Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations

Hayes, M. Geoffrey; Urbanek, Margrit; Ehrmann, David A.; Armstrong, Loren L.; Lee, Ji Young; Sisk, Ryan; Karaderi, Tugce; Barber, Thomas M.; McCarthy, Mark I.; Franks, Stephen; Lindgren, Cecilia M.; Welt, Corrine K.; Diamanti-Kandarakis, Evanthia; Panidis, Dimitrios; Goodarzi, Mark O.; Azziz, Ricardo; Zhang, Yi; James, Roland; Olivier, Michael; Kissebah, Ahmed H.; Stener-Victorin, Elisabet; Legro, Richard S.; Dunaif, Andrea; Alvero, Ruben; Barnhart, Huiman X.; Baker, Valerie L.; Barnhart, Kurt T.; Bates, G. Wright; Brzyski, Robert G.; Carr, Bruce R.; Carson, Sandra Ann; Casson, Peter; Cataldo, Nicholas A.; Christman, Gregory M.; Coutifaris, Christos; Diamond, Michael P.; Eisenberg, Esther; Gosman, Gabriella G.; Giudice, Linda C.; Haisenleder, Daniel J.; Huang, Hao; Krawetz, Stephen A.; Lucidi, Scott; McGovern, Peter G.; Myers, Evan R.; Nestler, John E.; Ohl, Dana A.; Santoro, Nanette; Schlaff, William D.; Snyder, Peter J.; Steinkampf, Michael P.; Trussell, J. C.; Usadi, Rebecca; Yan, Qingshang; Zhang, Heping

doi:10.1038/ncomms8502

Cited by 353 publications

(260 citation statements)

References 69 publications

(132 reference statements)

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“…Our data demonstrate that, in particular, extraovarian neuroendocrine AR sites of androgen action are predominantly involved in the pathogenesis of multiple key PCOS characteristics. This provides strong experimental support for recent GWAS findings that highlight the importance of gonadotropin action in the genetic origins of susceptibility to PCOS (24)(25)(26). In concert, these Serum concentrations of dihydrotestosterone, testosterone, dehydroepiandrosterone, 5α-androstane-3α,17β-diol, 5α-androstane-3β,17β-diol, progesterone, luteinizing hormone, and follicle-stimulating hormone.…”

Section: Discussionsupporting

confidence: 78%

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Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Caldwell

Edwards

Desai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

177

185

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Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanismbased treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS.PCOS | androgen | animal model | neuroendocrine P olycystic ovary syndrome (PCOS) is the most frequent endocrine disorder of young women, with a prevalence of 6 to 15% (1), and accounts for more than 75% of anovulatory infertility (2). It is characterized by reproductive hormone dysregulation involving luteinizing hormone (LH) hypersecretion and hyperandrogenism (3), the consequences of which can be acne and hirsutism, as well as reduced fertility, due to aberrant follicular maturation, ovulatory disturbance, and miscarriage (3). Associated nonreproductive abnormalities, such as obesity, metabolic syndrome, hyperinsulinemia, insulin resistance, hepatic steatosis, and dyslipidemia predispose affected women to heightened risk of cardiovascular disease and type 2 diabetes (3, 4). However, despite the high prevalence and significant health impact, the pathogenesis of PCOS remains unclear so that mechanism-based treatments remain unattainable.Hyperandrogenism, the most consistent feature of PCOS (5), is implicated as a key mediator in the pathogenesis of PCOS. Supportive evidence includes that androgen excess from endogenous [congenital adrenal hyperplasia (6)] or exogenous [female-to-male transsexuals (7)] sources can produce polycystic ovaries. Furthermore, androgens induce reproductive, metabolic, and endocrine features of PCOS in rodent, sheep, and primate animal models of PCOS (8-10). As all androgen action is mediated via the androgen receptor (AR),...

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Section: Discussionsupporting

confidence: 78%

“…1). Our findings highlight the importance of extraovarian AR-mediated androgen actions in the origins of PCOS features, which is strongly supported by findings from recent genome-wide association studies (GWAS) of PCOS highlighting the importance of gonadotropins in PCOS (24)(25)(26).…”

supporting

confidence: 84%

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Caldwell

Edwards

Desai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

177

185

View full text Add to dashboard Cite

show abstract

“…The advent of large-scale GWAS with their stringent statistical thresholds has brought robust new insights, although as yet these have been limited to adult PCOS cases and their direct relevance to adolescent PCOS is yet to be established. The first GWAS for PCOS were performed in Han Chinese populations [92, 93]; while the identified genomic loci were replicable in that population, their effects estimates are consistently smaller in Caucasian PCOS cases, possibly due to population differences in genetic architecture or even PCOS sub-phenotypes [94, 95]. …”

Section: A Pathophysiologymentioning

confidence: 99%

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence

Ibáñez¹,

et al. 2017

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This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)¹. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.

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“…Interestingly, genetic studies have revealed a significant overlap of findings when different diagnostic criteria of PCOS have been applied, highlighting greater homogeneity than previously appreciated. 16,56,57 Clinical features and co-morbidities…”

Section: Recent Insights From Genetic Studiesmentioning

confidence: 99%

Polycystic ovary syndrome: a common reproductive syndrome with long-term metabolic consequences

Yau

Cheung

et al. 2017

Hong Kong Med J

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Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations

Cited by 353 publications

References 69 publications

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence

Polycystic ovary syndrome: a common reproductive syndrome with long-term metabolic consequences

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