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Causal association of immune cells and polycystic ovarian syndrome: a Mendelian randomization study.Frontiers in Endocrinology 2023Polycystic ovarian syndrome (PCOS) is a common reproductive disorder that affects a considerable number of women worldwide. It is accompanied by irregular menstruation,...
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], = 0.003), CD39+ CD4+ %CD4+ (IVW: OR [95%]: 0.869[0.784 to 0.963], = 0.008), CD20 on CD20- CD38-(IVW: OR [95%]:1.297[1.088 to 1.546], = 0.004), and HLA DR on CD14- CD16+ monocyte (IVW: OR [95%]:1.225[1.074 to 1.397], = 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.
Topics: Humans; Female; Polycystic Ovary Syndrome; Mendelian Randomization Analysis; Reproducibility of Results; Causality; Clinical Decision-Making
PubMed: 38189053
DOI: 10.3389/fendo.2023.1326344 -
BMC Medicine Aug 2023The results of human observational studies on the correlation between gut microbiota perturbations and polycystic ovary syndrome (PCOS) have been contradictory. This... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The results of human observational studies on the correlation between gut microbiota perturbations and polycystic ovary syndrome (PCOS) have been contradictory. This study aimed to perform the first systematic review and meta-analysis to evaluate the specificity of the gut microbiota in PCOS patients compared to healthy women.
METHODS
Literature through May 22, 2023, was searched on PubMed, Web of Science, Medline, Embase, Cochrane Library, and Wiley Online Library databases. Unreported data in diversity indices were filled by downloading and processing raw sequencing data. Systematic review inclusion: original studies were eligible if they applied an observational case-control design, performed gut microbiota analysis and reported diversity or abundance measures, sampled general pre-menopausal women with PCOS, and are longitudinal studies with baseline comparison between PCOS patients and healthy females. Systematic review exclusion: studies that conducted interventional or longitudinal comparisons in the absence of a control group. Two researchers made abstract, full-text, and data extraction decisions, independently. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the methodologic quality. Hedge's g standardized mean difference (SMD), confidence intervals (CIs), and heterogeneity (I) for alpha diversity were calculated. Qualitative syntheses of beta-diversity and microbe alterations were performed.
RESULTS
Twenty-eight studies (n = 1022 patients, n = 928 control) that investigated gut microbiota by collecting stool samples were included, with 26 and 27 studies having provided alpha-diversity and beta-diversity results respectively. A significant decrease in microbial evenness and phylogenetic diversity was observed in PCOS patients when compared with control participants (Shannon index: SMD = - 0.27; 95% CI, - 0.37 to - 0.16; phylogenetic diversity: SMD = - 0.39; 95% CI, -- 0.74 to - 0.03). We also found that reported beta-diversity was inconsistent between studies. Despite heterogeneity in bacterial relative abundance, we observed depletion of Lachnospira and Prevotella and enrichment of Bacteroides, Parabacteroides, Lactobacillus, Fusobacterium, and Escherichia/Shigella in PCOS. Gut dysbiosis in PCOS, which might be characterized by the reduction of short-chain fatty acid (SCFA)-producing and bile-acid-metabolizing bacteria, suggests a shift in balance to favor pro-inflammatory rather than anti-inflammatory bacteria.
CONCLUSIONS
Gut dysbiosis in PCOS is associated with decreased diversity and alterations in bacteria involved in microbiota-host crosstalk.
TRIAL REGISTRATION
PROSPERO registration: CRD42021285206, May 22, 2023.
Topics: Humans; Female; Gastrointestinal Microbiome; Polycystic Ovary Syndrome; Dysbiosis; Phylogeny; Microbiota
PubMed: 37559119
DOI: 10.1186/s12916-023-02975-8 -
Frontiers in Endocrinology 2023Uterine leiomyoma is the most common benign tumor in females of reproductive age. However, its causes have never been fully understood. The objective of our study was to... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
Uterine leiomyoma is the most common benign tumor in females of reproductive age. However, its causes have never been fully understood. The objective of our study was to analyze the causal association between various factors and uterine leiomyoma using Mendelian randomization (MR).
METHODS
Genetic variables associated with risk factors were obtained from genome-wide association studies. Summary-level statistical data for uterine leiomyoma were obtained from FinnGen and the UK Biobank (UKB) consortium. We used inverse variance weighted, MR-Egger, and weighted median methods in univariate analysis. Multivariable MR analysis was used to identify independent risk factors. A fixed-effect model meta-analysis was used to combine the results of the FinnGen and UKB data.
RESULTS
In the FinnGen data, higher genetically predicted age at natural menopause, systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting insulin were associated with an increased risk of uterine leiomyoma, while higher age at menarche was associated with a reduced risk of uterine leiomyoma. Multivariable MR analysis of SBP and DBP showed that higher DBP might be an independent risk factor of uterine leiomyoma. In the UKB data, the results for age at natural menopause, SBP, DBP, and age at menarche were replicated. The result of the meta-analysis suggested that uterine leiomyoma could also be affected by polycystic ovary syndrome (PCOS), endometriosis, and 2-hour glucose level.
CONCLUSION
Our MR study confirmed that earlier menstrual age, hypertension, obesity, and elevated 2-hour glucose post-challenge were risk factors for uterine leiomyoma, and the causal relationship between smoking and uterine leiomyoma was ruled out. In addition, later age of menopause and endometriosis were found to increase the risk of uterine leiomyoma, while PCOS was found to decrease the risk.
Topics: Female; Humans; Endometriosis; Genome-Wide Association Study; Mendelian Randomization Analysis; Leiomyoma; Polycystic Ovary Syndrome; Glucose
PubMed: 37576957
DOI: 10.3389/fendo.2023.1133260 -
Frontiers in Endocrinology 2023
Topics: Humans; Female; Hyperprolactinemia; Prolactin; Polycystic Ovary Syndrome
PubMed: 38274234
DOI: 10.3389/fendo.2023.1351471 -
Frontiers in Endocrinology 2023The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various...
PURPOSE
The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs.
METHODS
In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility.
RESULTS
PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea.
CONCLUSION
The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.
Topics: Humans; Female; Proprotein Convertase 9; Polycystic Ovary Syndrome; Genome-Wide Association Study; Mendelian Randomization Analysis; Menorrhagia; Oligomenorrhea; PCSK9 Inhibitors; Hypolipidemic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Coronary Disease; Lipids; Infertility
PubMed: 38027179
DOI: 10.3389/fendo.2023.1295412 -
The Journal of Clinical Endocrinology... Jan 2024Polycystic ovary syndrome (PCOS) affects more than 1 in 10 women. (Meta-Analysis)
Meta-Analysis
CONTEXT
Polycystic ovary syndrome (PCOS) affects more than 1 in 10 women.
OBJECTIVE
As part of the 2023 International PCOS Guidelines update, comparisons between combined oral contraceptive pills (COCP), metformin, and combination treatment were evaluated.
DATA SOURCES
Ovid Medline, Embase, PsycINFO, All EBM, and CINAHL were searched.
STUDY SELECTION
Women with PCOS included in randomized controlled trials (RCTs).
DATA EXTRACTION
We calculated mean differences and 95% CIs regarding anthropometrics, metabolic, and hyperandrogenic outcomes. Meta-analyses and quality assessment using GRADE were performed.
DATA SYNTHESIS
The search identified 1660 publications; 36 RCTs were included. For hirsutism, no differences were seen when comparing metformin vs COCP, nor when comparing COCP vs combination treatment with metformin and COCP. Metformin was inferior on free androgen index (FAI) (7.08; 95% CI 4.81, 9.36), sex hormone binding globulin (SHBG) (-118.61 nmol/L; 95% CI -174.46, -62.75) and testosterone (0.48 nmol/L; 95% CI 0.32, 0.64) compared with COCP. COCP was inferior for FAI (0.58; 95% CI 0.36, 0.80) and SHBG (-16.61 nmol/L; 95% CI -28.51, -4.71) compared with combination treatment, whereas testosterone did not differ. Metformin lowered insulin (-27.12 pmol/L; 95% CI -40.65, -13.59) and triglycerides (-0.15 mmol/L; 95% CI -0.29, -0.01) compared with COCP. COCP was inferior for insulin (17.03 pmol/L; 95% CI 7.79, 26.26) and insulin resistance (0.44; 95% CI 0.17, 0.70) compared with combination treatment.
CONCLUSIONS
The choice of metformin or COCP treatment should be based on symptoms, noting some biochemical benefits from combination treatment targeting both major endocrine disturbances seen in PCOS (hyperinsulinemia and hyperandrogenism).
Topics: Female; Humans; Metformin; Polycystic Ovary Syndrome; Contraceptives, Oral, Combined; Hypoglycemic Agents; Testosterone; Insulins
PubMed: 37554096
DOI: 10.1210/clinem/dgad465 -
Human Reproduction (Oxford, England) Sep 2023What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer...
STUDY QUESTION
What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference?
SUMMARY ANSWER
International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS.
WHAT IS KNOWN ALREADY
The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist.
STUDY DESIGN, SIZE, DURATION
The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout.
PARTICIPANTS/MATERIALS, SETTING, METHODS
This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC).
MAIN RESULTS AND THE ROLE OF CHANCE
The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management.
LIMITATIONS, REASONS FOR CAUTION
Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided.
WIDER IMPLICATIONS OF THE FINDINGS
The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the Guideline with an integrated evaluation program.
STUDY FUNDING/COMPETING INTEREST(S)
This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.
Topics: Pregnancy; Adult; Female; Humans; Child; Polycystic Ovary Syndrome; Quality of Life; Australia; Risk Factors; Gynecology
PubMed: 37580037
DOI: 10.1093/humrep/dead156 -
International Immunopharmacology Dec 2023Hyperandrogenemia and persistent chronic inflammation, two main striking features of polycystic ovary syndrome (PCOS), have been proven involved in follicular dysgenesis...
Hyperandrogenemia and persistent chronic inflammation, two main striking features of polycystic ovary syndrome (PCOS), have been proven involved in follicular dysgenesis in PCOS. However, the association between hyperandrogenism and inflammation activation in PCOS is not fully understood. Excess testosterone(T) induces inflammation and pyroptosis activation in a mouse model of PCOS, leading to ovarian dysfunction and fibrosis. Excessive endoplasmic reticulum (ER) stress is present in ovarian granulosa cells (GCs), testosterone-induced PCOS mouse and cellular models. This study found higher levels of interleukin (IL)-1β, IL-8, IL-17, and IL-18 in the follicular fluid of PCOS patients with hyperandrogenemia undergoing IVF treatment. In addition, pyroptosis in GCs was demonstrated, which was significantly elevated in PCOS patients. To clarify the association of hyperandrogenism, inflammation, and pyroptosis activation in PCOS, dehydroepiandrosterone(DHEA)-treated mouse PCOS model and T-treated KGN cell line were explored for PCOS mechanism. Markers of inflammatory activation and pyroptosis were significantly increased after DHEA treatment in mice and T treatment in KGN cells. In addition, ER stress sensor proteins were increased simultaneously. However, suppression of inflammation by genipin(GP) led to decreased pyroptosis in KGN cells but no variation in ER stress sensor proteins. In contrast, when treated with tauroursodeoxycholic acid(TUDCA) to attenuate ER stress, the markers of inflammatory factors were significantly reduced, accompanied by a reduction in pyroptosis. Our results suggest that persistent hyperandrogenemia of PCOS promotes local inflammatory activation of the ovary, and the imbalanced inflammatory microenvironment leads to pyroptosis of GCs, which is mediated by ER stress activation.
Topics: Humans; Female; Mice; Animals; Polycystic Ovary Syndrome; Hyperandrogenism; Pyroptosis; Testosterone; Inflammation; Dehydroepiandrosterone; Tumor Microenvironment
PubMed: 37918087
DOI: 10.1016/j.intimp.2023.111141 -
Frontiers in Endocrinology 2023The ovarian microenvironment is critical for follicular development and oocyte maturation. Maternal conditions, including polycystic ovary syndrome (PCOS),... (Review)
Review
The ovarian microenvironment is critical for follicular development and oocyte maturation. Maternal conditions, including polycystic ovary syndrome (PCOS), endometriosis, and aging, may compromise the ovarian microenvironment, follicular development, and oocyte quality. Chronic low-grade inflammation can induce oxidative stress and tissue fibrosis in the ovary. In PCOS, endometriosis, and aging, pro-inflammatory cytokine levels are often elevated in follicular fluids. In women with obesity and PCOS, hyperandrogenemia and insulin resistance induce ovarian chronic low-grade inflammation, thereby disrupting follicular development by increasing oxidative stress. In endometriosis, ovarian endometrioma-derived iron overload can induce chronic inflammation and oxidative stress, leading to ovarian ferroptosis and fibrosis. In inflammatory aging (inflammaging), senescent cells may secrete senescence-associated secretory phenotype factors, causing chronic inflammation and oxidative stress in the ovary. Therefore, controlling chronic low-grade inflammation and fibrosis in the ovary would present a novel therapeutic strategy for improving the follicular microenvironment and minimizing ovarian dysfunction.
Topics: Female; Humans; Polycystic Ovary Syndrome; Endometriosis; Aging; Inflammation; Fibrosis; Tumor Microenvironment
PubMed: 38192421
DOI: 10.3389/fendo.2023.1324429 -
Journal of Nanobiotechnology Nov 2023The immune system is closely associated with the pathogenesis of polycystic ovary syndrome (PCOS). Macrophages are one of the important immune cell types in the ovarian...
The immune system is closely associated with the pathogenesis of polycystic ovary syndrome (PCOS). Macrophages are one of the important immune cell types in the ovarian proinflammatory microenvironment, and ameliorate the inflammatory status mainly through M2 phenotype polarization during PCOS. Current therapeutic approaches lack efficacy and immunomodulatory capacity, and a new therapeutic method is needed to prevent inflammation and alleviate PCOS. Here, octahedral nanoceria nanoparticles with powerful antioxidative ability were bonded to the anti-inflammatory drug resveratrol (CeO@RSV), which demonstrates a crucial strategy that involves anti-inflammatory and antioxidative efficacy, thereby facilitating the proliferation of granulosa cells during PCOS. Notably, our nanoparticles were demonstrated to possess potent therapeutic efficacy via anti-inflammatory activities and effectively alleviated endocrine dysfunction, inflammation and ovarian injury in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Collectively, this study revealed the tremendous potential of the newly developed nanoparticles in ameliorating the proinflammatory microenvironment and promoting the function of granulosa cells, representing the first attempt to treat PCOS by using CeO@RSV nanoparticles and providing new insights in combating clinical PCOS.
Topics: Mice; Animals; Female; Humans; Polycystic Ovary Syndrome; Inflammation; Anti-Inflammatory Agents; Nanocomposites; Tumor Microenvironment
PubMed: 37936120
DOI: 10.1186/s12951-023-02182-w