Piperine's potential in treating polycystic ovarian syndrome explored through in-silico docking.

Polycystic Ovarian Syndrome (PCOS) is a multifaceted metabolic and hormonal condition that impacts women in their procreative ages, identified by ovarian dysfunction, hyperandrogenaemia overweight and insulin insensitivity. The piperine, an important alkaloid compound of black pepper has shown promise in modulating various physiological processes. In this work, employed computational docking studies to explore the potential of piperine as a treatment for PCOS. Utilizing computational methods, we analyzed the binding interactions between piperine and key molecular targets implicated in PCOS pathogenesis, including hyperandrogenism, and "oligomenorrhea. The network pharmacology analysis report found 988 PCOS-related genes, 108 hyperandrogenism-related genes, and 377 oligomenorrhea-related genes, and we finally shortlisted 5 common genes in PCOS, hyperandrogenism, and "oligomenorrhea": NR3C1, PPARG, FOS, CYP17A1, and H6PD. Our results reveal favorable binding affinities with PPARG (-8.34 Kcal/mol) and H6PD (-8.70 Kcal/mol) and interaction patterns, suggesting the potential of piperine to modulate these targets. Moreover, the reliability of the piperine-target interactions was revealed by molecular simulations studies. These findings support further experimental investigations to validate the therapeutic efficacy of piperine in PCOS management. The integration of computational approaches with experimental studies has the potential to lay the groundwork for the creation of new therapies specifically targeting PCOS and related endocrine disorders.

Mechanism of YJKL Decoction in Treating of PCOS Infertility by Integrative Approach of Network Pharmacology and Experimental Verification.

Purpose: Currently, there is still no clear treatment for polycystic ovary syndrome (PCOS). YJKL has better therapeutic effects and lower toxic side effects for PCOS type infertility. This study aims to clarify the potential mechanism of YJKL Decoction in the treatment of PCOS based on network pharmacology and experiments verification. Patients and Methods: Network pharmacology and experimental validation approach were used to investigate the bioactive ingredients, critical targets and potential mechanisms of YJKL Decoction against PCOS. Firstly, we use network pharmacology methods to collect core targets, and then validate their effects on diseases through experiments. Results: Five core targets were screened, Threonine kinase 1 (AKT1), Cellular tumor antigen p53 (TP53), Tumor necrosis factor (TNF), Albumin (ALB) and Vascular endothelial growthfactor A (VEGFA). KEGG analysis showed that YJKL treatment for PCOS mainly include AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway and HIF-1 signaling pathway. The molecular docking results showed that compounds have higher affinity with targets. Finally, experimental results had shown that YJKL Decoction had an better therapeutic effects in the treatment of PCOS. Conclusion: Based on a systematic network pharmacology approach and experimental verification, our results comprehensively illustrated the active ingredients, potential targets, and molecular mechanism of YJKL for application to PCOS and helps to illustrate mechanism of action on a comprehensive level.

Acetate attenuates hypothalamic pyroptosis in experimentally induced polycystic ovarian syndrome.

This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.

Role of Omega-3 Fatty Acids in Improving Metabolic Dysfunctions in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that impacts women of reproductive age. In addition to reproductive and psychological complications, women with PCOS are also at a higher risk of developing metabolic diseases such as obesity, type 2 diabetes and cardiovascular disease. While weight reduction can help manage these complications in overweight or obese women, many weight loss interventions have been ineffective due to weight stigma and its psychological impact on women with PCOS. Therefore, exploring alternative dietary strategies which do not focus on weight loss per se is of importance. In this regard, omega-3 polyunsaturated fatty acids of marine origin (n-3 PUFAs), which are known for their hypotriglyceridemic, cardioprotective and anti-inflammatory effects, have emerged as a potential therapy for prevention and reversal of metabolic complications in PCOS. Several clinical trials showed that n-3 PUFAs can improve components of metabolic syndrome in women with PCOS. In this review, we first summarize the available clinical evidence for different dietary patterns in improving PCOS complications. Next, we summarize the clinical evidence for n-3 PUFAs for alleviating metabolic complications in PCOS. Finally, we explore the mechanisms by which n-3 PUFAs improve the metabolic disorders in PCOS in depth.

Semaglutide Alleviates Ovary Inflammation via the AMPK/SIRT1/NF­κB Signaling Pathway in Polycystic Ovary Syndrome Mice.

Background: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice. Methods: Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1ß, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1ß were measured using Western blotting. Results: First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1ß levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1ß, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway. Conclusion: Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NF­κB signaling pathway in PCOS mice.

Patuletin Ameliorates Inflammation and Letrozole-Induced Polycystic Ovarian Syndrome in Rats.

Concerns about inflammation-related issues affecting female reproductive health are growing. Chronic low-grade inflammation in women with polycystic ovarian syndrome (PCOS) affects follicular growth, ovulation, and androgen production. The present investigation aimed to elucidate the efficacy of flavonoid patuletin in ameliorating the letrozole-induced PCOS and associated inflammation in rats. Female Wistar rats (32 days old) were divided into five groups (n = 12): Group I, control; Group II, vehicle control; Group III, letrozole oral (1 mg/kg) for 28 days; Group IV and Group V treatment groups, patuletin i.p. (25 mg/kg) and clomiphene citrate + metformin i.p. (50 mg/kg + 300 mg/kg), respectively. Leterozole-induced PCOS and ovarian inflammation were ameliorated by patuletin, as reflected in the improved histopathology, prevention of cyst formation, significant upregulation of growth factors such as growth differentiation factor 9 (GDF-9) and bone morphogenetic protein-15 (BMP-15) expression, and a decrease in the pro-inflammatory cytokines TNF-α, IL-6, and COX-2. Additionally, the plasma levels of reproductive hormones were restored. Upregulation of FSH-R, PR, and CYP19a1, along with downregulation of ERα, LHR, CYP17a1, CYP11a1 and HSDß17a1, showed the regulation of gonadotropin receptors and steroid biosynthesis genes in ovarian tissues. Patuletin demonstrated a promising protective approach against the biological model of PCOS by increasing the inflammation in ovarian tissues with consequent regulation of growth factors, enzymes, and hormones, and might be used as adjuvant therapy in the treatment of problems related to female reproductive health.

Assessing medication use patterns among patients with polycystic ovary syndrome at a tertiary care teaching hospital in South Korea: A retrospective study.

Polycystic ovary syndrome (PCOS) is a disease caused by excessive ovarian androgen secretion due to hypothalamic-pituitary-ovarian hormone abnormalities. We retrospectively investigated the treatment status of patients diagnosed with PCOS who visited a domestic tertiary hospital in order to analyze the use patterns and safety of drugs. Patients diagnosed with PCOS between July 2014 and September 2022 were examined, excluding patients younger than 13 years and those not receiving medication. Patients aged 21 years or younger were designated as the adolescent group and patients aged 22 years or older were designated as the adult group for comparative statistical analysis. The total number of patients was 212, including 105 adolescents (49.5%) and 107 adults (50.5%). Comorbidities were ovarian cyst in 20 (9.4%) patients, endometriosis in 19 (9%), diabetes in 14 (6.6%), thyroid dysfunction in 12 (5.7%), hypertension in 10 (4.7%), dyslipidemia in 10 (4.7%), and androgenic alopecia in 6 (2.8%). Symptoms were oligomenorrhea in 91 (42.9%) patients, amenorrhea in 72 (34%), hirsutism in 36 (17%), acne in 24 (11.3%), and infertility in 10 (4.7%). During the study period, 114 patients (53.8%) were prescribed medroxyprogesterone acetate (MPA), 66 (31.1%) were given oral contraceptives (specifically, ethinyl estradiol + drospirenone prescribed to 52 (24.5%)), and 17 (8%) were concurrently prescribed MPA and oral contraceptives. Forty-five (21.2%) patients changed prescriptions, with 10 (22.2%) switching due to side effects and 8 (17.8%) due to a therapeutic failure. A total of 5 patients (2.4%) discontinued the drug. Adverse drug reactions occurred in 15 patients (7.1%), with 5 being adolescents (4.8%) and 10 being adults (9.3%). MPA alone and ethinyl estradiol with drospirenone were the most prescribed medications for PCOS. Over the study, 45 patients changed prescriptions, 50 were lost to follow-up, and 5 adults discontinued medications.

Effects of Zishen Yutai pills combined with metformin on women with polycystic ovary syndrome undergoing in vitro fertilization.

In this study, we analyzed the clinical efficacy of Zishen Yutai pills (ZSYTP) combined with metformin hydrochloride on infertile women diagnosed with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization and embryo transfer (IVF-ET). Patients were assigned into 3 groups: the ZSYTP group (n = 50), the metformin group (n = 50), and the combination group (ZSYTP combined with metformin hydrochloride, n = 50), based on their respective and the indicated treatments before undergoing IVF-ET. Then, their glucose metabolism indices, sex hormone indices, traditional Chinese medicine (TCM) syndrome scores, and outcomes of IVF-ET were compared. Baseline characteristics were not significantly different between the 2 groups. After treatment, various parameters such as body mass index (BMI), fasting plasma glucose (FPG), fasting insulin (FIN), homeostatic model assessment of insulin resistance (HOMA-IR), luteinizing hormone (LH), estradiol (E2), follicle-stimulating hormone (FSH), testosterone (T) levels, and TCM syndrome scores were found to be reduced compared to pretreatment levels in both groups. Moreover, the improvement observed in the treatment group exceeded that of the control group. Specifically, the observation group displayed significantly lower gonadotropin (Gn) dosage and duration, as well as a reduced abortion rate compared to the control group. Furthermore, the observation group had higher numbers of obtained eggs, high-quality embryos, eggs obtained through IVF-ET, average transferred embryos, clinical pregnancy rate, and embryo implantation rate compared to the control group. Pretreatment with ZSYTP combined with metformin before IVF-ET in PCOS patients improves the outcome of IVF-ET.

Effect of berberine combined with metformin on autophagy in polycystic ovary syndrome by regulating AMPK/AKT/mTOR pathway.

The pathologic mechanism of polycystic ovary syndrome (PCOS) is related to increased autophagy of granulosa cells. Both berberine and metformin have been shown to improve PCOS, but whether the combination of berberine and metformin can better improve PCOS by inhibiting autophagy remains unclear. PCOS models were constructed by injecting dehydroepiandrosterone into rats, and berberine, metformin or berberine combined with metformin was administered to rats after modeling. Rats' body weight and ovarian weight were measured before and after modeling. Histopathological examination of ovarian tissue and estrous cycle analysis of rats were performed. Insulin resistance, hormone levels, oxidative stress, and lipid metabolism in PCOS rats were assessed. Expression of the AMPK/AKT/mTOR pathway and autophagy-related proteins was analyzed by Western blot assays. Granulosa cells were isolated from rat ovarian tissue and identified by immunofluorescence staining followed by transmission electron microscopy analysis. Berberine combined with metformin reduced the body weight and ovarian weight of PCOS rats, increased the number of primordial and primary follicles, decreased the number of secondary and atretic follicles, normalized the estrous cycle, and improved insulin resistance, androgen biosynthesis, oxidative stress and lipid metabolism disorders, and increased estrogen production. In addition, berberine combined with metformin reduced the number of autophagosomes in granulosa cells, which may be related to AMPK/AKT/mTOR pathway activation, decreased Beclin1 and LC3II/LC3I levels, and increased p62 expression. Berberine combined with metformin could inhibit autophagy by activating the AMPK/AKT/mTOR pathway in PCOS, indicating that berberine combined with metformin is a potential treatment strategy for PCOS.

Pterostilbene Ameliorates Cognitive Impairment in Polycystic Ovary Syndrome Rat Model through Improving Insulin Resistance via the IRS-1/PI3K/Akt/GSK-3ß Pathway: A Comparative Study with Metformin.

Polycystic ovary syndrome (PCOS) is an intricate endocrine disorder that targets millions of women globally. Recent research has drawn attention to its association with cognitive impairment and Alzheimer's disease (AD) risk, yet the exact mechanism remains elusive. This study aimed to explore the potential role of PCOS-associated insulin resistance (IR) and inflammation in linking PCOS to AD pathogenesis. It additionally investigated the therapeutic merits of pterostilbene (PTS) in ameliorating PCOS and associated cognitive deficits in comparison to metformin (MET). Rats were divided into five groups; vehicle group, PTS group [30 mg/kg, per os (p.o.) for 13 days], and the remaining three groups received letrozole (1 mg/kg, p.o. for 21 days) to represent the PCOS, PCOS + MET (300 mg/kg, p.o. for 13 days), and PCOS + PTS groups, respectively. Behavioral tests were conducted, along with a histopathological investigation of brains and ovaries. Assessment of serum hormonal profile and hippocampal IRS-1/PI3K/AKT/GSK-3ß insulin signaling pathway components were performed. PTS rats exhibited improved insulin sensitivity and hormonal profile, besides enhanced neurobehavioral tests performance and histopathological findings. These effects may be attributed to modulation of the IRS-1/PI3K/AKT/GSK-3ß pathway, reducing GSK-3ß activity, and mitigating Tau hyperphosphorylation and Aß accumulation in the brain. Likewise, PTS attenuated nuclear factor kappa B-mediated inflammation and reversed AChE elevation, suggesting multifaceted neuroprotective effects. Comparatively, PTS showed outcomes similar to those of MET in most parameters. The obtained findings validated that dysregulated insulin signaling in PCOS rats detrimentally affects cognitive function, which is halted by PTS, unveiling the potential of PTS as a novel therapy for PCOS and related cognitive deficits.

[Resveratrol enhances the local antioxidant ability of the ovary in rats with polycystic ovary syndrome].

OBJECTIVE: To investigate the effects of resveratrol (RSV) on ovarian morphology, plasma anti-Müllerian hormone (AMH) and insulin-like growth factor 1 levels (IGF-1), and oxidative stress parameters in rats with polycystic ovary syndrome (PCOS). METHODS: Forty-six rats were randomly divided into a normal control (n = 12), a PCOS model control (n = 12), a rosiglitazone (RSG, n = 11), and an RSV group (n = 11). The PCOS model was established in the latter three groups by rejection of epidehydroandrosterone. The rats in the normal control and PCOS model control groups were treated by gavage of normal saline and those in the RSG and RSV groups by intragastric administration of RSG at 10 mg/(kg·d) and RSV at 3.0 mg/(kg·d), respectively. After 4 weeks of treatment, the ovarian histology was observed under the light microscope, the levels of plasma AMH and IGF-1 measured by ELISA, and the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) in the ovarian tissue detected using the Ellman, Sun and AEBI methods, respectively. RESULTS: After a 4-week treatment, statistically significant differences were observed in the above indicators between the normal control and PCOS model control groups (P<0.05). The rats treated with RSG and RSV also showed significant differences in these parameters from the model controls (P<0.05). CONCLUSION: RSV can enhance the local antioxidant capacity of the ovary, reduce the levels of AMH and IGF-1, and improve the morphology of the ovarian tissue in rats with PCOS, indicating its potential value in the treatment of PCOS.

Zishen Qingre Lishi Huayu Recipe May Ameliorate the Symptoms of PCOS Model Rats via Alleviating Systemic and Ovarian Inflammation.

BACKGROUND: Zishen Qingre Lishi Huayu recipe (ZQLHR) has shown significant therapeutic effects in treating sex hormone levels and follicular developmental disorders in patients with polycystic ovary syndrome (PCOS). However, little is known about the potential mechanisms of its treatment. METHODS: Dehydroepiandrosterone and a high-fat diet induced the PCOS model rat. The serum of rats was collected to detect the levels of sex hormones and inflammatory cytokines by enzyme-linked immunosorbent assay, and the ovaries were collected for ovarian histopathology and qPCR assay to detect the levels of inflammatory cytokines in ovarian tissues. Granulosa cells (GCs) were collected for western blot assay to detect of IL-1ß, IL-6R, and LOX protein expression levels. RESULTS: ZQLHR could reduce body weight, regulate estrous cycles, and improve serum sex hormone levels, follicular development, and insulin resistance (IR) in PCOS model rats. In addition, ZQLHR treatment improved the levels of inflammatory cytokines in serum and ovary, and regulated the protein expression of IL-6R, IL-1ß, and LOX in GCs of PCOS model rats. The results showed that the HOMA-IR index increased with the increasing levels of IL-6, IL-1ß, and CRP, and decreased with the increased IL-10. CONCLUSION: This study reveals that the treatment of endocrine disorders and ovulation disorders in PCOS with ZQLHR may be closely related to the improvement of systemic and ovarian inflammation in PCOS patients, as well as the inhibition of IL-6R, IL-1ß, and LOX expression in GCs, which reemphasizes the role of reducing chronic inflammatory states in the treatment of PCOS. Moreover, this study reemphasizes the correlation between multiple inflammatory mediators and IR.

Effects of inulin on intestinal flora and metabolism-related indicators in obese polycystic ovary syndrome patients.

CONTEXT: Polycystic ovary syndrome (PCOS), a common endocrine disorder in women of reproductive age, is closely associated with chronic low-grade inflammation and metabolic disturbances. In PCOS mice, dietary inulin has been demonstrated to regulate intestinal flora and inflammation. However, the efficacy of dietary inulin in clinical PCOS remains unclear. OBJECTIVE: The intestinal flora and related metabolic indexes of obese patients with polycystic ovary syndrome (PCOS) after 3 months of inulin treatment were analyzed. SETTING AND DESIGN: To analyze the intestinal flora and related metabolic indexes in healthy controls and obese patients with polycystic ovary syndrome after 3 months of inulin treatment. RESULTS: The results showed that dietary inulin improved sex hormone disorders, reduced BMI and WHR levels in obese women with PCOS. In addition, the inulin intervention reduced plasma TNF-α, IL-1ß, IL-6, and MCP-1levels. Inulin intervention increased the abundance of Actinobacteria, Fusobacteria, Lachnospira, and Bifidobacterium, as well as decreased the ratio of F/B and the abundance of proteobacteria, Sutterella, and Enterobacter. Correlation analyses showed a strong relationship among plasma inflammatory factors, sex steroid hormones, and the intestinal flora of patients. CONCLUSIONS: Dietary inulin may improve obese PCOS women disease through the gut flora-inflammation-steroid hormone pathway. THE CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IOR-17012281.

Dendrobium nobile-derived polysaccharides stimulate the glycolytic pathway by activating SIRT2 to regulate insulin resistance in polycystic ovary syndrome granulosa cells.

Insulin resistance (IR) is one of the major complications of polycystic ovary syndrome (PCOS). This study aimed to investigate the effects and the molecular regulatory mechanism by which Dendrobium nobile-derived polysaccharides (DNP) improve IR in rats with letrozole and high-fat-diet induced PCOS. In vivo, DNP (200 mg/kg/d) administration not only reduced body weight, blood glucose, and insulin levels in PCOS rats, but also improve the disrupted estrous cycle. In addition, DNP treatment reduced atretic and cystic follicles and enhanced granulosa cell layer thickness, thereby restoring follicle development. In vitro, DNP treatment (100 µM) increased lactate levels and decreased pyruvate levels in insulin-treated (8 µg/mL) KGN cells. Additionally, DNP also decreased the expression of IGF1 and increased that of IGF1R, SIRT2, LDHA, PKM2 and HK2 both in vivo and in vitro. Also, SIRT2 expression was specifically inhibited by AGK2, while DNP significantly improved IR and glycolysis by reversing the effect of AGK2 treatment on lactate and pyruvate production, upregulating the expression levels of IGF1R, LDHA, HK2, and PKM2 and downregulating the expression level of IGF1. The results indicate that DNP can effectively improve IR and restore glycolytic pathway by activating SIRT2, which may provide a potential therapeutic approach for PCOS patients.

The efficacy and safety of GLP-1 agonists in PCOS women living with obesity in promoting weight loss and hormonal regulation: A meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of GLP1 receptor agonists (GLP1-RAs) in treating polycystic ovarian syndrome (PCOS) remains unclear. While GLP1-RAs are known to promote weight loss in patients with diabetes and living with obesity, their impact on weight reduction and hormonal regulation in women with PCOS is understudied. Therefore, we aimed to assess the efficacy of GLP1-RAs in PCOS women living with obesity through a meta-analysis, comparing their effects to placebo. HYPOTHESIS: The use of GLP1-RAs in PCOS women living with obesity can reduce body mass index and waist circumference as well as improve hyperinsulinism, and hyperandrogenism as well as normalize total testosterone, total cholesterol and HOMA-IR markers in PCOS women living with obesity. METHODS: We systematically searched the PubMed, Cochrane Central, Scopus and Embase databases to identify randomized controlled trials (RCT) comparing GLP1-RAs versus placebo among women diagnosed with PCOS based on the Rotterdam Criteria. Our primary outcomes of interest included body mass index (BMI), triglycerides, waist circumference, total testosterone, total cholesterol, and HOMA-IR. We performed data extraction and quality assessment for studies that met the inclusion criteria. We pooled mean difference (MD) and 95 % confidence intervals (CI) with a random-effect model for continuous endpoints. RESULTS: We included 176 participants from four RCTs. Semaglutide and Liraglutide were used in 23 (13 %) and 103 (58 %) participants, respectively. GLP1-RAs use was associated with a significant reduction in waist circumference (MD: -5.16 cm; 95 % CI: -6.11 to -4.21; p ˂ 0.00001), body mass index (BMI) (MD: -2.42; 95 % CI: -3.10 to -1.74; p ˂ 0.00001), serum triglycerides (MD: -0.20; 95 % CI: -0.30 to -0.11; p ˂ 0.00001) and total testosterone levels (MD: -1.33; 95 % CI: -2.55 to -0.12; p = 0.03) when compared to placebo. There was no significant difference in total cholesterol (MD: -0.04; 95 % CI: -0.10 to 0.01; p = 0.15) and HOMA-IR (MD: -0.30; 95 % CI: -0.92 to 0.32; p = 0.35) levels. Adverse events information was available for 112 patients, where 49 had light side effects such as nausea and abdominal pain. CONCLUSION: The use of GLP1-RAs demonstrates efficacy in reducing BMI, triglycerides, waist circumference and total testosterone. There was no significant difference in total cholesterol and HOMA-IR levels. These results signify its viability as a favourable treatment option for managing PCOS symptoms in women living with obesity.

Innovative berberine nanoethosomal vaginal in situ gel: Unraveling polycystic ovary syndrome treatment on female Wistar rats.

PURPOSE: The present work seeks to develop, assess and refine a nanoethosomal vaginal in situ gel containing Berberine, aimed at enhancing its efficacy in treating Poly Cystic Ovary Syndrome (PCOS). This formulation aims to augment drug permeation, enable controlled release kinetics, and mitigate oral adverse effects commonly associated with Berberine administration. METHOD: Nanoethosomes formulated using diverse soya lecithin-ethanol concentrations within a 32 full-factorial-design, sought optimal formulations based on particle size and %entrapment-efficiency. Subsequent scrutiny involved PDI, Zeta potential and drug-content evaluation. TEM analysis authenticated morphology, while in vitro drug release from Nanoethosomes was examined. Pluronic F-127 concentrations (16%-21%w/v) were explored for the in situ gel, analyzing pH, gelation time and gelation temperature. The refined gel underwent evaluations for viscosity and in vitro diffusion. In vivo assessment covered pharmacokinetics, vaginal irritancy and Mifepristone-induced PCOS management, validated through histopathological and biochemical analysis, juxtaposing findings across normal, diseased, plain Berberine gel and standard metformin administered groups. RESULTS: Optimized Nanoethosomal Formulation(F3) displayed particle size of 183.5 nm, 82.58 % as %entrapment-efficiency, PDI of 0.137, -50.34 mV as zeta potential and 81.64 ± 1.57 % drug-content. TEM analysis confirmed spherical, nano-sized particles. In vitro studies exhibited 80.45 % drug release over 24 h. The formulated gel with 18 % Pluronic F-127 showed viscosity ranging from 193.01 ± 0.16cps to 1817.08 ± 1.67cps with temperature changes from 25 ± 2.0 °C to 38 ± 2.0 °C. In vitro diffusion revealed 85.99 %drug release from optimized gel. In vivo animal studies demonstrated increased plasma drug concentration, non-irritating properties in vaginal tests, and efficacy in managing Mifepristone-induced PCOS compared to other treatments. Short-term stability evaluations confirmed thermodynamic stability at room-temperature.

Jiawei Buzhong Yiqi Decoction attenuates polycystic ovary syndrome through regulating kisspeptin-GPR54-AKT-SHBG system.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders. Accumulated evidence has suggested the indispensable role of kisspeptin-G protein-coupled receptor (GPR54) system and SHBG in development of PCOS. However, potential mechanisms and their relationship are unclear. Jiawei Buzhong Yiqi Decoction (JWBZYQ) has been reported to ameliorate obese PCOS. Whereas, potential mechanisms remain elusive. PURPOSE: To determine whether JWBZYQ attenuates PCOS by regulating the kisspeptin-GPR54 system and SHBG production. And to explore potential mechanisms. METHODS: An overweight PCOS rat model was developed with testosterone propionate (TP) and high-fat diet (HFD). The efficacy of JWBZYQ was assessed by tracking changes in weight, estrous cycle, ovarian morphology, and serum sex hormone levels. Additionally, kisspeptin-GPR54 system expression in multiple organs and PI3K-AKT pathway activity in liver of different rats were detected. Modifications in SHBG production were also measured. Kisspeptin54 was administered to establish a cellular model. The levels of AKT phosphorylation and SHBG protein within HepG2 cells were analyzed. Finally, confirmatory studies were performed using AKT phosphorylation activator and inhibitor. RESULTS: JWBZYQ effectively attenuated the overweight, disrupted estrous cycle, altered sex hormone levels, and aberrant ovarian morphology in PCOS rats. Meanwhile, PCOS rats exhibited elevated levels of kisspeptin and GPR54, along with reduced SHBG levels, which could be reversed by JWBZYQ. These alterations might be connected with the activation of AKT phosphorylation. In vitro experiment identified that JWBZYQ could rectify the hyperactivated AKT phosphorylation and deficient production of SHBG caused by kisspeptin54. CONCLUSIONS: Overexpressed kisspeptin-GPR54 system inhibited SHBG synthesis in PCOS. JWBZYQ curtailed the exorbitant expression of kisspeptin and GPR54, which moderated the rise in AKT phosphorylation and subsequently promoted the production of SHBG.

The Pathophysiological Mechanism and Clinical Treatment of Polycystic Ovary Syndrome: A Molecular and Cellular Review of the Literature.

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder among women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The pathogenesis of PCOS involves a complex interplay of genetic and environmental factors, including insulin resistance (IR) and resultant hyperinsulinemia. Insulin receptors, primarily in skeletal muscle, liver, and adipose tissue, activate downstream signaling pathways like PI3K-AKT and MAPK-ERK upon binding. These pathways regulate glucose uptake, storage, and lipid metabolism. Genome-wide association studies (GWASs) have identified several candidate genes related to steroidogenesis and insulin signaling. Environmental factors such as endocrine-disrupting chemicals and lifestyle choices also exacerbate PCOS traits. Other than lifestyle modification and surgical intervention, management strategies for PCOS can be achieved by using pharmacological treatments like antiandrogens, metformin, thiazolidinediones, aromatase inhibitor, and ovulation drugs to improve insulin sensitivity and ovulatory function, as well as combined oral contraceptives with or without cyproterone to resume menstrual regularity. Despite the complex pathophysiology and significant economic burden of PCOS, a comprehensive understanding of its molecular and cellular mechanisms is crucial for developing effective public health policies and treatment strategies. Nevertheless, many unknown aspects of PCOS, including detailed mechanisms of actions, along with the safety and effectiveness for the treatment, warrant further investigation.

Liraglutide improves follicle development in polycystic ovary syndrome by inhibiting CXCL10 secretion.

BACKGROUND: At present, a number of clinical trials have been carried out on GLP-1 receptor agonist liraglutide in the treatment of polycystic ovary syndrome (PCOS). However, the effect of liraglutide on follicle development and its specific mechanism are still unclear. METHODS: RNA sequencing was used to explore the molecular characteristics of granulosa cells from patients with PCOS treated with liraglutide. The levels of C-X-C motif chemokine ligand 10 (CXCL10) in follicular fluid were detected by ELISA, the expression levels of ovulation related genes and inflammatory factor genes in follicles and granulosa cells were detected by qPCR and the protein levels of connexin 43 (Cx43), Janus Kinase 2 (JAK2) and phosphorylated JAK2 were detected by Western blot. The mouse ovarian follicles culture system in vitro was used to detect the status of follicle development and ovulation. RESULTS: In the present study, we found that liraglutide inhibited the secretion of inflammatory factors in PCOS granulosa cells, among which CXCL10 was the most significant. In addition, CXCL10 was significantly higher in granulosa cells and follicular fluid in PCOS patients than in non-PCOS patients. We applied in vitro follicle culture and other techniques to carry out the mechanism exploration which revealed that CXCL10 disrupted the homeostasis of gap junction protein alpha 1 (GJA1) between oocyte and granulosa cells before physiological ovulation, thus inhibiting follicular development and ovulation. Liraglutide inhibited CXCL10 secretion in PCOS granulosa cells by inhibiting the JAK signaling pathway and can improved dehydroepiandrosterone (DHEA)-induced follicle development disorders, which is reversed by CXCL10 supplementation. CONCLUSIONS: The present study suggests that liraglutide inhibits CXCL10 secretion in granulosa cells through JAK signaling pathway, thereby improving the homeostasis of GJA1 between oocyte and granulosa cells before physiological ovulation and ultimately improving the follicular development and ovulation of PCOS, which provides more supportive evidence for the clinical application of liraglutide in the treatment of ovulatory disorders in PCOS. TRIAL REGISTRATION: Not applicable.

Competence of Combined Low Dose of Human Chorionic Gonadotropin (HCG) and Clomiphene Citrate (CC) Versus Continued CC during Ovulation Induction in Women with CC-Resistant Polycystic Ovarian Syndrome: A Randomized Controlled Trial.

Background and Objectives: Polycystic ovarian syndrome (PCOS) is a widespread endocrine disorder affecting 5-18% of females in their childbearing age. The aim of this study is to assess the efficacy of combining a low dosage of human chorionic gonadotropin (HCG) along with clomiphene citrate (CC) for stimulating ovulation in infertile women diagnosed with CC-resistant PCOS. Materials and Methods: A randomized controlled trial was carried out on 300 infertile CC-resistant PCOS women. All participants were assigned to two groups: the CC-HCG group and the CC-Placebo group. Subjects in the CC-HCG group were given CC (150 mg/day for 5 days starting on the 2nd day of the cycle) and HCG (200 IU/day SC starting on the 7th day of the cycle). Subjects in the CC-Placebo group were given CC and a placebo. The number of ovarian follicles > 18 mm, cycle cancellation rate, endometrial thickness, ovulation rate, clinical pregnancy rate, and occurrence of early ovarian hyper-stimulation syndrome were all outcome variables in the primary research. Results: Data from 138 individuals in the CC-HCG group and 131 participants in the CC-Placebo group were subjected to final analysis. In comparison to the CC-Placebo group, the cycle cancellation rate in the CC-HCG group was considerably lower. The CC-HCG group exhibited a substantial increase in ovarian follicles reaching > 18 mm, endometrial thickness, and ovulation rate. The clinical pregnancy rate was higher in the CC-HCG group (7.2% vs. 2.3%; CC-HCG vs. CC-Placebo). Upon adjusting for BMI and age, the findings of our study revealed that individuals in the CC-HCG group who had serum prolactin levels below 20 (ng/mL), secondary infertility, infertility duration less than 4 years, baseline LH/FSH ratios below 1.5, and serum AMH levels more than 4 (ng/mL) had a higher likelihood of achieving pregnancy. In the CC-Placebo group, there was a greater prediction of clinical pregnancy for those with serum AMH (<4), primary infertility, serum prolactin ≤ 20 (ng/mL), baseline LH/FSH < 1.5, and infertility duration < 4 years. Conclusions: The use of a small dose of HCG along with CC appeared to be an effective treatment in reducing cycle cancelation, improving the clinical pregnancy rate and ovulation rate in CC-resistant PCOS patients. The trial was registered with Clinical Trials.gov, identifier NCT02436226.