Treatment Of Polycystic Ovary Syndrome Research Articles

Low-Calorie Ketogenic Diet: Potential Application in the Treatment of Polycystic Ovary Syndrome in Adolescents.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Hyperandrogenism, hyperinsulinism and insulin resistance (IR) are the main drivers of clinical, metabolic and reproductive phenotypes of PCOS. In adolescence, the cornerstones of PCOS treatment are lifestyle and dietary interventions. In particular, the quality and quantity of carbohydrates introduced with the diet play a crucial role in the benefits of diet on PCOS. Recently, the ketogenic diet (KD) has attracted significant interest for the treatment of IR and for the control of carbohydrate metabolism, which has proven to be beneficial for several dysmetabolic conditions, including PCOS. The goal of the KD is to induce a fasting-like metabolism with production of chetonic bodies. Ketosis is a good regulator of calorie intake and mimics the starvation effect in the body, leading to body weight control and consequent metabolism. Additionally, during ketogenesis, insulin receptor sensitivity is also promoted. We proposed a broad overview of the available literature regarding KD indications and considered its metabolic benefits useful for improving PCOS management. The reported data support that a low-calorie ketogenic diet (LCKD) plays a positive role as a regulator of control weight, IR, glucose and lipid homeostasis and hormonal profile. Unfortunately, the evidence concerning the benefits of the very LCKD in adolescents with PCOS and excessive body weight is still numerically scarce. Further studies are necessary to understand whether these effects are due to weight loss or to the nutritional characteristics of this diet. Considering the long-term consequences of PCOS, it is crucial to detect the prospects of nutritional interventions to protect fertility, starting in adolescence.

Metformin combined with spironolactone vs. metformin alone in polycystic ovary syndrome: a meta-analysis.

Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer, combined with spironolactone, an antiandrogen medication, may exert complementary effects on PCOS. We therefore performed a meta-analysis of trials in which metformin combined with spironolactone was applied to treat PCOS to evaluate the efficacy and safety of the combination therapy. We retrieved the PubMed, Embase, Scopus, Cochrane Library, CNKI, CBM, Wangfang, and VIP databases for literatures published from their inception to December 16, 2022 on the effects of metformin combined with spironolactone in the treatment of PCOS. Inclusion criteria according to P.I.C.O.S criteria were: PCOS patients, metformin combined with spironolactone interventions, metformin alone control group, and randomized controlled trials with the following outcome data: body mass index (BMI), hirsutism score, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), fasting blood glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and side effects including nausea, vomiting, diarrhea and drug withdrawal. Our results revealed that metformin combined with spironolactone significantly reduced BMI and TT, but that it exerted no significant effects on hirsutism score, or on FSH or LH concentrations. Combined treatment also resulted in a significant diminution in FBG and insulin resistance using the HOMA-IR when the interventional time was greater than 6 months. In addition, the combination did not have a higher occurrence of adverse reactions than metformin alone. Compared with metformin alone, metformin combined with spironolactone therapy may be more effective in reducing BMI and serum androgen levels, but the combination showed no significant effect on the hirsutism score or gonadotropin hormone levels, and was not associated with an elevation in side-effects. Moreover, when the treatment course was greater than 6 months, combination therapy reduced FBG and improved insulin resistance more effectively than metformin alone. However, more research is needed to determine the most effective course of treatment. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022355515.

The effects of low-level laser therapy on polycystic ovarian syndrome in rats: three different dosages.

The main objective of this in vivo study was to investigate the effect of different low-level laser therapy (LLLT) doses on polycystic ovary syndrome (PCOS). In the present experimental study, a single dosage of estradiol valerate (EV) was administered to induce PCOS in female rats. After administration of the EV for induction of PCOS, rats were divided into 5 groups (n = 8/group): C group (animals that were not exposed to any form of procedure), PC group (no treatment following EV induction), L1 group (1 J/cm2 LLLT treatment following EV induction), L2 group (2 J/cm2 LLLT treatment following EV induction), L3 group (6 J/cm2 LLLT treatment following EV induction). The results indicated that no significant difference was found in the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone (P4) between the C and L2 groups (p < 0.05). Although the serum levels of testosterone (T) were significantly higher in the C group compared with other groups (p < 0.05), the L2 group was determined to be the closest to the C group. Additionally, the LH, FSH, and T receptor level of the L2 group was closest to the C group. In conclusion, a 2 J/cm2 dosage of LLLT (L2 group) can be considered the most potentially effective treatment of PCOS in the rat. However, more studies are needed to determine the optimal dose of LLLT for the treatment of PCOS.

CangFu Daotan decoction improves polycystic ovarian syndrome by downregulating FOXK1

Objective: Polycystic ovarian syndrome (PCOS) is a prevalent gynecologic disorder, often associated with abnormal follicular development. Cangfu Daotan decoction (CFD) is a traditional Chinese medicine formula that is effective in alleviating PCOS clinically, but the specific mechanism remains unclear. Forkhead box K1 (FOXK1) is associated with cellular function. This study aimed to explore the effects of CFD and FOXK1 on PCOS.Methods: High-fat diet and letrozole were combined to establish PCOS rat models. Next, primary GCs were extracted from those PCOS rats. Then, GC cells were transfected with si-FOXK1 or oe-FOXK1. CFD-contain serum was prepared, and experiments were conducted to investigate the regulation of FOXK1 by CFD.Results: FOXK1 was highly expressed in GCs of PCOS rats. Further investigation revealed that FOXK1 overexpression resulted in inhibition of proliferation and DNA synthesis, along with promotion of apoptosis and autophagy in GCs. Additionally, it was found that FOXK1 promoted the expressions of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway-related proteins. Interestingly, treatment with CFD reversed all the effects of FOXK1 overexpression in GCs. Conclusion: This study demonstrated that CFD exerted a protective role in PCOS by inhibiting FOXK1, which provided a research basis for the application of CFD in PCOS, and suggested that FOXK1 is a novel therapeutic target in PCOS treatment.

PAK2/beta-catenin/c-Myc/PKM2 signal transduction suppresses ovarian granulosa cell apoptosis in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) exhibits the highest morbidity among endocrine diseases in women ranging from age 18 to 44. However, its pathogenesis remains unclear. The imbalance between systemic and ovarian oxidative stress (OS) is a key characteristic of PCOS, and accumulating evidence indicates that the antioxidative protein nuclear factor erythroid-2-related factor 2 (Nrf2) is implicated in cell apoptosis and inflammation caused by OS. The activated kinase 2 (PAK2)/-catenin/c-Myc/pyruvate kinase M2 (PKM2) axis is a newly identified signaling pathway that may regulate Nrf2 expression and thereby influence OS. In this study, we sought to identify PAK2 expression and function in PCOS cells. PAK2 and downstream PKM2 expression in KGN cells and tissues were detected by microarray and qPCR. Cell viability was determined using CCK-8 and colony formation assays (CFAs). Apoptosis was examined by flow cytometry. qPCR and ELISA were used to examine cell inflammation. Oxidant and OS-related enzymes were examined by ELISA. We found that PAK2 and PKM2 expression levels were reduced in KGN cells and PCOS ovarian cortex tissues. PAK2 overexpression activated β-catenin/c-Myc/PKM2 while PAK2 silencing deactivated it. PAK2 overexpression was reduced, whereas PAK2 silencing promoted, KGN cell proliferation and colony formation. Cell apoptosis and inflammation were also induced by PAK2 overexpression but were alleviated by its silencing. Furthermore, increased peroxidation product levels decreased antioxidative protein activities, and deactivated antioxidative Nrf2/HO-1 pathway were detected in PAK2-overexpressing KGN cells, whereas these effects were counteracted in PAK2 silenced cells. Our data suggest that PAK2 and its associated β-catenin/c-Myc/PKM2 inhibited cell viability and induced apoptosis and inflammation by triggering OS by deactivating the Nrf2/HO-1 pathway, suggesting the potential of PAK2 as a therapeutic PCOS treatment target.

Metabolic characteristics of obese patients with polycystic ovarian syndrome: a meta-analysis

Objective Though recent studies have pointed out different manifestations between obese and nonobese patients with polycystic ovarian syndrome (PCOS), there is no clear evidence to confirm this viewpoint. Therefore, the metabolic characteristics of obese and nonobese patients with PCOS were systematically compared through meta-analysis in this study. Methods Data were searched from PubMed, Web of Science, Embase, Cochrane Library, CNKI, and Wanfang databases. Articles on obese and nonobese patients with PCOS published from database inception to January 2022 were included. Meta-analysis was performed using Stata 16.0 statistical software. Results A total of 739 articles were initially retrieved, and ultimately 14 studies were involved in the meta-analysis. Specifically, there were 801 patients in the observation group (obese patients with PCOS) and 925 patients in the control group (nonobese patients with PCOS). Compared with the control group, the observation group had significantly lower levels of sex hormone-binding globulin (SHBG), high-density lipoprotein (HDL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and higher levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL). Nevertheless, there were no significant differences between the two groups in systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, and testosterone. Conclusion Compared with nonobese patients with PCOS, obese patients with PCOS have worse blood lipid parameters and lower levels of LH and FSH. Also, there are significant differences in metabolic characteristics between the two groups of patients. Most importantly, our findings provide guidance for the clinical diagnosis and treatment of PCOS.

Extracellular Vesicle-Derived Cord Blood Plasma and Photobiomodulation Therapy Down-Regulated Caspase 3, LC3 and Beclin 1 Markers in the PCOS Oocyte: An In Vitro Study.

Introduction: Polycystic ovary syndrome (PCOS) is the communal endocrine illness in women and the most common cause of infertility due to lack of ovulation. The exact cause of PCOS is still unknown. Affected women may have difficulty getting pregnant due to ovulation problems. Various methods have not been effective in the treatment of PCOS due to the positive role of photobiomodulation therapy (PBMT) and extracellular vesicles (ECV) obtained from cord blood plasma in the treatment of various diseases. The aim of this study was to study the role of ECV and PBMT in maturation and improvement of infertility in women with PCOS. Methods: In this research, a number of oocytes were obtained after ovarian stimulation from women who had been referred to the hospital for infertility treatment after obtaining personal consent, and they were divided into three groups: control, ECV and PBMT. Subsequently, in vitro maturation (IVM) was assessed, then some oocytes were cultured with a routine medium and others were treated with ECV and PBMT. Real-time PCR was used to evaluate BCL-2, BAX, caspase-3, and autophagy gene (ATG5, LC3, Beclin 1). Oocyte glutathione (GSH), oxidised gluathione (GSSG), and reactive oxygen species (ROS) were measured. Results: The metaphase II (MII) oocyte ratio formation significantly increased in the ECV and PBMT groups (P<0.05). The expression of the BCL-2 gene was significantly up-regulated in the ECV and PBMT groups, but the expression of BAX and caspase-3 significantly decreased (P<0.05). The expression of the ATG5, LC3, BECLIN-2 genes significantly decreased in the ECV and PBMT groups (P<0.05). ROS, GSSG decreased in ECV and PBMT groups but GSH increased (P<0.05). Conclusion: The use of ECV and PBMT can increase the rate of fertilization and maturation of an oocyte and cause a decrease in apoptosis, autophagy, and ROS in a PCOS oocyte.

Alpha Lipoic Acid Efficacy in PCOS Treatment: What Is the Truth?

Polycystic ovary syndrome (PCOS) is among the most common female endocrinopathies, affecting about 4-25% of women of reproductive age. Women affected by PCOS have an increased risk of developing metabolic syndrome, type 2 diabetes mellitus, cardiovascular diseases, and endometrial cancer. Given the pivotal role of insulin resistance (IR) in the pathogenesis of PCOS, in the last years, many insulin-sensitizing factors have been proposed for PCOS treatment. The first insulin sensitizer recommended by evidence-based guidelines for the assessment and treatment of PCOS was metformin, but the burden of side effects is responsible for treatment discontinuation in many patients. Inositols have insulin-mimetic properties and contribute to decreasing postprandial blood glucose, acting by different pathways. ALA is a natural amphipathic compound with a very strong anti-inflammatory and antioxidant effect and a very noteworthy role in the improvement of insulin metabolic pathway. Given the multiple effects of ALA, a therapeutic strategy based on the synergy between inositols and ALA has been recently proposed by many groups with the aim of improving insulin resistance, reducing androgen levels, and ameliorating reproductive outcomes in PCOS patients. The purpose of this study is to review the existing literature and to evaluate the existing data showing the efficacy and the limitation of a treatment strategy based on this promising molecule. ALA is a valid therapeutic strategy applicable in the treatment of PCOS patients: Its multiple actions, including antinflammatory, antioxidant, and insulin-sensitizing, may be of utmost importance in the treatment of a very complex syndrome. Specifically, the combination of MYO plus ALA creates a synergistic effect that improves insulin resistance in PCOS patients, especially in obese/overweight patients with T2DM familiarity. Moreover, ALA treatment also exerts beneficial effects on endocrine patterns, especially if combined with MYO, improving menstrual regularity and ovulation rhythm. The purpose of our study is to review the existing literature and to evaluate the data showing the efficacy and the limitations of a treatment strategy based on this promising molecule.

FABP5 inhibitor SBFI-26 regulates FOXM1 expression and Wnt signaling pathway in ovarian granulosa cell of patients with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy among females of reproductive age. Due to its unclear etiopathogenesis, it is of vital significance to take a deeper understanding of molecular mechanisms underlying PCOS. Quantitative real-time PCR (RT-qPCR) and western blot were applied for detection of gene expression and protein expression individually. Cell Counting Kit-8 (CCK-8) and colony formation assays were used for the evaluation of cell proliferation while Caspase-3/9 activity was measured for the assessment of cell apoptosis. We found that FOXM1 was overexpressed in ovarian granulosa cell (OGC) of patients with PCOS. Functionally, upregulation of FOXM1 promotes the proliferative ability of PCOS-OGC cells. As for mechanism, FOXM1 exerts its functions in PCOS-OGC cell through activation of the Wnt signaling pathway. More importantly, a novel FABP5 inhibitor, SBFI-26, was verified to downregulate the expression of FOXM1 to impede the proliferation of PCOS-OGC cells. In addition, SBFI-26 inactivates Wnt signaling pathway in PCOS-OGC cells. FABP5 inhibitor SBFI-26 regulates FOXM1 expression and Wnt signaling pathway in OGC of patients with PCOS, which might provide a new perspective into PCOS treatment.

Rubus chingii Hu relieved the polycystic ovary syndrome with enhanced insulin sensitivity through inhibiting TXNIP/NLRP3 inflammasome signaling

Background Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in gynecology with severe metabolic abnormalities. Therefore, identifying effective treatments and drugs for PCOS is important. We aimed to investigate effect of the traditional Chinese medicine (TCM) Rubus chingii Hu (R. chingii) on ovarian function and insulin resistance (IR) of PCOS rat models, and to explore the underlying mechanisms Methods A PCOS rat model was established by subcutaneous injection of dehydroepiandrosterone (DHEA) solution for 20 days. PCOS rats were randomly divided into a control group (CON), model group (MOD), metformin group (MET), TCM R. chingii group (RCG), and RCG + Ad-TXNIP groups. After 28 days of treatment, the samples were collected for subsequent experiments. Results R. chingii treatment alleviated hormone imbalance and IR while improving ovarian pathology in the PCOS model. R. chingi inhibited the activation of the thioredoxin-interacting protein (TXNIP)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in the ovarian tissue of PCOS rats. Furthermore, TXNIP overexpression hindered the protective effect of R. chingii intervention in PCOS rats, as evidenced by the increase of homeostasis model assessment of insulin resistance (HOMA-IR), luteinizing hormone (LH), testosterone (T), C-reactive protein (CRP) levels, and atretic follicles. Conclusion R. chingii intervention improved ovarian polycystic development by suppressing the TXNIP/NLRP3 inflammasome, which may be an effective treatment for PCOS.

Effect of Curcumin towards Metabolic Disturbance Parameters in Patient with PCOS: A Systematic Review and Meta-Analysis of Clinical and Preclinical Randomized Controlled Trials

Objective: Polycystic Ovarian Syndrome (PCOS) is a gynecologic and endocrine disorder with metabolic disturbances and infertility as the most common long-term consequences. Curcumin comes up as one of the alternative herbal remedies in PCOS treatment options. This study aimed to investigate the therapeutic effect of curcumin on metabolic disturbance parameters in PCOS patients and PCOS-modeled rats. Method: A systematic search of eligible studies was done using PubMed, Google Scholar, EBSCO-Host, and ProQuest according to the PRISMA 2009 guideline. We further assessed for risk of bias using SYRCLE’s risk of bias tool for preclinical studies and The Cochrane risk of bias assessment tool for the clinical studies. We used Review Manager (version 5.4) with random effect model to obtain a pooled mean difference with 95% CIs. Results: Five preclinical studies and three clinical studies were selected and pooled. The significant decrease in the level of Fasting Plasma Glucose (FPG), Fasting Insulin (FI), lipid profile, and Homeostatic Model of Insulin Resistance (HOMA-IR) value, and a significant increase in Quantitative Insulin-Sensitivity Check Index (QUICKI) value found in preclinical studies. The result for clinical studies showed a significantly decreased HOMA-IR values (SMD=-0.36, p=0.001), FPG level (SMD=-3.32, p=0.0001), Serum Insulin level (SMD=-1.47, p=0.002), and increased QUICKI value (SMD=0.01, p=0.006). Conclusion: Curcumin offers a substantial effect on metabolic disturbance parameters in PCOS patients and could be an alternative promising treatment for PCOS patients in the future.

Exploring the therapeutic potential of phytoconstituents in treatment of polycystic ovarian syndrome: An study

Polycystic ovary syndrome (PCOS) is a prevalent condition among women of reproductive age, characterised by hyperinsulinemia, hyperandrogenism, menstrual irregularities, and long-term metabolic disturbances. At present, the conventional approach to managing PCOS involves implementing lifestyle changes, administering pharmacological interventions, and performing surgical procedures. Nevertheless, these therapies do not exhibit promising outcomes for the comprehensive eradication of it. Consequently, natural sources have been regarded as a highly esteemed means of medication and aid in enhancing and regulating PCOS conditions. The current study was designed to conduct a screening of various phytoconstituents with a focus on their potential interaction with androgenic targets (1E3G &amp; 2PIV), estrogenic receptors (1U3S), and insulin receptors (3EKK). An assessment was conducted on a compilation of phytoconstituents documented in PCOS with the aim of forecasting drug-like characteristics through an methodology. Thirteen phytoconstituents were selected for the study, namely apigenin, berberine, erdosteine, colchicine, diacerin, mogroside V, naringenin, quercetin, resveratrol, rhamnocitrin, silibinin, tanshinone IIA, and troxerutin. The phytoconstituents were subjected to molecular docking studies using AutoDock Vina to investigate their binding interactions with proposed targets. Additionally, in silico prediction of the toxicity of these phytoconstituents was conducted. The phytoconstituents that were chosen exhibited favourable pharmacokinetic characteristics for oral bioavailability and drug-likeness, as determined by Lipinski's rule of five. As per the docking results, it was observed that four compounds, namely Apigenin, Tanshinone IIA, Naringenin, and Berberine, exhibited significant binding interactions with the allosteric site residues of the targets. The identified phytoconstituents that underwent screening exhibit potential as prospective candidates for subsequent development. However, it is imperative to validate the findings through in vitro and in vivo investigations.

Circular RNA as a Novel Regulator and Promising Biomarker in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive disorder that causes low fertility in females. Despite its detrimental effects on women's health, care for PCOS has been impeded by its undefined pathogenesis. Thus, there is an urgent need to explore novel biomarkers and therapeutic targets for the diagnosis and treatment of PCOS. Circular RNAs (circRNAs) are a class of noncoding RNAs with covalently closed cyclic structures, present in high abundance, and show development-stage specific expression patterns. Recent studies have demonstrated that circRNAs participate in PCOS progression by modulating various biological functions, including cell proliferation, apoptosis, and steroidogenesis. In addition, circRNAs are widely present in the follicular fluid of women with PCOS, indicating their potential as diagnostic biomarkers and therapeutic targets for PCOS. This review provides the current knowledge of circRNAs in PCOS, including their regulatory functions and molecular mechanisms, and explores their potential as diagnostic biomarkers and therapeutic targets.

Myoinositol Versus Metformin in the Treatment of Polycystic Ovarian Syndrome: A Systematic Review.

Polycystic ovarian syndrome (PCOS) is a widespread, complex, and multi-system hormonal disorder that occurs in women of reproductive age. The wide variation in practice in the treatment of PCOS is a direct consequence of the lack of sufficient evidence on alternative treatment strategies, as well as a poor understanding of the disorder itself. The aim of our systematic reviewwas to assess the therapeutic advantages and adverse effects of metformin (MET), a standard treatment modality, with myoinositol (MI), a recent substitute that may be used alone or in combination with other remedies to treat PCOS. A literature search was done using PubMed Central, PubMed, Medline, Cochrane, Science Direct, and Google Scholar. Studies were limited to those published in English between 2012 and 2022 that focused on the management of PCOS with both MET and MI. The systematic review complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Using standard quality assessment tools, two reviewers independently assessed the content of the incorporated studies. Three meta-analyses, eight randomized controlled trials (RCTs), and one non-randomized non-controlled trial (NN-RCT) were deemed eligible. Following extensive analysis, we found that MET and MI are comparable in their effects on clinical, hormonal, and biochemical profiles. MI, however, had a better safety profile and tolerance due to minimal side effects compared to MET. These results demonstrate the potential role of MI as a novel asset in the armamentarium in the management of PCOS.

The Potential Utility of Tirzepatide for the Management of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age. The metabolic dysfunction associated with PCOS increases the probability of developing type 2 diabetes (T2D), endometrial cancer, and cardiovascular disease. Research has shown that the metabolic features of PCOS may be improved by weight loss following treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists. Tirzepatide is a dual GLP-GIP (gastric inhibitory polypeptide) receptor agonist that shares a very similar mechanism of action with GLP-1R agonists, and it is hypothesized that it may be a potential contender in the treatment of PCOS. The success of GLP-1R agonists is usually hindered by their adverse gastrointestinal effects, leading to reduced compliance. The mechanism of action of Tirzepatide partly addresses this issue, as its dual receptor affinity may reduce the intensity of gastrointestinal symptoms. Tirzepatide has been licensed for the treatment of type 2 diabetes and given the metabolic issues and obesity that accompanies PCOS, it may be of value in its management for those PCOS patients who are obese with metabolic syndrome, although it may not benefit those who are of normal weight. This study reviews the current therapies for the treatment of PCOS and evaluates the potential use of Tirzepatide to address the symptoms of PCOS, including reproductive dysfunction, obesity, and insulin resistance.

The Role of Circadian Rhythms in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS), as a most common metabolic disrupted disease, has several main symptoms, including ovarian insufficiency, hyperandrogenism, insulin resistance, etc., which may lead to female infertility. Many studies on the processes of PCOS have been done throughout the years, but unfortunately, the pathophysiology of PCOS is still not fully figured out. The circadian rhythm is the metronomic adjustment of the organisms to the external environment at all levels, from the molecular to the individual. It is revealed in multiple studies that there is a clear association between the progression of PCOS and the disturbance of circadian rhythms. Numerous studies have demonstrated that circadian rhythms can influence the development of PCOS by altering the Wnt/β-catenin, GPCR/cAMP/PKA, PI3K/AKT, and MAPK signaling pathways of the hypothalamic-pituitary-ovarian/hypothalamic-pituitary-adrenal axis, which result in abnormal hormone expression, receptor resistance, and metabolic disorders. The circadian rhythm misalignment may contribute to the formation and development of PCOS through the expression of certain genes that control the canonical signaling pathway. It is foreseeable that more preventive and targeted treatment for PCOS is the hot zone of clinical research in the future. This article aimed to review the state regarding the link between circadian rhythm disorder and PCOS, focus on the pathophysiology of PCOS, explore the pathways of circadian rhythm in the process of PCOS, and seek to offer a clear direction and practical approach for the prevention and treatment of PCOS.

Hyperandrogenism.

Hyperandrogenism is a common condition encountered by pediatric and adolescent physicians. Most girls with hyperandrogenism represent physiological pubertal variation; pathology may be present in a substantial minority. Systematic evaluation is essential to avoid unnecessary work-up in physiological causes while not missing pathological causes. Polycystic ovarian syndrome (PCOS), unexplained, persistent hyperandrogenism of ovarian origin, is the most common form in adolescent girls. The high prevalence of physiological peripubertal hirsutism, anovulation, and polycystic ovarian morphology results in mislabeling many girls as having the polycystic ovarian syndrome, a disorder with lifelong implications. The use of strict criteria of age-specific anovulation, hyperandrogenism, and duration is essential to reduce their stigmatization. The exclusion of secondary causes by screening tests (cortisol, thyroid profile, prolactin, and 17OHP) is essential before undertaking treatment for PCOS. Lifestyle measures, estrogen-progesterone preparations, antiandrogens, and metformin are the cornerstone of managing the disorder.

Changes in the microbiome in women with polycystic ovary syndrome

The gut microbiome (GM) is actively studied in terms of its impact on the development of oncological pathology, immune diseases, and metabolic disorders. Women with polycystic ovary syndrome (PCOS) have an imbalance of GM, which indirectly affects the intestinal mucosal barrier. Compared with non-obese patients and a healthy population, obese individuals with PCOS have increased numbers of Enterobacteriaceae, decreased numbers of Lactobacillus and Bifidobacterium, and changes in GM are associated with inflammation and insulin resistance.Fecal microbiota transplantation is a new method of treating inflammatory bowel diseases. GM regulation to improve the metabolism of PCOS may be one of the potential options for the future treatment of PCOS, but the specific mechanism of its action remains to be investigated.There is increasing evidence that probiotics, prebiotics, and synbiotics are effective treatment options for PCOS patients. Studies show that probiotics can restore the diversity of the GM of mice with PCOS, reduce the disruption of the flora and improve the reproductive function of the mice.The altered microbiome of the lower genital tract in PCOS can cause changes that are related to hormone levels during the menstrual cycle. Studies show that the vaginal microbiome of women with PCOS differs from healthy women due to the domination of Mycoplasma, Prevotella, Gardnerella, Actinomyces, Enterococcus, and Atopobium.The level of female sex hormones is associated with the composition of the oral cavity microbiome, which is associated with such oral pathology as periodontal disease. A study of periodontal pathogens and their prevalence in women with PCOS found that healthy women had higher levels of Peptostreptococcus and a higher percentage of women infected with Treponema denticola.New views on the management of women with PCOS indicate the importance of considering microbiome changes and open up new therapeutic opportunities. Research in this area is still ongoing, and additional studies are needed to clarify the microbial composition in women with PCOS.

Effect of Canagliflozin Alone and in Combination with Metformin on Ovarian Histology of a Polycystic Ovary Syndrome Rat Model

&lt;p&gt;&lt;strong&gt;Background and Objective:&lt;/strong&gt; Canagliflozin reduces insulin resistance in diabetics and is hypothesized to produce a beneficial effect in polycystic ovarian syndrome (PCOS). Therefore, this study is planned to compare the effects of canagliflozin and metformin alone and in combination on ovarian histology of rat models with letrozole-induced PCOS.&lt;/p&gt;&#x0D; &lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; It was a randomized experimental study on Sprague Dawley rats. A total of N = 40 female rats were divided randomly into six groups (A-F). With the exception of normal control group A, rats were given letrozole 1 mg/kg daily for 21 days till PCOS was induced. Group B was disease control, while rats in groups C-F were administered canagliflozin (10 mg/kg), metformin (100 mg/kg), a combination of canagliflozin (10 mg/kg) with metformin (100 mg/kg), and combination of canagliflozin (5 mg/kg) with metformin (50 mg/kg), respectively. Animals were sacrificed on the 48th day. Ovaries and uterus were removed, weighed, and processed for further histopathological analysis.&lt;/p&gt;&#x0D; &lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; All treatment groups showed significant improvement in ovarian histology. The number of primary and secondary follicles and cystic follicles was significantly lower (p &amp;lt; 0.001) in all treatment groups as compared to the disease control group.&lt;/p&gt;&#x0D; &lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; Canagliflozin is effective for the treatment of PCOS and augments the effect of metformin in a rat model.&lt;/p&gt;

P-476 Metformin ameliorated testosterone-induced ferroptosis via inhibiting ferritinophagy in trophoblasts of polycystic ovary syndrome (PCOS) placentas

Abstract Study question Does trophoblasts of PCOS patients with aberrant iron metabolism, and how does metformin ameliorate androgen-induced ferroptosis in trophoblasts in vivo and in vitro? Summary answer Metformin ameliorates placental development and attenuates spontaneous miscarriage rate in early gestation by inhibiting ferritinophagy in trophoblasts of PCOS patients with hyperandrogenism. What is known already PCOS is a common reproductive endocrine disease in women of reproductive age, and a large proportion of patients present with hyperandrogenism. Studies have found that the incidences of spontaneous miscarriage and adverse pregnancy outcomes in PCOS patients are higher than those in healthy controls, which placental dysfunction is an important factor. It is related to mitochondrial dysfunction, oxidative stress and metabolic disorders. Ferroptosis is an iron-dependent and phospholipid peroxidation-mediated cell death. Studies have shown that iron ions participate in a variety of biochemical reactions in humans, and its abnormal metabolism may lead to some diseases especially in the reproductive system. Study design, size, duration Villi at gestational weeks of 6-8 were collected from 18 healthy controls and 18 women with PCOS. Human trophoblast stem cells (hTSCs) were isolated from fresh villi (6-8 weeks, n = 3) and cultured with testosterone, ferroptosis or autophagy inhibitors, metformin, or NCOA4 small interfering RNA. A dihydrotestosterone (DHT)-induced PCOS C57BL/6 mouse model was treated with or without metformin (3 months before mating) (n = 20 per group). Mouse placentas were obtained at embryonic days 11.5 (n = 50 per group). Participants/materials, setting, methods The levels of iron ions and lipid peroxidation were measured by PGSK staining, BODIPYC11 staining and MDA assay kit. The expressions of ferroptosis-related genes and proteins were assessed by qPCR, western blot and immunofluorescence. The binding of androgen receptor (AR) and NCOA4 to the putative androgen response element (ARE) was examined by ChIP, EMSA and luciferase assay. The influence of metformin on ferritinophagy in placentas of PCOS mice was confirmed by western blot and immunofluorescence. Main results and the role of chance The levels of iron ions and lipid peroxidation in villi at gestational weeks of 6-8 were higher in PCOS patients than in healthy controls. In vitro experiments, testosterone-induced ferroptosis was ameliorated by ferroptosis inhibitors, and ferritinophagy was mitigated by autophagy inhibitors or NCOA4 knockdown in primary cultured hTSCs. Testosterone induced ARs into the nucleus, where the recruitment of AR homodimers along with NCOA4 to the positive ARE on the SQSTM1 promoter, leading to autophagy induction and degradation of ferritin heavy chain 1 (FTH1) in autophagosomes, resulting in the release of ferritin bound irons as free ferrous irons. Metformin ameliorated testosterone-induced ferroptosis in hTSCs to a certain extent by inhibiting ferritinophagy. Compared to those of control mice, the placentas of DHT-treated PCOS mice showed increased levels of iron ions and lipid peroxidation, and altered expressions of ferroptosis-related proteins. Hyperandrogenism also induced ferritinophagy in labyrinthine zone of placentas in PCOS mice. Metformin ameliorated placental development was associated with decreased iron ions accumulation by inhibiting ferritinophagy in PCOS mouse placentas, which observably attenuated embryo absorption rate and spontaneous miscarriage incidence in the early gestation of PCOS mice. Limitations, reasons for caution The numbers of PCOS patients and mouse placentas in this study were small. The placental labyrinthine zone was not separated from the endocrine junctional zone and maternal decidua for molecular analyses. In addition, it would be better to isolated and cultured mouse TSCs to explore mechanisms on ferritinophagy in further. Wider implications of the findings This study provides further evidence for metformin as a PCOS treatment, which ameliorates placental development and attenuates spontaneous miscarriage rate in early gestation. Trial registration number not applicable