Unraveling the Clinical Relevance of Ferroptosis-Related Genes in Human Ovarian Aging.

Ferroptosis, a recently discovered form of cell death, has been implicated in various diseases. However, the genetic relationship between ferroptosis and ovarian aging has not been thoroughly investigated through informatics analysis. In this study, we conducted bioinformatics analysis using ovarian aging and ferroptosis datasets to identify potential ferroptosis-related genes using R software. The expression levels of these genes at different ages were analyzed using the GTEx public database. To validate these findings at the genetic level, we performed clinical infertility biopsies. Bioinformatics analysis of a mouse ovary dataset revealed significantly higher expression of Tfrc, Ncoa4, and Slc3a2 in the aging group compared to the young group, while Gpx4 showed the opposite pattern. Consistent results were observed in biopsies from clinically aged infertile patients. This study is the first to identify a ferroptosis-related gene associated with ovarian aging, highlighting its potential as a diagnostic biomarker.

Investigating the Role of Ferroptosis-Related Genes in Ovarian Aging and the Potential for Nutritional Intervention.

With advancing age, women experience irreversible deterioration in the quality of their oocytes, resulting in reduced fertility. To gain a deeper understanding of the influence of ferroptosis-related genes on ovarian aging, we employed a comprehensive approach encompassing spatial transcriptomics, single-cell RNA sequencing, human ovarian pathology, and clinical biopsy. This investigation revealed the intricate interactions between ferroptosis and cellular energy metabolism in aging germ cells, shedding light on the underlying mechanisms. Our study involved 75 patients with ovarian senescence insufficiency, and we utilized multi-histological predictions of ferroptosis-related genes. Following a two-month supplementation period with DHEA, Ubiquinol CoQ10, and Cleo-20 T3, we examined the changes in hub genes. Our results showed that TFRC, NCOA4, and SLC3A2 were significantly reduced and GPX4 was increased in the supplement group, confirming our prediction based on multi-omic analysis. Our hypothesis is that supplementation would enhance the mitochondrial tricarboxylic acid cycle (TCA) or electron transport chain (ETC), resulting in increased levels of the antioxidant enzyme GPX4, reduced lipid peroxide accumulation, and reduced ferroptosis. Overall, our results suggest that supplementation interventions have a notable positive impact on in vitro fertilization (IVF) outcomes in aging cells by improving metal ion and energy metabolism, thereby enhancing oocyte quality in older women.

Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen-thawed embryo transfer cycle: a retrospective cohort study.

BACKGROUND: GnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression. METHODS: The retrospective cohort study included a total of 350 patients undergoing GnRHa-HRT FET cycles. The study group included 179 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 171 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups. RESULTS: Baseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 2.04, 95% CI 1.20-3.47, P = 0.008) and live birth (OR 2.03, 95% CI 1.20-3.45, P = 0.009). When the subgroup of patients with recurrent implantation failure was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 4.55, 95% CI 1.69-12.30, P = 0.003) and live birth (OR 4.30, 95% CI 1.59-11.65, P = 0.004). CONCLUSIONS: Our data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol.

The Translational Role of miRNA in Polycystic Ovary Syndrome: From Bench to Bedside-A Systematic Literature Review.

MicroRNAs (miRNAs) are small, non-coding RNAs that are essential for the regulation of post-transcriptional gene expression during tissue development and differentiation. They are involved in the regulation of manifold metabolic and hormonal processes and, within the female reproductive tract, in oocyte maturation and folliculogenesis. Altered miRNA levels have been observed in oncological and inflammatory diseases, diabetes or polycystic ovary syndrome (PCOS). Therefore, miRNAs are proving to be promising potential biomarkers. In women with PCOS, circulating miRNAs can be obtained from whole blood, serum, plasma, urine, and follicular fluid. Our systematic review summarizes data from 2010-2021 on miRNA expression in granulosa and theca cells; the relationship between miRNAs, hormonal changes, glucose and lipid metabolism in women with PCOS; and the potential role of altered miRNAs in fertility (oocyte quality) in PCOS. Furthermore, we discuss miRNAs as a potential therapeutic target in PCOS and as a diagnostic marker for PCOS.

Expression status and prognostic significance of mitochondrial dynamics OPA3 in human ovarian cancer.

Early diagnosis of ovarian cancer and the discovery of prognostic markers can significantly improve survival and reduce mortality. OPA3 protein exists in a structure called mitochondria, which is the energy production center of cells, but its molecular and biological functions in ovarian cancer are still unclear. Here, the expression of OPA3 mRNA in ovarian cancer was estimated using TCGA, Oncomine, TIMER databases. We found that functional OPA3 activation caused by mutations and profound deletions predicted poor prognosis in OV patients. OPA3 was highly expressed in both OV tissues and cells compared to normal ovarian tissues/cells. High OPA3 expression is associated with poorer overall survival (OS). The association between OPA3 and immune infiltration of ovarian cancer was assessed by TIMER and CIBERSORT algorithms. OPA3 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of OV cell lines revealed that OPA3 inactivation was associated with increased sensitivity to PFI-1, and WZ4003. Therefore, we investigated the clinical application of OPA3 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of ovarian cancer.

Abnormal Uterine Bleeding in Perimenopausal Women: The Role of Hysteroscopy and Its Impact on Quality of Life and Sexuality.

Abnormal uterine bleeding (AUB) is a frequent symptom in perimenopausal women. It is defined as uterine bleeding in which the duration, frequency, or amount of bleeding is considered excessive and negatively affects the woman's quality of life (QoL) and psychological well-being. In cases of structural uterine pathology, hysterectomy (usually performed via a minimally invasive approach) offers definitive symptom relief and is associated with long-lasting improvement of QoL and sexuality. However, over the past 30 years, uterus-preserving treatments have been introduced as alternatives to hysterectomy. Hysteroscopic polypectomy, myomectomy, or endometrial resection/endometrial ablation are minimally invasive techniques that can be used as an alternative to hysterectomy to treat AUB due to benign conditions. Although associated with high patient satisfaction and short-term improvement in their QoL, hysteroscopic treatments do not eliminate the risk of AUB recurrence or the need for further intervention. Therefore, considering the impact of different treatment options on QoL and sexuality during preoperative shared decision making could help identify the most appropriate and personalized treatment options for perimenopausal women suffering from AUB.

Identification of Novel Biomarkers and Candidate Drug in Ovarian Cancer.

This paper investigates the expression of the CREB1 gene in ovarian cancer (OV) by deeply excavating the gene information in the multiple databases and the mechanism thereof. In short, we found that the expression of the CREB1 gene in ovarian cancer tissue was significantly higher than that of normal ovarian tissue. Kaplan-Meier survival analysis showed that the overall survival was significantly shorter in patients with high expression of the CREB1 gene than those in patients with low expression of the CREB1 gene, and the prognosis of patients with low expression of the CREB1 gene was better. The CREB1 gene may play a role in the occurrence and development of ovarian cancer by regulating the process of protein. Based on differentially expressed genes, 20 small-molecule drugs that potentially target CREB1 with abnormal expression in OV were obtained from the CMap database. Among these compounds, we found that naloxone has the greatest therapeutic value for OV. The high expression of the CREB1 gene may be an indicator of poor prognosis in ovarian cancer patients. Targeting CREB1 may be a potential tool for the diagnosis and treatment of OV.

Serum testosterone levels are positively associated with serum anti-mullerian hormone levels in infertile women.

Anti-Mullerian hormone (AMH) and testosterone (T) both play distinct roles in the early stages of folliculogenesis. However, the relationship between serum T and AMH levels is poorly understood. This study aimed to investigate the association between serum T and AMH levels in infertile women. A total of 1935 infertile women aged 20-46 years were included in the cross-sectional study and divided into four quartile groups (Q1 to Q4) based on serum T levels. Compared to the subjects in the highest T quartile (Q4), those in the lowest T quartile (Q1) showed significantly lower AMH levels. After adjustment for age, body weight, body mass index and FSH, increasing T quartile categories were associated with higher AMH levels. Binary logistic regression analyses revealed that the odds for the risk of diminished ovarian reserve (DOR) were 11.44-fold higher in Q1 than in Q4 and the odds for the risk of excess ovarian reserve (EOR) were 10.41-fold higher in Q4 than in Q1. Our data show that serum T levels are positively associated with serum AMH levels and suggest that androgen insufficiency may be a potential risk factor for DOR; androgen excess may lead to EOR in infertile women.

Factors that infertile couples from mainland China may take into consideration for cross-border reproductive care - A cross-sectional questionnaire study.

OBJECTIVE: Cross-border reproductive care (CBRC) has become popular in the world, including mainland China. We designed a questionnaire and aimed to determine the main factors that infertile couples from mainland China may consider for CBRC. MATERIALS AND METHODS: In this cross-sectional questionnaire-based study, we retrospectively analyzed the data from questionnaires collected at the Reproductive Center of Beijing BaoDao Obstetrics and Gynecology Hospital from January 2018 to June 2018. The questionnaire contained 38 items that belonged to six different categories (environment and equipment, service quality, patient safety, medical quality, information acquisition channel and overseas medical services). The item scores for each factor were calculated and then weighted using principal component analysis. RESULTS: A total of 297 infertile couples were identified. Most of the infertile women were aged 31-35 years, were married 1-3 years, and had a bachelor's degree. In the weighted factor analysis, "clean outpatient clinic and medical equipment" had the highest weight in the dimension of environment and equipment. The item with the highest weight in the dimension of service quality was "wait time for examination". In the dimension of patient safety, "health education on medication and surgery by counselors" had the highest weight. The item with the highest weight in the dimension of medical quality was "fee charged for ART treatment". The items with the three highest weights in the dimension of information acquisition channel were "other (seminar, exhibition, dissertation …)", "introduction from friends and relatives", and "telephone inquiry". In the dimension of overseas medical services, the two items with the highest weights were "cultural similarities" and "language similarities". CONCLUSION: For CBRC, infertile couples from mainland China may take following significant factors into consideration: a high success rate and inexpensive treatment, cultural and linguistic familiarity, high-quality service and short wait time.

PD­L1/PD­1 blockade in breast cancer: The immunotherapy era (Review).

Breast cancer is a common malignant tumor in women. Triple­negative breast cancer (TNBC) is highly invasive with a high rate of metastasis and poor prognosis. Programmed death ligand 1 (PD­L1) plays an important role in mediating the escape of tumor cells from immune surveillance. There have been significant advances in understanding the biology of TNBC. This review presents a detailed discourse on the available data on the expression of PD­L1 in breast cancer and preliminary clinical outcome of PD­L1/PD­1 inhibitors in breast cancer patients. Early clinical trials involving PD­L1/PD­1 inhibitors have exhibited efficacy in tumor response and/or disease control in patients with refractory metastatic breast cancer, particularly TNBC. Furthermore, the mechanisms and factors that influence the immunoediting process are summarized and their functions in detail are analyzed.

Gynecological cancers and urinary dysfunction: a comparison between endometrial cancer and other gynecological malignancies.

The purpose of this paper is to provide a narrative overview of the available literature about voiding dysfunction in women with gynecological cancer before and after surgical, chemo- and radiotherapy treatments. Radical surgery, radiotherapy, and chemotherapy may cause lower urinary tract dysfunction such as stress and urge urinary incontinence, and voiding difficulties. However, nerve-sparing radical hysterectomy may be a valid surgical approach in order to reduce bladder innervation impairment and maintain normal urinary function. Also, newer radiotherapy techniques significantly reduce the number of adverse effects, including bladder dysfunction. Pelvic floor muscle physiotherapy and training with biofeedback and urethral bulking agents represent some additional therapies that can be used in oncologically treated patients with urinary symptoms in order to improve a significant aspect of their quality of life. Considering the important impact on the patients' quality of life, a full urogynecological evaluation should be considered as an important part of oncological treatment and follow-up.

Multi-Omics Analysis Identifying Key Biomarkers in Ovarian Cancer.

Ovarian cancer is one of the most common malignant tumors. Here, we aimed to study the expression and function of the CREB1 gene in ovarian cancer via the bioinformatic analyses of multiple databases. Previously, the prognosis of ovarian cancer was based on single-factor or single-gene studies. In this study, different bioinformatics tools (such as TCGA, GEPIA, UALCAN, MEXPRESS, and Metascape) have been used to assess the expression and prognostic value of the CREB1 gene. We used the Reactome and cBioPortal databases to identify and analyze CREB1 mutations, copy number changes, expression changes, and protein-protein interactions. By analyzing data on the CREB1 differential expression in ovarian cancer tissues and normal tissues from 12 studies collected from the "Human Protein Atlas" database, we found a significantly higher expression of CREB1 in normal ovarian tissues. Using this database, we collected information on the expression of 25 different CREB-related proteins, including TP53, AKT1, and AKT3. The enrichment of these factors depended on tumor metabolism, invasion, proliferation, and survival. Individualized tumors based on gene therapy related to prognosis have become a new possibility. In summary, we established a new type of prognostic gene profile for ovarian cancer using the tools of bioinformatics.

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5-10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5-15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30-90% and final pregnancy rates of 13-88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of "toxic" follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the "hypothalamus-pituitary-ovary" axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

Dual-trigger improves the outcomes of in vitro fertilization cycles in older patients with diminished ovarian reserve: A retrospective cohort study.

BACKGROUND: Dual-trigger for final oocyte maturation has been applied on the women with poor ovarian response or diminished ovarian reserve. However, the results were controversial. The Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) stratification is a set of newly established criteria for low prognosis patients. The aim of this study was to examine the effectiveness of dual-trigger for final oocyte maturation on the in vitro fertilization (IVF) outcomes of patients who fulfill the POSEIDON group 4 criteria. METHODS: This retrospective cohort study investigated 384 cycles fulfilling the POSEIDON group 4 criteria. The patients underwent IVF treatment using the gonadotropin-releasing hormone (GnRH) antagonist protocol. The study group contained 194 cycles that received dual-trigger (human chorionic gonadotropin [hCG] plus GnRH-agonist) for final oocyte maturation. The control group included 114 cycles where final oocyte maturation was performed with only hCG. Baseline characteristics and cycle parameters, as well as IVF outcomes of both groups were compared. RESULTS: Baseline characteristics were similar between the dual trigger group and the control group. In terms of IVF outcomes, the dual trigger group demonstrated significantly higher number of retrieved oocytes, metaphase II oocytes, fertilized oocytes, day-3 embryos, and top-quality day-3 embryos. A statistically significant improvement in clinical pregnancy rate and live birth rate was also observed in the dual trigger group. CONCLUSIONS: Our data suggests that dual trigger for final oocyte maturation might improve clinical pregnancy rates and live birth rates of IVF cycles in patients fulfilling the POSEIDON group 4 criteria.

Laser irradiation pretreatment improves endometrial preparation of frozen-thawed embryo transfer in recurrent implantation failure patients.

Recurrent implantation failure (RIF) remains a clinical dilemma. Helium-Neon (He-Ne) laser irradiation has recently become more popular under certain clinical conditions. Given the unique therapeutic effects, we were interested in determining whether pretreatment with He-Ne laser irradiation prior to frozen-thawed embryo transfer (FET) would improve the microcirculation and cause the release of growth factors and cytokines, thus improving endometrial receptivity and the clinical pregnancy rates. Patients chose for themselves whether to proceed with (n = 29) or without (n = 31) pretreatment with He-Ne laser irradiation prior to FET. The clinical pregnancy rate (37.9%) and implantation rate (20.3%) were higher in the laser-treatment group than in the control group (35.5% and 15.9%, respectively, p = .844 and .518, respectively). The live birth rate was higher in the laser-treatment group (27.6% vs. 25.8%, respectively, p = .876) and the miscarriage rate was lower in the laser-treatment group (18.2% and 27.3%, respectively, p = .611). No side effects or complications from laser irradiation were encountered in patients who received the laser treatment. We concluded that pretreatment with He-Ne laser prior to FET may be an alternative choice for RIF-affected women; however, additional well-designed prospective studies are necessary to determine the precise clinical value of this treatment.

Quality of life and fertility preservation counseling for women with gynecological cancer: an integrated psychological and clinical perspective.

Purpose: Relational and sexual problems are frequent in patients with a diagnosis of gynecological cancer, because this disease has a strong negative impact on female identity and sexuality. Psychological and sexual functioning is affected by inauspicious diagnosis. Furthermore, therapies may compromise reproductive function. The aim of this study is to propose a general overview on the impact of gynecological cancer on quality of life and psychological and sexual functioning, as well as on the importance of adequate counseling related to fertility preservation techniques.Materials and methods: We provide a narrative overview of the recent literature about quality of life and fertility preservation counselling in women with gynecological cancer.Results and conclusions: According to recent studies, 75% of women between 18 and 45 years with a diagnosis of cancer wish to have children. When cancer affects the reproductive system, the psychological distress is even stronger because there is a loss of menstrual function and fertility. Currently, fertility preservation techniques in women with gynecological cancer are beneficial and lead to an improvement in the quality of life.

Disruption of mitochondrial homeostasis with artemisinin unravels anti-angiogenesis effects via auto-paracrine mechanisms.

Rationale: Tumor angiogenesis promotes tumor development, progression, growth, and metastasis. Metronomic chemotherapy involves the frequent administration of low-dose chemotherapeutic agents to block angiogenic activity and reduce side effects. Methods: MDA-MB-231 cells were treated with various concentrations of artemisinin (ART) and vinorelbine (NVB) and the cytotoxic effects of ART/NVB were determined using the CCK-8 assay. Mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) and mass were assessed using MitoSOX, TMRE and MitoTracker green staining. Western blot analysis was used to quantify the expression of autophagy-related proteins. Herein, by using bioinformatics analysis and experimental verification, we identified CREB as a master in MDA-MB-231 cells. Results: We found that artemisinin (ART), which exhibits anti-angiogenic and anti-cancer effects via mitochondrial regulation, synergized with vinorelbine (NVB) to inhibit MDA-MB-231 cell proliferation. ART and NVB cooperated to regulate mitochondrial biogenesis. CREB acted as a crucial regulator of PGC1α and VEGF, which played critical roles in NVB-dependent growth factor depletion. Moreover, CREB suppression significantly reversed mitochondrial dysfunction following ART/NVB co-treatment. In addition, combination treatment with ART and NVB significantly suppressed tumor growth in a nude mouse xenograft model, with downregulated CREB and PGC1α expression levels observed in tumor biopsies, in agreement with our in vitro and ex vivo data. Conclusions: These findings support the hypothesis that ART affects cancer and endothelial cells by targeting the auto-paracrine effects of VEGF to suppress mitochondrial biogenesis, angiogenesis, and migration between cancer cells and endothelial cells.

MicroRNA in Ovarian Cancer: Biology, Pathogenesis, and Therapeutic Opportunities.

Ovarian cancer comprises one of the three major malignant tumor types in the female reproductive system. The mortality rate of this cancer is the highest among all gynecological tumors, with ovarian cancer metastasis constituting an important cause of death. Therefore, markers for disease prediction and prognosis are highly desirable for early diagnosis as well as for helping optimize and personalize treatment. Recently, microRNAs (miRNAs), which consist of short-sequence RNAs that do not encode a protein, have emerged as new biomarkers in the clinical diagnosis and treatment of ovarian cancer. By pairing with bases specific to the target messenger RNA (mRNA), miRNAs cause degradation of the target mRNA or inhibit its translation, thereby regulating various cellular processes including cell proliferation and adhesion. Increasing numbers of studies have shown that miRNA expression abnormality plays an important role in the development of ovarian cancer. In this review, we discuss the mechanisms of miRNA action, current research regarding their role in the suppression or promotion of ovarian cancer, and their use as markers for diagnosis of prognosis or as therapeutic targets for this disease. Finally, we present future perspectives regarding the clinical management of ovarian cancer and the role for miRNAs therein.