The ovarian system comprises vital organs in females and is of great significance for the maintenance of reproductive potential and endocrine stability. Although complex pathogenesis undoubtedly contributes to ovarian aging, increasing attention is being paid to the extensive influence of oxidative stress. However, the role of oxidative stress in ovarian aging is yet to be fully elucidated. Exploring oxidative stress-related processes might be a promising strategy against ovarian aging. In this review, compelling evidence is shown that oxidative stress plays a role in the etiology of ovarian aging and promotes the development of other ovarian aging-related etiologies, including telomere shortening, mitochondrial dysfunction, apoptosis, and inflammation. In addition, some natural antioxidants such as quercetin, resveratrol, and curcumin have a protective role in the ovaries through multiple mechanisms. These findings raise the prospect of oxidative stress modulator-natural antioxidants as therapeutic interventions for delaying ovarian aging.

Background: Exposure to cyclophosphamide (CTX) induces premature ovarian insufficiency (POI). Quercetin is a natural flavonoid that exhibits anti-inflammatory and antioxidant properties, and its antioxidant activity is correlated with POI. However, the mechanism underlying its protective role in CTX-induced ovarian dysfunction is unclear. This study aimed to explore whether quercetin can protect ovarian reserves by activating mitochondrial biogenesis and inhibiting pyroptosis. Methods: Thirty-six female C57BL/6 mice were randomly subdivided into six groups. Except for the control group, all groups were injected with 90 mg/kg CTX to establish a POI model and further treated with coenzyme 10 or various doses of quercetin. The mice were sacrificed 48 h after 10 IU pregnant mare serum gonadotropin was injected four weeks after treatments. We used enzyme-linked immunosorbent assays to detect serum hormone expression and light and transmission electron microscopy to assess ovarian tissue morphology and mitochondria. Additionally, we tested oxidant and antioxidant levels in ovarian tissues and mitochondrial function in granulosa cells (GCs). The expression of mitochondrial biogenesis and pyroptosis-related proteins and mRNA was analyzed using western blotting and RT-qPCR. Results: Quercetin elevated serum anti-Müllerian hormone, estradiol, and progesterone levels, decreased serum follicle-stimulating hormone and luteinizing hormone levels, and alleviated ovarian pathology. It reduced the mitochondrial DNA content and mitochondrial membrane potential. Furthermore, it upregulated ATP levels and the mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mitochondrial transcription factor A, and superoxide dismutase 2. In addition, it suppressed NOD-like receptor pyrin domain containing 3, caspase-1, interleukin-1β, and gasdermin D levels in the GCs of POI mice. Conclusions: Quercetin protected the ovarian reserve from CTX-induced ovarian damage by reversing mitochondrial dysfunction and activating mitochondrial biogenesis via the PGC1-α pathway. Moreover, quercetin may improve ovarian functions by downregulating pyroptosis in the CTX-induced POI model. Thus, quercetin can be considered a potential agent for treating POI.

The aim of the present meta‑analysis was to evaluate the effect of vitamin D supplementation on patients with polycystic ovary syndrome (PCOS). A literature search was performed to identify all of the relevant studies comparing the effect of vitamin D supplementation with placebo in PCOS patients, in the PubMed, Embase and Web of Science databases. All statistical analyses were performed on case‑control studies using Review Manager 5.3 software, provided by the Cochrane Collaboration. A total of 11 studies involving 483 participants were included in the current meta‑analysis. Vitamin D supplementation appeared to lead to an improvement in the levels of total testosterone [weighted mean differences (WMD) = ‑0.10, 95% CI (‑0.18, ‑0.02)], homeostasis model assessment of insulin resistance [WMD = ‑0.44, 95% CI (‑0.86, ‑0.03)], homeostasis model assessment of β‑cell function [WMD = ‑16.65, 95% CI (‑19.49, ‑13.80)], total cholesterol [WMD = ‑11.90, 95% CI (‑15.67, ‑8.13)] and low‑density lipoprotein‑cholesterol [WMD = ‑4.54; 95% CI (‑7.29, ‑1.80)]. The results failed to show a positive effect of vitamin D supplementation on the body mass index, dehydroepiandrosterone sulfate, triglyceride levels or high‑density lipoprotein‑cholesterol. In conclusion, the data from the available randomized controlled trials (RCTs) suggested vitamin D supplementation reduced insulin resistance and hyperandrogenism, as well improving the lipid metabolism of patients with PCOS to an extent. Further high‑quality RCTs from a variety of regions in the world are required to determine the effectiveness of vitamin D supplementation in PCOS patients, and to determine a suitable dose and unit of vitamin D.

Objective: This meta-analysis evaluated the effect of probiotics and synbiotics on insulin resistance in patients with polycystic ovary syndrome (PCOS). Methods: A systematic search was performed to identify all relevant publications listed on the electronic databases (PubMed®, Web of Science, Embase® and China National Knowledge Infrastructure) between inception and 30 October 2020. All statistical analyses were performed on randomized controlled trials (RCTs) using RevMan version 5.3 software provided by the Cochrane Collaboration. Results: A total of 486 patients from seven RCTs were included in the meta-analysis. Probiotic and synbiotic supplementation appeared to improve levels of homeostatic model assessment of insulin resistance (mean difference = –0.37; 95% confidence interval –0.69, –0.05) and serum insulin (standardized mean difference = –0.66; 95% confidence interval –1.19, –0.12). The results failed to show any influence of probiotic and synbiotic supplementation on body mass index, waist circumference, hip circumference and fasting blood sugar. Conclusions: Probiotics and synbiotics appear to have a partially beneficial effect on indices of insulin resistance in patients with PCOS.

Background. Ovarian cancer (OC) is the eighth most common cause of cancer death and the second cause of gynecologic cancer death in women around the world. Ferroptosis, an iron-dependent regulated cell death, plays a vital role in the development of many cancers. Applying expression of ferroptosis-related gene to forecast the cancer progression is helpful for cancer treatment. However, the relationship between ferroptosis-related genes and OC patient prognosis is still vastly unknown, making it still a challenge for developing ferroptosis therapy for OC. Methods. The Cancer Genome Atlas (TCGA) data of OC were obtained and the datasets were randomly divided into training and test datasets. A novel ferroptosis-related gene signature associated with overall survival (OS) was constructed according to the training cohort. The test dataset and ICGC dataset were used to validate this signature. Results. We constructed a model containing nine ferroptosis-related genes, namely, LPCAT3, ACSL3, CRYAB, PTGS2, ALOX12, HSBP1, SLC1A5, SLC7A11, and ZEB1, and predicted the OS of OC in TCGA. At a suitable cutoff, patients were divided into low risk and high risk groups. The OS curves of the two groups of patients had significant differences, and the time-dependent receiver operating characteristics (ROCs) were as high as 0.664, respectively. Then, the test dataset and the ICGC dataset were used to evaluate our model, and the ROCs of test dataset were 0.667 and 0.777, respectively. In addition, functional analysis and correlation analysis showed that immune-related pathways were significantly enriched. Meanwhile, we also integrated with other clinical factors and we found the synthesized clinical factors and ferroptosis-related gene signature improved prognostic accuracy relative to the ferroptosis-related gene signature alone. Conclusion. The ferroptosis-related gene signature could predict the OS of OC patients and improve therapeutic decision-making.

Background: Primary ovarian insufficiency (POI) is a common gynecological disease with serious ramifications including low pregnancy rate and low estrogen symptoms. Traditional Chinese medicine is regarded as an effective treatment for POI. However, the therapeutic mechanism of it is unclear.Methods: In this study, a mouse model of primary ovarian insufficiency was established by intraperitoneal injection of cyclophosphamide (CTX) and He’s Yang Chao Recipe (HSYC) concentrate was used for intragastric administration. Serum hormone levels (Anti-Müllerian Hormone, Estradiol, Progesterone, Luteinizing Hormone and Follicle Stimulating Hormone) and Oxidative Stress (OS) related products, superoxide dismutase (SOD), GSH-Px, and malondialdehyde (MDA) were measured by enzyme-linked immunosorbent assay. Pathological changes in ovarian tissue were evaluated by hematoxylin and eosin staining, and flow cytometry was used to determine reactive oxygen species content and mitochondrial membrane potential levels in granulosa cells. Mitochondrial distribution and morphology were investigated using immunofluorescence staining. The level of mitophagy was evaluated by LC3 immunofluorescence staining and autophagosome counts using electron microscopy. Western blotting and qPCR were used to detect the expression of proteins and genes related to mitophagy and the NLRP3 inflammasome.Results: After HSYC treatment, the ovarian damage was milder than in the CTX group. Compared with the CTX group; SOD, GSH-Px, and the total antioxidant capacity were significantly increased, while MDA and ROS were decreased in the HSYC treatment groups. Furthermore, mitochondrial distribution and membrane potential levels were improved after HSYC treatment compared to the CTX group. After the HSYC treatment, the LC3 fluorescent intensity and autophagosome counts were decreased. Similarly, mitophagy related markers PINK1, Parkin, LC3, and Beclin1 were decreased, while p62 was significantly increased, compared with the CTX groups. The mRNA and protein expression of NLRP3 inflammasome, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β were significantly decreased in the HSYC treatment groups.Conclusion: This is the first study in molecular mechanisms underlying HSYC against granulosa cell injury in POI. HSYC protects ovaries from CTX-induced ovarian damage and oxidative stress. HSYC enhanced ovarian function in mice with primary ovarian insufficiency by inhibiting PINK1-Parkin mitophagy and NLRP3 inflammasome activation.