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Cannarella R, Rubulotta M, Leonardi A, Crafa A, Calvo A, Barbagallo F, La Vignera S, Calogero AE. Effects of ketogenic diets on polycystic ovary syndrome: a systematic review and meta-analysis. Reprod Biol Endocrinol 2025; 23:74. [PMID: 40394635 PMCID: PMC12090672 DOI: 10.1186/s12958-025-01411-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND This systematic review and meta-analysis aimed to evaluate the effects of ketogenic diet (KD) and very-low-energy ketogenic therapy (VLEKT) protocols on various health outcomes in patients with polycystic ovary syndrome (PCOS) and increased body weight. METHODS A systematic search was conducted across Scopus, PubMed, Cochrane, and Embase databases from their inception through January 2025, using a predefined search strategy. Studies were selected based on the PICOS criteria. Data extraction focused on anthropometric measures, glycometabolic and lipid profiles, and hormone levels. Controlled studies were analyzed to evaluate the effects of high-fat KDs and VLEKT compared to low calorie diets (LCDs). Additionally, uncontrolled studies were included, and the outcomes following high-fat KDs or VLEKT were compared to baseline values (before-after study design). A sub-analysis was also performed to compare VLEKT with high-fat KDs. We assessed the quality of the evidence, as well as heterogenity, sensitivity, and publication bias. RESULTS A total of 10 studies were included in the analyses, comprising three randomized controlle studies (RCTs), one non-randomized intervention study, four cohort studies, and two case series. Two RCTs comparing VLEKT and high-fat KDs with LCDs found no significant effect on body weight. However, both high-fat KDs and VLEKT were associated with reductions in body mass index (BMI) and fat mass percentage in patients with PCOS. Significant improvements in weight, BMI, fat mass, and lean mass were observed following high-fat KDs or VLEKT interventions compared to baseline values, with no substantial differences between the two diet types. Regarding glycometabolic outcomes, both high-fat KDs and VLEKT reduced serum glucose levels and the homeostatic model assessment index compared to LCDs, with VLEKT showing slightly more favorable effects. In terms of the lipid profile, both high-fat KDs and VLEKT lowered total cholesterol and triglyceride levels, and VLEKT showing greater efficacy in triglyceride reduction. Hormonal analyses from two RCTs showed that both high-fat KDs and VLEKT were associated with lower serum luteinizig hormone (LH) levels compared to LCDs. Additionally, both high-fat KDs and VLEKT led to reductions in LH and total testosterone levels relative to baseline, with VLEKT showing a slight advantage in lowering LH and follicle-stimulating hormone levels. CONCLUSIONS High-fat KDs and VLEKT show beneficial effects on weight, body composition, glycometabolic parameters, and hormone profile in women with PCOS. VLEKT may provide additional advantages, particularly in reducing fat mass and lowering triglyceride levels. Further studies with larger sample sizes and more robust study designs are needed to confirm these findings.
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Affiliation(s)
- Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy.
- Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
| | - Michele Rubulotta
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy
| | - Alessia Leonardi
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy
| | - Andrea Crafa
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy
| | - Antonio Calvo
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy
| | - Federica Barbagallo
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, Catania, 95123, Italy
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Pan P, Cao S, Gao H, Qu X, Ma Y, Yang J, Pei X, Yang Y. Immp2l gene knockout induces granulosa cell senescence by activation of cGAS-STING pathway via TFAM-mediated mtDNA leakage. Int J Biol Macromol 2025; 307:142368. [PMID: 40120895 DOI: 10.1016/j.ijbiomac.2025.142368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/18/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Abstract
Granulosa cell-produced inflammatory factors may be key contributors to ovarian dysfunction, and Immp2l deficiency accelerates ovarian aging via granulosa cell senescence; however, the role of inflammation in granulosa cell senescence is largely unknown. Therefore, in this study, cGAS-STING-mediated inflammation was explored in Immp2l deficiency-induced granulosa cell senescence. Immp2l deficiency led to senescence-associated secretory phenotype (SASP) and granulosa cell senescence. Immp2l knockout caused mitochondrial dysfunction and mitochondrial DNA (mtDNA) leakage into the cytoplasm. The cytoplasmic mtDNA was recognized by the DNA-sensing molecule cGAS-STING, which activates cGAS-STING and key downstream interferon-stimulated genes (ISGs) and then promotes the secretion of proinflammatory factors, leading to SASP in senescent granulosa cells. Interestingly, the mitochondrial inner membrane pore protein (Cyclophilin D40) CyPD40 and the outer membrane pore protein voltage-dependent-anion channel 1 (VDAC1) were markedly increased in senescent granulosa cells, accompanied by significantly increased expression of the mtDNA stability protein mitochondrial transcription factor A (TFAM). Downregulation of TFAM with siRNA in senescent granulosa cells improved mitochondrial function, significantly decreased mtDNA in the cytoplasm, inhibited the cGAS-STING pathway and markedly decreased CyPD40 and VDAC1 protein levels in TFAM-treated senescent granulosa cells. The SASP phenotype was also alleviated. In addition, senescent granulosa cells were treated with procyanidin B2 (PCB2), which has anti-inflammatory effects, and the TFAM-mediated mtDNA-cGAS-STING pathway was inhibited, accompanied by a markedly reduced SASP phenotype and granulosa cell senescence. In conclusion, Immp2l gene knockout induced granulosa cell senescence by activation of the cGAS-STING pathway via TFAM-mediated mtDNA leakage into the cytoplasm through the CyPD40 and the VDAC1.
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Affiliation(s)
- Pengge Pan
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Sinan Cao
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Hui Gao
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Xiaoya Qu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Yan Ma
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Jinyi Yang
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Xiuying Pei
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
| | - Yanzhou Yang
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Emergency Department, The First People's Hospital of Yinchuan, The Second Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China.
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Li L, Xiao Y, Wen W, Liu Q, Wei L, Liu P, Li M. The role of macrophages in polycystic ovary syndrome: A review. Medicine (Baltimore) 2025; 104:e42228. [PMID: 40295243 PMCID: PMC12040014 DOI: 10.1097/md.0000000000042228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 04/04/2025] [Accepted: 04/07/2025] [Indexed: 04/30/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder among fertile women, which is influenced by genetics and environment. A recent study revealed that PCOS patients were in a chronic inflammatory state, and they had abnormally activated macrophages. This paper introduces the relationship between PCOS and macrophages. The forkhead box protein O1 (FOXO-1), migration inhibitory factor, sympathetic conservation disorder, and vitamin D are believed to influence macrophages in PCOS. There is evidence that PCOS-associated abnormalities are associated with macrophages, including insulin resistance, obesity, hyperandrogenism (HA), hyperhomocysteinemia (HHcy), cardiometabolic disorder and gut microbiota dysbiosis. This review summarizes the research status of macrophages in PCOS. Macrophages might be a potential PCOS treatment candidate.
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Affiliation(s)
- Li Li
- Department of Histology and Embryology, Hunan University of Medicine, Huaihua, China
| | - Yubo Xiao
- School of Public Health and Laboratory Medicine, Hunan University of Medicine, Huaihua, China
| | - Wenwei Wen
- Department of Orthopedics, Sanming First Hospital Affiliated to Fujian Medical University, Sanming, Fujian, China
| | - Qi Liu
- School of Public Health and Laboratory Medicine, Hunan University of Medicine, Huaihua, China
| | - Le Wei
- Department of Histology and Embryology, Hunan University of Medicine, Huaihua, China
| | - Pinyue Liu
- Department of Histology and Embryology, Hunan University of Medicine, Huaihua, China
| | - Ming Li
- Department of Histology and Embryology, Hunan University of Medicine, Huaihua, China
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Rao HC, Meyer ML, Kominiarek MA, Daviglus ML, Gallo LC, Cordero C, Syan R, Perreira KM, Talavera GA, Fernández-Rhodes L. Polycystic Ovary Syndrome, Metabolic Syndrome, and Inflammation in the Hispanic Community Health Study/Study of Latinos. J Clin Endocrinol Metab 2025; 110:1384-1397. [PMID: 38888178 PMCID: PMC12012804 DOI: 10.1210/clinem/dgae426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is a multifaceted endocrine disorder with reproductive and metabolic dysregulation. PCOS has been associated with inflammation and metabolic syndrome (MetS); however, the moderating effects of inflammation as measured by C-reactive protein (CRP) and menopause on the PCOS-MetS association have not been studied in Hispanic/Latinas with PCOS who have a higher metabolic burden. OBJECTIVE We studied the cross-sectional association between PCOS and (1) MetS in 7316 females of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), (2) subcomponents of MetS including impaired fasting glucose (IFG) and elevated triglycerides (TGL), and (3) effect modification by menopausal status and CRP. DESIGN The HCHS/SOL is a multicenter, longitudinal, and observational study of US Hispanic/Latinos. Our study sample included females from visit 2 with self-reported PCOS and MetS (ages 23-82 years). RESULTS PCOS (prevalence = 18.8%) was significantly associated with MetS prevalence [odds ratio [odds ratio (OR) = 1.41 (95% confidence interval: 1.13-1.76)], IFG and TGL (OR = 1.42 (1.18-1.72), OR = 1.48 (1.20-1.83), respectively]. We observed effect modification by menopausal status (ORpre = 1.46, Pint= .02; ORpost = 1.34, Pint= .06) and CRP (ORelevated = 1.41, Pint= .04; ORnormal = 1.26, Pint= .16) on the PCOS-MetS association. We also observed a superadditive interaction between CRP and PCOS, adjusting for which resulted in an attenuated effect of PCOS on MetS (OR = 1.29 [0.93-1.78]). CONCLUSION Hispanic/Latino females with PCOS had higher odds of MetS, IFG, and elevated TGL than their peers without PCOS. Interaction analyses revealed that the odds of MetS are higher among PCOS females who have premenopausal status or high inflammation. Interventions in Hispanic/Latinas should target these outcomes for effective management of the disease.
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Affiliation(s)
- Hridya C Rao
- Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA 16802, USA
| | - Michelle L Meyer
- Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Michelle A Kominiarek
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA
| | - Martha L Daviglus
- Institute of Minority Health Research, University of Illinois, Chicago, IL 60612, USA
| | - Linda C Gallo
- Department of Psychology, San Diego State University, San Diego, CA 92182, USA
| | | | - Raveen Syan
- Department of Urology, University of Miami, Miami, FL 33136, USA
| | - Krista M Perreira
- Department of Social Medicine, HCHS/SOL Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Gregory A Talavera
- Department of Psychology, San Diego State University, San Diego, CA 92182, USA
| | - Lindsay Fernández-Rhodes
- Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA 16802, USA
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Li X, Li Y, Zhang B, Wang J, Yang Y, Du Y. Plasma cytokine levels and PCOS risk: Mendelian randomization analysis reveals IL6R as a preventive factor. J Ovarian Res 2025; 18:69. [PMID: 40181376 PMCID: PMC11966818 DOI: 10.1186/s13048-025-01647-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 03/15/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Polycystic ovary syndrome is a prevalent gynecological condition affecting primarily women of childbearing age. It is characterized by elevated androgen levels, ovulatory dysfunction, and morphological abnormalities. Despite extensive research from various perspectives, the etiology and pathogenesis of PCOS remain unclear. While controversial, many believe that individuals with PCOS exhibit a chronic low-grade inflammatory state. Cytokines play diverse roles in the initiation and progression of inflammation, contributing to this inflammatory milieu. Therefore, the aim of this study was to utilize publicly available genome-wide association study data to explore the potential causal relationship between cytokines and PCOS. METHODS To accurately investigate the causal relationship between cytokines and PCOS, we initially defined cytokines using the GeneCrad and then identified cytokines in two independent large-scale plasma proteins. Subsequently, we employed a two-sample Mendelian randomization analysis framework. A series of quality control procedures were implemented to select eligible instrumental variables closely associated with the exposure. MR analysis was conducted using genome-wide association studies of PCOS in two independent European ancestry groups. Cochran, s Q test, MR-Egger and intercept test were employed to assess heterogeneity and pleiotropy in PCOS. Co-localization analysis, summary-data-based Mendelian randomization analysis, and HEIDI testing were utilized to further corroborate the relationship between positive findings and PCOS. Finally, systematical Mendelian randomization analysis between healthy lifestyle factors and PCOS-related proteins was conducted to identify which proteins could act as interventional targets by lifestyle changes. RESULTS In our investigation, we performed Mendelian randomization analysis on 33 cytokines in relation to PCOS using data from the deCODE and the Fenland. Our findings revealed that the plasma level of IL6R emerges as a notable protective factor against PCOS, exhibiting a substantial effect size. Moreover, we identified CCL22 as a significant risk factor for PCOS, a finding that was similarly validated and supported by independent cohorts. CONCLUSION Our Mendelian randomization analysis, leveraging genome-wide association study data from a sizable population cohort, unequivocally delineated a causal relationship between IL6R and PCOS. These results underscore the involvement of cytokines in the pathogenesis of PCOS and highlight their potential as promising therapeutic targets for addressing this intricate disease.
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Affiliation(s)
- Xiaopei Li
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yan Li
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Bumei Zhang
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Jianmei Wang
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China.
| | - Yang Yang
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China.
- Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, China.
| | - Yongrui Du
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China.
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Patnaik N, Sarkar U, Jojula M, Vaddiraju H, Dey RJ. Comprehensive Assessment of Genital Infections and Reproductive Health in Women Visiting a Fertility Clinic in Warangal, India-A Case-Control Study. Health Sci Rep 2025; 8:e70659. [PMID: 40256136 PMCID: PMC12007467 DOI: 10.1002/hsr2.70659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 01/04/2025] [Accepted: 03/21/2025] [Indexed: 04/22/2025] Open
Abstract
Background Female infertility is a global health issue however, its link with genital infections is often overlooked due to asymptomatic nature of infections. Delayed diagnosis and treatment due to absence of reliable point-of-care (POC) tools result in long-term pathological consequences and infertility. This pilot-scale study aims to identify the most noteworthy prognostic symptoms of genital infections that exhibit a significant correlation with reproductive tract disorders and infertility. Methods We designed a detailed questionnaire and conducted a case-control, observational study with 100 female patients, categorized into infertile (n1 = 62) and healthy groups (n2 = 38) followed by statistical analysis. Results This study highlights an early onset of infertility (18-25 years). Approximately 27% of the infertile female patients are symptomatic for genital infections, and ~42% exhibit menstrual irregularities. Polycystic ovarian syndrome/disease (PCOS/PCOD, ~30%) appears to be the most predominant disorder, followed by endometrial disorders (~10%) and tubal damage (~8%) in infertile patients. A multivariate correlation analysis revealed a highly significant (p ≤ 0.05) and strong association (0.15 < Φ ≤ 1.0) between menstrual disorders, endometrial disorders, uterine/tubal blockage, and hormonal disruption with infection-associated symptoms, e.g. vaginitis, cervicitis, pelvic inflammatory disorder (PID), dyspareunia or infections like tuberculosis (TB) & urinary tract infection (UTI). Conclusions Our study shows a significant contribution of genital infections to female infertility. Nevertheless, a substantial 73% of infertile patients are ineligible for confirmatory diagnosis due to the absence of classical infection symptoms. This underscores the pressing requirement for comprehensive screening strategies for timely management of reproductive health and fertility. Patient or Public Contribution This study was performed in line with the principles of the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines (Supporting Information 1) [1]. The study was performed following an ethical approval of the Institutional Human Ethics Committee. All individuals who participated in the study were fully informed about various aspects, including the study's objectives, methodologies, sources of funding, potential conflicts of interest, institutional affiliations of the researcher, anticipated benefits, potential risks, and the discomfort they might experience. Their participation was contingent on obtaining their informed consent (See Supporting Information 2 for patient consent form). Furthermore, to safeguard patient confidentiality, we took measures to de-identify patient information. This included the removal of exact ages, which were replaced with age ranges, and the omission of exact dates or photographs during presentation of the data.
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Affiliation(s)
- Naresh Patnaik
- Department of Biological SciencesBirla Institute of Technology and Science, Pilani, Hyderabad CampusHyderabadTelangana StateIndia
| | - Uttam Sarkar
- Department of Animal Genetics and BreedingWest Bengal University of Animal and Fishery SciencesWest BengalIndia
| | - Malathi Jojula
- Department of MicrobiologySri Shivani College of PharmacyWarangalTelangana StateIndia
| | | | - Ruchi Jain Dey
- Department of Biological SciencesBirla Institute of Technology and Science, Pilani, Hyderabad CampusHyderabadTelangana StateIndia
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Zeb S, Gul R, Ashraf, Rumman. Comparative Analysis of Interleukin-6 Levels in Polycystic Ovary Syndrome (PCOS) Patients With and Without Insulin Resistance. Cureus 2025; 17:e81878. [PMID: 40226143 PMCID: PMC11986271 DOI: 10.7759/cureus.81878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2025] [Indexed: 04/15/2025] Open
Abstract
Background Polycystic ovary syndrome (PCOS) is an endocrine disorder prevalent in reproductive-aged women, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. It is often associated with insulin resistance, increasing risks for metabolic disorders such as diabetes and cardiovascular disease. Elevated interleukin-6 (IL-6) levels indicate chronic inflammation, a key component in PCOS pathogenesis, though its precise role and diagnostic potential remain unclear. Objective This study aims to evaluate the relationship between IL-6 concentrations and the severity of insulin resistance in patients with PCOS and to assess the potential of IL-6 as a diagnostic biomarker for insulin resistance within these patients. Methodology This cross-sectional study was carried out from February 2024 to January 2025 at the Departments of Medicine and Gynecology, Mardan Medical Complex Teaching Hospital, Khyber Pakhtunkhwa, Pakistan. Patients were divided into insulin-resistant and non-insulin-resistant groups based on clinical assessments. Pearson correlation and linear regression analyses were employed to investigate the relationship between IL-6 levels and study variables, adjusting for significant correlations and potential confounders. The relationship between insulin resistance and IL-6 levels was examined through linear regression. The study also evaluated IL-6's predictive ability for insulin resistance using receiver operating characteristic (ROC) curve analysis, calculating the area under the curve (AUC), with a significance threshold set at p<0.05. Results This study includes 112 patients with PCOS, and significant differences were identified between insulin-resistant (39.29%, 44 patients) and non-insulin-resistant patients (60.71%, 68 patients). IL-6 levels were notably higher in insulin-resistant patients (287.00±84.33 pg/mL) compared to non-resistant patients (159.16±52.36 pg/mL). PCOS patients revealed a complex relationship better described by a simple linear regression model (R²=0.56). Additionally, ROC curve analysis demonstrated the classifier's high diagnostic accuracy (AUC=0.91) Conclusion IL-6 levels in PCOS patients were significantly influenced by a combination of physiological, metabolic, and symptomatic factors. BMI, polycystic ovaries, and specific metabolic markers emerged as key predictors, underscoring the multifaceted role of IL-6 in the pathophysiology of PCOS.
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Affiliation(s)
- Shah Zeb
- Internal Medicine, Bacha Khan Medical College, MTI Mardan Medical Complex, Mardan, PAK
| | - Reema Gul
- Gynecology, MTI Mardan Medical Complex, Mardan, PAK
| | - Ashraf
- Research and Development, Pro-Gene Diagnostics and Research Laboratory, Mardan, PAK
| | - Rumman
- Pulmonology, MTI Mardan Medical Complex, Mardan, PAK
- Pharmacovigilance/Active Drug Safety Monitoring and Management, Association for Community Development, Peshawar, PAK
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Saedi A, Zarei S, Vatanparast M, Hajizadeh MR, Hosseiniara R, Esmaeili OS, Mohammad-Sadeghipour M, Mirzaei Z, Mahmoodi M. Therapeutic effects of stevia aqueous extract alone or in combination with metformin in induced polycystic ovary syndrome rats: Gene expression, hormonal balance, and metabolomics aspects. ANNALES PHARMACEUTIQUES FRANÇAISES 2025; 83:297-310. [PMID: 39182906 DOI: 10.1016/j.pharma.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 08/27/2024]
Abstract
OBJECTIVES This study aimed to assess the individual and combined effects of SAE and Met on the expression of genes related to insulin signaling, oxidative stress, hormonal imbalance, insulin resistance, and dyslipidemia in rats with induced PCOS. METHODS The estrous cycle of 50 adult Wistar female rats was monitored through vaginal smears. Subsequently, the rats were randomly assigned into five groups of 10, including control (receiving 1ml of carboxymethyl cellulose for 49 days), induction (letrozole at 1mg/kg/d for 21 days), SAE, Met, and SAE/Met. SAE and Met were orally administered at doses of 400mg/kg/d and 250mg/kg/d on day 22 and continued for an additional 28 days. Vaginal smears were analyzed, and gene expression levels of GLUT4, SIRT1, TNF-α, and INSR were evaluated using RT-qPCR. Antioxidant parameters were assessed using detection kits. RESULTS Treatment with SAE and Met restored a regular estrous cycle pattern in PCOS rats. Furthermore, SAE and Met treatment improved hormonal balance, dyslipidemia, and hyperglycemia in the rats. Administration of SAE and Met significantly elevated levels of antioxidant enzymes SOD and GPx in ovarian tissue (P<0.001). Additionally, mRNA levels of GLUT4, SIRT1, and INSR were significantly increased in ovarian tissue following SAE and Met treatment, while TNF-α gene expression decreased significantly (P<0.0001). CONCLUSION The findings suggest that SAE and Met aqueous extract exert protective effects on letrozole-induced PCOS in rats by modulating gene expression associated with insulin signaling and oxidative stress.
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Affiliation(s)
- A Saedi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - S Zarei
- Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - M Vatanparast
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - M R Hajizadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - R Hosseiniara
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - O S Esmaeili
- Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - M Mohammad-Sadeghipour
- Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Z Mirzaei
- Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - M Mahmoodi
- Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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Darlas M, Kalantaridou S, Valsamakis G. Maternal Hyperandrogenemia and the Long-Term Neuropsychological, Sex Developmental, and Metabolic Effects on Offspring. Int J Mol Sci 2025; 26:2199. [PMID: 40076815 PMCID: PMC11901017 DOI: 10.3390/ijms26052199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Maternal hormonal and metabolic disorders, such as diabetes and obesity, can adversely affect the intrauterine environment, resulting in suboptimal fetal growth and an elevated risk of cardiovascular and metabolic diseases in the later life of the offspring. In this review, we examine the long-term impact of elevated maternal androgen levels during pregnancy on offspring. Maternal hyperandrogenemia is linked to various neurodevelopmental disorders, including attention-deficit/hyperactivity disorder, autism spectrum disorder, and anxiety-like behaviors, mediated by alterations in key brain regions responsible for emotion and cognition. Furthermore, children born to mothers with hyperandrogenemia exhibit heightened risk of metabolic and cardiovascular dysfunctions, such as obesity, insulin resistance, and hypertension, which can manifest early in life. Prenatal exposure to androgens has also been linked to reduced birth weights and altered fetal growth, potentially due to impaired placental function. Additionally, maternal testosterone levels influence offspring sex ratios, often favoring male births, though exceptions occur in certain conditions, such as congenital adrenal hyperplasia. The findings of this review underscore the need for healthcare professionals to monitor maternal serum androgen profiles during pregnancy. Further research is needed to determine underlying mechanisms and potential interventions to mitigate these risks.
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Affiliation(s)
- Menelaos Darlas
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece;
| | - Sophia Kalantaridou
- 3nd Department of Obstetrics and Gynecology, ‘Attikon’ General Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Georgios Valsamakis
- 2nd Department of Obstetrics and Gynaecology, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece
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Abu-Zaid A, Alzayed MM, Albahrani SJ, Almaqhawi A, Al Shaikh MA, Baradwan S, Almudiheem NA, Abuzaid M, Adly HM, Saleh SAK, Alomar O. Does Magnesium Affect Sex Hormones and Cardiometabolic Risk Factors in Patients with PCOS? Findings from a Systematic Review and Meta-Analysis. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:280. [PMID: 40005397 PMCID: PMC11857371 DOI: 10.3390/medicina61020280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/22/2024] [Accepted: 02/04/2025] [Indexed: 02/27/2025]
Abstract
Background and Objectives: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with various cardiometabolic risk factors, including insulin resistance, dyslipidemia, hypertension, and obesity, which contribute to an increased risk of cardiovascular diseases. This inaugural systematic review and meta-analysis of randomized controlled trials (RCTs) evaluated the impact of magnesium supplementation on various cardiometabolic risk factors and hormonal parameters in patients with polycystic ovary syndrome (PCOS). Materials and Methods: We systematically searched the MEDLINE, Web of Science, Scopus, and Cochrane databases until 30 March 2024 for studies comparing magnesium supplementation to control in improving cardiometabolic and hormonal factors in PCOS patients. Endpoints were summarized as mean differences (MD) and 95% confidence intervals (CIs) in a random-effects model. Results: The primary search yielded 176 studies. After screening, six studies met our inclusion criteria. Our meta-analysis showed no significant effects of magnesium supplementation on cardiometabolic risk factors and hormonal parameters in patients with PCOS. Conclusions: Magnesium supplementation does not appear to influence the cardiometabolic and hormonal factors in PCOS patients. Further rigorous RCTs are needed to strengthen the evidence and support comprehensive analysis in this area. PROSPERO database (CRD42024526110).
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Affiliation(s)
- Ahmed Abu-Zaid
- Department of Biochemistry and Molecular Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Mooza M. Alzayed
- College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Bahrain
| | - Suha Jafar Albahrani
- Department of Family and Community Medicine, College of Medicine, King Faisal University, Al Hofuf 31982, Saudi Arabia
| | - Abdullah Almaqhawi
- Department of Family and Community Medicine, College of Medicine, King Faisal University, Al Hofuf 31982, Saudi Arabia
| | - Mona Ahmed Al Shaikh
- Department of Family Medicine, Eastern Health Cluster, Dammam 32253, Saudi Arabia
| | - Saeed Baradwan
- Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Jeddah 23433, Saudi Arabia
| | | | - Mohammed Abuzaid
- Department of Obstetrics and Gynecology, Al Birk General Hospital, Al Birk 63525, Saudi Arabia
| | - Heba M. Adly
- Department of Community Medicine and Pilgrims Healthcare, Faculty of Medicine, Umm Al-Qura University, Makkah 24382, Saudi Arabia
| | - Saleh A. K. Saleh
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah 24382, Saudi Arabia
| | - Osama Alomar
- Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia
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Yadav S, Dadge S, Garg R, Goand UK, Agarwal A, Chauhan D, Gayen JR. Pancreastatin inhibitor PSTi8 improves ovarian health in Letrozole-HFD induced PCOS rats by ameliorating metabolic and reproductive parameters. Steroids 2025; 214:109558. [PMID: 39742935 DOI: 10.1016/j.steroids.2024.109558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/24/2024] [Accepted: 12/28/2024] [Indexed: 01/04/2025]
Abstract
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder associated with insulin resistance (IR) and hyperandrogenism. IR plays a crucial role in the etiology of PCOS. An insulin-sensitizing agent like metformin is most commonly used as an off-label drug for the treatment of PCOS. PSTi8 (a pancreastatin inhibitor) is known as a promising therapeutic insulin-sensitizing agent for the treatment of IR in metabolic diseases. Thus, this study evaluates the insulin-sensitizing effects of PSTi8 compared to metformin on IR, hyperandrogenism, ovarian, and metabolic dysfunction in a PCOS model. To induce PCOS, rats were administered letrozole at a dose of 2 mg/kg via oral administration and fed a 60 % high-fat diet. Metformin and PSTi8 lowered serum insulin, testosterone, luteinizing hormone (LH) levels, and the LH/follicle-stimulating hormone ratio in the blood serum and improved steroidogenic gene expression in the PCOS ovaries. Both treatments increased the levels of sex hormone-binding globulin and estrogen hormone. Metformin and PSTi8 restore ovarian and uterine histomorphometry and improve the estrous cycle in PCOS rats. Metformin and PSTi8 treatments also improve blood glucose level and increase insulin sensitivity, inflammation, reactive oxygen species accumulation, lipid parameters, body weight, and fat mass in PCOS rats. This study revealed that PSTi8 is as helpful as metformin in decreasing hyperandrogenism by improving insulin sensitivity, free testosterone level and restoring disturbed reproductive and metabolic parameters in PCOS rats. PSTi8 has potential to serve as a therapeutic molecule for preventing IR induced by a western diet in PCOS.
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Affiliation(s)
- Shubhi Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Shailesh Dadge
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Richa Garg
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Umesh K Goand
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Arun Agarwal
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Divya Chauhan
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Jiaur R Gayen
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India.
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12
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Yang W, Ma Y, Wu Y, Lei X, Zhang J, Li M. Study on the effects of Mogroside V in inhibiting NLRP3-mediated granulosa cell pyroptosis and insulin resistance to improve PCOS. J Ovarian Res 2025; 18:10. [PMID: 39838421 PMCID: PMC11748252 DOI: 10.1186/s13048-024-01563-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 11/20/2024] [Indexed: 01/23/2025] Open
Abstract
OBJECTIVE Polycystic Ovary Syndrome (PCOS) is a prevalent endocrinopathy in reproductive-aged women, contributing to 75% of infertility cases due to ovulatory dysfunction. The condition poses significant health and psychological challenges, making the study of its pathogenesis and treatment a research priority. This study investigates the effects of Mogroside V (MV) on PCOS, focusing on its anti-inflammatory and anti-insulin resistance properties. METHODS Forty-five female Sprague-Dawley rats were divided into three groups: control, PCOS model, and MV treatment. The PCOS model was induced using a high-fat diet and letrozole. The MV treatment group was subsequently administered MV after the establishment of the PCOS model. The study monitored body mass, assessed estrous cycle changes, and measured serum hormone levels. Transcriptome sequencing and bioinformatics were used to identify differentially expressed genes related to inflammation and insulin resistance. Expression of pyroptosis and insulin resistance markers was analyzed using qRT-PCR, Western blot, and IHC. Additionally, an in vitro model assessed MV's impact on inflammation and insulin resistance. RESULTS The PCOS group exhibited elevated serum testosterone (T), luteinizing hormone (LH), insulin, and fasting glucose levels, along with increased insulin resistance (HOMA-IR) and decreased estradiol (E2), which were reversed by MV treatment. Transcriptome analysis identified significant gene expression changes between groups, particularly in pathways related to NLRP3 inflammation and insulin metabolism. MV treatment normalized the expression of ovarian pyroptosis factors (NLRP3, Caspase-1, GSDMD) and inflammatory cytokines (IL-1β, IL-18). In cellular models, MV increased E2 levels, reduced LDH release, and decreased the expression of insulin resistance and pyroptosis markers. Correlation analysis showed pyroptosis factors were positively correlated with HOMA-IR and IGF1, and negatively with IGF1R and E2 levels. CONCLUSION MV improves PCOS by reducing pyroptosis and insulin resistance, enhancing insulin sensitivity, and promoting estrogen synthesis, thereby restoring granulosa cell function and follicular development.
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Affiliation(s)
- Wenqin Yang
- The First Affiliated Hospital, Gynecology&Obstetrics and Reproductive Medical Center, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yujie Ma
- Reproductive Medical Center, The Central Hospital of Shaoyang, Shaoyang, Hunan, China
| | - Yafei Wu
- The First Affiliated Hospital, Gynecology&Obstetrics and Reproductive Medical Center, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaocan Lei
- The First Affiliated Hospital, Gynecology&Obstetrics and Reproductive Medical Center, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jing Zhang
- Gynecology & Obstetrics and Reproductive Medical Center, School of Basic Medical Sciences, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China.
| | - Meixiang Li
- The First Affiliated Hospital, Gynecology&Obstetrics and Reproductive Medical Center, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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13
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Gautam R, Maan P, Jyoti A, Kumar A, Malhotra N, Arora T. The Role of Lifestyle Interventions in PCOS Management: A Systematic Review. Nutrients 2025; 17:310. [PMID: 39861440 PMCID: PMC11767734 DOI: 10.3390/nu17020310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders among reproductive-aged women. It is characterized by hyperandrogenism, anovulation, and polycystic ovaries. Lifestyle changes are suggested as first-line interventions in managing PCOS. This systematic review aims to assess the scientific evidence regarding the role of lifestyle modifications (dietary changes, physical activity, and behavioral changes) in improving reproductive, anthropometric, metabolic, and psychological outcomes in women with PCOS. Dietary interventions such as foods with low glycemic index scores; caloric restrictions; high-fiber, omega three fatty acid-rich diets; ketogenic diets; Mediterranean diets; antioxidant-rich food; and anti-inflammatory diets improve insulin sensitivity and hormonal balance in women with PCOS. Physical activity, like aerobic and resistance exercise, enhances insulin sensitivity, helps weight loss, and improves metabolic and reproductive outcomes in women with PCOS. Further, behavioral and education modules can also be used to improve awareness, adherence, and the effectiveness of conventional treatment and to manage mental health issues related to PCOS. Collectively, lifestyle modifications not only improve the biochemical, hormonal, and anthropometric parameters in PCOS patients but also reduce the long-term risks of metabolic and cardiovascular diseases.
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Affiliation(s)
- Rohit Gautam
- Division of Reproductive Child Health and Nutrition, Indian Council of Medical Research (ICMR), New Delhi 110029, India; (R.G.); (P.M.)
| | - Pratibha Maan
- Division of Reproductive Child Health and Nutrition, Indian Council of Medical Research (ICMR), New Delhi 110029, India; (R.G.); (P.M.)
| | - Anshu Jyoti
- Department of Obstetrics and Gynecology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India; (A.J.); (A.K.)
| | - Anshu Kumar
- Department of Obstetrics and Gynecology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India; (A.J.); (A.K.)
| | - Neena Malhotra
- Department of Obstetrics and Gynecology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India; (A.J.); (A.K.)
| | - Taruna Arora
- Division of Reproductive Child Health and Nutrition, Indian Council of Medical Research (ICMR), New Delhi 110029, India; (R.G.); (P.M.)
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14
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Kumari D, Kumar M, Upadhyay AD, Malhotra N, Mahey R, Dadhwal V, Sehgal T, Mishra R, Dada R. Unveiling Therapeutic Potential of Yoga Mitigating Oxidative Stress and Mitochondrial Dysfunction in PCOS: A Randomized Controlled Trial. Int J Yoga 2025; 18:45-57. [PMID: 40365366 PMCID: PMC12068466 DOI: 10.4103/ijoy.ijoy_212_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 12/27/2024] [Accepted: 01/08/2025] [Indexed: 05/15/2025] Open
Abstract
Background Hormonal imbalance, mitochondrial dysfunctions, and oxidative stress (OS) have been implicated in the pathogenesis of polycystic ovarian syndrome (PCOS) and its associated clinical features. A sedentary lifestyle, exposure to air pollutants, prenatal exposure to endocrine-disrupting chemicals, processed and nutritionally depleted food, rich in trans fats, salts, and sugars, and high BMI specifically in visceral adiposity induce OS. OS damages the mitochondrial DNA, lipids, and proteins that impair mitochondrial function. Sequentially, dysfunctional mitochondria produce more reactive oxygen species that aggravate the OS. Mitochondria is pivotal for ovarian cell functioning for instance steroidogenesis, ovarian follicle development, and energy metabolism. Dysfunctional mitochondria can alter the ovarian follicle functioning leading to ovulatory dysfunction and infertility in PCOS. Aims and Objectives This study is designed to investigate the effect of 12-week yoga practice on endocrine parameters, OS, and mitochondrial health, comparing outcomes in yoga and non-yoga groups. Material and Methods A total of 75 participants, 32 PCOS females who completed yoga intervention in the yoga group and 29 in the nonyoga group. Hormonal levels were assessed through an immunoassay, while mitochondrial health markers, such as mtDNA copy number (mtDNA CN), reactive oxygen species, and lipid peroxidation were measured through quantitative polymerase chain reaction (qPCR), chemiluminescence, and ELISA respectively. Gene expression related to mitochondrial integrity, respiratory chain, and inflammation was analyzed via reverse transcription qPCR. Additionally, depression severity was also assessed using beck depression inventory II. Result The Yoga group showed a significant increase in mtDNA-CN and upregulation of transcripts responsible for maintaining mitochondrial integrity and the mitochondrial respiratory chain. In addition, the post-yoga group shows a reduction in, lipid peroxidation, inflammatory, OS markers, and an improvement in telomere length. Conclusion Yoga positively affects hormonal balance, mitochondrial health, OS, and inflammation in women with PCOS. It also alleviates depression symptoms, highlighting yoga as an effective adjunct therapy for managing PCOS. Regular yoga practice could prevent, delay, and help in managing PCOS symptoms.
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Affiliation(s)
- Deepika Kumari
- Department of Anatomy, Laboratory for Molecular Reproduction and Genetics, AIIMS, New Delhi, India
| | - Manoj Kumar
- Department of Anatomy, Laboratory for Molecular Reproduction and Genetics, AIIMS, New Delhi, India
| | | | - Neena Malhotra
- Department of Laboratory Medicine, AIIMS, New Delhi, India
| | - Reeta Mahey
- Department of Laboratory Medicine, AIIMS, New Delhi, India
| | | | - Tushar Sehgal
- Department of Obstetrics and Gynaecology, AIIMS, New Delhi, India
| | - Richa Mishra
- Department of Anatomy, Laboratory for Molecular Reproduction and Genetics, AIIMS, New Delhi, India
| | - Rima Dada
- Department of Anatomy, Laboratory for Molecular Reproduction and Genetics, AIIMS, New Delhi, India
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15
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Nandakumar M, Das P, Sathyapalan T, Butler AE, Atkin SL. Cardiovascular Risk Biomarkers in Women with and Without Polycystic Ovary Syndrome. Biomolecules 2024; 15:4. [PMID: 39858399 PMCID: PMC11763313 DOI: 10.3390/biom15010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, highlighting potential biomarkers for CVD in PCOS. METHODS In this exploratory cross-sectional study, plasma levels of 54 CVRPs were analyzed in women with PCOS (n = 147) and controls (n = 97). CVRPs were measured using the SOMAscan proteomic platform (version 3.1), with significant proteins identified through linear models, regression analysis, and receiver operating characteristic (ROC) analysis. Analysis on BMI-matched subsets of the cohort were undertaken. Functional enrichment and protein-protein interaction analyses elucidated the pathways involved. RESULTS Eleven CVRPs were dysregulated in PCOS (whole set, without matching for body mass index (BMI) or insulin resistance (IR)): leptin, Interleukin-1 receptor antagonist protein (IL-1Ra), polymeric immunoglobulin receptor (PIGR), interleukin-18 receptor (IL-18Ra), C-C motif chemokine 3 (MIP-1a), and angiopoietin-1 (ANGPT1) were upregulated whilst advanced glycosylation end product-specific receptor, soluble (sRAGE), bone morphogenetic protein 6 (BMP6); growth/differentiation factor 2 (GDF2), superoxide dismutase [Mn] mitochondrial (MnSOD), and SLAM family member 5 (SLAF5) were downregulated versus the controls. In BMI-matched (overweight/obese, BMI ≥ 26 kg/m2) subset analysis, six CVRPs were common to the whole set: ANGPT1 and IL-1Ra were upregulated; and sRAGE, BMP6, GDF2, and Mn-SOD were downregulated. In addition, lymphotactin (XCL1) was upregulated and placenta growth factor (PIGF), alpha-L-iduronidase (IDUA), angiopoietin-1 receptor, and soluble (sTie-2) and macrophage metalloelastase (MMP12) were downregulated. A subset analysis of BMI-matched plus insulin resistance (IR)-matched women revealed only upregulation of tissue factor (TF) and renin in PCOS, potentially serving as biomarkers for cardiovascular risk in overweight/obese women with PCOS. CONCLUSIONS A combination of upregulated obesity-related CVRPs (ANGPT1/IL/1Ra/XCL1) and downregulated cardioprotective proteins (sRAGE/BMP6/Mn-SOD/GDF2) in overweight/obese PCOS women may contribute to the increased risk for CVD. TF and renin upregulation observed in the BMI- and IR-matched limited sample PCOS subgroup indicates their potential risk of CVD.
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Affiliation(s)
- Manjula Nandakumar
- Research Department, Royal College of Surgeons of Ireland, Adliya, Busaiteen 15503, Bahrain; (M.N.); (P.D.); (S.L.A.)
| | - Priya Das
- Research Department, Royal College of Surgeons of Ireland, Adliya, Busaiteen 15503, Bahrain; (M.N.); (P.D.); (S.L.A.)
| | - Thozhukat Sathyapalan
- Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, Hull HU6 7RU, UK;
| | - Alexandra E. Butler
- Research Department, Royal College of Surgeons of Ireland, Adliya, Busaiteen 15503, Bahrain; (M.N.); (P.D.); (S.L.A.)
| | - Stephen L. Atkin
- Research Department, Royal College of Surgeons of Ireland, Adliya, Busaiteen 15503, Bahrain; (M.N.); (P.D.); (S.L.A.)
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16
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Wu R, Gragnoli C. The melanocortin receptor genes are linked to and associated with the risk of polycystic ovary syndrome in Italian families. J Ovarian Res 2024; 17:242. [PMID: 39633478 PMCID: PMC11619144 DOI: 10.1186/s13048-024-01567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder occurring in women of reproductive age. The disease is caused by a complex interplay of genetic and environmental factors including genes encoding components of the hypothalamic-pituitary-adrenal (HPA) axis. We have recently reported the association of melanocortin receptor genes (MC1R, MC2R, MC3R, MC4R, and MC5R) with the risk of type 2 diabetes (T2D) and/or major depressive disorder (MDD). The latter 2 disorders are comorbid with PCOS. In this study, we used microarray to test 12 single nucleotide polymorphisms (SNPs) in the MC1R gene, 10 SNPs in the MC2R gene, 5 SNPs in the MC3R gene, 6 SNPs in the MC4R gene, and 4 SNPs in the MC5R gene in 212 original Italian families with PCOS. We identified 1 SNP in MC1R, 1 SNP in MC2R, 2 SNPs in MC3R, and 2 SNPs in MC5R significantly linked and/or associated to/with the risk of PCOS in Italian families. This is the first study to report the novel implication of melanocortin receptor genes (MC1R, MC2R, and MC5R) in PCOS. MC3R and MC4R were previously reported in PCOS. However, functional studies are needed to validate these results.
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MESH Headings
- Humans
- Polycystic Ovary Syndrome/genetics
- Female
- Polymorphism, Single Nucleotide
- Italy/epidemiology
- Genetic Predisposition to Disease
- Receptors, Melanocortin/genetics
- Receptor, Melanocortin, Type 1/genetics
- Receptor, Melanocortin, Type 4/genetics
- Adult
- Receptor, Melanocortin, Type 2/genetics
- Receptor, Melanocortin, Type 3/genetics
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Affiliation(s)
- Rongling Wu
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA
- Department of Statistics, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Claudia Gragnoli
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA.
- Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USA.
- Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, Rome, 00197, Italy.
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Jia MJ, Zhou L, Liu XN, Li HL. Genetically predicted serum metabolites mediate the association between inflammatory proteins and polycystic ovary syndrome: a Mendelian randomization study. Front Med (Lausanne) 2024; 11:1433612. [PMID: 39691364 PMCID: PMC11649973 DOI: 10.3389/fmed.2024.1433612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 11/18/2024] [Indexed: 12/19/2024] Open
Abstract
Objective To investigate the association between polycystic ovary syndrome (PCOS) and inflammatory proteins, and to identify and quantify the role of serum metabolites as potential mediators. Methods Utilizing summary-level data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian Randomization (MR) analysis, a genetic approach that uses genetic variants as instrumental variables to assess the causal relationships between risk factors and outcomes. This analysis involved genetically predicted PCOS (1,639 cases and 218,970 controls) and inflammatory proteins (14,824 participants of primarily European descent). Additionally, a two-step MR analysis was performed to quantify the proportion of the effect of serum metabolites-mediated inflammatory proteins on PCOS. The Inverse Variance Weighted (IVW) method, a statistical technique used within MR to combine data from multiple genetic variants, was used to estimate the causal effects. Results The IVW method revealed that the inflammatory proteins IFN-γ (p-value = 0.037, OR = 1.396, 95% CI = 1.020-1.910) and CCL7 (p-value = 0.033, OR = 1.294, 95% CI = 1.021-1.641) were associated with an increased risk of PCOS, while IL-6 (p-value = 0.015, OR = 0.678, 95% CI = 0.495-0.929) and MMP-10 (p-value = 0.025, OR = 0.753, 95% CI = 0.587-0.967) were associated with a decreased risk. No significant evidence suggested an effect of genetically predicted PCOS on inflammatory proteins. The serum metabolite X-11444 was found to mediate 5.44% (95% CI: 10.8-0.0383%) of the effect of MMP-10 on PCOS. Conclusion This study not only introduces novel causal associations between inflammatory proteins and PCOS but also highlights the mediating role of serum metabolites in these associations. By applying MR, we were able to minimize confounding and reverse causality, offering robust insights into the biological mechanisms underlying PCOS. These findings advance the understanding of PCOS pathogenesis, particularly in relation to inflammatory pathways and serum metabolite interactions, and suggest potential therapeutic targets that could inform future clinical interventions aimed at mitigating inflammation-related PCOS risks.
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Affiliation(s)
- Ming-Jie Jia
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Li Zhou
- Institute of Depression and Comorbidity, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xing-Ning Liu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Hui-Lin Li
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
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Bahreiny SS, Ahangarpour A, Harooni E, Amraei M, Aghaei M, Fard RM. Closer look at circulating nitric oxide levels and their association with polycystic ovary syndrome: A meta-analytical exploration. Int J Reprod Biomed 2024; 22:943-962. [PMID: 39968366 PMCID: PMC11830925 DOI: 10.18502/ijrm.v22i12.18061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 10/08/2024] [Accepted: 11/16/2024] [Indexed: 02/20/2025] Open
Abstract
Background Polycystic ovary syndrome (PCOS) casts a wide shadow over the reproductive health of millions of women worldwide, emerging as one of the most complex and multifaceted endocrine disorders. In addition, nitric oxide (NO) stands out as a pivotal signaling molecule, orchestrating a symphony of physiological processes. Objective This meta-analysis aims to elucidate the association between NO levels and PCOS, investigate the potential of NO as a biomarker for PCOS diagnosis, and evaluate its clinical significance. Materials and Methods A systematic review was conducted in several electronic databases, including PubMed, Web of Science, Cochrane Library, Scopus, EMBASE, and Google Scholar, to identify relevant studies published up to January 2024. Standardized mean difference and 95% CI were calculated using a random effects model to assess the overall effect size. Meta-regressions and subgroup analysis were performed to investigate sources of heterogeneity. Results A meta-analysis of 14 studies with 1171 participants showed that NO levels were significantly lower in the PCOS group than in the control group. The pooled analysis yielded a standardized mean difference of -0.482; 95% CI: -0.908 to -0.056; p = 0.027. Subgroup analyses further demonstrated variations in NO levels between different PCOS phenotypes and in relation to metabolic parameters. Conclusion This meta-analysis provides evidence for an association between PCOS and dysregulated NO levels and suggests a potential role of NO as a biomarker in the diagnosis and pathogenesis of PCOS.
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Affiliation(s)
- Seyed Sobhan Bahreiny
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Medical Basic Sciences Research Institute, Physiology Research Center, Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Akram Ahangarpour
- Medical Basic Sciences Research Institute, Physiology Research Center, Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Elnaz Harooni
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Medical Basic Sciences Research Institute, Physiology Research Center, Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahdi Amraei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Mohammadpour Fard
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Zhang G, He M, Wang Z, Zheng J, Zhao D, Nie L, Yuan D, Zhao Z, Wang W, Yue L. Synergistic Effect and Mechanism of Combined Astaxanthin and Curcumin Administration on Ovarian Function in PCOS Mice. Food Sci Nutr 2024; 12:10618-10627. [PMID: 39723041 PMCID: PMC11666913 DOI: 10.1002/fsn3.4597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/11/2024] [Accepted: 10/25/2024] [Indexed: 12/28/2024] Open
Abstract
To investigate the synergistic effect of astaxanthin and curcumin on ovarian function in polycystic ovary syndrome (PCOS) mice and to elucidate the underlying mechanisms, fifty 4-week-old female mice were randomly divided into five groups: (i) normal control group; (ii) PCOS model group; (iii) PCOS + astaxanthin group; (iv) PCOS + curcumin group; and (v) PCOS + astaxanthin-curcumin. Throughout the study, various parameters were meticulously evaluated, including serum levels of key reproductive hormones (testosterone (T), estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Müllerian hormone (AMH)), as well as monitoring alterations in the estrous cycle, follicle development, and ovulation rates. Additionally, markers of oxidative stress and inflammation were measured. Findings revealed that PCOS mice exhibited disordered estrous cycle, polycystic ovarian morphologies, abnormal serum reproductive hormones and lipid metabolism, heightened oxidative stress, and augmented inflammatory responses. Notably, upon administration of the combined astaxanthin and curcumin, PCOS mice exhibited significant improvements in their estrous cyclicity and ovarian histology. The treatment led to a significant reduction in serum total cholesterol (TC) levels and normalization of T, E2, FSH, LH, and AMH levels. Moreover, there was a marked decrease in the levels of serum reactive oxygen species (ROS) and malondialdehyde (MDA), indicating attenuation of oxidative stress. Concurrently, the activity of the antioxidant enzyme catalase (CAT) significantly increased, while proinflammatory cytokines interferon-γ (IFN-γ) and interleukin-6 (IL-6) in the ovarian tissue were notably decreased. The combined treatment also resulted in a substantial increase in the number of ova and a significant decline in the rate of abnormal ova, with these therapeutic effects proving more effective compared to either astaxanthin or curcumin alone. In conclusion, the co-administration of astaxanthin and curcumin demonstrated a remarkable effect in improving abnormal lipid metabolism and restoring reproductive endocrine functions in PCOS mice. Furthermore, it effectively mitigated systemic and local oxidative stress and chronic inflammatory injury, thereby promoting follicular growth and enhancing ovulatory function in the context of PCOS.
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Affiliation(s)
- Gao Zhang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Man He
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Zun Wang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Jinrong Zheng
- South China Biopharmaceutical (Shenzhen) Co, LtdShenzhenChina
| | - Dan Zhao
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Li Nie
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Dongzhi Yuan
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Ziyu Zhao
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Wei Wang
- South China Biopharmaceutical (Shenzhen) Co, LtdShenzhenChina
| | - Limin Yue
- Department of Physiology, West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
- Reproductive Endocrinology and Regulation Joint Laboratory, West China Second HospitalSichuan UniversityChengduChina
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20
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Tian D, Chen J, Liu L. Causal relationship between inflammatory cytokines and polycystic ovary syndrome: a bidirectional mendelian randomization study. J Ovarian Res 2024; 17:217. [PMID: 39501339 PMCID: PMC11539607 DOI: 10.1186/s13048-024-01525-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/30/2024] [Indexed: 11/08/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is defined as a chronic low-grade inflammatory reproductive endocrine disorder. PCOS can induce various metabolic disorders, which are associated with a state of mild and slow-acting inflammation. Nevertheless, the causal relationship between polycystic ovary syndrome and inflammatory factors is uncertain. The causality between inflammatory cytokines and PCOS was analyzed by bidirectional Mendelian randomization (MR) in this current probe. We performed an interactive MR study to assess the causal relationships between 91 inflammatory cytokines and PCOS using Genome Wide Association Study (GWAS) data. We underwent dual-sample MR analysis with inverse variance weights (IVW) as the predominant MR methodology with multiple validity and heterogeneity analyses. MR-Egger, weighted median, simple mode, weighted mode and MR-PRESSO were analyzed as multiple likelihood sensitivity analyses to enhance the final results.The results came out interleukin-1-alpha (IL-1 A) levels (odds ratio [OR] = 1.051, 95% fiducial interval [95% CI] = 1.009-1.095, P = 0.02) and oncostatin-M (OSM) levels ( [OR] = 1.041, [95% CI] = 1.001-1.082, P = 0.04) were positively associated with the development of PCOS. Moreover, interleukin-7 (IL-7) levels ([OR] = 0.935, [95% CI] = 0.884-0.989, P = 0.02); interleukin-15 receptor subunit alpha (IL15RA) levels ([OR] = 0.959, [95% CI] = 0.929-0.99, P = 0.01); and C-X-C motif chemokine 11 (CXCL11) levels ([OR] = 0.959, [95% CI] = 0.922-0.996. P = 0.03) were strongly negatively associated with PCOS. However, we did not find any strong positive results in the reverse analysis, suggesting that although inflammatory factors contribute to the pathogenesis of PCOS, PCOS itself does not trigger inflammatory factor production.Our study provides genetic evidence for the connection between systemic inflammatory regulators and PCOS. Treatments targeting specific inflammatory factors may help to mitigate the risk of PCOS. The levels of five of the 91 inflammatory factors included in this study, namely, IL1A and OSM, were associated with PCOS. IL1A and OSM contribute to the progression of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively correlated with the development of PCOS.
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Affiliation(s)
- Danling Tian
- Department of Endocrinology and Metabolism, Zhangzhou Affiliated Hospital of Fujian medical University, Fujian, 363000, China
| | - Jinfeng Chen
- Department of Endocrinology and Metabolism, Zhangzhou Affiliated Hospital of Fujian medical University, Fujian, 363000, China.
| | - Liang Liu
- Department of Endocrinology and Metabolism, Zhangzhou Affiliated Hospital of Fujian medical University, Fujian, 363000, China
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21
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Yuan Y, Mao Y, Yang L, Wang Y, Zhang X. Analysis of macrophage polarization and regulation characteristics in ovarian tissues of polycystic ovary syndrome. Front Med (Lausanne) 2024; 11:1417983. [PMID: 39323470 PMCID: PMC11422077 DOI: 10.3389/fmed.2024.1417983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/09/2024] [Indexed: 09/27/2024] Open
Abstract
Background Polycystic ovary syndrome (PCOS) can lead to infertility and increase the risk of endometrial cancer. Analyzing the macrophage polarization characteristics in ovarian tissues of PCOS is crucial for clinical treatment. Methods We obtained 13 PCOS and nine control ovarian samples from the CEO database and analyzed differentially expressed genes (DEGs). Macrophage polarization-related genes (MPRGs) were sourced from the GeneCards and MSigDB databases. Intersection of DEGs with MPRGs identified DEGs associated with macrophage polarization (MPRDEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-protein interaction (PPI) Network analysis were conducted on MPRDEGs. Moreover, the top 10 genes from three algorithms were identified as the hub genes of MPRGs. In addition, miRNAs, transcription factors (TFs), and drugs were retrieved from relevant databases for regulatory network analysis of mRNA-miRNA, mRNA-TF, and mRNA-Drug interactions. Immune cell composition analysis between the PCOS and control groups was performed using the CIBERSORT algorithm to calculate correlations across 22 immune cell types. Results A total of 13 PCOS samples and nine control ovarian samples were obtained in this study. We identified 714 DEGs between the two groups, with 394 up-regulated and 320 down-regulated. Additionally, we identified 774 MPRGs, from which we derived 30 MPRDEGs by intersecting with DEGs, among which 21 exhibited interaction relationships. GO and KEGG analyses revealed the enrichment of MPRDEGs in five biological processes, five cell components, five molecular functions, and three biological pathways. Immune infiltration analysis indicated a strong positive correlation between activated nature killer (NK) cells and memory B cells, while neutrophils and monocytes showed the strongest negative correlation. Further investigation of MPRDEGs identified nine hub genes associated with 41 TFs, 82 miRNAs, and 44 drugs or molecular compounds. Additionally, qRT-PCR results demonstrated overexpression of the CD163, TREM1, and TREM2 genes in ovarian tissues from the PCOS group. Conclusion This study elucidated the polarization status and regulatory characteristics of macrophages in ovarian tissues of the PCOS subjects, confirming significant overexpression of CD163, TREM1, and TREM2. These findings contribute to a deeper understanding of the pathogenesis of PCOS.
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Affiliation(s)
- Yue Yuan
- The First Hospital of Lanzhou University, Lanzhou, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Key Laboratory for Reproductive Medicine and Embryo of Gansu, Lanzhou, China
| | - Yan Mao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Gansu Provincial Hosipital, Lanzhou, China
| | - Liu Yang
- The First Hospital of Lanzhou University, Lanzhou, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Key Laboratory for Reproductive Medicine and Embryo of Gansu, Lanzhou, China
| | - Yilin Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xuehong Zhang
- The First Hospital of Lanzhou University, Lanzhou, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Key Laboratory for Reproductive Medicine and Embryo of Gansu, Lanzhou, China
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22
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Danduga RCSR, Kurapati AS, Shaik RA, Kola PK, Konidala SK, Varada HB. Synergistic Amelioration of Letrozole-induced Polycystic Ovary Syndrome in Rats: A Therapeutic Approach with Apple Cider Vinegar and Metformin Combination. Reprod Sci 2024; 31:2861-2876. [PMID: 38777948 DOI: 10.1007/s43032-024-01545-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 04/02/2024] [Indexed: 05/25/2024]
Abstract
The present study was conducted to evaluate the combination effect of apple cider vinegar (ACV) and metformin against letrozole-induced polycystic ovary syndrome (PCOS). Female Wistar rats were administered letrozole (1 mg/kg/day, p.o) for 21 days, except for the control group of animals. On the 22nd day, PCOS-induced animals were segregated into 4 groups and administered with CMC, ACV, metformin, and a combination of ACV and metformin, respectively. The treatments were continued for 15 days, and on the 36th day, all the animals were sacrificed for biochemical (blood glucose, lipid profile), hormonal (sex hormones and adiponectin), and pro-inflammatory mediator estimations in blood samples. The ovarian tissue samples were used for oxidative stress parameters and histological alterations. The PCOS control animals showed a significant alteration in the estrous cycle. The administration of letrozole resulted in the alteration of hormonal balance and elevation of body weights, glycemic state, lipid profile, pro-inflammatory mediators in serum, and oxidative stress in ovarian samples. Individual treatment groups and combination treatment groups reversed the letrozole-induced alterations in PCOS animals, and more promising results were observed with combination therapy than with individual treatment groups. Further, the therapeutic potential of the combination treatment group was also confirmed by the histological observations in the ovarian samples. The study showed that the combination of ACV and metformin significantly alleviated letrozole-induced PCOS complications in rats. This might have been achieved by mitigating the hormonal imbalance, pro-inflammatory, hyperglycemic, and hyperlipidemic states in serum, and oxidative stress in the ovary samples.
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Affiliation(s)
- Ravi Chandra Sekhara Reddy Danduga
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400056, India.
| | - Aarathi Shalom Kurapati
- Department of Pharmacology, Acharya Nagarjuna University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, 522510, India
| | - Roohi Anju Shaik
- Department of Pharmacology, Acharya Nagarjuna University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, 522510, India
| | - Phani Kumar Kola
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58203, USA
| | - Sathish Kumar Konidala
- Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Sciences, Technology, and Research, Vadlamudi, Guntur, 522213, India
| | - Hema Bharathi Varada
- Department of Pharmacology, Acharya Nagarjuna University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, 522510, India
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23
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Violette CJ, Aberle LS, Anderson ZS, Komatsu EJ, Song BB, Mandelbaum RS, Matsuzaki S, Ouzounian JG, Matsuo K. Pregnancy with endometriosis: Assessment of national-level trends, characteristics, and maternal morbidity at delivery. Eur J Obstet Gynecol Reprod Biol 2024; 299:1-11. [PMID: 38815411 DOI: 10.1016/j.ejogrb.2024.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/01/2024] [Accepted: 05/11/2024] [Indexed: 06/01/2024]
Abstract
OBJECTIVE To examine pregnancy characteristics and maternal morbidity at delivery among pregnant patients with a diagnosis of endometriosis. STUDY DESIGN This cross-sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample. Study population was 17,796,365 hospital deliveries from 2016 to 2020, excluded adenomyosis and uterine myoma. The exposure was endometriosis diagnosis. Main outcome measures were clinical and pregnancy characteristics and severe maternal morbidity at delivery related to endometriosis, assessed with multivariable regression model. RESULTS Endometriosis was diagnosed in 17,590 patients. The prevalence of endometriosis increased by 24 % from one in 1,191 patients in 2016 to one in 853 patients in 2020 (adjusted-odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.19-1.30). Clinical and pregnancy characteristics that had greater than two-fold association to endometriosis included polycystic ovary syndrome, placenta previa, cesarean delivery, maternal age of ≥30 years, prior pregnancy loss, and anxiety disorder. Pregnant patients with endometriosis were more likely to have the diagnosis of measured severe maternal morbidity during the index hospitalization for delivery (47.8 vs 17.3 per 1,000 deliveries, aOR 1.91, 95%CI 1.78-2.06); these associations were more prominent following vaginal (aOR 2.82, 95%CI 2.41-3.30) compared to cesarean (aOR 1.85, 95%CI 1.71-2.00) deliveries. Among the individual morbidity indicators, endometriosis was most strongly associated with thromboembolism (aOR 5.05, 95%CI 3.70-6.91), followed by sepsis (aOR 2.39, 95%CI 1.85-3.09) and hysterectomy (aOR 2.18, 95%CI 1.85-2.56). When stratified for endometriosis anatomical site, odds of thromboembolism was increased in endometriosis at distant site (aOR 9.10, 95%CI 3.76-22.02) and adnexa (aOR 7.37, 95%CI 4.43-12.28); odds of sepsis was most increased in endometriosis at multi-classifier locations (aOR 7.33, 95%CI 2.93-18.31) followed by pelvic peritoneum (aOR 5.54, 95%CI 2.95-10.40); and odds of hysterectomy exceeded three-fold in endometriosis at adnexa (aOR 3.00, 95%CI 2.30-3.90), distant site (aOR 5.36, 95%CI 3.48-8.24), and multi-classifier location (aOR 4.46, 95%CI 2.11-9.41). CONCLUSION The results of this nationwide analysis suggest that pregnancy with endometriosis is uncommon but gradually increasing over time in the United States. The data also suggest that endometriosis during pregnancy is associated with increased risk of severe maternal morbidity at delivery, especially for thromboembolism, sepsis, and hysterectomy. These morbidity risks differed by the anatomical location of endometriosis.
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Affiliation(s)
- Caroline J Violette
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Laurel S Aberle
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Zachary S Anderson
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Emi J Komatsu
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Bonnie B Song
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Rachel S Mandelbaum
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Shinya Matsuzaki
- Department of Gynecology, Osaka International Cancer Institute, Osaka, Japan
| | - Joseph G Ouzounian
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
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24
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Yang Y, Chen X, Liao X, Jiang W, Zhou Y, Sun Y, Zheng B. Identification of MAP1LC3A as a promising mitophagy-related gene in polycystic ovary syndrome. Sci Rep 2024; 14:16982. [PMID: 39043888 PMCID: PMC11266624 DOI: 10.1038/s41598-024-67969-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 07/18/2024] [Indexed: 07/25/2024] Open
Abstract
Increasing evidence suggests that mitophagy is crucially involved in the progression of polycystic ovary syndrome (PCOS). Exploration of PCOS-specific biomarkers related to mitophagy is expected to provide critical insights into disease pathogenesis. In this study, we employed bioinformatic analyses and machine learning algorithms to determine novel biomarkers for PCOS that may be tied with mitophagy. A grand total of 12 differential expressed mitophagy-related genes (DE-MRGs) associated with PCOS were identified. TOMM5 and MAP1LC3A among the 12 DE-MRGs were recognized as potential marker genes by LASSO, RF and SVM-RFE algorithms. The area under the ROC curve (AUROC) of MAP1LC3A were all greater than 0.8 both in the training set and validation sets. The CIBERSORT analysis indicated a potential association between alterations in the immune microenvironment of PCOS individuals and MAP1LC3A expression. In addition, we found that MAP1LC3A was positively related to the testosterone levels of PCOS patients. Overall, MAP1LC3A was identified as optimal PCOS-specific biomarkers related to mitophagy. Our findings created a diagnostic strength and offered a perspective for investigating the mitophagy process in PCOS.
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Affiliation(s)
- Yizhen Yang
- Reproductive Medicine Center of Fujian Maternity and Child Health Hospital, Fuzhou, 350001, Fujian, China
- Fujian Maternal-Fetal Clinical Medicine Research Center, Fuzhou, 350001, Fujian, China
| | - Xiaojing Chen
- Reproductive Medicine Center of Fujian Maternity and Child Health Hospital, Fuzhou, 350001, Fujian, China
- Fujian Maternal-Fetal Clinical Medicine Research Center, Fuzhou, 350001, Fujian, China
| | - Xiuhua Liao
- Reproductive Medicine Center of Fujian Maternity and Child Health Hospital, Fuzhou, 350001, Fujian, China
| | - Wenwen Jiang
- Reproductive Medicine Center of Fujian Maternity and Child Health Hospital, Fuzhou, 350001, Fujian, China
| | - Yuan Zhou
- Reproductive Medicine Center of Fujian Maternity and Child Health Hospital, Fuzhou, 350001, Fujian, China
| | - Yan Sun
- Reproductive Medicine Center of Fujian Maternity and Child Health Hospital, Fuzhou, 350001, Fujian, China.
- Fujian Maternal-Fetal Clinical Medicine Research Center, Fuzhou, 350001, Fujian, China.
| | - Beihong Zheng
- Reproductive Medicine Center of Fujian Maternity and Child Health Hospital, Fuzhou, 350001, Fujian, China.
- Fujian Maternal-Fetal Clinical Medicine Research Center, Fuzhou, 350001, Fujian, China.
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25
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Liu L, Liu S, Bai F, Deng Y, Zhang X, Wang L. Investigating the Role of Inflammatory Response in Polycystic Ovary Syndrome Using Integrated RNA-Seq Analysis. J Inflamm Res 2024; 17:4701-4719. [PMID: 39051051 PMCID: PMC11268657 DOI: 10.2147/jir.s460437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/29/2024] [Indexed: 07/27/2024] Open
Abstract
Background An important factor in the pathogenesis of polycystic ovary syndrome (PCOS) is chronic low-grade inflammation. However, the exact pathophysiology of PCOS is currently unknown, which makes clinical diagnosis and the development of effective treatments more difficult. We aimed to investigate the role of the inflammatory response in initiating and progressing PCOS. Methods 13 control granulosa cell samples and 15 granulosa cell samples from patients with PCOS were obtained from the GSE102293, GSE34526, and GSE5850 datasets. The gene set variation analysis (GSVA) method was used to calculate the inflammatory response score. Subsequently, the genes associated with inflammation in the hub were identified using differential expression analysis and weighted gene co-expression network analysis (WGCNA). The findings were confirmed by analysis of independent datasets and examination of clinical samples by qRT-PCR analysis. A consensus cluster analysis was conducted to categorize the PCOS samples into subtypes related to inflammation. Functional enrichment and analysis of immune cell infiltration were conducted to explore the potential mechanisms involved. Additionally, the CMap database was utilized to predict potential drugs, and the results were confirmed through molecular docking. Results During the training cohort analysis, we identified five distinct genes (TGFBR2, ICAM3, WIPF1, SLC11A1, and NCF2) that could serve as potential diagnostic markers for PCOS. The expression levels of these genes were confirmed through validation in both the test set and clinical samples. In training cohort, two distinct inflammatory patterns (C1 and C2) were identified, and the C2 subtype exhibited activated immune- and inflammation-related pathways. Esmolol was shown to have potential as a drug to treat PCOS and it showed good results for molecular binding at TGFBR2, ICAM3, WIPF1, SLC11A1, and NCF2 proteins. Conclusion Five diagnostic biomarkers and two inflammation-related molecular types associated with PCOS were identified, and esmolol was a potential drug for PCOS treatment. Our findings provided new diagnostic markers and potential small-molecule drugs for PCOS diagnosis and prevention.
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Affiliation(s)
- Lei Liu
- Department of Endocrinology, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, People’s Republic of China
| | - Shanshan Liu
- General Gynecology, the Tai ‘an Central Hospital, Taian, Shandong, People’s Republic of China
| | - Fuyan Bai
- Department of Endocrinology, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, People’s Republic of China
| | - Yangxin Deng
- Department of Endocrinology, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, People’s Republic of China
| | - Xinhuan Zhang
- Department of Endocrinology, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, People’s Republic of China
| | - Li Wang
- Department of Pharmacy, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, People’s Republic of China
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26
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Hu R, Long S, Luo M, Tang B, Tan T, Dong W, Wang Q, Zhang J. Hyperglycemia Inhibits Hepatic SHBG Synthesis Through the NGBR-AMPK-HNF4 Pathway in Rats with Polycystic Ovary Syndrome Induced by Letrozole in Combination with a High-Fat Diet. Mol Nutr Food Res 2024; 68:e2300915. [PMID: 38862276 DOI: 10.1002/mnfr.202300915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 02/25/2024] [Indexed: 06/13/2024]
Abstract
SCOPE Polycystic ovary syndrome (PCOS) is closely related to non-alcoholic fatty liver disease (NAFLD), and sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver. Hepatic lipogenesis inhibits hepatic SHBG synthesis, which leads to hyperandrogenemia and ovarian dysfunction in PCOS. Therefore, this study aims to characterize the mechanism whereby liver lipogenesis inhibits SHBG synthesis. METHODS AND RESULTS This study establishes a rat model of PCOS complicated by NAFLD using a high-fat diet in combination with letrozole and performs transcriptomic analysis of the liver. Transcriptomic analysis of the liver shows that the expression of neurite growth inhibitor-B receptor (NgBR), hepatocyte nuclear factor 4α (HNF4α), and SHBG is low. Meantime, HepG2 cells are treated with palmitic acid (PA) to model NAFLD in vitro, which causes decreases in the expression of NgBR, HNF4α, and SHBG. However, the expression of HNF4α and SHBG is restored by treatment with the AMP-activated protein kinase (AMPK) agonist AICAR. CONCLUSIONS NgBR regulates the expression of HNF4α by activating the AMPK signaling pathway, thereby affecting the synthesis of SHBG in the liver. Further mechanistic studies regarding the effect of liver fat on NGBR expression are warranted.
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Affiliation(s)
- Rao Hu
- The First Affiliated Hospital, Gynecology &Obstetrics and Reproductive Medical Center, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Institute of Applied Anatomy and Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Shuanglian Long
- The First Affiliated Hospital, Gynecology &Obstetrics and Reproductive Medical Center, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Institute of Applied Anatomy and Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Min Luo
- The First Affiliated Hospital, Gynecology &Obstetrics and Reproductive Medical Center, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Institute of Applied Anatomy and Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Bowen Tang
- Institute of Applied Anatomy and Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Tao Tan
- Institute of Applied Anatomy and Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Weilei Dong
- The First Affiliated Hospital, Gynecology &Obstetrics and Reproductive Medical Center, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Qian Wang
- The First Affiliated Hospital, Gynecology &Obstetrics and Reproductive Medical Center, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jiaming Zhang
- The First Affiliated Hospital, Gynecology &Obstetrics and Reproductive Medical Center, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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Jabarpour M, Amidi F, Aleyasin A, Nashtaei MS, Marghmaleki MS. Randomized clinical trial of astaxanthin supplement on serum inflammatory markers and ER stress-apoptosis gene expression in PBMCs of women with PCOS. J Cell Mol Med 2024; 28:e18464. [PMID: 39036884 PMCID: PMC11261353 DOI: 10.1111/jcmm.18464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 04/27/2024] [Accepted: 05/19/2024] [Indexed: 07/23/2024] Open
Abstract
Polycystic ovarian syndrome (PCOS) is related to pro-apoptotic and pro-inflammatory conditions generated by Endoplasmic reticulum (ER) stress. This study aimed to determine the effect of Astaxanthin (ASX), as carotenoid with potent antioxidant and anti-inflammatory properties, on serum inflammatory markers, apoptotic factors and ER stress-apoptotic genes in peripheral blood mononuclear cells (PBMCs) of women with PCOS. This randomized, double-blind clinical trial included 56 PCOS patients aged 18-40. For 8 weeks, subjects were randomly assigned to one of two groups: either 12 mg ASX (n = 28) or placebo (n = 28). Real-time PCR was used to quantify gene expression associated with ER stress-apoptosis in PCOS women's PBMCs. The levels of TNF-α, IL18, IL6 and CRP were determined by obtaining blood samples from all patients before and after the intervention using Enzyme-linked immunosorbent assay (ELISA). Also, the levels of active caspase-3 and caspase-8 were detected in the PBMC by ELISA kit. Furthermore, we evaluated the efficacy of ASX on disease symptoms. Following the 8-week intervention, ASX supplementation was able to reduce the expression of GRP78 (p = 0.051), CHOP (p = 0.008), XBP1 (p = 0.002), ATF4 (0.038), ATF6 (0.157) and DR5 (0.016) when compared to the placebo. However, this decrease was not statistically significant for ATF6 (p = 0.067) and marginally significant for GRP78 (p = 0.051). The levels of TNF-α (p = 0.009), IL-18 (p = 0.003), IL-6 (p = 0.013) and active caspase-3 (p = 0.012) were also statistically significant lower in the therapy group. However, there was no significant difference in CRP (p = 0.177) and caspase-8 (p = 0.491) levels between the treatment and control groups. In our study, ASX had no significant positive effect on BMI, hirsutism, hair loss and regularity of the menstrual cycle. It appears that ASX may benefit PCOS by changing the ER stress-apoptotic pathway and reducing serum inflammatory markers; however, additional research is required to determine this compound's potential relevance.
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Affiliation(s)
- Masoome Jabarpour
- Department of Anatomy, School of MedicineTehran University of Medical SciencesTehranIran
- Department of Infertility, Shariati HospitalTehran University of Medical SciencesTehranIran
| | - Fardin Amidi
- Department of Anatomy, School of MedicineTehran University of Medical SciencesTehranIran
- Department of Infertility, Yas HospitalTehran University of Medical SciencesTehranIran
| | - Ashraf Aleyasin
- Department of Infertility, Shariati HospitalTehran University of Medical SciencesTehranIran
| | - Maryam Shabani Nashtaei
- Department of Anatomy, School of MedicineTehran University of Medical SciencesTehranIran
- Department of Infertility, Shariati HospitalTehran University of Medical SciencesTehranIran
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Gao G, Li L, Li C, Liu D, Wang Y, Li C. Mesenchymal stem cells: Guardians of women's health. Regen Ther 2024; 26:1087-1098. [PMID: 39582803 PMCID: PMC11585475 DOI: 10.1016/j.reth.2024.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/13/2024] [Accepted: 10/23/2024] [Indexed: 11/26/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted more and more attention because of their multidirectional differentiation potential, immune regulatory abilities and self-renewal capacity. In recent years, their use has become prominent in the domains of regenerative medicine and tissue engineering. MSCs have shown promise in therapeutic studies for a variety of diseases and have become a new source of innovative solutions for the treatment of some obstetric and gynecological diseases. This review systematically presents the latest research on the use of MSCs in the treatment of obstetrics- and gynecology-related diseases. Specifically, this review encompasses the latest findings related to the role of MSCs in premature ovarian failure, polycystic ovary syndrome, ovarian cancer, fallopian tube-related diseases, uterine adhesions, endometriosis, cesarean scar defects, postmenopausal osteoporosis, and pelvic floor dysfunction. The shortcomings and challenges of the future use of MSCs in disease treatment are also discussed, with the intent to motivate improvements in MSC applications in clinical therapy. It is believed that with further research, MSCs will play a more important role in the treatment of obstetrics- and gynecology-related diseases.
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Affiliation(s)
- Guanwen Gao
- Peking University Shenzhen Clinical Institute of Shantou University Medical College, Shenzhen, 518036, China
- Center of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, 518036, China
- Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, 518036, China
| | - Li Li
- Department of Internal Medicine, Jinan Central Hospital Affiliated to Shandong University, Ji Nan, 250000, China
| | - Changling Li
- Department of Obstetrics and Gynecology, Pingyi People's Hospital, Linyi City, Shandong Province, 276000, China
| | - Degao Liu
- Center of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, 518036, China
- Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, 518036, China
| | - Yunfei Wang
- Center of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, 518036, China
- Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, 518036, China
| | - Changzhong Li
- Center of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, 518036, China
- Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases, Shenzhen, 518036, China
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Weidner AE, Roy A, Vann K, Walczyk AC, Astapova O. Paxillin regulates androgen receptor expression associated with granulosa cell focal adhesions. Mol Hum Reprod 2024; 30:gaae018. [PMID: 38718206 PMCID: PMC11136451 DOI: 10.1093/molehr/gaae018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 04/19/2024] [Indexed: 05/31/2024] Open
Abstract
Paxillin is a ubiquitously expressed adaptor protein integral to focal adhesions, cell motility, and apoptosis. Paxillin has also recently been implicated as a mediator of nongenomic androgen receptor (AR) signaling in prostate cancer and other cells. We sought to investigate the relationship between paxillin and AR in granulosa cells (GCs), where androgen actions, apoptosis, and focal adhesions are of known importance, but where the role of paxillin is understudied. We recently showed that paxillin knockout in mouse GCs increases fertility in older mice. Here, we demonstrate that paxillin knockdown in human granulosa-derived KGN cells, as well as knockout in mouse primary GCs, results in reduced AR protein but not reduced mRNA expression. Further, we find that both AR protein and mRNA half-lives are reduced by approximately one-third in the absence of paxillin, but that cells adapt to chronic loss of paxillin by upregulating AR gene expression. Using co-immunofluorescence and proximity ligation assays, we show that paxillin and AR co-localize at the plasma membrane in GCs in a focal adhesion kinase-dependent way, and that disruption of focal adhesions leads to reduced AR protein level. Our findings suggest that paxillin recruits AR to the GC membrane, where it may be sequestered from proteasomal degradation and poised for nongenomic signaling, as reported in other tissues. To investigate the physiological significance of this in disorders of androgen excess, we tested the effect of GC-specific paxillin knockout in a mouse model of polycystic ovary syndrome (PCOS) induced by chronic postnatal dihydrotestosterone (DHT) exposure. While none of the control mice had estrous cycles, 33% of paxillin knockout mice were cycling, indicating that paxillin deletion may offer partial protection from the negative effects of androgen excess by reducing AR expression. Paxillin-knockout GCs from mice with DHT-induced PCOS also produced more estradiol than GCs from littermate controls. Thus, paxillin may be a novel target in the management of androgen-related disorders in women, such as PCOS.
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Affiliation(s)
- Adelaide E Weidner
- Division of Endocrinology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Anna Roy
- Division of Endocrinology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Kenji Vann
- Division of Endocrinology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Ariana C Walczyk
- Division of Endocrinology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Olga Astapova
- Division of Endocrinology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
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Zhao D, Wang Y, Wu S, Ji X, Gong K, Zheng H, Zhu M. Research progress on the role of macrophages in acne and regulation by natural plant products. Front Immunol 2024; 15:1383263. [PMID: 38736879 PMCID: PMC11082307 DOI: 10.3389/fimmu.2024.1383263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/01/2024] [Indexed: 05/14/2024] Open
Abstract
Acne vulgaris is one of the most common skin diseases. The current understanding of acne primarily revolves around inflammatory responses, sebum metabolism disorders, aberrant hormone and receptor expression, colonization by Cutibacterium acnes, and abnormal keratinization of follicular sebaceous glands. Although the precise mechanism of action remains incompletely understood, it is plausible that macrophages exert an influence on these pathological features. Macrophages, as a constituent of the human innate immune system, typically manifest distinct phenotypes across various diseases. It has been observed that the polarization of macrophages toward the M1 phenotype plays a pivotal role in the pathogenesis of acne. In recent years, extensive research on acne has revealed an increasing number of natural remedies exhibiting therapeutic efficacy through the modulation of macrophage polarization. This review investigates the role of cutaneous macrophages, elucidates their potential significance in the pathogenesis of acne, a prevalent chronic inflammatory skin disorder, and explores the therapeutic mechanisms of natural plant products targeting macrophages. Despite these insights, the precise role of macrophages in the pathogenesis of acne remains poorly elucidated. Subsequent investigations in this domain will further illuminate the pathogenesis of acne and potentially offer guidance for identifying novel therapeutic targets for this condition.
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Affiliation(s)
- Dan Zhao
- Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yun Wang
- Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Shuhui Wu
- Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Xiaotian Ji
- Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Ke Gong
- Department of Traditional Chinese Medicine, Cangzhou Central Hospital, Cangzhou, China
| | - Huie Zheng
- Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Mingfang Zhu
- Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
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Alenazi A, Virk P, Almoqhem R, Alsharidah A, Al-Ghadi MQ, Aljabr W, Alasmari F, Albasher G. The Efficacy of Hispidin and Magnesium Nanoparticles against Zearalenone-Induced Fungal Toxicity Causing Polycystic Ovarian Syndrome in Rats. Biomedicines 2024; 12:943. [PMID: 38790905 PMCID: PMC11118902 DOI: 10.3390/biomedicines12050943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/05/2024] [Accepted: 04/11/2024] [Indexed: 05/26/2024] Open
Abstract
Contamination by fungi and the toxins they secrete is a worldwide health concern. One such toxin is zearalenone (Zea), which is structurally similar to the hormone estrogen, interferes with its action on the reproductive system, and is therefore classified as an endocrine disruptor. This study aims to determine the effectiveness of hispidin and magnesium nanoparticles (MgONPs) against zearalenone-induced myotoxicity, which causes polycystic ovary syndrome (PCOS) in rats. A three-month exposure study was performed using female Wistar rats (n = 42) with an average weight of 100-150 g. The animals were divided into six groups (I to VI) of seven rats each. Group I was administered distilled water as a negative control. Group II was exposed to Zea 0.1 mg/kg b.w. through gavage daily. Group III was treated with 0.1 mg/kg of hispidin through gavage daily. Group IV was given 150 µg/mL MgONPs orally each day. Group V was treated with Zea 0.1 mg/kg b.w. + 0.1 mg/kg hispidin orally each day. Group VI was treated with Zea 0.1 mg/kg b.w. and the combination treatment of 0.1 mg/kg hispidin + 150 µg/mL MgONPs through gavage every day. The effectiveness of hispidin and MgONPs against Zea toxicity was evaluated in terms of ovarian histological changes, gene expression, oxidative stress biomarkers, biochemical variables, and hormone levels. The findings showed that exposure to Zea promotes PCOS in rats, with Zea-treated rats displaying hyper-ovulation with large cysts; elevated testosterone, luteinizing hormone, insulin, and glucose; and reduced sex hormone-binding globulin. In addition, qRT-PCR for aromatase (Cyp19α1) showed it to be downregulated. Treatment with hispidin improved the histopathological and hormonal situation and rescued expression of Cyp19α. Our data indicate the potential therapeutic effects of hispidin against Zea-induced Fungal Toxicity.
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Affiliation(s)
- Amenah Alenazi
- Department of Zoology, College of Science, King Saud University, Riyadh 11459, Saudi Arabia; (A.A.); (P.V.); (R.A.); (A.A.); (M.Q.A.-G.)
- Department of Biological Sciences, College of Science, Northern Border University, Arar 73213, Saudi Arabia
| | - Promy Virk
- Department of Zoology, College of Science, King Saud University, Riyadh 11459, Saudi Arabia; (A.A.); (P.V.); (R.A.); (A.A.); (M.Q.A.-G.)
| | - Reem Almoqhem
- Department of Zoology, College of Science, King Saud University, Riyadh 11459, Saudi Arabia; (A.A.); (P.V.); (R.A.); (A.A.); (M.Q.A.-G.)
| | - Amani Alsharidah
- Department of Zoology, College of Science, King Saud University, Riyadh 11459, Saudi Arabia; (A.A.); (P.V.); (R.A.); (A.A.); (M.Q.A.-G.)
| | - Muath Q. Al-Ghadi
- Department of Zoology, College of Science, King Saud University, Riyadh 11459, Saudi Arabia; (A.A.); (P.V.); (R.A.); (A.A.); (M.Q.A.-G.)
| | - Waleed Aljabr
- King Fahad Medical City, Riyadh 11525, Saudi Arabia;
| | - Fawaz Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11459, Saudi Arabia;
| | - Gadah Albasher
- Department of Zoology, College of Science, King Saud University, Riyadh 11459, Saudi Arabia; (A.A.); (P.V.); (R.A.); (A.A.); (M.Q.A.-G.)
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32
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Upadhyay N, Almeida EA, Singh A, Madhu SV, Puri D, Mehndiratta M. Evaluation of CRP/Albumin Ratio in Polycystic Ovarian Syndrome. J Obstet Gynaecol India 2024; 74:165-169. [PMID: 38707880 PMCID: PMC11065824 DOI: 10.1007/s13224-023-01897-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/24/2023] [Indexed: 05/07/2024] Open
Abstract
Background Polycystic ovarian syndrome is a common endocrine disorder among women of reproductive age. It is characterized by menstrual abnormalities, hyperandrogenism and polycystic ovaries and can lead to many complications. Studies have postulated the role of inflammation in the pathophysiology of PCOS. As acute phase reactants often serve as markers of inflammation, this study aimed to evaluate the role of inflammatory markers in women with PCOS and healthy controls. Material and Methods A total of 60 participants were enrolled; 30 cases of PCOS and 30 age matched healthy controls. Peripheral venous blood was collected for assessment of CRP, serum albumin, serum total testosterone, serum fasting insulin and fasting blood glucose, following which statistical analysis was done. Results The CRP/albumin ratio was found to be significantly higher in women with PCOS as compared to healthy controls along with serum total testosterone and HOMA-IR. Correlation between CRP/albumin ratio and the levels of serum total testosterone and insulin resistance was found to be non-significant. Conclusion An elevated CRP/albumin ratio in cases of PCOS compared to healthy controls supports the hypothesis of inflammation playing a key role in the pathophysiology of PCOS. CRP/albumin ratio can serve as a cheaper biochemical marker of the disease subject to further validation studies to establish its use in Indian population.
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Affiliation(s)
- Nandini Upadhyay
- Third Year Part 1, UCMS & GTBH, University of Delhi, New Delhi, India
| | | | - Alpana Singh
- Department of Obstetrics and Gynaecology, University College of Medical Sciences and GTB Hospital (UCMS & GTBH), University of Delhi, Dilshad Garden, New Delhi, 110095 India
| | - S. V. Madhu
- Department of Endocrinology, UCMS & GTBH, University of Delhi, New Delhi, India
| | - Dinesh Puri
- Department of Biochemistry, UCMS & GTBH, University of Delhi, New Delhi, India
| | - Mohit Mehndiratta
- Department of Biochemistry, UCMS & GTBH, University of Delhi, New Delhi, India
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Parker J, O’Brien CL, Yeoh C, Gersh FL, Brennecke S. Reducing the Risk of Pre-Eclampsia in Women with Polycystic Ovary Syndrome Using a Combination of Pregnancy Screening, Lifestyle, and Medical Management Strategies. J Clin Med 2024; 13:1774. [PMID: 38541997 PMCID: PMC10971491 DOI: 10.3390/jcm13061774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/12/2024] [Accepted: 03/17/2024] [Indexed: 05/04/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is a multisystem disorder that presents with a variety of phenotypes involving metabolic, endocrine, reproductive, and psychological symptoms and signs. Women with PCOS are at increased risk of pregnancy complications including implantation failure, miscarriage, gestational diabetes, fetal growth restriction, preterm labor, and pre-eclampsia (PE). This may be attributed to the presence of specific susceptibility features associated with PCOS before and during pregnancy, such as chronic systemic inflammation, insulin resistance (IR), and hyperandrogenism, all of which have been associated with an increased risk of pregnancy complications. Many of the features of PCOS are reversible following lifestyle interventions such as diet and exercise, and pregnant women following a healthy lifestyle have been found to have a lower risk of complications, including PE. This narrative synthesis summarizes the evidence investigating the risk of PE and the role of nutritional factors in women with PCOS. The findings suggest that the beneficial aspects of lifestyle management of PCOS, as recommended in the evidence-based international guidelines, extend to improved pregnancy outcomes. Identifying high-risk women with PCOS will allow targeted interventions, early-pregnancy screening, and increased surveillance for PE. Women with PCOS should be included in risk assessment algorithms for PE.
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Affiliation(s)
- Jim Parker
- School of Medicine, University of Wollongong, Wollongong 2522, Australia
| | - Claire Louise O’Brien
- Faculty of Science and Technology, University of Canberra, Canberra 2617, Australia;
| | - Christabelle Yeoh
- Next Practice Genbiome, 2/2 New McLean Street, Edgecliff 2027, Australia;
| | - Felice L. Gersh
- College of Medicine, University of Arizona, Tucson, AZ 85004, USA;
| | - Shaun Brennecke
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, The Royal Women’s Hospital, Melbourne 3052, Australia;
- Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne 3052, Australia
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Stamou MI, Smith KT, Kim H, Balasubramanian R, Gray KJ, Udler MS. Polycystic Ovary Syndrome Physiologic Pathways Implicated Through Clustering of Genetic Loci. J Clin Endocrinol Metab 2024; 109:968-977. [PMID: 37967238 PMCID: PMC10940264 DOI: 10.1210/clinem/dgad664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/05/2023] [Accepted: 11/09/2023] [Indexed: 11/17/2023]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, with disease loci identified from genome-wide association studies (GWAS) having largely unknown relationships to disease pathogenesis. OBJECTIVE This work aimed to group PCOS GWAS loci into genetic clusters associated with disease pathophysiology. METHODS Cluster analysis was performed for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N = 62 252). Associations with clinical outcomes (type 2 diabetes [T2D], coronary artery disease [CAD], and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N = 898,130, CARDIOGRAM/UKBB, N = 547 261) and individual-level pPS in MGBB. RESULTS Four PCOS genetic clusters were identified with top loci indicated as following: (i) cluster 1/obesity/insulin resistance (FTO); (ii) cluster 2/hormonal/menstrual cycle changes (FSHB); (iii) cluster 3/blood markers/inflammation (ATXN2/SH2B3); (iv) cluster 4/metabolic changes (MAF, SLC38A11). Cluster pPS were associated with distinct clinical traits: Cluster 1 with increased body mass index (P = 6.6 × 10-29); cluster 2 with increased age of menarche (P = 1.5 × 10-4); cluster 3 with multiple decreased blood markers, including mean platelet volume (P = 3.1 ×10-5); and cluster 4 with increased alkaline phosphatase (P = .007). PCOS genetic clusters GWAS-pPSs were also associated with disease outcomes: cluster 1 pPS with increased T2D (odds ratio [OR] 1.07; P = 7.3 × 10-50), with replication in MGBB all participants (OR 1.09, P = 2.7 × 10-7) and females only (OR 1.11, 4.8 × 10-5). CONCLUSION Distinct genetic backgrounds in individuals with PCOS may underlie clinical heterogeneity and disease outcomes.
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Affiliation(s)
- Maria I Stamou
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Kirk T Smith
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA
- Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Hyunkyung Kim
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA
- Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Ravikumar Balasubramanian
- Reproductive Endocrine Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Kathryn J Gray
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Miriam S Udler
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA
- Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
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Saei Ghare Naz M, Ghasemi V, Amirshekari S, Ramezani Tehrani F. Polycystic Ovary Syndrome and Irritable Bowel Syndrome: Is There a Common Pathway? Endocrinol Diabetes Metab 2024; 7:e00477. [PMID: 38494583 PMCID: PMC10944984 DOI: 10.1002/edm2.477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/13/2024] [Accepted: 02/16/2024] [Indexed: 03/19/2024] Open
Abstract
OBJECTIVE Little is known about how polycystic ovary syndrome (PCOS) is linked to irritable bowel syndrome (IBS). This study aimed to review the existing literature regarding the association between PCOS or its symptoms and complications with IBS. METHODS In this review, studies that investigated the proposed cross-link between features of PCOS and IBS were included. This review collectively focused on recent findings on the mechanism and novel insight regarding the association between IBS and PCOS in future clinical practice. An electronic search of PubMed, Scopus, Epistemonikos, Cochrane Library and Google Scholar was performed. We did not restrict the study setting and publication date. RESULTS The existing evidence has not completely answered the question of whether there is an association between PCOS and IBS and vice versa. Six case-control studies (793 women with PCOS and 547 women in the control group) directly assessed the association between PCOS and IBS. The prevalence of IBS among women with PCOS in these studies has ranged from 10% to 52% compared with 5%-50% in control groups. Evidence suggested the common pathways may have contributed to the interaction between IBS and PCOS, including metabolic syndrome, sex hormone fluctuation, dysregulation of neurotransmitters, psychological problems and environmental and lifestyle factors. To date, it is still ambiguous which of the mentioned components largely contributes to the pathogenesis of both. CONCLUSION Although limited evidence has shown a higher prevalence of IBS in women with PCOS, there are several potential, direct and common indirect pathways contributing to the development of both IBS and PCOS.
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Affiliation(s)
- Marzieh Saei Ghare Naz
- Reproductive Endocrinology Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | | | - Shabahang Amirshekari
- Reproductive Endocrinology Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Fahimeh Ramezani Tehrani
- Reproductive Endocrinology Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
- The Foundation for Research & Education ExcellenceVestavia HillsAlabamaUSA
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Dai M, Hong L, Yin T, Liu S. Disturbed Follicular Microenvironment in Polycystic Ovary Syndrome: Relationship to Oocyte Quality and Infertility. Endocrinology 2024; 165:bqae023. [PMID: 38375912 DOI: 10.1210/endocr/bqae023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 02/15/2024] [Accepted: 02/15/2024] [Indexed: 02/21/2024]
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with infertility and poor reproductive outcomes. The follicular fluid (FF) microenvironment plays a crucial role in oocyte development. This review summarizes evidence elucidating the alterations in FF composition in PCOS. Various studies demonstrated a pronounced proinflammatory milieu in PCOS FF, characterized by increased levels of cytokines, including but not limited to interleukin-6 (IL-6), tumor necrosis factor α, C-reactive protein, and IL-1β, concomitant with a reduction in anti-inflammatory IL-10. T lymphocytes and antigen-presenting cells are dysregulated in PCOS FF. PCOS FF exhibit heightened reactive oxygen species production and the accumulation of lipid peroxidation byproducts, and impaired antioxidant defenses. Multiple microRNAs are dysregulated in PCOS FF, disrupting signaling critical to granulosa cell function. Proteomic analysis reveals changes in pathways related to immune responses, metabolic perturbations, angiogenesis, and hormone regulation. Metabolomics identify disturbances in glucose metabolism, amino acids, lipid profiles, and steroid levels with PCOS FF. Collectively, these pathological alterations may adversely affect oocyte quality, embryo development, and fertility outcomes. Further research on larger cohorts is needed to validate these findings and to forge the development of prognostic biomarkers of oocyte developmental competence within FF. Characterizing the follicular environment in PCOS is key to elucidating the mechanisms underlying subfertility in this challenging disorder.
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Affiliation(s)
- Mengyang Dai
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430061, China
| | - Ling Hong
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Shenzhen 518000, China
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, Shenzhen 518000, China
| | - Tailang Yin
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430061, China
| | - Su Liu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Shenzhen 518000, China
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, Shenzhen 518000, China
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Azarbayjani K, Jahanian Sadatmahalleh S, Mottaghi A, Nasiri M. Association of dietary inflammatory index with C-reactive protein and interleukin-6 in women with and without polycystic ovarian syndrome. Sci Rep 2024; 14:3972. [PMID: 38368454 PMCID: PMC10874425 DOI: 10.1038/s41598-024-53958-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 02/07/2024] [Indexed: 02/19/2024] Open
Abstract
Considering that interventions related to lifestyle, especially nutrition have been proposed as the first line of prevention and treatment of polycystic ovarian syndrome (PCOS), and regarding the proven relationship between PCOS and inflammation, the present study was designed to find out the possible association of Diet Inflammatory Index (DII) with the inflammatory markers like C-reactive protein (CRP) and Interleukin-6 (IL-6), and compare the obtained results in PCOS and non-PCOS women. This case-control study was conducted on 45 PCOS and 40 non-PCOS women. Food intake and DII were measured using a 147-item Food Frequency Questionnaire. All participants were tested for the serum levels of IL-6 and CRP. Finally, the obtained results were compared between the two groups of PCOS and non-PCOS women. Significant differences were observed between the two groups in terms of age, menstrual status and number of pregnancies (P < 0.05). Comparison of DII values showed no significant difference between the two groups of women (P = 0.68), but IL-6 was significantly higher in the PCOS group than in the control group (4.94 ± 1.97 vs. 3.48 ± 1.77, P < 0.001). Also in terms of CRP, no significant difference was observed between the two groups (P > 0.05). The difference of DII between the case and control groups were not significant and Pearson's correlation test did not show a significant correlation between DII and IL-6 (P˃0.05). This result can be due to the influence of several factors affecting the determination of DII such as education level, health status, physical activity level, age, and calorie intake. It seems that diet, especially consumption of more carbohydrates plays a role in causing chronic inflammation, as well as the occurrence and exacerbation of PCOS.
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Affiliation(s)
- Khadijeh Azarbayjani
- Department of Reproductive Health and Midwifery, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Azadeh Mottaghi
- Research Center for Prevention of Cardiovascular Diseases, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Maliheh Nasiri
- Department of Basic Sciences, Faculty of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zheng CY, Yu YX, Bai X. Polycystic ovary syndrome and related inflammation in radiomics; relationship with patient outcome. Semin Cell Dev Biol 2024; 154:328-333. [PMID: 36933953 DOI: 10.1016/j.semcdb.2023.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 02/26/2023] [Accepted: 02/26/2023] [Indexed: 03/19/2023]
Abstract
Polycystic ovary syndrome (PCOS) refers to a condition that often has 'poly' liquid containing sacks around ovaries. It affects reproductive-aged females giving rise to menstrual and related reproductive issues. PCOS is marked by hormonal imbalance often resulting in hyperandrogenism. Inflammation is now considered a central manifestation of this disease with several inflammatory biomarkers such as TNF-α, C-reactive protein and Interleukins-6/18 found to be particularly elevated in PCOS patients. Diagnosis is often late, and MRI-based diagnosis, along with blood-based analyses, are still the best bet for a definitive diagnosis. Radiomics also offers several advantages and should be exploited to the maximum. The mechanisms of PCOS onset and progression are not very well known but pituitary dysfunction and elevated gonadotrophin releasing hormone resulting in high levels of luteinizing hormone are indicative of an activated hypothalamic-pituitary-ovarian axis in PCOS. A number of studies have also identified signaling pathways such as PI3K/Akt, NF-κB and STAT in PCOS etiology. The links of these signaling pathways to inflammation further underline the importance of inflammation in PCOS, which needs to be resolved for improving patient outcomes.
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Affiliation(s)
- Chun-Yang Zheng
- Embryo Laboratory, Jinghua Hospital of Shenyang, No. 83, Zhongshan Road, Heping District, Shenyang 110000, Liaoning Province, China
| | - Yue-Xin Yu
- Department of Reproductive Medicine, General Hospital of Northern Theater Command, No. 5, Guangrong Street, Heping District, Shenyang 110000, Liaoning Province, China
| | - Xue Bai
- Department of Reproductive Medicine, General Hospital of Northern Theater Command, No. 5, Guangrong Street, Heping District, Shenyang 110000, Liaoning Province, China.
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Mizgier M, Więckowska B, Formanowicz D, Lombardi G, Brożek A, Nowicki M, Durkalec-Michalski K, Kędzia W, Jarząbek-Bielecka G. Effects of AIDiet intervention to improve diet quality, immuno-metabolic health in normal and overweight PCOS girls: a pilot study. Sci Rep 2024; 14:3525. [PMID: 38347150 PMCID: PMC10861446 DOI: 10.1038/s41598-024-54100-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 02/08/2024] [Indexed: 02/15/2024] Open
Abstract
This study was conducted in two groups of girls with PCOS (polycystic ovary syndrome) categorized as slim (group N) and overweight-to-obese (group Ov/Ob). The study's primary outcome was to assess the impact of a 12-week anti-inflammatory diet (AIDiet) intervention, without energy deficit, on daily diet quality improvement, evaluated according to the KIDMED index. The secondary outcome was improving inflammatory, redox, hormonal, and metabolic statuses. In the study, which was completed by 13 girls from the Ov/Ob group and 19 girls from the N group, a significant improvement in the mean KIDMED score was obtained. Moreover, the intervention significantly improves concentration of total antioxidant capacity (TAC), fasting insulin, and the homeostatic model assessment for insulin resistance (HOMA-IR) index, in the Ov/Ob group, while both groups experienced a reduction in the concentration of interleukin (IL)-1 and IL-6, tumour necrosis factor (TNF-α), and androstenedione. The AIDiet intervention effectively improved the quality of the subjects' diets, which was associated with the improvement of hormonal and immuno-metabolic markers. However, these changes in normal-weight patients were observed regardless of body weight reduction. ClinicalTrials.gov Identifier NCT04738409.
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Affiliation(s)
- Małgorzata Mizgier
- Department of Sports Dietetics, Chair of Dietetics, Faculty of Health Sciences, Poznan University of Physical Education, Królowej Jadwigi 27/39, 61-871, Poznan, Poland.
| | - Barbara Więckowska
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-806, Poznan, Poland
| | - Dorota Formanowicz
- Chair and Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, 60-806, Poznan, Poland
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20157, Milan, Italy
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, 61-871, Poznan, Poland
| | - Alicja Brożek
- Chair and Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, 60-806, Poznan, Poland
| | - Marcin Nowicki
- Chair and Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, 60-806, Poznan, Poland
| | - Krzysztof Durkalec-Michalski
- Department of Sports Dietetics, Chair of Dietetics, Faculty of Health Sciences, Poznan University of Physical Education, Królowej Jadwigi 27/39, 61-871, Poznan, Poland
| | - Witold Kędzia
- Division of Developmental Gynaecology and Sexology, Department of Gynaecology, Poznan University of Medical Sciences, 60-535, Poznan, Poland
| | - Grażyna Jarząbek-Bielecka
- Division of Developmental Gynaecology and Sexology, Department of Gynaecology, Poznan University of Medical Sciences, 60-535, Poznan, Poland
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Fu Y, Xie P, Yang Q, Chen P, Yu J. Analysis on the therapeutic effect of Cangfu Daotan Decoction combined with drospirenone and ethinylestradiol tablets (II) on patients with polycystic ovary syndrome. Prostaglandins Other Lipid Mediat 2024; 170:106801. [PMID: 37984794 DOI: 10.1016/j.prostaglandins.2023.106801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/10/2023] [Accepted: 11/15/2023] [Indexed: 11/22/2023]
Abstract
OBJECTIVE This study was designed to investigate the therapeutic effect of Cangfu Daotan Decoction (CDD) combined with drospirenone and ethinylestradiol tablets (II) on patients with polycystic ovary syndrome (PCOS). METHODS Patients with PCOS were gathered from September 2020 to September 2022 and divided into the experimental group (n = 36), treated with CDD combined with drospirenone and ethinylestradiol tablets (II), and the control group (n = 41), received only drospirenone and ethinylestradiol tablets (II). Levels of sex hormone, obesity, blood glucose, blood lipid were detected and compared between the two groups pre- and post-treatment. The treatment efficacy, Traditional Chinese Medicine (TCM) syndrome score, adverse drug reactions, and pregnancy rate were compared as well. RESULTS After treatment, the experimental group had a higher treatment efficacy (94.44% vs 73.17%, P < 0.05) and a higher pregnancy rate (44.44% vs 21.95%, P < 0.05) than the control group, but the difference in the incidence of adverse drug reactions was not statistically significant (P > 0.05). Compared with control group, TCM syndrome score and levels of fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and waist circumference of the experimental group after treatment displayed remarkable reduction (P < 0.05), while the levels of estradiol (E2) and high-density lipoprotein cholesterol (HDL-C) showed a remarkable increase (P < 0.05). CONCLUSION CDD in combination with drospirenone and ethinylestradiol tablets (II) may be effective in treating PCOS by improving obesity, glucose metabolism and lipid metabolism with no serious adverse events, making it a feasible clinical practice option.
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Affiliation(s)
- Yanhong Fu
- Department of Gynecology, Guangzhou Huadu District Maternal And Child Care Service Centre, Guangzhou City, Guangdong Province 510800, China
| | - Pengpeng Xie
- Department of TCM Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou City, Guangdong Province 510623, China
| | - Qingping Yang
- Department of Gynecology, Guangzhou Huadu District Maternal And Child Care Service Centre, Guangzhou City, Guangdong Province 510800, China
| | - Peng Chen
- Department of Gynecology, Guangzhou Huadu District Maternal And Child Care Service Centre, Guangzhou City, Guangdong Province 510800, China
| | - Jingwei Yu
- Gynecology of Traditonal Chinese Medicine, Panyu Matermal and Child Care Service Centre (Panyu He Xian Memorial Hospital), Guangzhou City, Guangdong Province 511442, China.
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Sun J, Wang M, Kan Z. Causal relationship between gut microbiota and polycystic ovary syndrome: a literature review and Mendelian randomization study. Front Endocrinol (Lausanne) 2024; 15:1280983. [PMID: 38362275 PMCID: PMC10867277 DOI: 10.3389/fendo.2024.1280983] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 01/12/2024] [Indexed: 02/17/2024] Open
Abstract
Introduction Numerous studies have suggested an association between gut microbiota and polycystic ovarian syndrome (PCOS). However, the causal relationship between these two factors remains unclear. Methods A review of observational studies was conducted to compare changes in gut microbiota between PCOS patients and controls. The analysis focused on four levels of classification, namely, phylum, family, genus, and species/genus subgroups. To further investigate the causal relationship, Mendelian randomization (MR) was employed using genome-wide association study (GWAS) data on gut microbiota from the MiBioGen consortium, as well as GWAS data from a large meta-analysis of PCOS. Additionally, a reverse MR was performed, and the results were verified through sensitivity analyses. Results The present review included 18 observational studies that met the inclusion and exclusion criteria. The abundance of 64 gut microbiota taxa significantly differed between PCOS patients and controls. Using the MR method, eight bacteria were identified as causally associated with PCOS. The protective effects of the genus Sellimonas on PCOS remained significant after applying Bonferroni correction. No significant heterogeneity or horizontal pleiotropy was found in the instrumental variables (IVs). Reverse MR analyses did not reveal a significant causal effect of PCOS on gut microbiota. Conclusion The differences in gut microbiota between PCOS patients and controls vary across observational studies. However, MR analyses identified specific gut microbiota taxa that are causally related to PCOS. Future studies should investigate the gut microbiota that showed significant results in the MR analyses, as well as the underlying mechanisms of this causal relationship and its potential clinical significance.
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Affiliation(s)
- Junwei Sun
- Department of Neurosurgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
- Department of Neurosurgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Mingyu Wang
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Zhisheng Kan
- Department of Neurosurgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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Sharkesh EZ, Keshavarz SA, Nazari L, Abbasi B. Empirical Dietary Inflammatory Pattern is positively associated with polycystic ovary syndrome: A case control study. Nutr Res 2024; 122:123-129. [PMID: 38219291 DOI: 10.1016/j.nutres.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 01/16/2024]
Abstract
Polycystic ovary syndrome (PCOS), as the most common endocrine disorder in women of reproductive age, is influenced by various factors. Because there is evidence linking inflammation with chronic diseases, we hypothesized that there is a relationship between an empirical dietary inflammatory pattern score (EDIP) with odds of PCOS among the adult population. This case control study was conducted on Tehranian women in Iran. A total of 494 participants (203 women with PCOS in the case group and 291 healthy people in the control group), aged 18 to 45 years, were recruited for the study. Demographic information, anthropometric indices, physical activity level, and dietary intake were collected by a trained nutritionist. EDIP score was calculated to estimate overall dietary inflammatory potential based on 18 food groups. Statistical analysis was performed with SPSS version 19. Based on the results, the mean age of participants in the case and control groups were 28.98 ± 5.43 and 30.15 ± 6.21 years, respectively. Individuals with PCOS had a significantly higher difference in EDIP score compared with healthy participants (2.03 ± 1.13 vs 1.70 ± 0.93, P < .001). Also, the odds ratio and 95% confidence interval for the risk of PCOS across quartiles of EDIP showed a significant direct relationship (P = .003). In conclusion, our study showed that there was a direct association between PCOS risk and EDIP score. Findings suggest that inflammatory index might be a potential mechanism linking diet and PCOS development.
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Affiliation(s)
- Elnaz Zirak Sharkesh
- Department of Nutrition, Electronic Health and Statistics Surveillance Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Ali Keshavarz
- Department of Nutrition and Biochemistry, Faculty of Public Health, Tehran University of Medical Science, Tehran, Iran
| | - Leila Nazari
- Department of Obstetrics and Gynecology, Preventative Gynecology Research Center (PGRC), Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Behnood Abbasi
- Department of Nutrition, Electronic Health and Statistics Surveillance Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran.
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Knight AK, Spencer JB, Smith AK. DNA methylation as a window into female reproductive aging. Epigenomics 2024; 16:175-188. [PMID: 38131149 PMCID: PMC10841041 DOI: 10.2217/epi-2023-0298] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
People with ovaries experience reproductive aging as their reproductive function and system declines. This has significant implications for both fertility and long-term health, with people experiencing an increased risk of cardiometabolic disorders after menopause. Reproductive aging can be assessed through markers of ovarian reserve, response to fertility treatment or molecular biomarkers, including DNA methylation. Changes in DNA methylation with age associate with poorer reproductive outcomes, and epigenome-wide studies can provide insight into genes and pathways involved. DNA methylation-based epigenetic clocks can quantify biological age in reproductive tissues and systemically. This review provides an overview of hallmarks and theories of aging in the context of the reproductive system, and then focuses on studies of DNA methylation in reproductive tissues.
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Affiliation(s)
- Anna K Knight
- Research Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jessica B Spencer
- Reproductive Endocrinology & Infertility Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Alicia K Smith
- Research Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Reproductive Endocrinology & Infertility Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA
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44
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Chamanara S, Hozouri V, Irandoost E. Inhibition of NLRP3 inflammasome-A potential mechanistic therapeutic for treatment of polycystic ovary syndrome? J Biochem Mol Toxicol 2024; 38:e23592. [PMID: 38054794 DOI: 10.1002/jbt.23592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 11/05/2023] [Accepted: 11/20/2023] [Indexed: 12/07/2023]
Abstract
This review article explores the relationship between the NOD-like receptor protein 3 (NLRP3) inflammasome and the risk of developing polycystic ovary syndrome (PCOS). The NLRP3 inflammasome, a fundamental element of the innate immune system, plays a crucial role in the production of proinflammatory mediators and pyroptosis, a type inflammatory cell death. We conducted a thorough search on scientific databases to gather relevant information on this topic, utilizing relevant keywords. The reviewed studies indicated a correlation between PCOS and a higher incidence of granulosa cell (GC) death and the presence of ovarian tissue fibrosis. NLRP3 inflammasome stimulation and subsequent pyroptosis in GCs play a significant role in the pathophysiology of PCOS. Active NLRP3 inflammasome is involved in the production of inflammatory mediators like interleukin-1β (IL-1β) and IL-18, contributing to the development of PCOS, particularly in overweight patients. Therefore, inhibiting NLRP3 activation and pyroptosis could potentially offer novel therapeutic strategies for PCOS. Some limited studies have explored the use of agents with antioxidant and anti-inflammatory properties, as well as gene therapy approaches, to target the NLRP3 and pyroptosis signaling pathways. This study overview the understanding of the relationship between NLRP3 inflammasome activation, pyroptosis, and PCOS. It highlights the potential of targeting the NLRP3 inflammasome as an approach for treating PCOS. Nonetheless, further research and clinical trials are imperative to validate these results and explore the effectiveness of NLRP3 inflammasome inhibition in the management of PCOS.
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Affiliation(s)
- Solmaz Chamanara
- Department of Gynecology and Obstetrics, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Vahid Hozouri
- Internal Medicine Department, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Elnaz Irandoost
- Department of Gynecology and Obstetrics, Tehran University of Medical Sciences, Tehran, Iran
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45
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Nisa KU, Tarfeen N, Mir SA, Waza AA, Ahmad MB, Ganai BA. Molecular Mechanisms in the Etiology of Polycystic Ovary Syndrome (PCOS): A Multifaceted Hypothesis Towards the Disease with Potential Therapeutics. Indian J Clin Biochem 2024; 39:18-36. [PMID: 38223007 PMCID: PMC10784448 DOI: 10.1007/s12291-023-01130-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 03/01/2023] [Indexed: 03/28/2023]
Abstract
Among the premenopausal women, Polycystic Ovary Syndrome (PCOS) is the most prevalent endocrinopathy affecting the reproductive system and metabolic rhythms leading to disrupted menstrual cycle. Being heterogeneous in nature it is characterized by complex symptomology of oligomennorhoea, excess of androgens triggering masculine phenotypic appearance and/or multiple follicular ovaries. The etiology of this complex disorder remains somewhat doubtful and the researchers hypothesize multisystem links in the pathogenesis of this disease. In this review, we attempt to present several hypotheses that tend to contribute to the etiology of PCOS. Metabolic inflexibility, aberrant pattern of gonadotropin signaling along with the evolutionary, genetic and environmental factors have been discussed. Considered a lifelong endocrinological implication, no universal treatment is available for PCOS so far however; multiple drug therapy is often advised along with simple life style intervention is mainly advised to manage its cardinal symptoms. Here we aimed to present a summarized view of pathophysiological links of PCOS with potential therapeutic strategies.
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Affiliation(s)
- Khair Ul Nisa
- Department of Environmental Science, University of Kashmir, Srinagar, 190006 India
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, 190006 India
| | - Najeebul Tarfeen
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, 190006 India
| | - Shahnaz Ahmad Mir
- Department of Endocrinology, Government Medical College, Shireen Bagh, Srinagar, 190010 India
| | - Ajaz Ahmad Waza
- Multidisciplinary Research Unit (MRU), Government Medical Collage (GMC), Srinagar, 190010 India
| | - Mir Bilal Ahmad
- Department of Biochemistry, University of Kashmir, Srinagar, 190006 India
| | - Bashir Ahmad Ganai
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, 190006 India
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Bhattacharya K, Dey R, Sen D, Paul N, Basak AK, Purkait MP, Shukla N, Chaudhuri GR, Bhattacharya A, Maiti R, Adhikary K, Chatterjee P, Karak P, Syamal AK. Polycystic ovary syndrome and its management: In view of oxidative stress. Biomol Concepts 2024; 15:bmc-2022-0038. [PMID: 38242137 DOI: 10.1515/bmc-2022-0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/11/2023] [Indexed: 01/21/2024] Open
Abstract
In the past two decades, oxidative stress (OS) has drawn a lot of interest due to the revelation that individuals with many persistent disorders including diabetes, polycystic ovarian syndrome (PCOS), cardiovascular, and other disorders often have aberrant oxidation statuses. OS has a close interplay with PCOS features such as insulin resistance, hyperandrogenism, and chronic inflammation; there is a belief that OS might contribute to the development of PCOS. PCOS is currently recognized as not only one of the most prevalent endocrine disorders but also a significant contributor to female infertility, affecting a considerable proportion of women globally. Therefore, the understanding of the relationship between OS and PCOS is crucial to the development of therapeutic and preventive strategies for PCOS. Moreover, the mechanistic study of intracellular reactive oxygen species/ reactive nitrogen species formation and its possible interaction with women's reproductive health is required, which includes complex enzymatic and non-enzymatic antioxidant systems. Apart from that, our current review includes possible regulation of the pathogenesis of OS. A change in lifestyle, including physical activity, various supplements that boost antioxidant levels, particularly vitamins, and the usage of medicinal herbs, is thought to be the best way to combat this occurrence of OS and improve the pathophysiologic conditions associated with PCOS.
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Affiliation(s)
- Koushik Bhattacharya
- School of Paramedics and Allied Health Sciences, Centurion University of Technology and Management, Khurda Road, Bhubaneswar, Odisha, India
| | - Rajen Dey
- Department of Medical Laboratory Technology, Swami Vivekananda University, Barrackpore, West Bengal, India
| | - Debanjana Sen
- Post-Graduate Department of Physiology, Hooghly Mohsin College, Chinsurah, West-Bengal, India
| | - Nimisha Paul
- Department of General Human Physiology and Biochemistry, Hitkarini Dental College and Hospital, Jabalpur, Madhya Pradesh, India
| | - Asim Kumar Basak
- School of Allied Health Sciences, Brainware University, Barasat, West-Bengal, India
| | | | - Nandini Shukla
- Department of Anatomy, Pt. J.N.M. Medical College, Raipur, Chhattisgarh, India
| | - Gargi Ray Chaudhuri
- Department of Physiotherapy, Nopany Institute of Health Care Studies, Kolkata, West-Bengal, India
| | - Aniruddha Bhattacharya
- Department of Physiology, International Medical School, Management and Science University, Selangor, Malaysia
| | - Rajkumar Maiti
- Department of Physiology, Bankura Christian College, Bankura, West Bengal, India
| | - Krishnendu Adhikary
- Department of Interdisciplinary Science, Centurion University of Technology and Management, Khurda Road, Bhubaneswar, Odisha, India
| | - Prity Chatterjee
- Department of Biotechnology, Paramedical College, Durgapur, West Bengal, India
| | - Prithviraj Karak
- Department of Physiology, Bankura Christian College, Bankura, West Bengal, India
| | - Alak Kumar Syamal
- Post-Graduate Department of Physiology, Hooghly Mohsin College, Chinsurah, West-Bengal, India
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Mukherjee P, Sanyal S, Chadha S, Mukherjee S. The Impact of Polycystic Ovary Syndrome (PCOS) on the Risk of Developing Ovarian Cancer and Thyroid Disorders: A Comprehensive Review. Endocr Metab Immune Disord Drug Targets 2024; 24:562-572. [PMID: 37986267 DOI: 10.2174/0118715303266512231103075551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 09/13/2023] [Accepted: 09/26/2023] [Indexed: 11/22/2023]
Abstract
Polycystic ovary syndrome (PCOS) is a common hormonal disorder that affects women. It is characterized by hyperandrogenism, polycystic ovarian morphology, and other related disorders. It is associated with various health conditions, such as infertility and increased risk of heart problems. Ovarian cancer is also a significant concern, as it is the fifth leading cause of death in women. While there is evidence suggesting a potential association between PCOS and ovarian cancer, the exact nature of this relationship remains unclear. Thyroid disorders, particularly hypothyroidism and Hashimoto's thyroiditis, have also been linked to PCOS. The presence of hypothyroidism can contribute to the development of polycystic ovarian morphology, affecting ovulation and hormone balance. Many works have shown a higher ubiquity of autoimmune thyroid disease in PCOS patients, indicating a potential association between the two conditions. The occurrence of PCOS, hirsutism, and acne underscores the frequency of endocrine disorders in women. This review paper examines the present relevant work on the association between PCOS and ovarian cancer as well as PCOS and thyroid disorders. A systematic literature search was conducted on the internet, such as PubMed, Scopus, and Google Scholar database, to identify peer-reviewed publications pertaining to PCOS, ovarian cancer, and thyroid disorders. While some studies have delineated a significant link between PCOS and ovarian cancer or thyroid disorders, others have yielded inconclusive results. Further research is necessary to establish a definitive causal relationship between these conditions. Understanding the relationship between PCOS, ovarian cancer, and thyroid disorders is crucial for early detection, accurate diagnosis, and effective management of these conditions. Identifying potential risk factors and developing appropriate screening strategies can improve women's health outcomes and reduce the burden associated with these disorders.
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Affiliation(s)
- Payal Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Somali Sanyal
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Sonia Chadha
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
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Aru N, Yang C, Chen Y, Liu J. Causal association of immune cells and polycystic ovarian syndrome: a Mendelian randomization study. Front Endocrinol (Lausanne) 2023; 14:1326344. [PMID: 38189053 PMCID: PMC10770856 DOI: 10.3389/fendo.2023.1326344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Background Polycystic ovarian syndrome (PCOS) is a common reproductive disorder that affects a considerable number of women worldwide. It is accompanied by irregular menstruation, hyperandrogenism, metabolic abnormalities, reproductive disorders and other clinical symptoms, which seriously endangers women's physical and mental health. The etiology and pathogenesis of PCOS are not completely clear, but it is hypothesized that immune system may play a key role in it. However, previous studies investigating the connection between immune cells and PCOS have produced conflicting results. Methods Mendelian randomization (MR) is a powerful study design that uses genetic variants as instrumental variables to enable examination of the causal effect of an exposure on an outcome in observational data. In this study, we utilized a comprehensive two-sample MR analysis to examine the causal link between 731 immune cells and PCOS. We employed complementary MR methods, such as the inverse-variance weighted (IVW) method, and conducted sensitivity analyses to evaluate the reliability of the outcomes. Results Four immunophenotypes were identified to be significantly associated with PCOS risk: Memory B cell AC (IVW: OR [95%]: 1.123[1.040 to 1.213], p = 0.003), CD39+ CD4+ %CD4+ (IVW: OR [95%]: 0.869[0.784 to 0.963], p = 0.008), CD20 on CD20- CD38-(IVW: OR [95%]:1.297[1.088 to 1.546], p = 0.004), and HLA DR on CD14- CD16+ monocyte (IVW: OR [95%]:1.225[1.074 to 1.397], p = 0.003). The results of the sensitivity analyses were consistent with the main findings. Conclusions Our MR analysis provides strong evidence supporting a causal association between immune cells and the susceptibility of PCOS. This discovery can assist in clinical decision-making regarding disease prognosis and treatment options, and also provides a new direction for drug development.
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Affiliation(s)
- Na Aru
- Department of Reproductive Endocrinology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Congyu Yang
- Department of Reproductive Endocrinology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yuntian Chen
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Jiaming Liu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
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Gan J, Chen J, Ma RL, Deng Y, Ding XS, Zhu SY, Sun AJ. Action Mechanisms of Metformin Combined with Exenatide and Metformin Only in the Treatment of PCOS in Obese Patients. Int J Endocrinol 2023; 2023:4288004. [PMID: 38131036 PMCID: PMC10735721 DOI: 10.1155/2023/4288004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 07/14/2023] [Accepted: 10/28/2023] [Indexed: 12/23/2023] Open
Abstract
Background Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women of reproductive age, whose clinical characteristics are hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovary, often accompanied by insulin resistance (IR) and metabolic abnormalities. Glucagon-like peptide (GLP)-1 receptor agonists (GLP-1Ra), such as exenatide, can bind to specific receptors on tissues such as the ovaries to improve the clinical phenotype of PCOS, while insulin-sensitizing agents, such as metformin, can also benefit to metabolic abnormalities in PCOS. Liquid chromatography-mass spectrometry (LC/MS) metabolomics revealed differences between the mechanisms of exenatide and metformin treatment of PCOS to some extent. Methods In this study, 50 obese subjects with PCOS were randomly divided into the exenatide combined with metformin group (COM group, n = 28) and the metformin group (MF group, n = 22) for 12-week treatment. Before and after, serum samples were subjected to LC/MS analysis. Results After treatment, there were 153 named differential metabolites in the COM group and 99 in the MF group. Most phosphatidylcholines (PC) and deoxycholic acid 3-glucuronide (DA3G) were significantly upregulated, while most glycerophosphoethanolamine (PE-NMe2), glycerophosphocholine (GPC), and threonine were downregulated in both groups. Only the decrease of neuromedin B, glutamate, and glutamyl groups and the increase of chenodeoxycholic acid sulfate docosadienoate (22: 2n6), and prostaglandin E2 have been observed in the COM group. In addition, salicylic acid and spisulosine increased and decanoylcarnitine decreased in the MF group. Both groups were enriched in glycerophospholipid, choline, and sphingolipid metabolism, while the COM group was especially superior in the glutamine and glutamate, bile secretion, and amino acid metabolism. Conclusion Compared with metformin alone in the treatment of PCOS, the differential metabolites of the exenatide combined with metformin group are more extensive. The COM group may act on the hypothalamic-pituitary-gonadal axis (HPO) and its bypass, regulate multiple metabolism pathways such as phospholipids, amino acids, fatty acids, carnitine, bile acids, and glucose directly or indirectly in obese PCOS patients.
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Affiliation(s)
- Jingwen Gan
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Jie Chen
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Rui-lin Ma
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Yan Deng
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Xue-song Ding
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Shi-yang Zhu
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Ai-jun Sun
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
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Liu L, Li X, Chen Y, Li YZ, Liu Z, Duan Y, Chen Y. Interleukin-22 promotes proliferation and reverses LPS-induced apoptosis and steroidogenesis attenuation in human ovarian granulosa cells: implications for polycystic ovary syndrome pathogenesis. J Matern Fetal Neonatal Med 2023; 36:2253347. [PMID: 37661176 DOI: 10.1080/14767058.2023.2253347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 08/09/2023] [Accepted: 08/24/2023] [Indexed: 09/05/2023]
Abstract
OBJECTIVE Interleukin 22 (IL-22) plays a role in inflammatory diseases. However, whether IL-22 affects the function of ovarian granulosa cells (GCs) and its relationship with Polycystic Ovary Syndrome (PCOS)remains unclear. METHODS We investigated the level of IL-22 in human follicular fluid using ELISA. The expression and localization of the IL-22 receptor 1 (IL-22R1) in GCs were investigated by RT-PCR and immunofluorescence staining, respectively. The proliferation of KGN cells (human GCs line) was assessed by CCK-8 assay and EdU assay after treatment with recombinant human IL-22 (rhIL-22) and lipopolysaccharide (LPS). Apoptosis was assessed using flow cytometry. Apoptotic proteins and steroidogenic genes were detected by western blotting. RESULTS ELISA's results showed that compared with the control group, PCOS patients showed lower expression of IL-22 in follicular fluid. Immunofluorescence showed that IL-22R1 is expressed and localized in human granulosa cell membranes. IL-22 promoted cell proliferation and reversed LPS-induced inhibition of cell proliferation. IL-22 alone did not affect apoptotic or steroidogenic protein expression, however, it reversed LPS-induced apoptosis via downregulation of Bcl-2, upregulation of Bax and cleaved caspase-3, and restoration of LPS-downregulated StAR, CYP11A1, and CYP19A1 expression. Western blotting confirmed that IL-22 activated the JAK2/STAT3 signaling. CONCLUSION IL-22 promotes cell proliferation, inhibits apoptosis, and regulates KGN cell steroidogenesis confronted with LPS, and decreased IL-22 may be involved in the development of PCOS.
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Affiliation(s)
- Linhong Liu
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xu Li
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ying Chen
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Zhe Li
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhen Liu
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuhan Duan
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ying Chen
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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