Nonhuman primate models of polycystic ovary syndrome

Abbott, David H.; Nicol, Lindsey; Levine, Jon E.; Xu, Ning; Goodarzi, Mark O.; Dumesic, Daniel A.

doi:10.1016/j.mce.2013.01.013

Cited by 90 publications

(67 citation statements)

References 112 publications

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“…Animal studies suggest that high maternal androgen concentrations during gestation result in PCOS-like phenotypes, in primates (14,15,34), sheep (35) and rodents (36). Especially studies by Abbott (13,14,15,34,37), in prenatally exposed rhesus monkeys, have strongly encouraged the hypothesis that the intra-uterine exposure to androgens can cause clinical and biochemical features of PCOS in later life, though these androgen concentrations are supraphysiological.…”

Section: Discussionmentioning

confidence: 99%

“…Especially studies by Abbott (13,14,15,34,37), in prenatally exposed rhesus monkeys, have strongly encouraged the hypothesis that the intra-uterine exposure to androgens can cause clinical and biochemical features of PCOS in later life, though these androgen concentrations are supraphysiological.…”

Section: Discussionmentioning

confidence: 99%

“…The pathophysiology of PCOS is still poorly understood. From animal studies it is known that prenatal exposure to supraphysiological androgen concentrations in mothers leads to PCOS phenotypes in the offspring (13,14,15). In addition, in cultured mice cells, androgens seem to stimulate growth of pre-antral and small follicles.…”

Section: Introductionmentioning

confidence: 99%

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Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

Caanen

Kuijper

Hompes

et al. 2016

European Journal of Endocrinology

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Objective: Little is known about the aetiology of polycystic ovary syndrome (PCOS). Some suggest that elevated maternal androgens during gestation play a causative role. This implies placental passage of androgens during pregnancy. The aim of this study is to compare androgen and estrogen concentrations in maternal serum during pregnancy and in umbilical cord blood, between mothers with PCOS and their offspring compared to controls. Design: Prospective case-control study. Methods: Maternal blood samples were collected around 20 weeks of gestation and at delivery. Umbilical cord blood was also taken at delivery. Androgens (testosterone (T), androstenedione (ADION), dehydroepiandrostenedione (DHEA)) and estrogens (estrone (E 1 ), estradiol (E 2 ), estriol (E 3 )) were measured using the liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Results: At 20 weeks of gestation: T (PZ0.019) and ADION (PZ0.034) were higher in the PCOS mothers (pregnant with a girl), whereas DHEA, E 1 , E 2 , and E 3 were not different. Maternal concentration at birth: T (PZ0.004) and ADION (PZ0.009) were also higher in the subgroup of PCOS mothers that were pregnant with a girl compared to the girl pregnancy controls. DHEA, E 1 , E 2 and E 3 were not different. In umbilical cord blood, no differences were found for T, ADION, DHEA, E 2 , E 3 , and AMH between the PCOS mothers and the controls respectively. E 1 was lower in girls from PCOS mothers (PZ0.007). Conclusions: Despite elevated maternal androgen concentrations during pregnancy in PCOS mothers, offspring showed no signs of elevated androgen concentrations in cord blood at birth using the latest highly specific LC-MS/MS methods.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

Caanen

Kuijper

Hompes

et al. 2016

European Journal of Endocrinology

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“…Available studies do not support the concept that the common PCOS is due to a single-gene defect, although large association studies have suggested that a cluster of genes may increase the individual susceptibility to develop it (22,23). Animal studies have also suggested that fetal exposure to androgen excess may contribute to development of the PCOS phenotype later in time (24,25). These theories imply the potential direct role of intrauterine androgen excess in favoring the metabolic derangements, including hypertrophy of the visceral fat and associated insulin resistance coupled with compensatory hyperinsulinemia.…”

Section: Arguments In Favor Of the Definition Of Secondary Pcosmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

Pasquali

Diamanti-Kandarakis

Gambineri

2016

European Journal of Endocrinology

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PCOS is a clinical heterogeneous entity of female androgen excess diagnosed by exclusion of other disorders responsible for androgen excess. The concept of secondary PCOS implies that there is a primary well-defined cause leading to the PCOS phenotype with underlying androgen overproduction, regardless of the origin. In these cases, we presume the term of 'secondary PCOS' could be used. In all these conditions, the potential complete recovery of the hyperandrogenemic state as well as the remission of the PCOS phenotype should follow the removal of the cause. If accepted, these concepts could help clinicians to perform in-depth investigations of the potential factors or disorders responsible for the development of these specific forms of secondary PCOS. Additionally, this could contribute to develop further research on factors and mechanisms involved in the development of the classic and the nonclassic PCOS phenotypes. Invited author's profileRenato Pasquali is full professor of Endocrinology & Metabolism and Director of the division of Endocrinology of the S.Orsola-Malpighi Hospital, Bologna, Italy. He also heads the School of Specialization in Endocrinology and Metabolism, University Alma Mater Studiorum of Bologna, Italy. He is a member of numerous national and international scientific societies and serves on the editorial boards of international journals. His scientific interests relate to (i) the pathophysiology and treatment of the polycystic ovary syndrome; (ii) the endocrinology of obesity (sex hormones, the hypothalamic-pituitary-adrenal axis, and the endocannabinoid system).

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“…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)(9)(10). As all androgen action is mediated via the androgen receptor (AR), AR-mediated actions are thereby strongly implicated in the development of PCOS.…”

mentioning

confidence: 99%

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.

171

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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Nonhuman primate models of polycystic ovary syndrome

Cited by 90 publications

References 112 publications

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

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

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