Context:
Polycystic ovary syndrome (PCOS) is a common complex genetic disease. It is characterized by hyperandrogenism, gonadotropin secretory changes, polycystic ovarian morphology, and insulin ...resistance. The etiology of PCOS remains unknown, but modern genetic approaches, such as genome-wide association studies (GWAS), Mendelian randomization, and next-generation sequencing, promise to identify the pathways that are primarily disrupted.
Evidence Acquisition:
The literature on PCOS, including the author's research, is discussed.
Evidence Synthesis:
Recent genetic analyses are reviewed.
Conclusions:
Considerable progress has been made mapping PCOS susceptibility genes. GWAS have implicated gonadotropin secretion and action as important primary defects in disease pathogenesis in European and Han Chinese PCOS cohorts, respectively. European women with the National Institutes of Health and Rotterdam phenotypes as well as those with self-reported PCOS have some gene regions in common, such as chromosome 11p14.1 region containing the FSH B polypeptide (FSHB) gene, suggesting shared genetic susceptibility. Several chromosomal signals are significant in both Han Chinese and European PCOS cohorts, suggesting that the susceptibility genes in these regions are evolutionarily conserved. In addition, GWAS have suggested that DENND1A, epidermal growth factor signaling, and DNA repair pathways play a role in PCOS pathogenesis. Only a small amount of the heritability of PCOS is accounted for by the common susceptibility variants mapped so far. Future studies should clarify the contribution of rare genetic variants and epigenetic factors to the PCOS phenotype. Furthermore, Mendelian randomization can be used to clarify causal relationships, and phenome-wide association studies can provide insight into health risks associated with PCOS susceptibility variants.
Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic as well as reproductive disorder conferring substantially increased risk for type 2 diabetes. Affected women have marked ...insulin resistance, independent of obesity. This article summarizes the state of the science since we last reviewed the field in the Endocrine Reviews in 1997. There is general agreement that obese women with PCOS are insulin resistant, but some groups of lean affected women may have normal insulin sensitivity. There is a post-binding defect in receptor signaling likely due to increased receptor and insulin receptor substrate-1 serine phosphorylation that selectively affects metabolic but not mitogenic pathways in classic insulin target tissues and in the ovary. Constitutive activation of serine kinases in the MAPK-ERK pathway may contribute to resistance to insulin's metabolic actions in skeletal muscle. Insulin functions as a co-gonadotropin through its cognate receptor to modulate ovarian steroidogenesis. Genetic disruption of insulin signaling in the brain has indicated that this pathway is important for ovulation and body weight regulation. These insights have been directly translated into a novel therapy for PCOS with insulin-sensitizing drugs. Furthermore, androgens contribute to insulin resistance in PCOS. PCOS may also have developmental origins due to androgen exposure at critical periods or to intrauterine growth restriction. PCOS is a complex genetic disease, and first-degree relatives have reproductive and metabolic phenotypes. Several PCOS genetic susceptibility loci have been mapped and replicated. Some of the same susceptibility genes contribute to disease risk in Chinese and European PCOS populations, suggesting that PCOS is an ancient trait.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females, with a high prevalence. The etiology of this heterogeneous condition remains obscure, and its phenotype expression ...varies. Two widely cited previous ESHRE/ASRM sponsored PCOS consensus workshops focused on diagnosis (published in 2004) and infertility management (published in 2008), respectively. The present third PCOS consensus report summarizes current knowledge and identifies knowledge gaps regarding various women’s health aspects of PCOS. Relevant topics addressed—all dealt with in a systematic fashion—include adolescence, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health, and finally cancer risk. Additional, comprehensive background information is provided separately in an extended online publication.
PRO —A large majority of women with PCOS have insulin resistance, compensatory hyperinsulinemia with consequent reproductive and metabolic abnormalities. Metformin has been shown to be effective ...therapy and could be used more widely in obese adolescents with hyperandrogenemia, a forerunner of PCOS. CON —The severity of insulin resistance is highly variable in women with PCOS and may not be clinically relevant in milder phenotypes. Treatment should be directed at specific metabolic or reproductive problems and insulin sensitizing drugs are not always the optimum therapy.
Polycystic 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.
Using biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range IQR: age = 28 25-32, body mass index BMI = 35.4 28.2-41.5). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 24-33, BMI = 35.7 28.4-42.3). The clustering revealed 2 distinct PCOS subtypes: a "reproductive" group (21%-23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low 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 4 loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN, 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 developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS (median and IQR: age = 28 25-33, BMI = 34.3 27.8-42.3) and found that the subtypes tended to cluster in families and that carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, 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 National Institutes of Health (NIH) criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated.
In conclusion, we have found reproducible reproductive and metabolic subtypes of PCOS. Furthermore, these subtypes were associated with novel, to our knowledge, susceptibility loci. Our results suggest that these subtypes are biologically relevant because they appear to have distinct genetic architecture. This study demonstrates how phenotypic subtyping can be used to gain additional insights from GWAS data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polycystic ovary syndrome (PCOS) is among the most common disorders in women of reproductive age, affecting up to 15% worldwide, depending on the diagnostic criteria. PCOS is characterized by a ...constellation of interrelated reproductive abnormalities, including disordered gonadotropin secretion, increased androgen production, chronic anovulation, and polycystic ovarian morphology. It is frequently associated with insulin resistance and obesity. These reproductive and metabolic derangements cause major morbidities across the lifespan, including anovulatory infertility and type 2 diabetes (T2D). Despite decades of investigative effort, the etiology of PCOS remains unknown. Familial clustering of PCOS cases has indicated a genetic contribution to PCOS. There are rare Mendelian forms of PCOS associated with extreme phenotypes, but PCOS typically follows a non-Mendelian pattern of inheritance consistent with a complex genetic architecture, analogous to T2D and obesity, that reflects the interaction of susceptibility genes and environmental factors. Genomic studies of PCOS have provided important insights into disease pathways and have indicated that current diagnostic criteria do not capture underlying differences in biology associated with different forms of PCOS. We provide a state-of-the-science review of genetic analyses of PCOS, including an overview of genomic methodologies aimed at a general audience of non-geneticists and clinicians. Applications in PCOS will be discussed, including strengths and limitations of each study. The contributions of environmental factors, including developmental origins, will be reviewed. Insights into the pathogenesis and genetic architecture of PCOS will be summarized. Future directions for PCOS genetic studies will be outlined.
Current diagnostic criteria for polycystic ovary syndrome (PCOS) are based on expert opinion. This article reviews the rationale for and the limitations of these criteria as well as which criteria to ...use and when. The insights provided into PCOS pathogenesis by modern genetic analyses and the promise of objective data mining approaches for biologically relevant disease classification are discussed.
Objective To investigate for differences in reproductive hormone levels in male relatives of women with polycystic ovary syndrome (PCOS). Design Cross-sectional study. Setting Academic medical ...center. Patient(s) Sixty-three fathers and 66 brothers of women with PCOS as well as two groups of control men of comparable age to fathers (older control, n = 30) and brothers (younger control, n = 58). Intervention(s) A single early morning fasting blood sample was obtained for the measurement of reproductive hormone levels. Main Outcome Measure(s) Testosterone, LH, FSH, antimüllerian hormone (AMH), inhibin B, estradiol (E2 ), and estrone (E1 ) levels were measured. Result(s) The AMH, LH, and FSH levels were significantly increased in male relatives compared with their respective control groups. The levels of E2 , E1 , T, and inhibin B did not differ between the groups. Conclusion(s) The AMH, LH, and FSH levels were increased in adult male relatives of women with PCOS, suggesting that they may have altered testicular function and changes in neuroendocrine regulation of gonadotropin secretion. These changes may reflect effects of PCOS susceptibility genes such as the recently mapped chromosome 11p14.1 locus in the region of the FSH B polypeptide gene.
Over the past 20 years, it has been clearly documented that the polycystic
ovary syndrome (PCOS) has major metabolic sequelae related to insulin
resistance and that insulin resistance plays an ...important role in the
pathogenesis of the reproductive disturbances of the disorder. Family studies
have indicated a genetic susceptibility to PCOS. Polycystic ovaries and
hyperandrogenemia are present in ∼50% of sisters of affected women.
Increased androgen secretion and insulin resistance persist in cultured theca
cells and skin fibroblasts, respectively, from women with PCOS; this finding
suggests that these are intrinsic, presumably genetic, defects. Insulin
resistance and elevated low-density lipoprotein (LDL) levels also cluster in
the sisters of women with PCOS, consistent with genetic traits. Moreover, the
brothers of women with PCOS have insulin resistance and elevated
dehydroepiandrosterone sulfate (DHEAS) levels, which supports a genetic basis
for these findings. Family-based studies of linkage and association have
implicated several genes in the pathogenesis of PCOS. The strongest evidence to
date points to a gene in the region of the insulin receptor.
Insulin-sensitizing therapy mitigates the reproductive disturbances of
PCOS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Enhanced Mitogenic Signaling in Skeletal Muscle of Women With Polycystic Ovary Syndrome
Anne Corbould 1 2 ,
Haiyan Zhao 1 ,
Salida Mirzoeva 1 ,
Fraser Aird 1 and
Andrea Dunaif 1 2
1 Division of ...Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago,
Illinois
2 Division of Women’s Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Andrea Dunaif, MD, Division of Endocrinology, MetabolismMolecular Medicine,
Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. E-mail: a-dunaif{at}northwestern.edu
Abstract
Insulin resistance in polycystic ovary syndrome (PCOS) results from a postbinding defect in signaling. Insulin receptor and
insulin receptor substrate (IRS)-1 serine hyperphosphorylation by an unidentified kinase(s) contributes to this defect. We
investigated whether insulin resistance is selective, affecting metabolic but not mitogenic pathways, in skeletal muscle as
it is in cultured skin fibroblasts in PCOS. Extracellular signal–regulated kinase (ERK)1/2 activation was increased in skeletal
muscle tissue and in cultured myotubes basally and in response to insulin in women with PCOS compared with control women.
Mitogen-activated/extracellular signal–regulated kinase kinase (MEK)1/2 was also activated in PCOS, whereas p38 mitogen-activated
protein kinase phosphorylation and signaling from the insulin receptor to Grb2 was similar in both groups. The activity of
p21Ras was decreased and Raf-1 abundance increased in PCOS, suggesting that altered mitogenic signaling began at this level.
MEK1/2 inhibition reduced IRS-1 Ser 312 phosphorylation and increased IRS-1 association with the p85 subunit of phosphatidylinositol 3-kinase in both groups. We
conclude that in PCOS skeletal muscle, 1 ) mitogenic signaling is enhanced in vivo and in culture, 2 ) ERK1/2 activation inhibits association of IRS-1 with p85 via IRS-1 Ser 312 phosphorylation, and 3 ) ERK1/2 activation may play a role in normal feedback of insulin signaling and contribute to resistance to insulin’s metabolic
actions in PCOS.
AMPK, AMP-activated protein kinase
ERK, extracellular signal–regulated kinase
FBS, fetal bovine serum
IRS, insulin receptor substrate
MAPK, mitogen-activated protein kinase
MEK, mitogen-activated/extracellular signal–regulated kinase kinase
PCOS, polycystic ovary syndrome
PI, phosphatidylinositol
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
A.C. and H.Z. contributed equally to this study.
Accepted November 18, 2005.
Received April 7, 2005.
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