alter the microbiome. They are heading towards individualized microbiome-based therapies and diagnostics, aided by artificial intelligence and standardized biomarkers. This review explains the emerging role of the gut-insulin axis as an important factor in the pathogenesis of PCOS and uses a novel way of combining them as a radical intervention for personalized and innovative PCOS treatment, which has the potential to enhance metabolic and endocrine health, as well as reproductive outcomes.

The prostate is a hormone-sensitive gland, in which stromal composition is important for epithelial regulation. Fibrotic alterations in the stroma may enhance epithelial imbalance and pre-neoplastic lesions. The purpose of this study was to assess the time-dependent antifibrotic effects of mycophenolate mofetil (MMF) in rat prostate. Male Wistar rats were treated with MMF for 7 or 30 days, and prostate samples were histologically and immunohistochemically examined. Stromal fiber content, hormone receptor expression, and immune cell incidence were analyzed. Collagen III and elastin fibers decreased at 7 days, with increased matrix metalloproteinases 2 expression and reduced androgen receptor in the epithelium, resulting in decreased proliferation and enhanced apoptosis. Collagen I breakdown at 30 days was associated with increased matrix metalloproteinases 13 and reduced smooth muscle area, with increased non-muscular stroma and vascular density. Degranulated mast cells were increased early on, and macrophages at 30 days, reflecting their successive involvement in stromal remodeling. These findings define two time windows of MMF-induced remodeling: initial extracellular matrix disassembly with epithelial influence, and later structural reorganization with vascular and immune components. This study provides relevant information about MMF as a potential tool for the study of antifibrotic response and stroma-epithelium interactions in androgen-dependent organs.

Early follicular development and primordial follicle formation are essential for ovarian reserve establishment, and disruption of this process may contribute to fertility disorders such as premature ovarian insufficiency (POI). Figla is an oocyte-specific transcription factor required for primordial follicle formation, but its candidate downstream genes and associated pathways remain incompletely understood. This study aimed to investigate the role of Figla in early follicular development and to explore its potential downstream regulatory events. A Figla knockout mouse model was generated to evaluate the effects of Figla deficiency on ovarian development and primordial follicle formation. ChIP-seq, motif analysis, and promoter activity assays were performed to identify FIGLA-associated chromatin regions and candidate genes. In addition, Figla overexpression and Ywhab knockdown experiments were conducted in a granulosa cell line, together with ovarian tissue Western blot analysis, to assess changes in growth activity, migration, ERK phosphorylation, and apoptosis-related markers. Figla was highly expressed in late embryonic and early postnatal ovaries, and its deletion primarily disrupted perinatal primordial follicle assembly, accompanied by progressive oocyte loss. ChIP-seq, motif, and promoter analyses supported Ywhab as a candidate gene potentially regulated by Figla. In KGN cells, Figla overexpression increased Ywhab expression and coincided with greater growth activity, migration, ERK phosphorylation, and changes in BAD/BCL-2/BAX-related markers. These cellular and signaling changes were attenuated by Ywhab knockdown. Additional ovarian tissue analysis showed reduced p-ERK/ERK and increased p-BAD/BAD ratios in Figla(-/-) ovaries. These findings support Ywhab as a candidate downstream gene potentially regulated by Figla and suggest a possible link between Figla-associated transcriptional regulation and cellular processes relevant to early follicular development. Further validation is needed before extending these findings to ovarian reserve establishment more broadly or to POI-related reproductive disorders.

Sertoli cells play a pivotal role in spermatogenesis by providing structural support and delivering essential nutrients and signaling molecules to developing germ cells. A key function of these cells is the regulation of androgen-binding protein (ABP), which maintains the high intratesticular testosterone levels necessary for proper spermatogenic progression. Despite the critical nature of ABP, the mechanisms underlying its degradation within Sertoli cells remain poorly understood. This study investigates the role of the valosin-containing protein (p97/VCP) in the autophagic degradation of ABP, with a particular focus on molecular pathways that may contribute to male infertility and testicular dysfunction. Sertoli 15P-1 cells were treated with testosterone, chloroquine, and rapamycin, and subjected to single and double immunofluorescence staining, Western blotting, and siRNA-mediated knockdown experiments to explore the interaction between p97/VCP and ABP. Western blot analysis demonstrated that p62 expression was highest in the chloroquine + testosterone (CQ + T) group compared to control siRNA (Csi), although not statistically significant (p > 0.05). LC3 expression peaked in the chloroquine (CQ) group (p > 0.05). As expected, the lowest expression of p97/VCP was detected in the VCPsi group following siRNA transfection. Immunofluorescence analyses revealed significant differences in protein colocalization patterns across all treatment groups, except for p62 in rapamycin-treated samples. These findings provide the first evidence in the literature of a direct relationship between p97/VCP and ABP within Sertoli cells, underscoring the relevance of autophagic pathways in the regulation of male reproductive hormones. The data suggest a novel regulatory mechanism by which p97/VCP may influence spermatogenesis and male fertility through ABP degradation. Furthermore, this work lays a foundational framework for future investigations in other ABP-expressing tissues such as the brain, liver, and placenta, potentially linking p97/VCP expression to ABP-associated endocrine and pathophysiological disorders beyond the testis.

The endoplasmic reticulum (ER) plays a pivotal role in protein folding and cellular homeostasis and is highly sensitive to oxidative stress. Nicotine is a potent pro-oxidant; however, its effects on ER stress signaling in testicular tissue and the protective potential of melatonin and coenzyme Q10 (CoQ10) remain insufficiently defined. This study investigated nicotine-induced sperm dysfunction and the involvement of oxidative stress-mediated ER stress pathways in rat testes. Two-month-old male Wistar albino rats (n = 48) were assigned to control, nicotine, nicotine + melatonin, nicotine + CoQ10, nicotine + melatonin + CoQ10, and melatonin + CoQ10 groups. Sperm quality was evaluated, and testicular tissue was analyzed for oxidative stress markers, ER stress-related gene expression, histopathological alterations, and immunohistochemical localization of proteins. Nicotine exposure significantly impaired sperm motility and membrane integrity and increased abnormal morphology, mortality, and apoptosis (p < 0.001). These effects were associated with elevated lipid peroxidation and depletion of antioxidant defenses, including reduced glutathione, glutathione peroxidase, and catalase (p < 0.001). Melatonin and/or CoQ10 partially restored sperm quality and antioxidant capacity. Moreover, antioxidant treatment significantly downregulated ER stress-associated genes (Activating transcription factor 4-ATF4; Activating transcription factor 6-ATF6; C/EBP homologous protein-CHOP; 78 kDa glucose-regulated protein-GRP78; inositol-requiring enzyme 1 alpha-IRE1α; and protein kinase RNA-like endoplasmic reticulum kinase-PERK) and reduced CHOP immunoreactivity, while CoQ10 selectively enhanced XBP-1 immunoreactivity. In conclusion, nicotine-induced testicular dysfunction is mediated by oxidative stress-driven ER stress activation, whereas melatonin and CoQ10 confer protection through modulation of redox balance and ER stress signaling.

This study aimed to develop trimester-specific and combined prediction models for early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) based on maternal clinical characteristics, uterine artery pulsatility index (UtA-PI), and 3D placental parameters, identify the optimal models, and construct static nomograms. A total of 1602 singleton pregnant women were prospectively enrolled from October 8, 2020 to May 31, 2025. All maternal clinical data were collected and participants were followed up until delivery. UtA-PI and 3D placental ultrasound parameters, including placental volume (PV), placental quotient (PQ), and placental blood flow vascularization index (PBVFI), were measured at 11-14 and 15-18 weeks of gestation, and the placental vascular growth rate (PVGR) was calculated. According to the gestational age at preeclampsia onset, participants were divided into the EOPE group (n = 29), LOPE group (n = 58), and normal control group (n = 1515). Univariable and multivariable Firth's logistic regression analyses were performed to identify independent predictors. Model performance was evaluated using receiver operating characteristic (ROC) curves, bootstrap-based calibration and decision curve analysis (DCA). Static nomograms were constructed based on the optimal combined models. Chronic hypertension was an independent risk factor for both EOPE and LOPE, while elevated placental perfusion parameters exerted a protetive effect. The combined model achieved optimal predictive performance, with AUCs of 0.980 (95% CI 0.968-0.992) for EOPE and 0.827 (95% CI 0.765-0.889) for LOPE. Internal bootstrap validation confirmed acceptable calibration, and DCA demonstrated positive net clinical benefit. Static nomograms established based on the optimal models enable individualized risk assessment for EOPE and LOPE. We developed and internally validated trimester-specific and combined prediction models to assess the risks of EOPE and LOPE, and constructed static nomograms based on the optimal models. The models achieved favorable apparent performance in this single-center cohort. Nevertheless, their generalizability remains unclear. External validation using independent cohorts is required before large-scale application in routine antenatal screening.

To evaluate and compare the protective effects of cytokine-rich serum (ACRS) and platelet-rich plasma (PRP) against ovarian ischemia-reperfusion (I/R) injury in a rat model of ovarian torsion and detorsion. Forty-two female Wistar albino rats were randomly allocated into control, PRP, ACRS, I/R, I/R + PRP, I/R+ACRS, and donor groups. Ovarian torsion was induced for two hours followed by detorsion. PRP or ACRS was administered following detorsion. Ovarian tissues were evaluated using histopathological assessment, follicle counting, and immunohistochemical analysis of anti-Müllerian hormone (AMH), cleaved Caspase-3, VEGFA, and α-SMA. Ischemia-reperfusion injury resulted in marked ovarian damage, characterized by increased follicular degeneration, congestion, hemorrhage, edema, stromal connective tissue changes, inflammatory cell infiltration, and elevated apoptotic activity. Both PRP and ACRS attenuated histopathological injury and apoptotic activity while improving follicular preservation. Compared with PRP, ACRS was associated with better preservation of primordial and tertiary follicles, fewer atretic follicles, higher AMH immunoreactivity, lower cleaved Caspase-3 immunoreactivity, and increased VEGFA immunoreactivity. No significant differences were observed in α-SMA immunoreactivity among groups. Both PRP and ACRS exert protective effects against ovarian I/R injury; however, ACRS was associated with more pronounced histological and molecular benefits. These findings suggest that ACRS may represent a promising biological approach in ischemic ovarian pathologies.

Embryologists could not know whether blastocysts were euploid or not in in-vitro fertilization treatments without preimplantation genetic testing for aneuploidy. However, preimplantation genetic testing for aneuploidy technology which might impair the developmental potency of blastocysts was in strict limitation in China. Therefore, a non-invasive method was necessary for embryologists to select euploid embryos as far as possible. A machine learning model based on preimplantation genetic testing for aneuploidy results, development dynamics, morphology of blastocysts and female age was built by two-logistic regression analysis. The area under the receiver operating characteristic curve of the model was 0.877. The accuracy rate, precision rate, recall rate, f-score, true negative rate, false positive rate, false negative rate of the model when performed in independent data set were 77.35%, 77.49%, 72.55%, 74.94%, 81.55%, 18.45%, 27.45%, respectively. Besides, the false positive rate of the model on predicting euploid blastocysts was significantly lower than Gardner grade and KIDScore D5. When selected blastocysts by the model, the frozen embryo transfer outcomes improved significantly than the frozen embryo transfer outcomes which selected blastocysts by Gardner selection. The predictive model had potency in selecting euploid blastocysts in in-vitro fertilization treatments without preimplantation genetic testing for aneuploidy technology.

Fetal growth restriction (FGR) is a leading cause of perinatal mortality, yet its molecular mechanisms remain poorly understood. This study integrated bioinformatic analysis with experimental validation to identify key genes involved in FGR pathogenesis. Transcriptome datasets GSE114691 and GSE24129 from the GEO database were analyzed, revealing 5,788 differentially expressed genes (1,450 upregulated, 4,338 downregulated) between FGR and control placental samples. Functional enrichment analysis indicated that downregulated genes were primarily involved in mitochondrial function, aerobic respiration, and amino acid metabolism, while upregulated genes were associated with cell adhesion and histone modification. Weighted gene co-expression network analysis (WGCNA) identified 19 modules, with the darkorange module showing the strongest positive correlation with FGR. LASSO regression further selected eight candidate genes, among which only TRIP10 demonstrated consistent and significant upregulation in the independent validation dataset and exhibited excellent diagnostic performance (AUC = 0.906). Western blot confirmed significant upregulation of TRIP10 protein in FGR placental tissues. Functional assays in JEG-3 trophoblast cells revealed that TRIP10 knockdown significantly enhanced cell migration and invasion, while TRIP10 overexpression suppressed these processes. Collectively, this study identifies TRIP10 as a key gene significantly upregulated in FGR placentas and establishes TRIP10 as a negative regulator of trophoblast migration and invasion, suggesting that TRIP10 dysregulation may contribute to impaired placental development and FGR pathogenesis, representing a promising biomarker and potential therapeutic target.

Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a multisystem endocrine-metabolic disorder that significantly increases the risk of adverse pregnancy outcomes, partly independently of obesity. PMOS patients frequently exhibit a characteristic metabolic-endocrine milieu of insulin resistance, hyperandrogenemia, dyslipidemia, and chronic low-grade inflammation. The physiological insulin resistance of pregnancy, driven by placental hormones, exacerbates these pre-existing disturbances and disrupts endometrial receptivity and placental function. These insults converge on conserved signaling pathways, phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mechanistic target of rapamycin (mTOR), nuclear factor kappa B (NF-κB)/ c-Jun N-terminal kinase (JNK), androgen receptor-mediated mitochondrial dysfunction and ferroptosis, and peroxisome proliferator-activated receptor (PPAR)-regulated lipid dysregulation, and impair trophoblast invasion, spiral artery remodeling, angiogenic balance, and nutrient transport. The resulting mitochondrial oxidative stress and lipotoxic injury contribute to early pregnancy loss, gestational diabetes, hypertensive disorders, preterm birth, and aberrant fetal growth. Concurrently, the dysmetabolic intrauterine environment programs offspring metabolic and reproductive dysfunction through epigenetic and developmental mechanisms. This review synthesizes current evidence linking the maternal metabolic milieu of PMOS to endometrial defects, placental structural and functional alterations, and long-term offspring outcomes. Emerging data on adipose-derived lipid mediators, fatty acid transporters, and inflammatory-metabolic crosstalk at the maternal-uteroplacental interface are examined. Therapeutic strategies such as lifestyle modification, metformin, and bariatric surgery in obese patients are appraised. Although some benefits have been reported, evidence across pregnancy outcomes remains inconsistent, and rigorous preconception trials are needed to establish efficacy. Elucidating how maternal metabolic signals contribute to placental injury and rigorously testing preconception interventions will be essential to refine risk stratification, develop targeted therapies, and interrupt the cycle of metabolic disease transmission in PMOS.

Obesity impairs male reproductive function via oxidative stress and mitochondrial dysfunction. Kisspeptin-10 may regulate redox balance and mitochondrial homeostasis, but its role in obesity-related testicular dysfunction remains unclear. This study aimed to investigate whether Kisspeptin-10 ameliorates obesity-induced testicular oxidative stress and sperm dysfunction, with particular emphasis on mitophagy, autophagy, and apoptosis-related pathways. Forty male Sprague Dawley rats were divided into four groups: Control, Obesity, Kisspeptin-10, and Obesity+Kisspeptin-10. Obesity was induced by feeding rats a high-fat diet (60% kcal from fat) for 12 weeks. At the end of week 12, rats with a Lee index ≥ 300 were considered obese. During the subsequent 4-week treatment period, the Obesity and Obesity+Kisspeptin-10 groups continued to receive the high-fat diet, whereas the Control and Kisspeptin-10 groups continued to receive the standard diet. Kisspeptin-10 (50 nmol/kg, i.p.) was administered to both the Kisspeptin-10 and Obesity+Kisspeptin-10 groups from week 13 to week 16. Oxidative stress markers in the testes, sperm parameters, sperm mitochondrial membrane potential (MMP), and sperm deoxyribonucleic acid (DNA) integrity were assessed; in addition, protein expression levels of markers for mitophagy, autophagy, and apoptosis were evaluated. Obesity impaired antioxidant capacity, sperm quality, mitochondrial function, and reproductive organ weight, while increasing lipid peroxidation and sperm abnormalities. Kisspeptin-10 reduced oxidative stress by lowering malondialdehyde (MDA) and increasing glutathione (GSH) levels, improved sperm motility and concentration, reduced tail abnormal sperm ratio, showed a non-significant tendency toward partial restoration of mitochondrial function, decreased DNA damage, and increased prostate weight. It was also associated with increased expression of the mitophagy-related proteins PTEN-induced putative kinase 1 (PINK1) and Prohibitin 2 (PHB2), and increased Beclin-1 expression, with no significant effects on Parkin, Microtubule-associated protein 1 light chain 3-II (LC3-II), or apoptosis-related proteins. Kisspeptin-10 may alleviate obesity-induced testicular dysfunction, potentially through modulation of redox balance and mitochondrial quality-control mechanisms, including changes in mitophagy- and autophagy-related protein expression. Although these findings suggest that Kisspeptin-10 is a promising candidate for the treatment of obesity-related male infertility, its effects on downstream autophagy-related signaling and apoptosis appear to be limited.

Recurrent implantation failure (RIF) affects approximately 10% of women undergoing embryo transfer. While laser-assisted hatching (LAH) has been proposed to improve outcomes, its efficacy remains uncertain in RIF patients. This study evaluated whether LAH improves outcomes for women with RIF. A systematic review was conducted in PubMed, Web of Science, Scopus, and Embase on January 22, 2025, for randomized controlled trials comparing embryo transfer outcomes following LAH versus controls in RIF. Random-effects meta-analyses generated log odds ratios (LOR), with evidence certainty graded using the Grading of Recommendations Assessment, Development and Evaluation tool. Nine studies involving 2,481 women with RIF were included. Meta-analysis revealed significantly higher rates in the LAH group compared to controls for clinical pregnancy (LOR = 0.643 [0.267, 1.019]; I[2] = 70.62%, very low certainty), ongoing pregnancy (LOR = 0.811 [0.076, 1.546]; I[2] = 63.54%, very low certainty), and live birth rate (LOR = 0.519 [0.127, 0.911]; I[2] = 15.21%, moderate certainty). Additionally, the LAH group had a significantly lower miscarriage rate (LOR = -0.632 [-1.136, -0.127]; I[2] = 0.00%, moderate certainty). No significant differences were observed for implantation rates (LOR = 0.691 [-0.036, 1.417]; I[2] = 87.14%, very low certainty) or multiple pregnancy rates per clinical pregnancy (LOR = 0.166 [-0.269, 0.600]; I[2] = 0.00%, moderate certainty). Our findings suggest that LAH before embryo transfer may improve pregnancy and live birth rates following embryo transfer in women with RIF; however, no significant effect was observed on implantation. Due to observed heterogeneity and the low quality of available studies, high-quality, large-scale randomized controlled trials are needed to confirm these results.

Premature ovarian insufficiency (POI) affects female fertility; however, the mechanisms are not yet fully understood. The aim of this study was to investigate the relationships among bisphenol A (BPA), microRNAs (miRNAs), and the cell cycle-related protein Cyclin D1 (CCND1) in ovarian granulosa cells. Using cell culture and transfection techniques, we analysed the effects of BPA on the proliferation of ovarian granulosa cells. Concurrently, qRT‒PCR and Western blotting were employed to assess miRNA expression levels and CCND1 protein levels, respectively. Our results demonstrated that BPA significantly inhibited the proliferation of ovarian granulosa cells. This inhibition was closely associated with the upregulation of specific miRNA expression and the downregulation of CCND1 protein expression. Furthermore, the overexpression of the identified miRNAs partially reversed the BPA-induced changes in CCND1 expression. These findings reveal a potential role for BPA in POI pathogenesis through the regulation of miRNAs and the cell cycle protein CCND1, providing a novel perspective on the mechanisms underlying this disorder. Future research should further elucidate the specific roles of these miRNAs and CCND1 in ovarian insufficiency and explore their potential application as therapeutic targets.