Polycystic Ovary Syndrome Cohort Research Articles

Clustering Identifies Subtypes With Different Phenotypic Characteristics in Women With Polycystic Ovary Syndrome.

Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS). This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes. Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of Health criteria (ovulatory dysfunction and hyperandrogenism). Main outcome measures included the identification of distinct PCOS subtypes using cluster analysis. Additional clinical variables associated with these subtypes were assessed. Metabolic, reproductive, and background PCOS subtypes were identified. In addition to high LH and SHBG levels, the reproductive subtype had the highest TFC and levels of AMH (all P < .001). In addition to high BMI and insulin levels, the metabolic subtype had higher low-density lipoprotein levels and higher systolic and diastolic blood pressure (all P < .001). The background subtype had lower androstenedione levels and features of the other 2 subtypes. Reproductive and metabolic traits not used for subtyping differed significantly in the subtypes. These findings suggest that the subtypes capture distinct PCOS causal pathways.

A Cross-Sectional Study of Glomerular Hyperfiltration in Polycystic Ovary Syndrome.

Glomerular hyperfiltration (GH) has been reported to be higher in women with polycystic ovary syndrome (PCOS) and is an independent risk factor for renal function deterioration, metabolic, and cardiovascular disease. The aim of this study was to determine GH in type A PCOS subjects and to identify whether inflammatory markers, markers of CKD, renal tubule injury markers, and complement system proteins were associated. In addition, a secondary cohort study was performed to determine if the eGFR had altered over time. In this comparative cross-sectional analysis, demographic, metabolic, and proteomic data from Caucasian women aged 18-40 years from a PCOS Biobank (137 with PCOS, 97 controls) was analyzed. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for inflammatory proteins, serum markers of chronic kidney disease (CKD), tubular renal injury markers, and complement system proteins. A total of 44.5% of the PCOS cohort had GH (eGFR ≥ 126 mL/min/1.73 m2 (n = 55)), and 12% (n = 17) eGFR ≥ 142 mL/min/1.73 m2 (super-GH(SGH)). PCOS-GH women were younger and had lower creatinine and urea versus PCOS-nonGH. C-reactive protein (CRP), white cell count (WCC), and systolic blood pressure (SBP) were higher in PCOS versus controls, but CRP correlated only with PCOS-SGH alone. Complement protein changes were seen between controls and PCOS-nonGH, and decay-accelerator factor (DAF) was decreased between PCOS-nonGH and PCOS-GSGH (p < 0.05). CRP correlated with eGFR in the PCOS-SGH group, but not with other inflammatory or complement parameters. Cystatin-c (a marker of CKD) was reduced between PCOS-nonGH and PCOS-GSGH (p < 0.05). No differences in tubular renal injury markers were found. A secondary cohort notes review of the biobank subjects 8.2-9.6 years later showed a reduction in eGFR: controls -6.4 ± 12.6 mL/min/1.73 m2 (-5.3 ± 11.5%; decrease 0.65%/year); PCOS-nonGH -11.3 ± 13.7 mL/min/1.73 m2 (-9.7 ± 12.2%; p < 0.05, decrease 1%/year); PCOS-GH (eGFR 126-140 mL/min/17.3 m2) -27.1 ± 12.8 mL/min/1.73 m2 (-19.1 ± 8.7%; p < 0.0001, decrease 2%/year); PCOS-SGH (eGFR ≥ 142 mL/min/17.3 m2) -33.7 ± 8.9 mL/min/17.3 m2 (-22.8 ± 6.0%; p < 0.0001, decrease 3.5%/year); PCOS-nonGH eGFR versus PCOS-GH and PCOS-SGH, p < 0.001; no difference PCOS-GH versus PCOS-SGH. GH was associated with PCOS and did not appear mediated through tubular renal injury; however, cystatin-c and DAF were decreased, and CRP correlated positively with PCOS-SGH, suggesting inflammation may be involved at higher GH. There were progressive eGFR decrements for PCOS-nonGH, PCOS-GH, and PCOS-SGH in the follow-up period which, in the presence of additional factors affecting renal function, may be clinically important in the development of CKD in PCOS.

Is thyroid function associated with polycystic ovary syndrome? A bidirectional Mendelian randomization study.

Some observational studies have suggested the association between thyroid function and polycystic ovary syndrome (PCOS). However, it remains to be determined whether these associations are causal or not. The aim of this study was to investigate the underlying causal association between different thyroid function status and PCOS. Bidirectional Mendelian randomization (MR) analysis was conducted to explore the impact of different thyroid function statuses on PCOS. The study included 10,074 individuals with PCOS and 103,164 controls for the primary analysis, with validation analysis repeated in the FinnGen R9 and EstBB PCOS cohorts. Female-specific thyroid function GWAS data were obtained from European population, including Hyperthyroidism (22,383 cases and 54,288 controls) and Hypothyroidism (27,383 cases and 54,288 controls) from the UK Biobank, and TSH (54,288 cases and 72,167 controls) and FT4 (49,269 cases and 72,167 controls) within the reference range from the ThyroidOmics Consortium. Inverse variance weighting (IVW) was chosen as the principal method, and sensitivity analysis was conducted to test for the presence of horizontal pleiotropy or heterogeneity. The IVW analysis indicated nominal significance between normal TSH levels and PCOS after adjusted for age and BMI [OR (95% CI) = 0.78(0.62,0.97), P = 0.029], suggesting that maintaining normal TSH levels might act as a protective factor against the pathogenesis of PCOS. Besides, in order to increase the statistical power, we pooled PCOS GWAS above together by meta-analysis and found PCOS contributed to the occurrence of hyperthyroidism [OR(95%CI) = 1.37(0.73,2.57), P = 0.012]. However, no causal relationship was found after Bonferroni correction (P-value < 0.0031). Although the MR analysis didn't indicate genetic causal association between thyroid function and PCOS after Bonferroni correction. Further efforts are needed to interpret the potential causal relationship between thyroid function and PCOS in different age and BMI subgroup.

Meteorin-like Protein and Zonulin in Polycystic Ovary Syndrome: Exploring Associations with Obesity, Metabolic Parameters, and Inflammation.

Polycystic ovary syndrome (PCOS) is a prevalent hormonal and metabolic disorder, wherein the adipose tissue and gut microbiome have been demonstrated to contribute to its pathogenesis. This study aims to assess the concentrations of the adipokine, meteorin-like protein (Metrnl) and the protein, zonulin, related to intestine permeability, in individuals with PCOS with a particular emphasis on their relationship with obesity, clinical manifestations, hormonal profiles, and metabolic parameters. A cohort comprising 58 women with PCOS, classified according to the Rotterdam criteria, was enrolled. The study also considered age, body mass index (BMI), and ethnicity-matched controls (n = 30). Comprehensive anthropometric and clinical evaluations, hormonal assays, and biochemical analyses were conducted during the follicular phase. Subsequent subgroup analyses were executed within the PCOS cohort based on waist-to-height ratio (WHtR), insulin resistance (IR), and free androgen index (FAI). Serum concentrations of Metrnl and zonulin were quantified via the enzyme-linked immunosorbent assay (ELISA) technique. The Metrnl and zonulin levels exhibited no significant disparity between PCOS patients and controls. Nevertheless, within the entire participant cohort and the PCOS group exclusively, overweight/obese participants demonstrated higher Metrnl concentrations relative to their normal-weight counterparts (p < 0.001, p = 0.001, respectively). Furthermore, higher Metrnl concentrations were identified in subgroups characterized by high WHtR and IR in comparison to those with low WHtR (p = 0.001) and without IR (p = 0.001), respectively. A correlation emerged between Metrnl levels and various anthropometric and metabolic parameters, as well as sex-hormone-binding globulin (SHBG) and interleukin-18 (IL-18) within the PCOS group. Multiple linear regression analysis identified HOMA-IR as the sole independent predictor of Metrnl levels. While Metrnl and zonulin levels do not serve as diagnostic indicators of PCOS, elevated Metrnl concentrations exhibited robust associations with proinflammatory and metabolic irregularities within the PCOS population.

Serum Irisin in Polycystic Ovary Syndrome and its Alteration with Metformin Intervention.

Studies investigating the alterations of serum irisin and its change with metformin therapy in patients with polycystic ovary syndrome (PCOS) are conflicting. Our aim is to study serum irisin in PCOS patients and the change of irisin levels with metformin therapy over 6 months. This is a randomized control study conducted in 187 PCOS cases and 94 age-matched controls aged 18-40 years. Detailed evaluation of anthropometric, biochemical, and hormonal parameters was performed. A subset of 99 overweight/obese patients with body mass index (BMI) ≥23 kg/m2 were stratified into a metformin group (n = 67) receiving 500 mg thrice daily and a lifestyle intervention-only group (n = 32). The effect of metformin therapy on serum irisin levels was measured at the end of 6 months. Statistical analyses were performed with SPSS version 26.0 Software. Serum irisin was higher in PCOS patients than in controls [12.47 (8.1-17.7) vs 8.3 (7.0-9.6) ng/ml, P < 0.001], independent of BMI. Serum irisin showed a significant positive association with BMI (β =0.168), waist-to-hip ratio (β =0.166), leutinizing hormone (β =0.225), TG (β =0.305), FAI (β =0.151), and testosterone (β =0.135). Serum irisin showed a significant positive association with homeostatic model assessment of insulin resistance (HOMA-IR) (β =0.14, P = 0.04) in overweight/obese PCOS patients only (n = 146) but not in the whole PCOS cohort (n = 187). Metformin reduced the median serum irisin levels significantly (13.9 to 12.1 ng/ml, P < 0.001), and the delta change in irisin levels was associated with HOMA-IR in the metformin group. Serum irisin is increased in PCOS patients independent of BMI. Metformin therapy reduced serum irisin levels in overweight/obese PCOS patients by improving insulin resistance.

Differential expression of plasma‑derived exosomal miRNAs in polycystic ovary syndrome as a circulating biomarker.

Identifying biomarkers with high sensitivity and stability is helpful for the timely and accurate diagnosis, and effective management of polycystic ovary syndrome (PCOS), a long-term, progressive endocrine disorder. Circulating microRNAs (miRNAs/miRs) are being increasingly recognized as promising biomarkers given the stability and enrichment of miRNAs in exosomes. The high sensitivity of the reverse transcription-quantitative PCR (RT-qPCR) has enabled accurate quantification of miRNAs and small fragments, present in a low abundance, in the circulation. In the present study, the potential of miRNAs in the diagnosis of PCOS was evaluated. Exosomal miRNAs were extracted and screened, and three miRNAs (miR-4488, miR-151a-5p, and miR-223-3p) were found to be differentially expressed between the PCOS group and age-matched controls by sequencing analysis. RT-qPCR was performed on a clinically confirmed PCOS cohort (n=107) and a non-PCOS control cohort (n=101) from South China to validate the PCOS-related RNA sequencing results. miR-151a-5p and miR-4488 expression levels were significantly upregulated, and miR-223-3p expression was downregulated in the PCOS cohort compared with the control cohort (P<0.05). The areas under the receiver operating characteristic curve were 0.889, 0.871, and 0.664 for miR-4488, miR-151a-5p, and miR-223-3p, respectively. Combining anti-Müllerian hormone levels with the three miRNAs resulted in an AUC of 0.967, and higher sensitivity and specificity. These results suggest that miRNAs may prove useful in the early diagnosis and effective management of PCOS, and that these three miRNAs may be involved in the pathogenesis of PCOS. In addition, bioinformatics analysis showed that these three exosomal miRNAs were involved in key signaling pathways related to cancer.

FRI457 Protein-coding Genetic Variation In Polycystic Ovary Syndrome

Abstract Disclosure: C. Parker: None. R. Bauer: None. C.K. Welt: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None. Background: Polycystic ovary syndrome (PCOS) is a multisystem endocrine disorder and is the most common form of anovulatory infertility of reproductive aged women (6-15%). PCOS is characterized by the presence of hyperandrogenemia, irregular menses, and polycystic ovarian morphology. A previous twin study has shown PCOS to be highly heritable (h2=0.72). Thus, we hypothesize that genetic variation is a major contributor to the etiology of PCOS. Objective: Our goal is to identify the genetic factors that contribute to the PCOS phenotype and how they define phenotypic subtypes of PCOS with the aim of better understanding PCOS pathology and optimizing treatment strategies for individual women. Methodology: We are performing whole exome sequencing (WES) supplemented with genomic regions mapping to PCOS GWAS loci on 772 subjects with PCOS and 300 age and ancestry-matched controls to generate a comprehensive catalog of PCOS-associated protein coding variants. We will use prediction tools to identify likely-to-be deleterious variants and in silico evidence of epigenetic modification to identify PCOS associated genes/pathways. We will then prioritize variants for molecular follow-up creating a comprehensive catalog of protein coding variants associated with PCOS. We expect the variants identified by WES to map to multiple genes and pathways including novel genes/pathways which have not previously been implicated in PCOS as well as genes/pathways that have previously been shown or predicted to play a major role in the etiology of PCOS by us or other groups. Results: To date we have obtained high quality sequencing data on 772 women with PCOS. Sequencing of 300 age and ancestry matched reproductively heathy women is being started. We have identified 81 rare protein coding genetic variants using targeted re-sequencing in three distinct pathways in an independent PCOS cohort. These genes are associated with insulin resistance, the gonadotropin signaling pathway and the Anti-Müllerian Hormone (AMH) signaling pathway. We identified 37 functionally validated deleterious variants in genes that encode AMH or its cognate receptor AMHR2, 7 rare variants that encode LMNA, 11 rare (MAF &amp;lt;0.1) variants that encode the insulin receptor, and 26 coding variants for the genes encoding the beta subunit of gonadotropins, LH and FSH, and their receptors, FSHR and LHCGR. Conclusion: We have identified 81 rare protein altering genetic variants in pathways that are predicted to be impaired in individuals with PCOS supporting a critical role for genetics in the etiology of PCOS. Our WES screen will allow us to generate a comprehensive catalog of likely to be deleterious PCOS associated variants. This catalog of variants will identify the genes/pathways that are mutated in PCOS leading to improved personalized phenotyping and treatment of PCOS. Presentation Date: Friday, June 16, 2023

THU629 Cluster Analysis Identifies Distinct Subtypes Of PCOS

Abstract Disclosure: K. van der Ham: None. L.M. Moolhuijsen: None. K. Brewer: None. R. Sisk: None. Y.V. Louwers: None. J.A. Visser: None. A.E. Dunaif: None. J.S. Laven: None. Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive-age. The different criteria that are used to diagnose PCOS reflect the heterogeneity of the syndrome. However, PCOS diagnosed by NIH or Rotterdam criteria have a similar genetic architecture. Using Hierarchical Clustering (HC) in cohort of ∼900 NIH PCOS cases from European ancestry, we have previously identified discrete and stable PCOS clusters, which were designated “reproductive subtype” (high LH, FSH and SHBG) and “metabolic subtype” (high BMI, insulin and glucose); cases that did not belong to these clusters were designated “indeterminate subtype”. The subtypes appeared to capture biologically meaningful differences because assessment by a genome-wide association study indicated that they were characterized by distinct and novel genome-wide significant loci. In the current study, we tested the hypothesis that these subtypes would be present in an independent PCOS cohort diagnosed with Rotterdam criteria using the traits drivers (BMI, LH, FSH, DHEAS, SHBG, testosterone, fasting insulin and fasting glucose). We also compared two clustering methods, HC and K-means. We assessed whether the following additional traits not used for clustering differed between the subtypes thus identified: total follicle count (TFC), modified Ferriman-Gallwey score, and levels of anti-Müllerian hormone (AMH), estradiol, TSH, DHEA, cortisol, androstenedione, prolactin, LDL, HDL, triglyceride (TC) and cholesterol. European ancestry PCOS cases, n=2502, fulfilling Rotterdam criteria, aged 13-45 years, were included; n=1067 cases also fulfilled NIH criteria. In the Rotterdam cases, the reproductive subtype (n=450) had significantly (all P&amp;lt;0.001) higher TFC and levels of AMH and HDL compared to the metabolic (n=1067) and indeterminate (n=1026) subtypes. These findings suggest that clustering identifies a discrete reproductive subtype of cases with alterations in folliculogenesis, without using AMH and TFC to define the subtype. In contrast, the metabolic subtype had significantly (all P&amp;lt;0.001) higher TC and LDL levels compared to the other subtypes providing further evidence that this subtype identifies cases at higher cardiometabolic risk. The results were similar when the analysis was limited to NIH PCOS cases only. Comparing both clustering methods showed that there was consensus for 50% (metabolic) and 57% (reproductive) of PCOS cases. The cases in the non-consensus group showed a less pronounced metabolic and reproductive phenotype, both in the trait drivers and in the additional traits. Overall, our findings suggest that clustering algorithms capture etiologically distinct subtypes of PCOS diagnosed by both NIH and Rotterdam criteria. Further, our findings provide an example of the power of modern disease classification based on objective biologic differences rather than expert opinion. Presentation: Thursday, June 15, 2023

Comparing Literature- and Subreddit-Derived Laboratory Values in Polycystic Ovary Syndrome (PCOS): Validation of Clinical Data Posted on PCOS Reddit Forums.

Polycystic ovary syndrome (PCOS) is a heterogeneous condition that affects 4% to 21% of people with ovaries. Inaccessibility or dissatisfaction with clinical treatment for PCOS has led to some individuals with the condition discussing their experiences in specialized web-based forums. This study explores the feasibility of using such web-based forums for clinical research purposes by gathering and analyzing laboratory test results posted in an active PCOS forum, specifically the PCOS subreddit hosted on Reddit. We gathered around 45,000 posts from the PCOS subreddit. A random subset of 5000 posts was manually read, and the presence of laboratory test results was labeled. These labeled posts were used to train a machine learning model to identify which of the remaining posts contained laboratory results. The laboratory results were extracted manually from the identified posts. These self-reported laboratory test results were compared with values in the published literature to assess whether the results were concordant with researcher-published values for PCOS cohorts. A total of 10 papers were chosen to represent published PCOS literature, with selection criteria including the Rotterdam diagnostic criteria for PCOS, a publication date within the last 20 years, and at least 50 participants with PCOS. Overall, the general trends observed in the laboratory test results from the PCOS web-based forum were consistent with clinically reported PCOS. A number of results, such as follicle stimulating hormone, fasting insulin, and anti-Mullerian hormone, were concordant with published values for patients with PCOS. The high consistency of these results among the literature and when compared to the subreddit suggests that follicle stimulating hormone, fasting insulin, and anti-Mullerian hormone are more consistent across PCOS phenotypes than other test results. Some results, such as testosterone, sex hormone-binding globulin, and homeostasis model assessment-estimated insulin resistance index, were between those of PCOS literature values and normal values, as defined by clinical testing limits. Interestingly, other results, including dehydroepiandrosterone sulfate, luteinizing hormone, and fasting glucose, appeared to be slightly more dysregulated than those reported in the literature. The differences between the forum-posted results and those published in the literature may be due to the selection process in clinical studies and the possibility that the forum disproportionally describes PCOS phenotypes that are less likely to be alleviated with medical intervention. However, the degree of concordance in most laboratory test values implied that the PCOS web-based forum participants were representative of research-identified PCOS cohorts. This validation of the PCOS subreddit grants the possibility for more research into the contents of the subreddit and the idea of undertaking similar research using the contents of other medical internet forums.

Serum Anti-Mullerian Hormone (AMH) Levels Among Different PCOS Phenotypes and Its Correlation with Clinical, Endocrine, and Metabolic Markers of PCOS.

Anti-Mullerian hormone (AMH) is one of the direct indicators of follicular pool but no standard cutoff has been defined for diagnosis of polycystic ovary syndrome (PCOS). The present study evaluated the serum AMH levels among different PCOS phenotypes and correlated the AMH levels with clinical, hormonal, and metabolic parameters among Indian PCOS women. Mean serum AMH was 12.39 ± 5.3ng/mL in PCOS cohort and 3.83 ± 1.5 ng/mL in non-PCOS cohort (P < 0.01). Out of 608 PCOS women, 273 (44.9%) women belonged to phenotype A, 230 (37.8%) women were phenotype D. Phenotypes C and B were 12.17% and 5.10% respectively. Among those with the highest AMH group (AMH>20ng/ml; 8.05%), majority belonged to phenotype A. Menstrual cycle length, serum testosterone, fasting total cholesterol levels, and follicle number per ovary had positive correlation with serum anti-Mullerian levels (P < 0.05). AMH cutoff for the diagnosis of PCOS was calculated as ≥ 6.06 ng/mL on ROC analysis with sensitivity and specificity of 91.45% and 90.71% respectively. The study shows high serum AMH levels in PCOS are associated with worse clinical, endocrinological, and metabolic parameters. These levels may be used to counsel patients regarding treatment response, help in individualized management and prediction of reproductive and long-term metabolic outcomes.

Risk of severe acute respiratory syndrome coronavirus 2 infection among women with polycystic ovary syndrome

To determine whether women with polycystic ovary syndrome (PCOS) had a higher incidence of testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than those without PCOS and evaluate whether PCOS diagnosis independently increased the risk of moderate or severe disease in those with positive SARS-CoV-2 test results. Retrospective cohort study using the National COVID Cohort Collaborative (N3C). National COVID Cohort Collaborative. Adult nonpregnant women (age, 18-65 years) enrolled in the N3C with confirmed SARS-CoV-2 testing for any indication. Sensitivity analyses were conducted in women aged 18-49 years and who were obese (body mass index, ≥30 kg/m2). The exposure was PCOS as identified by the N3C clinical diagnosis codes and concept sets, which are a compilation of terms, laboratory values, and International Classification of Diseases codes for the diagnosis of PCOS. To further capture patients with the symptoms of PCOS, we also included those who had concept sets for both hirsutism and irregular menses. Odds of testing positive for SARS-CoV-2 and odds of moderate or severe coronavirus disease 2019 (COVID-19) in the PCOS cohort compared with those in the non-PCOS cohort. Of the 2,089,913 women included in our study, 39,459 had PCOS. In the overall cohort, the adjusted odds ratio (aOR) of SARS-CoV-2 positivity was 0.98 (95% confidence interval [CI], 0.97-0.98) in women with PCOS compared to women without PCOS. The aORs of disease severity were as follows: mild disease, 1.02 (95% CI, 1.01-1.03); moderate disease, 0.99 (95% CI, 0.98-1.00); and severe disease, 0.99 (95% CI, 0.99-1.00). There was no difference in COVID-19-related mortality (aOR, 1.00; 95% CI, 0.99-1.00). These findings were similar in the reproductive-age and obese reproductive-age cohorts. Women with PCOS had a similar likelihood of testing positive for SARS-CoV-2. Among those who tested positive, they were no more likely to have moderate or severe COVID-19 than the non-PCOS cohort. Polycystic ovary syndrome is a chronic condition associated with several comorbidities, including cardiovascular disease and mental health issues. Although these comorbidities are also associated with COVID-19 morbidity, our findings suggest that the comorbidities themselves, rather than PCOS, drive the risk of disease severity.

Assessing the androgenic and metabolic heterogeneity in polycystic ovary syndrome using cluster analysis.

Some but not all women with polycystic ovary syndrome (PCOS) develop the metabolic syndrome (MS). The objective of this study was to determine if a subset of women with PCOS had higher androgen levels predisposing them to MSand whether routinely measured hormonal parameters impacted the metabolic syndrome score (siMS). We included data from a discovery (PCOS clinic data) and a replication cohort (Hull PCOS Biobank) and utilized eight routinely measured hormonal parameters in our clinics (free androgen index [FAI], sex hormone-binding globulin, dehydroepiandrosterone sulphate (DHEAS), androstenedione, luteinizing hormone [LH], follicular stimulating hormone, anti-Müllerian hormone and 17 hydroxyprogesterone [17-OHP]) to perform a K-means clustering (an unsupervised machine learning algorithm). We used NbClust Package in R to determine the best number of clusters. We estimated the siMS in each cluster and used regression analysis to evaluate the effect of hormonal parameters on SiMS. The study consisted of 310 women with PCOS (discovery cohort: n = 199, replication cohort: n = 111). The cluster analysis identified two clusters in both the discovery and replication cohorts. The discovery cohort identified a larger cluster (n = 137) and a smaller cluster (n = 62), with 31% of the study participants. Similarly, the replication cohort identified a larger cluster (n = 74) and a smaller cluster (n = 37) with 33% of the study participants. The smaller cluster in the discovery cohort had significantly higher levels of LH (7.26 vs. 16.1 IU/L, p < .001), FAI (5.21 vs. 9.22, p < .001), androstenedione (3.93 vs. 7.56 nmol/L, p < .001) and 17-OHP (1.59 vs.3.12 nmol/L, p < .001). These findings were replicated in the replication cohort. The mean (±SD) siMS score was higher in the smaller cluster, 3.1 (±1.1) versus 2.8 (±0.8); however, this was not statistically significant (p = .20). In the regression analysis, higher FAI (β = .05, p = .003) and androstenedione (β = .03, p = .02) were independently associated with a higher risk of SiMS score, while higher DHEAS levels were associated with a lower siMS score (β = -.07, p = .03) CONCLUSION: We identified a subset of women in our PCOS cohort with significantly higher LH, FAI, and androstenedione levels. We show that higher levels of androstenedione and FAI are associated with a higher siMS, while higher DHEAS levels were associated with lower siMS.

Significance of Hyperhomocysteinemia in Immediate As Well As Long-Term Health Risk/s in Women with Polycystic Ovary Syndrome: a Probabilistic Model Using Dynamic Bayesian Network Analysis.

Polycystic ovary syndrome (PCOS) is a heterogeneous entity comprising broad spectra of ovarian disorders with trademark features of metabolic syndrome like insulin resistance, obesity, and dyslipidaemia to name a few. Hyperhomocysteinemia, an independent risk factor of metabolic syndrome, has been suggested as a causative factor in spontaneous miscarriage in PCOS. However, it is yet to be resolved whether hyperhomocysteinemia has a contributory role in the pathogenesis or could direct long-term sequences of the syndrome. A total of 2355 women with history of one or more first trimester abortions were screened and 1539 were selected for the study. Selected patients were initially divided by the presence or absence of PCOS, while subsequent stratification was based on hyperhomocysteinemia, insulin resistance, and/or obesity. The miscarriage population/s was mostly represented by hyperhomocysteinemia in both the cohorts (PCOS: 69.08% vs. non-PCOS: 56.68%). ROC-AUC values suggest increased predisposition of hyperhomocysteinemia-mediated miscarriage (hyperhomocysteinemia: 0.778; insulin resistance: 0.601; BMI: 0.548). A probabilistic causal model was designed using dynamic Bayesian network to evaluate the time-series data points before, during, and after pregnancy which revealed a possibility of 32.24% (n = 79) of PCOS cohort developing hypertension, 26.94% (n = 66) of onset of diabetes and 4.49% cardiovascular disease 3years following pregnancy. We conclude hyperhomocysteinemia may possibly contribute to spontaneous miscarriage and related to metabolic derailments later in life.

Association between an AMH promoter polymorphism and serum AMH levels in PCOS patients.

STUDY QUESTIONDo polymorphisms in the anti-Müllerian hormone (AMH) promoter have an effect on AMH levels in patients with polycystic ovary syndrome (PCOS)?SUMMARY ANSWERWe have identified a novel AMH promoter polymorphism rs10406324 that is associated with lower serum AMH levels and is suggested to play a role in the mechanism of regulation of AMH gene expression in women.WHAT IS KNOWN ALREADYFollicle number is positively correlated with serum AMH levels, reflected by elevated AMH levels in women with PCOS. In addition, it is suggested that AMH production per follicle is higher in women with PCOS than in normo-ovulatory women, implying an altered regulation of AMH in PCOS.STUDY DESIGN, SIZE, DURATIONA discovery cohort of 655 PCOS women of Northern European ancestry and both an internal and external validation PCOS cohort (n = 458 and n = 321, respectively) were included in this study. Summary-level data of an AMH genome-wide association study meta-analysis including 7049 normo-ovulatory women was included as a control cohort. A genetic approach was taken through association analysis and in silico analysis of the associated variants in the AMH promoter. In vitro analysis was performed to investigate the functional mechanisms.PARTICIPANTS/MATERIALS, SETTING, METHODSAll common two-allelic single-nucleotide polymorphisms (SNPs) in the region Chr19:2 245 353–2 250 827 bp (Build 37) were selected for the analysis. Linear regression analyses were performed to determine the association between SNPs in the AMH promoter region and serum AMH levels. For the in silico analysis, the webtools ‘HaploReg’ v4.1 for ENCODE prediction weight matrices and ‘atSNP’ were used. In vitro analysis was performed using KK1 cells, a mouse granulosa cell line and COV434 cells, a human granulosa tumor cell line. Cells were transfected with the reference or the variant human AMH promoter reporter construct together with several transcription factors (TFs). Dual-Glo® Luciferase Assay was performed to measure the luciferase activity.MAIN RESULTS AND THE ROLE OF CHANCEPolymorphism rs10406324 was significantly associated with serum AMH levels in all three PCOS cohorts. Carriers of the minor allele G had significantly lower log-transformed serum AMH levels compared to non-carriers (P = 8.58 × 10−8, P = 1.35 × 10−3 and P = 1.24 × 10−3, respectively). This result was validated in a subsequent meta-analysis (P = 3.24 × 10−12). Interestingly, rs10406324 was not associated with follicle count, nor with other clinical traits. Also, in normo-ovulatory women, the minor allele of this variant was associated with lower serum AMH levels (P = 1.04 × 10−5). These findings suggest that polymorphism rs10406324 plays a role in the regulation of AMH expression, irrespective of clinical background. In silico analysis suggested a decreased binding affinity of the TFs steroidogenenic factor 1, estrogen-related receptor alpha and glucocorticoid receptor to the minor allele G variant, however in vitro analysis did not show a difference in promoter activity between the A and G allele.LIMITATIONS, REASONS FOR CAUTIONFunctional analyses were performed in a mouse and a human granulosa cell line using an AMH promoter reporter construct. This may have limited assessment of the impact of the polymorphism on higher order chromatin structures. Human granulosa cells generated from induced pluripotent stem cells, combined with gene editing, may provide a method to elucidate the exact mechanism behind the decrease in serum AMH levels in carriers of the −210 G allele. We acknowledge that the lack of follicle number in the external validation and the control cohort is a limitation of the paper. Although we observed that the association between rs10406324 and AMH levels was independent of follicle number in our discovery and internal validation PCOS cohorts, we cannot fully rule out that the observed effects on serum AMH levels are, in part, caused by differences in follicle number.WIDER IMPLICATIONS OF THE FINDINGSThese results suggest that variations in serum AMH levels are not only caused by differences in follicle number but also by genetic factors. Therefore, the genetic context should be taken into consideration when assessing serum AMH levels in women. This may have clinical consequences when serum AMH levels are used as a marker for the polycystic ovarian morphology phenotype.STUDY FUNDING/COMPETING INTEREST(S)No external funding was used. J.S.E.L. has received consultancy fees from the following companies: Ferring, Roche Diagnostics and Ansh Labs and has received travel reimbursement from Ferring. J.A.V. has received royalties from AMH assays, paid to the institute/lab with no personal financial gain. The other authors declare no competing interests.TRIAL REGISTRATION NUMBERN/A.

The Risk of Herpes Zoster in Women with Polycystic Ovary Syndrome: A Retrospective Population-Based Study.

Background: The association between polycystic ovary syndrome (PCOS) and the risk of herpes zoster (HZ) remains unclear. This study investigated the risk of HZ in women with PCOS. Methods: This study used data from the Longitudinal Generation Tracking Database (LGTD 2005) which contains the information of 2 million randomly selected from National Health Insurance beneficiaries. Patients who received a diagnosis of PCOS between 2000 and 2017 were included in the PCOS cohort. Patients who were not diagnosed as having PCOS were randomly selected from the LGTD 2005 and included in the control cohort. Patients who were aged <20 years and had a history of HZ before the index date were excluded. Patients who were in both the cohorts were matched at a ratio of 1:1 through propensity score matching based on age, comorbidities, and medication. The primary outcome was the diagnosis of HZ. Results: A total of 20,142 patients were included in each case and control cohorts. The incidence rates of HZ in the PCOS and control cohorts were 3.92 and 3.17 per 1000 person-years, respectively. The PCOS cohort had a significantly higher risk of HZ than did the control cohort (adjusted hazard ratios [aHR] = 1.26). Among the patients aged 30–39 years, those with PCOS had a significantly higher risk of HZ than did those without PCOS (aHR = 1.31). Among the patients without any comorbidities, those with PCOS had a significantly higher risk of HZ (aHR = 1.26) than did those without PCOS. Conclusion: PCOS is associated with the risk of HZ, especially in young women. The risk of HZ should be addressed while treating patients with PCOS. An HZ vaccine is recommended for these patients.

Accelerated osteoarthritis in women with polycystic ovary syndrome: a prospective nationwide registry-based cohort study

BackgroundOsteoarthritis (OA) is the most common form of arthritis with multiple risk factors implicated including female sex and obesity. Metabolic dysregulation associated with obesity leading to metabolic syndrome is a proposed component of that association. Polycystic ovary syndrome (PCOS) commonly affects women of reproductive age and these women are at higher risk of developing metabolic syndrome and thus likely to represent a high-risk group for early OA development. There are no published studies exploring the epidemiology of knee, hip and hand OA in women diagnosed with PCOS.Study aimTo assess the prevalence and incidence of knee, hip and hand osteoarthritis (OA) in women with polycystic ovary syndrome (PCOS) when compared with age-matched controls.MethodsProspective Danish national registry-based cohort study. The prevalence of OA in 2015 and incidence rates of OA over 11.1 years were calculated and compared in more than 75,000 Danish women with either a documented diagnosis of PCOS ± hirsutism (during the period of 1995 to 2012) or age-matched females without those diagnoses randomly drawn from the same population register.ResultsIn 2015, the prevalence of hospital treated knee, hip and hand OA was 5.2% in women with PCOS diagnosis. It was 73% higher than that seen in age-matched controls. Significantly higher incidence rates were observed in the PCOS cohort compared with the age-matched controls during the follow-up period (up to 20 years), with the following hazard ratios (HR): 1.9 (95% CI 1.7 to 2.1) for knee, 1.8 (95% CI 1.3–2.4) for hand and 1.3 (95% CI 1.1 to 1.6) for hip OA. After excluding women with obesity, similar associations were observed for knee and hand OA. However, risk of developing hip OA was no longer significant.ConclusionsIn this large prospective study, women with PCOS diagnosis had higher prevalence and accelerated onset of OA of both weight and non-weight bearing joints, when compared with age-matched controls. Further studies are needed to understand the relative effect of metabolic and hormonal changes linked with PCOS and their role in promoting development of OA.

The impact of ageing and menopause in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common hormonal, metabolic and reproductive disorder. Women with PCOS at reproductive age have increased risk and prevalence of prediabetes and diabetes and have multiple risk factors for cardiometabolic disease and other comorbidities such as obstructive sleep apnoea, endometrial cancerand mood disorders, which contribute to the overall health burden of the syndrome. However, little is known about the impact of PCOS on long-term health in ageing women. In this review, we aimed to give an updated overview regarding the long-term health outcomes of PCOS and their clinical implications in peri- and postmenopause. The PCOS phenotype ameliorates with ageing and limited available data suggest that there is no further deterioration in cardiometabolic profile in women with PCOS after menopause. Accordingly, the risk of cardiovascular disease in ageing women with PCOS seems to be no different from those without PCOS and lower than previously anticipated based on their risk during reproductive years. Regarding other comorbidities including sleep apnoea, mood disordersand endometrial cancer, it is difficult to determine the true risk in older women with PCOS due to the confounding factors and lack of long-term cohort studies. Large, prospective studies on community-based and well-phenotyped PCOS cohorts with extended follow-up into late menopause are needed to confirm these findings.

Skeletal Muscle Health in Polycystic Ovary Syndrome: Protective Effect of Hyperandrogenism or Detrimental Effect of Insulin Resistance? A Systematic Review and Meta-Analysis

Women with polycystic ovary syndrome (PCOS) exhibit reduced skeletal muscle insulin-mediated glucose uptake. Altered muscle mass may affect insulin resistance (IR) and inflammation, thereby potentially aggravating reproductive status including ovulatory cyclicity and fertility potential. However, the relationship between PCOS and skeletal muscle mass is elusive given conflicting reports on protective or detrimental influence of PCOS endocrine derangements (hyperandrogenism, IR) on muscle. We evaluated whether muscle mass and function are affected by PCOS in response to a call to elucidate musculoskeletal alterations in the International Evidence-based Guideline for the Assessment and Management of PCOS. Databases of MEDLINE, Web of Science, and Scopus were searched (January 1990 to September 2020) to identify observational studies on skeletal muscle mass (lean tissue mass) and function (strength) in PCOS and control groups. The primary outcome was total lean body mass (LBM) or fat-free mass (FFM). Data were pooled by random-effects models and expressed as weighted mean differences and 95% confidence intervals. Forty-five studies (n = 3,676 [1,854, PCOS; 1,822, controls]) were eligible. Forty-one evaluated lean tissue mass and five strength. PCOS groups had increased total (0.83 [0.08, 1.58] kg; P=0.03; I2 = 72.0%) yet comparable trunk (0.84 [-0.37, 2.05] kg; P = 0.15; I2 = 73.0%) LBM/FFM. There were no associations between mean differences of groups in total testosterone (TT) or homeostatic model assessment of IR (HOMA-IR) and total/trunk LBM/FFM (All: P ≥ 0.75) by meta-regressions. However, mean differences of groups in body mass index (BMI) were associated with total (0.65 [0.23, 1.06] kg; P < 0.01; I2 = 56.9%) and trunk (0.56 [0.11, 1.01] kg; P = 0.02; I2 = 42.8%) LBM/FFM. Accordingly, PCOS sub-group with overweight/obesity (BMI ≥ 25 kg/m2) exhibited greater total LBM/FFM than controls (1.58 [0.82, 2.34] kg; P < 0.01; I2 = 64.0%) unlike a lean (BMI < 25 kg/m2) sub-group (-0.45 [-1.94, 1.05] kg; P = 0.53; I2 = 69.5%). Some study results were contradictory (i.e., increased appendicular mass or strength in PCOS group or comparable findings between groups) and study methodology varied; thus, inclusion in meta-analyses was not possible. PCOS cohorts have a tendency for increased total and trunk lean tissue mass likely attributed to obesity. However, most critically, whether PCOS influences other lean tissue areas (appendicular), morphology, and function is unclear. Our observations do not support any protective/detrimental influence of hyperandrogenism (TT) or IR (HOMA-IR) on lean mass. Heterogeneity among studies warrants research to address any contributions of lifestyle, healthcare, and biological factors to observed differences for future guideline recommendations to improve PCOS musculoskeletal and reproductive health (www.crd.york.ac.uk/PROSPERO ID, CRD42020203490).

Knowledge, Attitudes, and Barriers towards Dietary Pulse Consumption in Women with Polycystic Ovary Syndrome Participating in a Multi-Disciplinary Lifestyle Intervention to Improve Women’s Health

Pulse (beans, lentils, chickpeas, peas) consumption is low in developed countries. Pulses have the potential to benefit the management of polycystic ovary syndrome (PCOS) because they improve aspects of metabolic derangements (dyslipidaemia, insulin resistance), which contribute to reproductive disturbances (oligo-amenorrhea, hyperandrogenism). We compared changes in knowledge, attitudes, and barriers towards pulse consumption in PCOS cohorts who participated in a pulse-based or a Therapeutic Lifestyle Changes (TLC) dietary intervention. Thirty women (18–35 years old) randomised to a pulse-based diet (supplied with pulse-based meals) and 31 women in a TLC group completed pulse consumption questionnaires before and after a 16-week intervention. The pulse-diet group demonstrated increased knowledge of pulses per Canada’s Food Guide recommendations versus the TLC group post-intervention (p &lt; 0.05). In both groups, increased scores were evident in the domain of attitude about pulses (p &lt; 0.01). The top-ranked barrier to pulse consumption in no-/low-consumers was lack of knowledge about cooking pulses pre- and post-intervention. We attributed increased knowledge about pulse consumption in the pulse group to greater awareness through education and consuming pulse foods during the intervention. Our observations highlight the importance of multi-dimensional behavioural counselling and education to integrate healthy dietary practices for improving reproductive and sexual health in this under-studied high-risk population (ClinicalTrials.gov identifier: NCT01288638).

Dermatologic manifestations in patients with polycystic ovary syndrome: their prevalence and assessment in relation to hormonal and metabolic changes

Polycystic ovary syndrome(PCOS) is considered the most common endocrine disorder affecting females in the reproductive years,and is characterized by being multisystemic with a variety of phenotypes and broad spectrum of manifestations that are strongly influenced by ethnic backgrounds. Cutaneous manifestations represent an important part of the syndrome.The aim of this study was to detect the prevalence of dermatologic manifestations among an Egyptian PCOS cohort and to study the correlation between these manifestations and the underlying hormonal and metabolic changesThe study was conducted on 53 patients diagnosed as PCOS aged 20-40 years and 50 non-PCOS controls of the same age group .In all participants history was taken including family, medical, drug and menstrual history. Anthropometric measurments were recorded and they were subjected to pelvic ultrasonography and to dermatologic examination focusing on hirsutism, acne, androgenetic alopecia and acanthosis nigricans. total Testosterone, free testosterone, DHEAS, prolactin and TSH were measured for the PCOS group. Additionally, the HOMA-IR for insulin resistance was calculated. Among the PCOS patients group prevalence percent of hirsutism 49%, followed by AGA 43.3%, , acne 39.6%and acanthosis nigricans 32% .Having hirsutism in PCOS patients was associated with higher levels of total and free testosterone than being free from hirsutism. the degree of hirsutism (mFGS) showed a weak positive correlation with the serum levels of total and free testosterone. Acne and AGA in PCOS patients seem not to be influenced by serum androgen levels, HOMA-IR nor anthropometric measures..Acanthosis nigricans is more related to the metabolic disorder rather than to hyperandrogenism.