scholarly journals Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations

2019 ◽  
Author(s):  
Matthew Dapas ◽  
Frederick T. J. Lin ◽  
Girish N. Nadkarni ◽  
Ryan Sisk ◽  
Richard S. Legro ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
European Ancestry ◽  
Sequencing Analysis ◽  
Ovary Syndrome ◽  
Biologically Relevant ◽  
Insulin Levels ◽  
Family Based

AbstractBackgroundPolycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS.Methods and FindingsUnsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped discovery cohort of 893 PCOS cases and an ungenotyped validation cohort of 263 PCOS cases. We identified two PCOS subtypes: a “reproductive” group (21-23%) characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low body mass index (BMI) and insulin levels; and a “metabolic” group (37-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in four novel loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN1, P=2.2×10-10; IQCA1, P=2.8×10-9; BMPR1B/UNC5C, P=9.7×10-9; CDH10, P=1.2×10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P=1.0×10-8). We have previously reported that rare variants in DENND1A, a gene regulating androgen biosynthesis, were associated with PCOS quantitative traits in a family-based whole genome sequencing analysis. We classified the reproductive and metabolic subtypes in this family-based PCOS cohort and found that the subtypes tended to cluster in families and that carriers of rare DENND1A variants were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by NIH criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated.ConclusionsIn conclusion, we have found stable reproductive and metabolic subtypes of PCOS. Further, these subtypes were associated with novel susceptibility loci. Our results suggest that these subtypes are biologically relevant since they have distinct genetic architectures. This study demonstrates how precise phenotypic delineation can be more powerful than increases in sample size for genetic association studies.

scholarly journals Polycystic ovary syndrome: reviewing diagnosis and management of metabolic disturbances

2014 ◽  
Vol 58 (2) ◽  
pp. 182-187 ◽  
Author(s):  
Poli Mara Spritzer
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Pharmacological Therapy ◽  
Lifestyle Changes ◽  
Reproductive Age ◽  
Metabolic Dysfunction ◽  
Metabolic Disturbances ◽  
Ovary Syndrome ◽  
Individual Woman

Polycystic ovary syndrome (PCOS) is a common condition in women at reproductive age associated with reproductive and metabolic dysfunction. Proposed diagnosed criteria for PCOS include two out of three features: androgen excess, menstrual irregularity, and polycystic ovary appearance on ultrasound (PCO), after other causes of hyperandrogenism and dysovulation are excluded. Based on these diagnostic criteria, the most common phenotypes are the “classic PCOS” – hyperandrogenism and oligomenorrhea, with or without PCO; the “ovulatory phenotype” – hyperandrogenism and PCO in ovulatory women; and the “non-hyperandrogenic phenotype”, in which there is oligomenorrhea and PCO, without overt hyperandrogenism. The presence of obesity may exacerbate the metabolic and reproductive disorders associated with the syndrome. In addition, PCOS women present higher risk for type 2 diabetes and higher prevalence of cardiovascular risk factors that seems to be associated with the classic phenotype. The main interventions to minimize cardiovascular and metabolic risks in PCOS are lifestyle changes, pharmacological therapy, and bariatric surgery. Treatment with metformin has been shown to improve insulin sensitivity, lowering blood glucose and androgen levels. These effects are more potent when combined with lifestyle interventions. In conclusion, besides reproductive abnormalities, PCOS has been associated to metabolic comorbidities, most of them linked to obesity. Confounders, such as the lack of standard diagnostic criteria, heterogeneity of the clinical presentation, and presence of obesity, make management of PCOS difficult. Therefore, the approach to metabolic abnormalities should be tailored to the risks and treatment goals of each individual woman.

scholarly journals Promotion of reproductive and metabolic health - current trends in the treatment and prevention of polycystic ovary syndrome in different periods of life

2021 ◽  
Vol 47 (3) ◽  
pp. 130-149
Author(s):  
Joanna Smyczyńska
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Hormonal Contraception ◽  
Reproductive Age ◽  
Metabolic Effects ◽  
Adult Women ◽  
Ovary Syndrome ◽  
Treatment And Prevention

Polycystic ovary syndrome (PCOS) is one of the most common hormonal disorders and causes of infertility in women in reproductive age. Diagnostic criteria of PCOS in adult women include: ovulation disorders, hyperandrogenism and  polycystic ovaries. According to most recommendations, 2 out of these 3 criteria are confirm the diagnosis of PCOS. In girls during puberty and in the first years after menarche, different diagnostic criteria of menstrual disorders should be taken into account (variable length of menstrual cycles, monophasic cycles) and the limited usefulness of ultrasound examination for PCOS diagnosis within 8 years after menarche. Fairly extensive differential diagnosis is also necessary, especially – exclusion of adrenal hyperandrogenism. Moreover, the diagnostic criteria of PCOS do not take into account the metabolic disorders found in most patients (obesity, insulin resistance, type 2 diabetes), which should be diagnosed as early as possible and treated appropriately. This is especially true for teenagers, in whom the unequivocal diagnosis of PCOS or its exclusion may be very difficult. Current recommendations regard hormonal contraception as the first-line therapy in PCOS, in both adult women and adolescents. Together with its beneficial effect on the reduction of hyperandrogenism and obtaining regular bleeding (which in fact are not menstruations), the unfavorable metabolic effects of hormonal contraception are emphasized, as well as the inadequacy of its use if it is expected to achieve or restore ovulation and fertility. The latest reports indicate the legitimacy of treatment aimed at correcting disorders of carbohydrate metabolism and its greater effectiveness compared to the use of oral contraceptives in both adult women and girls with PCOS. In the pharmacotherapy of insulin resistance, metformin is of fundamental importance, the use of pioglitazone, GLP-1 receptor agonists or inositols is also proposed. Adequate lifestyle and dietary modification are of major importance in the treatment and prevention of PCOS. The mechanisms of "inheritance" of PCOS and insulin resistance with the participation of epigenetic modifications are still better understood, taking into account the effects of exposure to androgen excess in utero, intrauterine growth retardation, and maternal obesity and hyperalimentation. This creates new possibilities for PCOS prophylaxis.

scholarly journals The Association Between Genetically Predicted Systemic Inflammatory Regulators and Polycystic Ovary Syndrome: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanxiao Chen ◽  
Yaoyao Zhang ◽  
Shangwei Li ◽  
Yuanzhi Tao ◽  
Rui Gao ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genome Wide Association Study ◽  
Metabolic Diseases ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Reproductive Age ◽  
European Ancestry ◽  
Ovary Syndrome ◽  
Increased Risk

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic diseases among women of reproductive age. Inflammation may be involved in the pathogenesis of PCOS, but its exact relationship with PCOS remains unclear. Herein, we investigate the causal association between systemic inflammatory regulators and PCOS risk through a two-sample Mendelian randomization (MR) approach based on the latest and largest genome-wide association study (GWAS) of 41 systemic inflammatory regulators in 8293 Finnish participants and a GWAS meta-analysis consisting of 10,074 PCOS cases and 103,164 controls of European ancestry. Our results suggest that higher levels of IL-17 and SDF1a, as well as lower levels of SCGFb and IL-4, are associated with an increased risk of PCOS (OR = 1.794, 95% CI = 1.150 – 2.801, P = 0.010; OR = 1.563, 95% CI = 1.055 – 2.315, P = 0.026; OR = 0.838, 95% CI = 0.712 – 0.986, P = 0.034; and OR = 0.637, 95% CI = 0.413 – 0.983, P = 0.042, respectively). In addition, genetically predicted PCOS is related to increased levels of IL-2 and VEGF (OR = 1.257, 95% CI = 1.022 – 1.546, P = 0.030 and OR = 1.112, 95% CI = 1.006 – 1.229, P = 0.038, respectively). Our results indicate the essential role of cytokines in the pathogenesis of PCOS. Further studies are warranted to assess the possibility of these biomarkers as targets for PCOS prevention and treatment.

scholarly journals Large-Scale Genome-Wide Meta Analysis of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture for Different Diagnosis Criteria

2018 ◽  
Author(s):  
Felix Day ◽  
Tugce Karaderi ◽  
Michelle R. Jones ◽  
Cindy Meun ◽  
Chunyan He ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Genetic Architecture ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Self Report ◽  
European Ancestry ◽  
Fasting Insulin ◽  
Ovary Syndrome ◽  
Shared Genetic

AbstractPolycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed with different criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease indicate shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. Only one locus differed in its association by diagnostic criteria, otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or Rotterdam criteria across common variants at 13 loci.

Polycystic ovary syndrome and probiotics: a natural approach to an inflammatory disease

2020 ◽  
Vol 16 ◽  
Author(s):  
Antonio Schiattarella ◽  
Gaetano Riemma ◽  
Marco La Verde ◽  
Gianluigi Franci ◽  
Annalisa Chianese ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Critical Role ◽  
Reproductive Age ◽  
Ovary Syndrome ◽  
Natural Approach ◽  
New Treatment ◽  
Gut Microbial Community ◽  
New Evidence

: Polycystic ovary syndrome (PCOS) is a condition that affects about 15% of women of reproductive age and is correlated with infertility, insulin resistance, and obesity. The etiology of PCOS is multifactorial and genetic, endocrine, and metabolic causes were involved. New evidence suggests a link between microorganisms residing in the digestive tracts of humans and the development of PCOS. Moreover, an imbalance in the gut microbial community could be a possible factor for the onset of insulin resistance and obesity. Hyperandrogenism, a key feature of PCOS, could also play a critical role in shaping the microbiome community. Probiotics could modify the gut microbiota and serve as a potential treatment for PCOS. Here we disclose the association between PCOS and intestinal microbiota and the possible role of probiotics as a new treatment approach.

scholarly journals Is polycystic ovary syndrome appropriately diagnosed by obstetricians and gynaecologists across China: a nationwide survey

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Deng Yan ◽  
Wang Yan-Fang ◽  
Zhu Shi-Yang ◽  
Ma Rui-Lin ◽  
Ding Xue-Song ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Final Analysis ◽  
Nationwide Survey ◽  
Care Quality ◽  
Cross Sectional Survey ◽  
Ovary Syndrome ◽  
Cross Sectional ◽  
Rotterdam Criteria

Abstract Background To describe the diagnostic criteria used and their application accuracy in the practice of polycystic ovary syndrome (PCOS) caring among obstetricians and gynaecologists across China. Methods This was an Online cross-sectional survey of Obstetricians and gynecologists involved in PCOS caring conducted via the largest continuing education platform of obstetrics and gynecology across China from September 2019 to November 2019. Results A total of 2,328 respondents were eligible for the final analysis. Of these, 94.5 % were general obstetricians and gynaecologists (Ge-ObGyn), and 5.5 % were reproductive endocrinologists (Re-ObGyn). Overall, the most frequently used criteria were the Androgen Excess and Polycystic Ovary Syndrome Society (AE-PCOS) criteria (48.2 %), followed by the Rotterdam criteria (35.7 %) and NIH criteria (12.1 %). Of the respondents, 31.3 % used their diagnostic criteria in their clinical practice. More respondents who chose the Rotterdam criteria could accurately apply the diagnostic criteria than those who chose the AE-PCOS criteria (41.2 % vs. 32.1 %, P < 0.001). Compared with Ge-ObGyn, Re-ObGyn were less likely to use the AE-PCOS criteria (adjusted odds ratio, 0.513; 95 % CI, 0.328–0.802; P < 0.05) and 1.492 times more likely to accurately use their criteria (95 % CI, 1.014–2.196; P < 0.05). Conclusions Less than one-third of obstetricians and gynaecologists across China could accurately use the diagnostic criteria they choose to diagnose PCOS. There is an urgent need to train obstetricians and gynaecologists on PCOS diagnosis in an effort to improve the medical care quality of patients with PCOS.

Health Care-Related Economic Burden of Polycystic Ovary Syndrome in the United States: Pregnancy-Related and Long-Term Health Consequences

2021 ◽  
Author(s):  
Carrie Riestenberg ◽  
Anika Jagasia ◽  
Daniela Markovic ◽  
Richard P Buyalos ◽  
Ricardo Azziz
Keyword(s):  
United States ◽  
Polycystic Ovary Syndrome ◽  
Economic Burden ◽  
Polycystic Ovary ◽  
The United States ◽  
Reproductive Age ◽  
Cochrane Library ◽  
Control Group ◽  
Ovary Syndrome

Abstract Context Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive-aged women, affecting approximately 5-20% of women of reproductive age. A previous estimate noted that the economic burden of PCOS approximates $3.7 billion annually in 2020 USD when considering only the costs of the initial diagnosis and of reproductive endocrine morbidities, not considering the costs of pregnancy-related and long-term morbidities. Objective To estimate the excess prevalence and economic burden of pregnancy-related and long-term health morbidities attributable to PCOS. Data Sources PubMed, EmBase and Cochrane Library. Study Selection Studies in which the diagnosis of PCOS was consistent with the Rotterdam, National Institutes of Health (NIH), or Androgen Excess & PCOS (AE-PCOS) Society criteria, or that used electronic medical record diagnosis codes, or diagnosis based on histopathologic sampling were eligible for inclusion. Studies that included an outcome of interest and a control group of non-PCOS patients who were matched or controlled for body mass index (BMI) were included. Data Extraction Two investigators working independently extracted data on study characteristics and outcomes. Data Synthesis Data was pooled using random-effects meta-analysis. The I 2statistic was used to assess inter-study heterogeneity. The quality of selected studies was assessed using the Newcastle-Ottawa Scale. Results The additional total healthcare-related economic burden due to pregnancy-related and long-term morbidities associated with PCOS in the United States is estimated to be $4.3 billion annually in 2020 USD. Conclusions Together with our prior analysis, the economic burden of PCOS is estimated at $8 billion annually in 2020 USD.

Disorders of steroid metabolism in women of reproductive age with polycystic ovary syndrome

2021 ◽  
Author(s):  
Olga Glavnova ◽  
Ludmila Velikanova ◽  
Natalia Vorokhobina ◽  
raviliy Galakhova ◽  
Ekaterina Malevanania ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Steroid Metabolism ◽  
Women Of Reproductive Age ◽  
Ovary Syndrome
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