scholarly journals Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause

Reproduction ◽  
2015 ◽  
Vol 150 (1) ◽  
pp. R11-R24 ◽  
Author(s):  
Anderson Sanches de Melo ◽  
Sabrine Vilan Dias ◽  
Ricardo de Carvalho Cavalli ◽  
Viviane Cunha Cardoso ◽  
Heloisa Bettiol ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Polycystic Ovary Syndrome ◽  
Structural Changes ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Visceral Obesity ◽  
Developmental Programming ◽  
Postnatal Life ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a multifactorial disorder that arises from interactions between genetic, environmental and intra-uterine factors. Small-for-gestational-age (SGA) babies and the daughters of mothers with PCOS represent possible postnatal clinical targets for developmental programming by steroid excess. The presence of excess glucocorticoids and/or androgens during foetal organogenesis and growth might promote changes in gene expression, and these changes might be related to an increase in the risk of PCOS-like reproductive and metabolic disorders in postnatal life, such as rapid growth and weight gain during the first 2 years of life (only in SGA babies), hyperinsulinaemia, adipocyte dysfunction and childhood visceral obesity, premature pubarche and adrenarche (only in SGA babies) and PCOS. In the fourth decade of life, women who have PCOS may be at higher risk for type 2 diabetes mellitus, dyslipidaemia and systemic arterial hypertension, which suggests that these women are also at higher risk for cardiovascular disease during menopause. However, PCOS can also occur in women who were born at appropriate weight for GA or in newborns of women without PCOS, which suggests that genetic variation and environmental factors play important roles in the development and maintenance of PCOS in a population. Genome-wide association studies based on adequate population samples have shown a higher frequency of genetic polymorphisms of the LHCGR, THADA and DENND1A genes in women with PCOS. Genetic studies of PCOS have also included analyses of structural changes in the chromosome based on an assessment of telomere length in single, cross-sectional evaluations, and these studies have produced controversial results. The present narrative review assesses the multifactorial origins of PCOS (including environmental, genetic and intra-uterine factors) and the development of conditions associated with this disorder. It is concluded that although PCOS might originate in the intra-uterine environment through developmental programming by steroid excess, the interaction between genetic and environmental factors is crucial for its appearance. Follow-up studies should be conducted to assess the same populations over their entire lifespans while taking into account different aspects of the pathogenesis of PCOS.

scholarly journals Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome

2019 ◽  
Vol 104 (9) ◽  
pp. 3835-3850 ◽  
Author(s):  
Matthew Dapas ◽  
Ryan Sisk ◽  
Richard S Legro ◽  
Margrit Urbanek ◽  
Andrea Dunaif ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Endocrine Disorders ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

AbstractContextPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.ObjectiveThe objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and MethodsWe performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis.ResultsWe found rare variants in DENND1A (P = 5.31 × 10−5, adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families.ConclusionsCommon variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

scholarly journals Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in pathogenesis of polycystic ovary syndrome

2018 ◽  
Author(s):  
Matthew Dapas ◽  
Ryan Sisk ◽  
Richard S. Legro ◽  
Margrit Urbanek ◽  
Andrea Dunaif ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Endocrine Disorders ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

ABSTRACTPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is a leading risk factor for type 2 diabetes in young women. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. To test the hypothesis that rare genetic variants contribute to PCOS pathogenesis, we performed whole-genome sequencing on DNA from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. We found rare variants in DENND1A (P=5.31×10−5, Padj=0.019) that were significantly associated with reproductive and metabolic traits in PCOS families. Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

scholarly journals Understanding Polycystic Ovary Syndrome: A Multifactorial Endocrine Disorder

2021 ◽  
Author(s):  
Surankita Sukul ◽  
Pushkal Sinduvadi Ramesh ◽  
Narahari Agasti
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Markers ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Reproductive Age ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome ◽  
Endocrine Disorder ◽  
Genome Wide

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting a significant population of women of reproductive age group worldwide. Due to the complex pathophysiology and overlapping symptoms, this disorder is often difficult to diagnose. Genome-wide association studies have identified several new risk loci and candidate genes for PCOS. However, currently, there are no standard genetic markers for PCOS susceptibility testing owing to the inconsistent findings. Despite the advent of the genomic era, the challenge to identify and pinpoint the heritable genetic basis of PCOS still exists. This mini-review explores the basic definition and phenotypes of PCOS, the different criteria for the diagnosis, the incidence, gestational complications associated with it, the basis of genetic heritability, and the influence of various gene polymorphisms. Also, this review briefly summarises the reports of genome-wide association studies conducted to identify candidate genetic markers to aid in understanding the complex pathophysiology of PCOS.

scholarly journals Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

2015 ◽  
Vol 36 (5) ◽  
pp. 487-525 ◽  
Author(s):  
Daniel A. Dumesic ◽  
Sharon E. Oberfield ◽  
Elisabet Stener-Victorin ◽  
John C. Marshall ◽  
Joop S. Laven ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Metabolic Phenotype ◽  
Genome Wide Association Studies ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Gonadotropin Secretion ◽  
Functional Changes

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown.

scholarly journals The Genetics of Polycystic Ovary Syndrome: An Overview of Candidate Gene Systematic Reviews and Genome-Wide Association Studies

2019 ◽  
Vol 8 (10) ◽  
pp. 1606 ◽  
Author(s):  
Hiam ◽  
Moreno-Asso ◽  
Teede ◽  
Laven ◽  
Stepto ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Candidate Gene ◽  
Systematic Reviews ◽  
Current Literature ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome ◽  
Genome Wide

Polycystic Ovary Syndrome (PCOS) is a complex condition with mechanisms likely to involve the interaction between genetics and lifestyle. Familial clustering of PCOS symptoms is well documented, providing evidence for a genetic contribution to the condition. This overview aims firstly to systematically summarise the current literature surrounding genetics and PCOS, and secondly, to assess the methodological quality of current systematic reviews and identify limitations. Four databases were searched to identify candidate gene systematic reviews, and quality was assessed with the AMSTAR tool. Genome-wide association studies (GWAS) were identified by a semi structured literature search. Of the candidate gene systematic reviews, 17 were of high to moderate quality and four were of low quality. A total of 19 gene loci have been associated with risk of PCOS in GWAS, and 11 of these have been replicated across two different ancestries. Gene loci were located in the neuroendocrine, metabolic, and reproductive pathways. Overall, the gene loci with the most robust findings were THADA, FSHR, INS-VNTR, and DENND1A, that now require validation. This overview also identified limitations of the current literature and important methodological considerations for future genetic studies. Much work remains to identify causal variants and functional relevance of genes associated with PCOS.

scholarly journals Colocalization of Polycystic Ovary Syndrome Candidate Gene Products in Theca Cells Suggests Novel Signaling Pathways

2019 ◽  
Vol 3 (12) ◽  
pp. 2204-2223 ◽  
Author(s):  
Rewa Kulkarni ◽  
Maria E Teves ◽  
Angela X Han ◽  
Jan M McAllister ◽  
Jerome F Strauss
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Receptor Gene ◽  
Genome Wide Association Studies ◽  
Nucleotide Exchange ◽  
Ovary Syndrome ◽  
Cytological Evidence ◽  
Theca Cells ◽  
Androgen Synthesis

Abstract Genome-wide association studies identified loci associated with polycystic ovary syndrome (PCOS), including those near the LH receptor gene (LHCGR), a clathrin-binding protein (DENND1A) that functions as a guanine nucleotide exchange factor, and the gene encoding RAB5B, a GTPase involved in vesicular trafficking. We proposed that these three PCOS loci could be assembled into a functional network that contributes to altered gene expression in theca cells, resulting in increased androgen synthesis. The functional significance of this network was supported by our discovery that a truncated protein splice variant of the DENND1A gene, termed DENND1A.V2, is elevated in PCOS theca cells, and that forced expression of DENND1A.V2 in normal theca cells increased CYP11A1 and CYP17A1 expression and androgen synthesis, a hallmark of PCOS. In this study, we demonstrate the colocalization of LHCGR, DENND1AV.2, and RAB5B proteins in various cellular compartments in normal and PCOS theca cells by immunofluorescence. Human chorionic gonadotropin and forskolin stimulation was shown to affect the cytoplasmic distribution of LHCGR, DENND1A.V2, and RAB5B. DENND1A.V2 accumulated in the nuclei of the theca cells. Moreover, PCOS theca cells, following forskolin treatment, had a significantly greater relative abundance of nuclear DENND1A.V2. RAB5B also accumulated in the nuclei of PCOS theca cells treated with forskolin. In contrast, LHCGR did not enter the nucleus. This cytological evidence, and the previously reported increase in androgen biosynthesis with forced expression of DENND1A.V2 in normal theca cells, raises the possibility that DENND1A.V2 and RAB5B participate in increasing transcription of genes involved in androgen synthesis.

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