Search Results (83)

Granulosa cells (GCs), an element of the ovarian follicle, are crucial for oocyte maturation, folliculogenesis, and steroidogenesis. Granulosa cells play a crucial role in fertilization by providing metabolic and hormonal support to the oocyte, maintaining its quality and regulating its meiotic arrest. Oocyte quality and fertilization efficiency depend on the proper activity of GCs, especially their mutual communication, providing metabolic support and protecting against oxidative stress. When interrupted, they may take part in the pathogenesis of polycystic ovary syndrome, premature ovarian failure, primary ovarian insufficiency, and diminished ovarian reserve. GCs are enclosed in the antrum where they communicate with surrounding cells, create a dynamic microenvironment, and regulate hormone biosynthesis. To analyze molecular mechanisms regulating endogenous signaling, it is important to consider the dynamic transcriptomic response of porcine GCs during in vitro culturing over 48, 96, and 144 h. Transcriptomic analysis revealed a variable and dynamic transcriptional upregulation of genes associated with cellular response to endogenous and external stimuli, chemical compound metabolism, vascular development, and GCs migration. Also, proven by Gene Ontology (GO) enrichment analysis, the following terms were highlighted: “cellular response to chemical stimulus” and “cellular response to organic substance”. Specific genes, such as HSD3B1, POSTN, LOX, SERPINB2, ITGB3, ANKRD1, SLC1A1, and SFRP2, exhibited significant expression changes, suggesting extensive GCs self-regulation and metabolism changes. Further analysis indicates improvements in cellular response to a cytokine stimulus, growth factor response, hormone response, enzyme-linked receptor protein signaling, and positive regulation of cell migration. These findings suggest interweaving of regulatory mechanisms underlying intercellular communication in GCs during in vitro culturing, despite the lack of signals from the native ovarian environment. Further investigating interplays of detecting pathways will provide a more comprehensive understanding and even insights into the potential clinical use of the knowledge about the role of GCs in folliculogenesis, oocyte maturation and ovulation. Full article

Cyclophosphamide (CTX)-induced premature ovarian failure (POF) is characterized by disruption of the follicular microenvironment, granulosa-cell loss, endocrine imbalance, and oxidative-inflammatory injury. Here, we evaluated two multi-bioactive formulations developed to enhance ovarian stress resilience: a base formulation containing coenzyme Q10, calcium L-5-methyltetrahydrofolate, and Vitex agnus-castus extract (Base), and a urolithin A-enriched formulation (Base + U). Using a CTX-induced female C57BL/6 mouse model, we integrated phenotypic, histological, endocrine, oxidative-inflammatory, and transcriptional readouts to assess efficacy and mechanistic consistency. CTX markedly reduced ovarian index, disrupted estrous cyclicity, shifted follicle development toward atresia, increased granulosa-cell apoptosis, and caused endocrine dysregulation, including decreased anti-Müllerian hormone and estradiol and increased GnRH, FSH, and LH. CoQ10, Base, and Base + U each partially alleviated these abnormalities, improving ovarian index and coat condition, showing a trend toward improved follicular distribution, and normalizing hormone profiles. CTX also induced an ovarian oxidative-inflammatory shift, as reflected by decreased GSH-Px, increased MDA, and elevated IL-1β, IL-6, and TNF-α, all of which were attenuated by the interventions. Notably, Base + U more effectively reduced lipid peroxidation and TNF-α than Base alone. Consistently, ovarian transcripts related to follicle responsiveness and steroid regulation, including Fshr, Esr1, and Hsd17b2, were restored, whereas hypothalamic qRT-PCR analysis did not reveal robust transcriptional alterations within the intervention window. These findings suggest that the urolithin A-enhanced formulation partially alleviates CTX-induced ovarian dysfunction by suppressing oxidative-inflammatory stress and preserving granulosa-cell and follicle fate. Full article

Premature ovarian insufficiency (POI) impairs fertility and health in reproductive-age women, with autoimmune factors contributing to 4–30% of cases. To investigate immune dysregulation in POI, we developed two mouse models using pZP3 induction: regular immune (RE-POI) and enhanced immune (EN-POI) cycles. The EN-POI model exhibited stable, irreversible ovarian dysfunction, including disrupted estrous cycles, hormonal changes (elevated FSH, decreased AMH, and estradiol), follicular depletion, and infertility. Immune profiling demonstrated consistent T-lymphocyte imbalance across both RE-POI and EN-POI model groups, characterized by expanded splenic CD4⁺ T cells, diminished regulatory T cells, elevated systemic inflammatory cytokines, and ovarian fibrosis. Proteomic comparison between the control and EN-POI groups identified 198 differentially expressed proteins, mainly enriched in immune and inflammatory pathways. Based on these differential proteins, subsequent network analysis further identified six key hub proteins, namely Mmp9, Isg15, Ikbke, Siglec1, Pf4, and Cdkn1b. This study establishes a stable autoimmune POI model, elucidates T-cell imbalance with cytokine storm and fibrosis, and identifies key molecules linking immune abnormalities to ovarian failure, offering new insights into POI research. Full article

The ovaries are crucial reproductive organs that regulate the menstrual cycle and support pregnancy through the production of steroid hormones. They are highly susceptible to various environmental pollutants, which can lead to ovarian disorders. Luteal phase defect (LPD) and premature ovarian failure (POF) are common ovarian disorders in women. In this study, we integrate network toxicology with molecular docking and molecular dynamics simulations to elucidate the toxicological mechanisms of Benzo(a)pyrene (BaP), a widespread endocrine disruptor, in LPD and POF. Through systematic data mining of the GeneCards and OMIM databases, we identified 1336 targets associated with LPD and 2066 targets related to POF, as well as 220 BaP targets. Venn diagram analysis revealed 36 potential targets for BaP-induced LPD and 43 for BaP-induced POF. GO and KEGG enrichment analyses suggest that BaP-induced LPD and POF may share toxicological mechanisms. PPI network visualization indicated that EGFR, ESR1, and STAT3 are critical common targets for BaP-induced LPD and POF. Molecular docking and molecular dynamics simulations revealed that BaP exhibits strong binding affinity with all three core genes. In KGN cells modeling LPD and POF phenotypes, cellular experiments confirmed that BaP downregulated EGFR and ESR1 expression while upregulating STAT3 expression, thereby supporting the reliability of these targets in BaP-induced ovarian dysfunction. These findings provide insights into BaP-induced reproductive toxicity and offer a foundation for targeted clinical interventions to mitigate the effects of environmental pollutants on women’s reproductive health. Full article

Background/Objectives: Hodgkin lymphoma (HL) primarily affects individuals of reproductive age, making gonadal dysfunction after chemotherapy a critical survivorship concern. While fertility preservation options including gamete and gonadal tissue cryopreservation are available before treatment, evidence-based counseling requires regimen-specific risk estimates accounting for patient age and sex. Therefore, a meta-analysis was performed to assess presumed infertility in HL patients, stratified by chemotherapy regimen, age, and sex. Methods: This systematic review and meta-analysis, conducted within the FertiTOX project, included studies published between 2000 and February 2024. Eligible studies reported gonadal function outcomes ≥ 1 year after chemotherapy, excluding patients who received pelvic radiotherapy or stem cell transplantation, or had recurrent disease. Presumed infertility was defined by surrogate markers, including amenorrhea, premature ovarian failure, or abnormal hormonal levels in women, and azoospermia, oligozoospermia, or abnormal hormonal levels in men. Results: Of 2376 screened studies, 50 were included (meta-analysis: 43 studies; 5564 female and 1631 male patients). Overall presumed infertility prevalence was 21% in women (95% CI: 0.14–0.29) and 45% in men (95% CI: 0.29–0.62). The highest prevalence occurred after BEACOPP (women 38%; men 81%), while ABVD was associated with the lowest (6% each in women and men). Childhood/adolescent HL treatment resulted in lower prevalence in women (8%) but remained high in men (67%). Conclusions: Fertility risk depends on regimen, age, and sex, requiring tailored counseling. For female children/adolescents and all patients receiving ABVD, post-treatment fertility evaluation and treatment may suffice. However, pre-treatment fertility preservation is strongly recommended for male adolescents and patients receiving other regimens. Full article

Background: Ovarian granulosa cells (GCs) play a pivotal role in folliculogenesis, and their dysfunction is central to disorders such as polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). MicroRNAs (miRNAs) have emerged as crucial post-transcriptional regulators of GC homeostasis. Method: This review synthesizes current evidence by systematically analyzing relevant studies, integrating data from in vitro GC models, animal experiments, human cell lines, and clinical samples to elucidate the specific mechanisms by which miRNAs regulate GCs. Results: miRNAs precisely modulate GC proliferation, apoptosis, steroidogenesis, and oxidative stress responses by targeting key signaling pathways (e.g., PI3K/AKT/mTOR, TGF-β/SMAD) and functional genes (e.g., TP53, CYP19A1). Exosomal miRNAs serve as vital mediators of communication within the follicular microenvironment. To date, nearly 200 miRNAs have been associated with PCOS. Conclusions: miRNAs constitute a decisive regulatory network governing GC fate, offering promising therapeutic targets for PCOS and POF. However, significant challenges remain, primarily miRNA pleiotropy and the lack of follicle-specific delivery systems. Future clinical translation requires rigorous validation in human-relevant models. Full article

Background/Objectives: Increasing evidence points to hypoxia and inflammation as two major causes of compromised ovarian function. Increased oxidative stress under hypoxic conditions can damage cellular components, leading to the dysfunction and apoptosis of granulosa cells (GCs). The inflammatory response induced by hypoxia may further impair the function of the ovaries and contribute to the development of premature ovarian insufficiency (POI). In animal models of premature ovarian failure, research has demonstrated that the transplantation of mesenchymal stem cells (MSCs) can enhance reproductive outcomes, increase the number of functioning ovarian follicles, and restore estradiol production. However, the specific mechanisms underlying the observed positive results are not well understood. Methods: The present study provides a comparative analysis of how MSCs influence human GC function under inflammatory and hypoxic conditions, using three different experimental approaches: direct co-culture, indirect co-culture with transwell cell culture inserts, and treatment with MSC-derived conditioned medium (MSCcm). Results: Inflammation significantly suppressed GC estradiol secretion and increased apoptosis. MSCs increased estradiol secretion in normal and hypoxic culture conditions when co-cultured directly with GCs. Our results also showed that, under inflammation, MSCs tended to decrease GC proliferation and that hypoxia alone did not have an effect on GC estradiol secretion or proliferation. Conclusions: The study emphasizes the dual nature of MSCs, which largely determines their effects on other cell types, and the need for the condition-specific optimization of MSC therapies for ovarian regeneration. Full article

Gynecological endocrine disorders, including polycystic ovary syndrome (PCOS), endometriosis as well as primary ovarian insufficiency (POI)/premature ovarian failure (POF), significantly impact women’s reproductive health and overall well-being. While these conditions are primarily driven by disturbances of the hypothalamic–pituitary–gonadal axis, yet growing evidence indicates that oxidative stress plays a crucial role in their development and progression. The combined impact of hormonal imbalance and impaired redox homeostasis contributes to infertility, metabolic dysfunction, and other co-morbidities, such as increased cardiovascular risk. Given that women may live for many years with these chronic conditions, investigating their pathophysiology and associated complications is of particular importance. This narrative review summarizes current knowledge on PCOS, endometriosis, and POI/PMF, emphasizing the contribution of oxidative stress and also highlights the association between these disorders and cardiovascular risk. Furthermore, the utility of rat models is presented to support the advancement of preventive and therapeutic research. Full article

Premature ovarian failure (POF) is characterized by oxidative stress, cellular senescence, and impaired steroidogenesis, yet current therapies remain limited in effectiveness. Thymol, a natural monoterpene, exhibits antioxidant and anti-inflammatory properties. Network pharmacology and molecular docking identified multiple potential targets, notably the Janus kinase 1 (JAK1)-signal transducer and activator of transcription 3 (STAT3) pathway. In tert-butyl hydroperoxide (t-BHP)-induced human granulosa-like tumor cells (n = 3), 40 μg/mL thymol increased cell viability by approximately 45%, restored superoxide dismutase, catalase, and glutathione peroxidase activities to nearly twice those of the model group, and reduced reactive oxygen species accumulation by about 35% (p < 0.05). It also decreased senescence markers p53, p21, and p16 by 40–60% and inhibited JAK1–STAT3 phosphorylation (n = 3, p < 0.05). In aged pregnant mice (n = 4 per group), thymol increased viable fetus numbers by about 40%, elevated serum estradiol and progesterone levels to 1.6–1.8-fold of aged controls, and downregulated ovarian aging markers (p < 0.05). Collectively, these findings indicate that thymol mitigates oxidative stress-induced ovarian aging by modulating JAK1–STAT3 signaling and restoring steroidogenic function, supporting its potential as a natural candidate for delaying ovarian senescence. Full article

Sea cucumber ovum are high-value compounds that remain after the processing of sea cucumbers, and their optimal utilization has long posed a challenge. In this research, we systematically examined the therapeutic effects of sea cucumber ovum hydrolysate (SCH) on premature ovarian failure (POF) and its underlying mechanism. We utilized a model of ICR mice induced with 100 mg/kg cyclophosphamide (CP) to evaluate the therapeutic influence of SCH on ovarian performance. The ovarian and uterine indices were significantly decreased in the POF group compared to the control group; however, these trends were notably reversed following SCH intervention. The therapeutic effects of SCH were positively reflected by the alterations induced by CP in levels of estradiol (E2), follicle-stimulating hormone (FSH), testosterone (T), luteinizing hormone (LH), and anti-Müllerian hormone (AMH). Regarding oxidative stress, SCH was found to enhance superoxide dismutase (SOD) activity and decrease malondialdehyde (MDA) levels, while also alleviating apoptosis in ovarian granulosa cells. Metabolomics analysis revealed hypoxanthine, mannitol, neocnidilide, tryptophan, palmitoleic acid, and protoporphyrinogen IX as potential biomarkers. In conclusion, SCH effectively improves POF induced by CP, thereby reinforcing the potential application of SCH in the domain of functional foods. Full article

Infertility remains a major global health concern, with diminished ovarian reserve (DOR), premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and impaired endometrial receptivity representing key contributors to poor assisted reproductive technology (ART) outcomes. Platelet-rich plasma (PRP), an autologous blood-derived concentrate enriched with growth factors and cytokines, has emerged as a promising regenerative therapy with angiogenic, anti-apoptotic, and proliferative properties. In reproductive medicine, intraovarian PRP has been evaluated for its potential to restore ovarian function in women with DOR and POI, improve oocyte competence and embryo euploidy, and promote ovulation in PCOS. Similarly, intrauterine PRP infusion or subendometrial zone injections has shown encouraging results in women with recurrent implantation failure and thin endometrium, enhancing endometrial thickness, receptivity, and implantation potential. Evidence from preclinical animal models and early clinical studies suggests multi-level mechanisms of action, including modulation of endocrine pathways, reduction in oxidative stress, activation of dormant follicles, and improvement of endometrial angiogenesis and receptivity. Despite these promising findings, results remain inconsistent due to heterogeneity in PRP preparation protocols, administration routes, timing, and study designs. Even though robust randomized controlled trials with standardized methodologies are needed to determine the efficacy and long-term reproductive outcomes of PRP in infertility treatment and anovulation in PCOS, PRP represents a novel and potentially transformative adjunct in reproductive endocrinology. Full article

Cisplatin remains a cornerstone chemotherapeutic agent; however, its off-target gonadotoxicity poses a significant risk for premature ovarian failure (POF) and infertility in young women. Strategies to preserve ovarian function during chemotherapy are critically needed. To investigate the protective effects of krill oil supplementation against cisplatin-induced ovarian damage in a rat model, with a focus on oxidative stress, inflammation, follicular dynamics, and stromal fibrosis. Twenty-one adult female Wistar albino rats were randomized into three groups: control, cisplatin-treated, and cisplatin + krill oil-treated. Ovarian toxicity was induced via intraperitoneal injection of cisplatin (2.5 mg/kg, twice weekly for four weeks). Krill oil (4 mL/kg/day) was administered orally during the same period. Ovarian histopathology, follicle counts (primordial, primary, secondary, tertiary), stromal fibrosis, and biochemical markers, including plasma anti-Müllerian hormone (AMH), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and ovarian levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Toll-like receptor 4 (TLR4), TNF-α, NOD-like receptor family pyrin domain containing 3 (NLRP3), and IL-1β were evaluated. Cisplatin significantly reduced primordial, primary, secondary, and tertiary follicle counts while increasing stromal fibrosis (p < 0.001). Krill oil co-treatment notably ameliorated follicular depletion—improving follicle counts by 38.16%, 54.74%, 62.5%, 40.43%, respectively—and reduced fibrosis (p = 0.017). Biochemically, cisplatin decreased AMH levels and Nrf2 expression while elevating MDA, TNF-α, TLR4, NLRP3, and IL-1β levels (p < 0.001). Krill oil supplementation restored AMH (p = 0.002) and Nrf2 (p = 0.003) levels, while reducing MDA (p = 0.009), NLRP3 (p < 0.001), ovarian IL-1β (p = 0.005), plasma IL-1β (p < 0.001), TLR4 (p = 0.001), plasma TNF-α (p = 0.001), and ovarian TNF-α (p < 0.001), compared to the cisplatin group. Krill oil exerts significant antioxidant and anti-inflammatory effects, offering a promising strategy to mitigate cisplatin-induced ovarian damage and preserve fertility in young cancer patients. Full article

The number of female astronauts participating in space missions is increasing, and concerns about the impact of spaceflight on reproductive health have emerged. Space radiation and microgravity pose potential threats to ovarian reserve and uterine function, but data on human female reproductive health in space remain scarce. This review explores current evidence from both real and simulated space conditions, including animal studies and ground-based cosmic radiation models. The relevant literature on cosmic radiation, fertility preservation strategies, and gynecological risk management in spaceflight was analyzed to provide a comprehensive synthesis. Space radiation might damage ovarian follicles and impair folliculogenesis, potentially leading to premature ovarian failure and microgravity might alter endocrine function. While human data are lacking, murine and in vitro model studies suggest significant reproductive risks. Embryo/oocyte and ovarian tissue cryopreservation are currently the most viable fertility preservation strategies. Shielding technologies, radioprotective agents, and hormonal modulation may offer adjunct protection. In conclusions, fertility counseling and preservation should become integral to pre-mission planning for female astronauts of reproductive age. A personalized approach, accounting for individual reproductive goals, age and mission duration, is essential. Further research is urgently needed to understand the reproductive effects of deep space travel and to develop targeted protective strategies. Full article

Calcium ions (Ca²⁺) play a vital role in many biological processes. Transmembrane and coiled-coil domain 1 (TMCO1) has been characterized as an endoplasmic reticulum (ER) transmembrane protein in recent years. It keeps the cytoplasm and ER’s Ca²⁺ homeostasis stable by acting as a novel calcium channel. Studies from different laboratories have revealed that the mutation or deficiency of TMCO1 is closely correlated with several diseases, including cerebro-facio-thoracic dysplasia (CFTD), glaucoma, premature ovarian failure (POF), osteoporosis, and cancer. Here, we review the characteristics of TMCO1 and its involvement in related diseases, which may provide useful information for developing therapeutic strategies for these diseases, as well as promote further research on this protein. Full article

In this study, we evaluated the protective effects of combined melatonin and vitamin D3 treatment on ovarian reserve and tissue architecture in a cyclophosphamide-induced premature ovarian failure (POF) rat model. Forty-nine adult female rats were randomly assigned to seven groups, including intact control (group 1), single-agent control (groups 2 and 3), POF (group 4), and POF + treatment (groups 5, 6, and 7) groups. Cyclophosphamide exposure led to elevated FSH and LH levels, reduced estradiol and progesterone levels, extensive follicular atresia, stromal fibrosis, and the marked degeneration of the ovarian ultrastructure. Additionally, the expression levels of PTEN, FOXO3a, and AMH were significantly downregulated, while caspase-3 and TNF-α immunoreactivities were increased. Notably, co-treatment with melatonin and vitamin D3 preserved primordial and growing follicle populations, restored hormonal balance, reduced stromal fibrosis, and attenuated apoptosis and inflammation markers. These findings highlight the potential of combined melatonin and vitamin D3 therapy as a fertility-preserving strategy that functions by mitigating chemotherapy-induced ovarian injury through multi-pathway modulation. Full article