scholarly journals Genetic Sex Effects of Polycystic Ovary Syndrome Reveal Distinct Metabolic Etiology

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A766-A766
Author(s):  
Ky’Era Actkins ◽  
Digna R Velez Edwards ◽  
Melinda Aldrich ◽  
Lea K Davis
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Risk ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Genetic Relationships ◽  
African Descent ◽  
Polygenic Risk Score ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Increased Risk

Abstract Females with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). High-risk groups or individuals with a family history are more likely to have a greater genetic susceptibility to these diseases, which drastically increases their risk of developing other chronic health conditions. In this study, we systematically evaluated the bidirectional genetic burden of PCOS and its comorbidities among females and males. First, we analyzed the pleiotropic effects of the PCOS polygenic risk score (PRS), a measurement of genetic liability to PCOS, across 1,857 medical conditions recorded in the Vanderbilt University Medical Center electronic health record. We conducted a phenome-wide association study (PheWAS) adjusted for median age, sex, and genetic ancestry. In the European sex-combined model (n = 72,824), we observed that PCOS PRS was significantly (Bonferroni corrected p < 7.86e-06) associated with T2D (OR = 1.11, p = 8.75e-08) and hypertension (OR = 1.06, p = 1.13e-07) in addition to polycystic ovaries (OR = 1.11, p = 1.91e-07). In the sex-stratified model, we found that males (n = 32,022) with a higher PRS for PCOS were more likely to develop cardiovascular diseases (CVD) compared to females (n = 40,802) who had higher odds of developing T2D. Although we were underpowered to detect any phenome-wide significant effects in our African descent sample (n=15,283), uterine leiomyoma (OR = 1.24, p = 3.79e-03), osteoarthritis (OR = 1.21, p = 3.94e-03), and benign neoplasm of uterus (OR = 1.24, p = 4.00e-03) were the top three nominal significant results (p < 0.05) in females (n = 9,418). To understand the genetic relationships observed in the PheWAS, we used LD score regression to determine the genetic correlation between the phenotypes. We found that PCOS was positively correlated with T2D (rg = 31%), systolic blood pressure (rg = 12%), and pulse pressure (rg = 15%). However, we found no significant associations between the genetic risk of CVD and PCOS diagnosis in the European or African descent samples. Our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but the genetic risk of those comorbidities is not predictive of a PCOS diagnosis. This suggests that other drivers are contributing to the endocrine and cardiovascular comorbid signatures that underlie PCOS.

scholarly journals Sex Modifies the Effect of Genetic Risk Scores for Polycystic Ovary Syndrome on Metabolic Phenotypes

2021 ◽  
Author(s):  
Ky'Era V. Actkins ◽  
Genevieve Jean-Pierre ◽  
Melinda C. Aldrich ◽  
Digna R. Velez Edwards ◽  
Lea K. Davis
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Risk ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Genetic Risk Score ◽  
Risk Scores ◽  
Ovary Syndrome ◽  
Biological Variables ◽  
Increased Risk ◽  
The Relationship

Females with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). Furthermore, while only diagnosable in females, males with a family history of PCOS can also exhibit a poor cardiometabolic profile. Therefore, we aimed to elucidate the role of sex in the relationship between PCOS and its comorbidities by conducting bidirectional genetic risk score analyses in both sexes. We conducted a phenome-wide association study (PheWAS) using PCOS polygenic risk scores (PCOSPRS) to understand the pleiotropic effects of PCOS genetic liability across 1,380 medical conditions in females and males recorded in the Vanderbilt University Medical Center electronic health record (EHR) database. After adjusting for age and genetic ancestry, we found that European descent males with higher PCOSPRS were significantly more likely to develop cardiovascular diseases than females at the same level of genetic risk, while females had a higher odds of developing T2D. Based on observed significant associations, we tested the relationship between PRS for comorbid conditions (e.g., T2D, body mass index, hypertension, etc.) and found that only PRS generated for BMI and T2D were associated with a PCOS diagnosis. We then further decomposed the T2DPRS association with PCOS by adjusting the model for measured BMI and BMIresidual (enriched for the environmental contribution to BMI). Results demonstrated that genetically regulated BMI primarily accounted for the relationship between T2DPRS and PCOS. This was further supported in a mediation analysis, which only revealed clinical BMI measurements, but not BMIresidual, as a strong mediator for both sexes. Overall, our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but these associations are only apparent when PCOSPRS is explicitly modeled. It is possible that these pathways are less explained by the direct genetic risk of metabolic traits than they are by the risk factors shared between them, which can be influenced by biological variables such as sex.

scholarly journals Polycystic Ovary Syndrome, Obesity and Reproductive Implications

2009 ◽  
Vol 5 (5) ◽  
pp. 529-542 ◽  
Author(s):  
Angelica Lindén Hirschberg
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Function ◽  
Negative Influence ◽  
Reproductive Age ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Increased Risk ◽  
Important Challenge ◽  
Pharmacologic Treatments

Polycystic ovary syndrome (PCOS) is one of the most common causes of female infertility, affecting 5–10% of women of reproductive age. The syndrome is characterized by anovulation, hyperandrogenism and polycystic ovaries. Furthermore, PCOS is associated with insulin resistance and obesity, which is present in approximately 50% of women with PCOS. Reproductive function in women with PCOS is strongly dependent on bodyweight and metabolic status. Obesity is associated with an increased risk of infertility and may also have a negative influence on pregnancy outcome. Considering the worldwide epidemic of obesity, clinical problems relating to PCOS may worsen and increase in frequency. Lifestyle interventions resulting in weight loss comprise the most successful strategy to improve symptoms of PCOS. However, many patients fail to lose weight or may quickly regain weight. It is an important challenge to develop effective lifestyle programs and adjuvant pharmacologic treatments in order to improve reproductive and metabolic health among women with PCOS.

scholarly journals Polycystic Ovary Syndrome as a systemic disease with multiple molecular pathways: a narrative review

2018 ◽  
Vol 52 (4) ◽  
pp. 208-221 ◽  
Author(s):  
Laura M. L. Carvalho ◽  
Fernando M. dos Reis ◽  
Ana Lucia Candido ◽  
Fernanda F. C. Nunes ◽  
Claudia N. Ferreira ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Systemic Disease ◽  
Cardiovascular Complications ◽  
Molecular Pathways ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Increased Risk ◽  
Cytokine Levels ◽  
Cytokine Gene Polymorphisms

AbstractPolycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, amenorrhea, and polycystic ovaries. This endocrinopathy is associated with many metabolic disorders such as dyslipidemia and insulin resistance, with increased risk of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular complications. Inflammation is likely to play an important role in the promoting these metabolic imbalances, while prothrombotic and pro-oxidative mechanisms further contribute to the cardiovascular risk of these patients. The etiology of PCOS is still not fully understood, but there is evidence of genetic and environmental components. This review aims to discuss some molecular pathways associated with PCOS that could contribute to the better understanding about this syndrome. Recent evidence suggests that intrauterine exposure of female mice to an excess of anti-Müllerian hormone may induce PCOS features in their post-natal life. High cytokine levels and cytokine gene polymorphisms also appear to be associated with the pathophysiology of PCOS. Furthermore, high levels of microparticles may contribute to the altered hemostasis and enhanced inflammation in PCOS. All these mechanisms may be relevant to clarify some aspects of PCOS pathogenesis and inspire new strategies to prevent the syndrome as well as treat its symptoms and mitigate the risk of long-term complications.

scholarly journals Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome

2015 ◽  
Vol 172 (5) ◽  
pp. 627-638 ◽  
Author(s):  
Dorte Glintborg ◽  
Katrine Hass Rubin ◽  
Mads Nybo ◽  
Bo Abrahamsen ◽  
Marianne Andersen
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Psychiatric Morbidity ◽  
Young Patients ◽  
University Hospital ◽  
Polycystic Ovaries ◽  
Danish Population ◽  
Ovary Syndrome ◽  
Increased Risk ◽  
The Mean

ObjectiveThe prevalence of type 2 diabetes is increased in polycystic ovary syndrome (PCOS), but the prevalence of other diseases is not clarified. We aimed to investigate morbidity and medicine prescriptions in PCOS.DesignA National Register-based study.MethodsPatients with PCOS (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital (OUH)) and one control population. Premenopausal women with PCOS underwent clinical and biochemical examination (PCOS OUH, n=1217). PCOS Denmark (n=19 199) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (n=57 483).Main outcome measuresDiagnosis codes and filled prescriptions.ResultsThe mean (range) age of the PCOS Denmark group and controls was 30.6 (12–60) years. Patients in PCOS Denmark had higher Charlson index, higher prevalence of diabetes, dyslipidemia, and hypertension than controls. PCOS was associated with a two times increased risk of stroke and thrombosis, whereas the risk of other cardiovascular diseases was not increased. Thyroid disease, asthma, migraine, and depression were more prevalent in PCOS Denmark vs controls, whereas fractures were rarer. Infertility was increased in patients compared with controls, but the mean number of births was higher in PCOS. Medicine prescriptions within all diagnosis areas were significantly higher in PCOS patients than in controls.In PCOS OUH, polycystic ovaries (PCO) and irregular menses were associated with a more adverse metabolic risk profile, but individual Rotterdam criteria were not associated with cardiometabolic diagnoses.ConclusionCardiometabolic and psychiatric morbidity were significantly increased in a Danish population with PCOS. Medical diseases are frequent also in young patients with PCOS.

scholarly journals Polycystic ovary syndrome and increased risk of psychiatric disorders

2020 ◽  
Vol 8 (6) ◽  
pp. 133-137
Author(s):  
Mohadetheh Moulana PhD ◽  
Anju P Sukumaran MD
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Psychological Disorders ◽  
Well Being ◽  
Reproductive Age ◽  
Physical And Mental Health ◽  
Ovary Syndrome ◽  
Increased Risk ◽  
First Time

Aim: This study is aimed to assess, for the first time the prevalence of polycystic ovary syndrome (PCOS) and associated psychological disorders among women at reproductive age in Mississippi. Methods: The data was collected through “the Patient Cohort Explorer” system at the University of Mississippi Medical Center (UMMC) from January 2013 to December 2018. De-identified patients were searched with diagnosis code for PCOS, age, ethnicity, and associated diagnosis including weight gain, anxiety, depression, attention-deficit/hyperactivity disorder (ADHD), and other psychological concerns. Results: Collected data from 166,748 females (19-45 years) showed 1.4% (95% CI: 1.32 – 1.44) prevalence of PCOS in women seen in UMMC clinics during the period of study. Almost 51% of patients with PCOS suffered from one or more psychological disorders; anxiety 21% (95% CI: 19.3 – 22.6), depression 20% (95% CI: 18.9 – 22.1), ADHD 3.2% (95% CI: 2.6 – 4.0), and bipolar disorder 2.5% (95% CI: 1.9 – 3.2). In addition, prevalence values suggest a positive correlation between obesity, anxiety, and depression in PCOS patients. Conclusion: Results from this study provide 1) for the first time an estimate regarding the prevalence of PCOS and associated psychological disorders in women with PCOS in a Mississippi, 2) associated psychological disorders in PCOS women may be diverse based on race and ethnicity. Our data clearly highlight that the psychological well-being of women with PCOS are affected. Therefore, it is critical for the primary care and specialty clinics to use appropriate psychological screenings. Left undiagnosed and/or untreated, chronic psychological disorders may exacerbate physical and mental health conditions.

scholarly journals Characterization of Reproductive, Metabolic, and Endocrine Features of Polycystic Ovary Syndrome in Female Hyperandrogenic Mouse Models

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 3146-3159 ◽  
Author(s):  
A. S. L. Caldwell ◽  
L. J. Middleton ◽  
M. Jimenez ◽  
R. Desai ◽  
A. C. McMahon ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Increased Risk ◽  
Long Term Treatment ◽  
Adipocyte Hypertrophy

Polycystic ovary syndrome (PCOS) affects 5–10% of women of reproductive age, causing a range of reproductive, metabolic and endocrine defects including anovulation, infertility, hyperandrogenism, obesity, hyperinsulinism, and an increased risk of type 2 diabetes and cardiovascular disease. Hyperandrogenism is the most consistent feature of PCOS, but its etiology remains unknown, and ethical and logistic constraints limit definitive experimentation in humans to determine mechanisms involved. In this study, we provide the first comprehensive characterization of reproductive, endocrine, and metabolic PCOS traits in 4 distinct murine models of hyperandrogenism, comprising prenatal dihydrotestosterone (DHT, potent nonaromatizable androgen) treatment during days 16–18 of gestation, or long-term treatment (90 days from 21 days of age) with DHT, dehydroepiandrosterone (DHEA), or letrozole (aromatase inhibitor). Prenatal DHT-treated mature mice exhibited irregular estrous cycles, oligo-ovulation, reduced preantral follicle health, hepatic steatosis, and adipocyte hypertrophy, but lacked overall changes in body-fat composition. Long-term DHT treatment induced polycystic ovaries displaying unhealthy antral follicles (degenerate oocyte and/or > 10% pyknotic granulosa cells), as well as anovulation and acyclicity in mature (16-week-old) females. Long-term DHT also increased body and fat pad weights and induced adipocyte hypertrophy and hypercholesterolemia. Long-term letrozole-treated mice exhibited absent or irregular cycles, oligo-ovulation, polycystic ovaries containing hemorrhagic cysts atypical of PCOS, and displayed no metabolic features of PCOS. Long-term dehydroepiandrosterone treatment produced no PCOS features in mature mice. Our findings reveal that long-term DHT treatment replicated a breadth of ovarian, endocrine, and metabolic features of human PCOS and provides the best mouse model for experimental studies of PCOS pathogenesis.

scholarly journals Relationships Between Biochemical Markers of Hyperandrogenism and Metabolic Parameters in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

2019 ◽  
Vol 51 (01) ◽  
pp. 22-34 ◽  
Author(s):  
Mina Amiri ◽  
Fahimeh Tehrani ◽  
Razieh Bidhendi-Yarandi ◽  
Samira Behboudi-Gandevani ◽  
Fereidoun Azizi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Polycystic Ovary Syndrome ◽  
Biochemical Markers ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Metabolic Parameters ◽  
High Density Lipoproteins ◽  
Total Testosterone ◽  
Ovary Syndrome ◽  
Increased Risk

AbstractWhile several studies have documented an increased risk of metabolic disorders in patients with polycystic ovary syndrome (PCOS), associations between androgenic and metabolic parameters in these patients are unclear. We aimed to investigate the relationships between biochemical markers of hyperandrogenism (HA) and metabolic parameters in women with PCOS. In this systematic review and meta-analysis, a literature search was performed in the PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science from 2000 to 2018 for assessing androgenic and metabolic parameters in PCOS patients. To assess the relationships between androgenic and metabolic parameters, meta-regression analysis was used. A total number of 33 studies involving 9905 patients with PCOS were included in this analysis. The associations of total testosterone (tT) with metabolic parameters were not significant; after adjustment for age and BMI, we detected associations of this androgen with low-density lipoproteins cholesterol (LDL-C) (β=0.006; 95% CI: 0.002, 0.01), high-density lipoproteins cholesterol (HDL-C) (β=–0.009; 95% CI: –0.02, –0.001), and systolic blood pressure (SBP) (β=–0.01; 95% CI: –0.03, –0.00). We observed a positive significant association between free testosterone (fT) and fasting insulin (β=0.49; 95% CI: 0.05, 0.91); this association remained significant after adjustment for confounders. We also detected a reverse association between fT and HDL-C (β=–0.41; 95% CI: –0.70, –0.12). There was a positive significant association between A4 and TG (β=0.02; 95% CI: 0.00, 0.04) after adjustment for PCOS diagnosis criteria. We also found significant negative associations between A4, TC, and LDL-C. Dehydroepiandrosterone sulfate (DHEAS) had a positive association with LDL-C (β=0.02; 95% CI: 0.001, 0.03) and a reverse significant association with HDL-C (β=–0.03; 95% CI: –0.06, –0.001). This meta-analysis confirmed the associations of some androgenic and metabolic parameters, indicating that measurement of these parameters may be useful for predicting metabolic risk in PCOS patients.

scholarly journals Association of CYP3A7*1C and Serum Dehydroepiandrosterone Sulfate Levels in Women with Polycystic Ovary Syndrome

2008 ◽  
Vol 93 (7) ◽  
pp. 2909-2912 ◽  
Author(s):  
Mark O. Goodarzi ◽  
Ning Xu ◽  
Ricardo Azziz
Keyword(s):  
Los Angeles ◽  
Polycystic Ovary Syndrome ◽  
White Women ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Free Testosterone ◽  
Total Testosterone ◽  
Adrenal Androgen ◽  
Androgen Excess ◽  
Ovary Syndrome

Abstract Context: Adrenal androgen excess is common in polycystic ovary syndrome (PCOS) and appears to be heritable. CYP3A7 metabolizes dehydroepiandrosterone and its sulfate (DHEAS). A promoter variant, CYP3A7*1C, which results in persistent expression in adults, was associated with reduced DHEAS levels in a previous study, which led us to consider CYP3A7*1C as a modulator of adrenal androgen excess in patients with PCOS. Objective: The objective was to replicate the association between CYP3A7*1C and reduced DHEAS levels in PCOS patients and assess its possible role in modulating testosterone levels. Design: Women with and without PCOS were genotyped for CYP3A7*1C, and this variant was tested for association with DHEAS and total and free testosterone. Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center (Los Angeles, CA). Participants: A total of 287 white women with PCOS and 187 controls were studied. Main Measurements: CYP3A7*1C genotype, PCOS risk, and androgen levels were measured. Results: PCOS subjects who carried the CYP3A7*1C variant had lower levels of serum DHEAS and total testosterone (P = 0.0006 and 0.046, respectively). The variant was not associated with PCOS risk. Conclusion: This study replicated prior work of the association of CYP3A7*1C and decreased DHEAS in a different population of young PCOS women, providing further genetic evidence that CYP3A7 plays a potential role in modulation of DHEAS levels. Adult expression of CYP3A7 may modify the PCOS phenotype by ameliorating adrenal androgen excess.

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