Journal of Ovarian Research最新文献

Background: Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification.

Methods: With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran's Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted.

Results: Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences.

Conclusion: By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.

Objective: To compare the ovarian reserve and the results of infertility treatment, as well as to investigate the relapse rate in the first year after the assisted reproductive technology (ART) cycle in patients with multiple sclerosis (MS) referred to Royan Institute.

Materials and methods: This retrospective study was carried out to evaluate all women diagnosed with MS and referred to Royan Institute for assessment and treatment of possible infertility between 2011 and 2022. The control group consisted of randomly selected healthy women with tubal factor infertility who were referred for treatment during the same time period and matched in terms of age. A comparison was made between groups in terms of ovarian reserve and infertility treatment outcomes. Additionally, patients with MS who met the criteria were monitored via telephone to evaluate the symptoms, disability and relapse rate both pre- and post-ART.

Results: Over the course of a decade, the database documented a total of 60 cases diagnosed with MS. Upon examination of the records, it was found that in 27 patients only admission was done without any hormonal assessment or infertility treatment cycle and 5 patients proceeded with the intrauterine insemination cycle. Eventually, 28 women with MS underwent the ART cycle and all of them were treated with interferon beta, glatiramer acetate, or some oral disease modifying therapies. No statistically significant difference in terms of the basal levels of luteinizing hormone, follicle-stimulating hormone and anti-Müllerian hormone was found between the MS and control groups (P > 0.05). Two groups were comparable in terms of menstrual status. The study revealed that both groups exhibited similarities in terms of the controlled ovarian stimulation protocol and duration, the dosage of gonadotropin administered, as well as the ovarian response type, clinical pregnancy rate, and live birth rate (P > 0.05). After follow up, only 2 patients (9.5%) reported relapse of symptoms within one year after ART.

Conclusion: The ovarian reserve and ovarian stimulation cycle and pregnancy outcomes following the ART cycle in MS patients were similar to the age-matched control group. The relapse rate of multiple sclerosis did not show a significant increase within a year following the ART cycle.

Context: Oxidative stress (OS) plays a harmful role in female reproduction and fertility. Several studies explored various dietary interventions and antioxidant supplements, such as astaxanthin (AST), to mitigate the adverse effects of OS on female fertility. Ameliorative effects of AST on female fertility and the redox status of reproductive organs have been shown in several animal and clinical studies.

Objectives: The main objective of present systematic review and meta-analysis of both animal and clinical studies was to provide a comprehensive overview of the current evidence on the effects of AST on female fertility and reproductive outcomes. The effect of AST on redox status, inflammatory and apoptotic markers in reproductive organs were included as the secondary outcomes.

Data sources: We systematically searched electronic databases including PubMed, Scopus, and Web of Science, until January 1, 2024, using specified search terms related to AST, female reproductive performance, and infertility, considering the diverse synonyms found in the literature for interventional studies that compared oral AST supplementation with placebo or control in human or animal models.

Data extraction: Two independent reviewers extracted data on study characteristics, outcomes, and risk of bias. We pooled the results using random-effects models and assessed the heterogeneity and quality of evidence. We descriptively reported the data from animal models, as meta-analysis was not possible.

Data analysis: The meta-analysis of clinical trials showed that AST significantly increased the oocyte maturation rate (MD: 8.40, 95% CI: 4.57 to 12.23, I²: 0%) and the total antioxidant capacity levels in the follicular fluid (MD: 0.04, 95% CI: 0.02 to 0.06, I²: 0%). The other ART and pregnancy outcomes and redox status markers did not show statistically significant changes. The animal studies reported ameliorative effects of AST on redox status, inflammation, apoptosis, and ovarian tissue histomorphology.

Conclusion: This systematic review shows that AST supplementation may improve assisted reproductive technology outcomes by enhancing oocyte quality and reducing OS in the reproductive organs. However, the evidence is limited by the heterogeneity, risk of bias, and small sample size of the included studies.

Ovarian cancer (OC) is the most lethal gynecological cancer in the developed world. Most cases are diagnosed at late stage III-IV with a very low 5-year overall survival rate. Several studies revealed an elevated risk of OC in users of hormone treatment (HT) compared with non-users. The extended duration of HT is a statistically significant risk factor. Carbohydrate antigen or cancer antigen 125 (CA-125) remains the best screening tool for OC; however, its value is limited due to low specificity, leading to unnecessary interventions, surgeries, and psychological harm. Additionally, the variability of ultrasound interpretation highlights the urgent need to develop a univariate index with higher sensitivity and specificity for early diagnosis of OC in women under HT. Herein we critically review the limitations of biomarkers for the detection of OC aiming to suggest an accurate and cost-effective diagnostic ratio that eliminates the impact of body mass index, age, HT, smoking, and benign ovarian diseases on measurements. Numerous studies combine biomarkers such as CA-125, human epididymis protein 4, and thymidine kinase 1 into diagnostic algorithms. Data suggest that the expression of estrogen receptors may have diagnostic and prognostic value, as the estrogen receptor α (ERα):estrogen receptor β (ERβ) ratio is significantly higher in OC than in normal tissue due to ERβ downregulation. A high positive correlation between expression of CA-125 and carbohydrate antigen or cancer antigen 72 - 4 (CA72-4) with ERα and ERβ, respectively, poses that a novel ratio CA-125:CA72-4 could be nodal for monitoring post-menopausal women under HT.

Background: Dachsous cadherin related 1 (DCHS1) is one of calcium-dependent adhesion membrane proteins and is mainly involved in the development of mammalian tissues. There is a lack of more detailed research on the biological function of DCHS1 in pan-cancer.

Materials and methods: We evaluated the expression, the prognostic value, the diagnostic value and genomic alterations of DCHS1 by using the databases, including TCGA, UALCAN, HPA, GEPIA2.0 and GSCA. We employed the databases of UCSC, TIMER2.0, TISIDB, GSCA to analyze the association between DCHS1 expression and the immune microenvironment, stemness, TMB, MSI and anticancer drug sensitivity. BioGRID, STRING and GEPIA2.0 were used to perform protein interaction and functional enrichment analysis. Real-time quantitative PCR, CCK8, Transwell assay and Western blot were performed to determine the function of DCHS1 in UCEC.

Results: DCHS1 is differentially expressed in many cancers and its expression is significantly associated with tumor prognosis and diagnosis. DCHS1 expression was significantly correlated with the infiltration of cancer-associated fibroblasts (CAFs), Endothelial cell (ECs), and Hematopoietic stem cell in most cancers. In addition, DCHS1 was significantly associated with sensitivity to many antitumor drugs. Functional enrichment analysis revealed that DCHS1-related proteins were involved in Focal adhesion, Endometrial cancer and Wnt signaling pathway. GSEA results showed that DCHS1 was related to epithelial-mesenchymal transition (EMT) in many cancers. In vitro experiments in UCEC showed that DCHS1 regulated cell proliferation, migration and EMT.

Conclusions: Our findings indicated that DCHS1 might be a novel prognostic and diagnostic biomarker and immunotherapy target, and plays an important role in the proliferation, migration and EMT in UCEC.

Ovarian cancer stands as the deadliest gynecologic malignancy, responsible for nearly 65% of all gynecologic cancer-related deaths. The challenges in early detection and diagnosis, coupled with the widespread intraperitoneal spread of cancer cells and resistance to chemotherapy, contribute significantly to the high mortality rate of this disease. Due to the absence of specific symptoms and the lack of effective screening methods, most ovarian cancer cases are diagnosed at advanced stages. While chemotherapy is a common treatment, it often leads to tumor recurrence, necessitating further interventions. In recent years, antibody-drug conjugates (ADCs) have emerged as a valuable tool in targeted cancer therapy. These complex biotherapeutics combine an antibody that specifically targets tumor specific/associated antigen(s) with a high potency anti-cancer drug through a linker, offering a promising approach for ovarian cancer treatment. The identification of molecular targets in various human tumors has paved the way for the development of targeted therapies, with ADCs being at the forefront of this innovation. By delivering cytotoxic agents directly to tumors and metastatic lesions, ADCs show potential in managing chemo-resistant ovarian cancers. Mucins such as MUC16, MUC13, and MUC1 have shown significantly higher expression in ovarian tumors as compared to normal and/or benign samples, thus have become promising targets for ADC generation. While traditional markers are limited by their elevated levels in non-cancerous conditions, mucins offer a new possibility for targeted treatment in ovarian cancer. This review comprehensively described the potential of mucins for the generation of ADC therapy, highlighting their importance in the quest to improve the outcome of ovarian cancer patients.

Extracellular vesicles (EVs), particles enriched in bioactive molecules like proteins, nucleic acids, and lipids, are crucial mediators of intercellular communication and play key roles in various physiological and pathological processes. EVs have been shown to be involved in ovarian follicular function and to be altered in two prevalent gynecological disorders; polycystic ovarian syndrome (PCOS) and endometriosis.Ovarian follicles are complex microenvironments where folliculogenesis takes place with well-orchestrated interactions between granulosa cells, oocytes, and their surrounding stromal cells. Recent research unveiled the presence of EVs, including exosomes and microvesicles, in the follicular fluid (FFEVs), which constitutes part of the developing oocyte's microenvironment. In the context of PCOS, a multifaceted endocrine, reproductive, and metabolic disorder, studies have explored the dysregulation of these FFEVs and their cargo. Nine PCOS studies were included in this review and two miRNAs were commonly reported in two different studies, miR-379 and miR-200, both known to play a role in female reproduction. Studies have also demonstrated the potential use of EVs as diagnostic tools and treatment options.Endometriosis, another prevalent gynecological disorder characterized by ectopic growth of endometrial-like tissue, has also been linked to aberrant EV signaling. EVs in the peritoneal fluid of women with endometriosis carry molecules that modulate the immune response and promote the establishment and maintenance of endometriosis lesions. EVs derived from endometriosis lesions, serum and peritoneal fluid obtained from patients with endometriosis showed no commonly reported biomolecules between the eleven reviewed studies. Importantly, circulating EVs have been shown to be potential biomarkers, also reflecting the severity of the pathology.Understanding the interplay of EVs within human ovarian follicles may provide valuable insights into the pathophysiology of both PCOS and endometriosis. Targeting EV-mediated communication may open avenues for novel diagnostic and therapeutic approaches for these common gynecological disorders. More research is essential to unravel the mechanisms underlying EV involvement in folliculogenesis and its dysregulation in PCOS and endometriosis, ultimately leading to more effective and personalized interventions.

Background: The clinicopathological parameters such as residual tumor, grade, the International Federation of Gynecology and Obstetrics (FIGO) score are often used to predict the survival of ovarian cancer patients, but the 5-year survival of high grade serous ovarian cancer (HGSOC) still remains around 30%. Hence, the relentless pursuit of enhanced prognostic tools for HGSOC, this study introduces an unprecedented gene expression-based molecular prognostic score (mPS). Derived from a novel 20-gene signature through Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression, the mPS stands out for its predictive prowess.

Results: Validation across diverse datasets, including training and test sets (n = 491 each) and a large HGSOC patient cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium (n = 7542), consistently shows an area-under-curve (AUC) around 0.7 for predicting 5-year overall survival. The mPS's impact on prognosis resonates profoundly, yielding an adjusted hazard-ratio (HR) of 6.1 (95% CI: 3.65-10.3; p < 0.001), overshadowing conventional parameters-FIGO score, residual disease, and age. Molecular insights gleaned from mPS stratification uncover intriguing pathways, with focal-adhesion, Wnt, and Notch signaling upregulated, and antigen processing and presentation downregulated (p < 0.001) in high-risk HGSOC cohorts.

Conclusion: Positioned as a robust prognostic marker, the 20-gene signature-derived mPS emerges as a potential game-changer in clinical settings. Beyond its role in predicting overall survival, its implications extend to guiding alternative therapies, especially targeting Wnt/Notch signaling pathways and immune evasion-a promising avenue for improving outcomes in high-risk HGSOC patients.

Background: Drug-free in vitro activation (IVA) is a new protocol to activate residual dormant follicles for fertility restoration in patients with premature ovarian insufficiency (POI). However, several deficiencies have reduced its clinical efficacy rate. Our previous studies have confirmed that the combination of adipose-derived stem cells (ADSCs) and drug-free IVA can improve the effectiveness of drug-free IVA and restore ovarian function of rats with POI. Increasing evidence has demonstrated that mesenchymal stem cell-derived exosomes have similar therapeutic effects as their source cells. Here, we performed a preclinical study to evaluate the therapeutic effects of ADSCs-derived exosomes (ADSCs-Exos) combined with drug-free IVA in the POI rats and the mechanism in restoring ovarian function.

Results: In vivo, the effects of ADSCs-Exos were comparable to those of ADSCs, and the ADSCs-Exos combined with drug-free IVA was better than ADSCs-Exos alone therapy in promoting follicular development. Moreover, transplantation of ADSCs/ADSCs-Exos lead to up-regulation of BCL-2 expression and down-regulation of the expression of Bax and Cleaved Caspase-3, thus reducing the apoptosis of chemotherapy-induced follicle cells, and further promoting the development of the follicles and rescuing ovarian function in POI-damaged ovary. In vitro, ovarian fragmentation could activate follicular growth and development, and in combination with ADSCs-Exos could prevent the loss of follicles, promote follicular proliferation and inhibit apoptosis.

Conclusions: ADSCs-Exos combined drug-free IVA had remarkable therapeutic effects in restoring ovarian function of POI rats, and markedly promoted follicular development and inhibited apoptosis of ovarian cells in vitro. Our study confirmed that the combination therapy might be a promising and effective treatment for POI.

Background: Polycystic ovary syndrome (PCOS) is the most common ovarian dysfunction. Recent studies showed the effectiveness of licorice on metabolic profiles with inconsistent findings. So, we investigated the effect of licorice on obesity indices, glycemic indices, and lipid profiles in women with PCOS.

Methods: This randomized, double-blind, placebo-controlled trial was performed on 66 overweight/obese women with PCOS. The participants were randomly assigned to receive either 1.5 gr/day licorice extract plus a low-calorie diet (n = 33) or placebo plus a low-calorie diet (n = 33) for 8 weeks. Participants' anthropometric indices and body composition were assessed using standard protocols. Fasting blood sugar (FBS), insulin levels, low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein-cholesterol (HDL-C) were measured using enzymatic kits. The homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA of β-cell function (HOMA-B) were calculated using valid formulas.

Results: Between-group comparisons demonstrated significant differences between the groups in terms of obesity indices (body weight, BMI, and body fat), lipid profiles (TG, TC, LDL-C, and HDL-C), FBS and insulin levels, HOMA-IR, and HOMA-B at the end of the study (P < 0.05). Supplementation with licorice plus a low-calorie diet was also more effective in improving all parameters than a low-calorie diet alone after adjusting for confounders (baseline values, age, weight changes, and physical activity changes) (P < 0.05).

Conclusion: The findings showed that licorice consumption leads to improvements in obesity indices, glucose homeostasis, and lipid profiles compared to placebo. Due to possible limitations of the study, further research is needed to confirm these findings.