Rodent Models of Polycystic Ovary Syndrome: Phenotypic Presentation, Pathophysiology, and the Effects of Different Interventions

Maliqueo, Manuel; Benrick, Anna; Stener-Victorin, Elisabet

doi:10.1055/s-0034-1371090

Cited by 55 publications

(36 citation statements)

References 96 publications

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“…Opposite to what is seen with women with PCOS, DHT-exposed rodents have unchanged (50, 51) or decreased ovarian weight (52). As previously reported, the DHT-induced model shows reproductive characteristics associated with PCOS in humans (e.g., anestrous and PCO morphology, including follicular cysts, increased theca cell layer, and decreased granulosa cell layer) (50-52).…”

Section: Discussionmentioning

confidence: 86%

“…In this regard, it is important to select the most suitable model for the pathophysiological experiment to be performed or the treatment strategy to be tested. We selected the DHT-induced model based on its reproducible metabolic features (52), but one of the limitations of the model is the lack of a neuroendocrine phenotype. In this regard, the letrozole-induced PCOS-like model or prenatal androgenization of female mice with DHT may offer better models to study the role of adiponectin on reproductive dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Benrick

Chanclón

Micallef

et al. 2017

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

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100

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Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits. As expected, DHT exposure led to reproductive dysfunction, as judged by continuous anestrus, smaller ovaries with a decreased number of corpus luteum, and an increased number of cystic/atretic follicles. A two-way between-groups analysis showed that there was a significant main effect for DHT exposure, but not for genotype, indicating adiponectin does not influence follicle development. Adiponectin had, however, some protective effects on ovarian function. Similar to in many women with PCOS, DHT exposure led to reduced adiponectin levels, larger adipocyte size, and reduced insulin sensitivity in WTs. APNtg mice remained metabolically healthy despite DHT exposure, while APNko-DHT mice were even more insulin resistant than their DHT-exposed littermate WTs. DHT exposure also reduced the mRNA expression of genes involved in metabolic pathways in gonadal adipose tissue of WT and APNko, but this effect of DHT was not observed in APNtg mice. Moreover, APNtg-DHT mice displayed increased pancreatic mRNA levels of insulin receptors, Pdx1 and Igf1R, suggesting adiponectin stimulates beta cell viability/hyperplasia in the context of PCOS. In conclusion, adiponectin improves metabolic health but has only minor effects on reproductive functions in this PCOS-like mouse model. polycystic ovary syndrome | insulin resistance | adipose tissue P olycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder occurring in females (1). PCOS is one of the leading causes of poor fertility and is associated with abdominal obesity, metabolic syndrome, and an increased risk of developing type 2 diabetes (1, 2). Indeed, it has been demonstrated that 30-40% of women with PCOS have impaired glucose tolerance, and as many as 10% develop diabetes by the age of 40 y (3, 4). Despite the negative effect of PCOS on women's health, very little is known about its etiology, including the causal relationship between the reproductive and metabolic features of PCOS. Adipose tissue dysfunction is implicated as a key feature, and both lean and obese women with PCOS have aberrant adipose tissue morphology (5-7). Specifically, we have found that large adipocyte size, low circulating adiponectin levels, and increased waist circumference, but surprisingly, not androgen excess, are factors that are most strongly associated with insulin resistance in women with PCOS (8). Others have shown that hyperandrogenism is associated with intra-abdominal fat deposition (9). Adiponectin is an adipocyte-derived hormone exerting potent positive effec...

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Benrick

Chanclón

Micallef

et al. 2017

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

Self Cite

100

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show abstract

“…In addition to being a means to address causal and mechanistic events that lead to the development of PCOS phenotype, animal models allow preventive and therapeutic strategies to be tested. Among the various animal models, rats, mice, sheep, and rhesus macaques are the most commonly used in PCOS research with each offering different benefits (Maliqueo et al, 2014, van Houten and Visser, 2014, Padmanabhan and Veiga-Lopez, 2013b, Abbott et al, 2008b, Padmanabhan and Veiga-Lopez, 2013a). Rhesus macaques are genealogically closer to humans and thus can be a good translational model.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Many of the animal models developed to study PCOS involve perinatal treatment with testosterone or other steroids such as dihydrotestosterone, estradiol valerate and steroid synthesis inhibitors (Abbott et al, 2008b, Padmanabhan et al, 2006, Maliqueo et al, 2014, Kauffman et al, 2015). The comparative aspects, advantages, and limitations of these models have been extensively reviewed elsewhere (Padmanabhan and Veiga-Lopez, 2013a).…”

Section: Animal Modelsmentioning

confidence: 99%

Effect of maternal PCOS and PCOS-like phenotype on the offspring's health

Puttabyatappa

Cardoso

Padmanabhan

2016

Molecular and Cellular Endocrinology

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Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities affecting women of reproductive age. While the exact origin of PCOS is unknown, observations from clinical and animal studies suggest that maternal hyperandrogenism may be a contributing factor. Because women with PCOS manifest hyperandrogenism during pregnancy, changes in the gestational endocrine milieu may play a role in the vertical transmission of this syndrome. This review discusses the potential developmental origins of PCOS, the impact of maternal PCOS on the offspring’s health and contributions of the postnatal environment, capitalizing on findings from animal models that exhibit a PCOS-like phenotype. In addition, this review highlights the scarcity of data at early gestational stages in humans and the importance of animal experimentation to better understand the cellular and molecular mechanisms involved in the programming of adult diseases, therefore, helping identify therapeutic targets for preventive and treatment strategies.

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“…PCOS experimental models have been developed on various animals, such as rodents (reviewed by Shi & Vine 2012, Walters et al 2012, McNeilly & Colin Duncan 2013, Maliqueo et al 2014, sheep (reviewed by Padmanabhan & Veiga-Lopez 2013) or rhesus monkeys (reviewed by Abbott et al 2013). Rhesus monkeys and sheep models provide promising perspectives and obvious advantages related to their intrinsic physiological characteristics which resemble those of humans.…”

Section: Introductionmentioning

confidence: 99%

Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment

et al. 2016

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The objective of our study was to investigate glycemic, oxidative/antioxidative and inflammatory status in letrozole and estradiol valerate induced polycystic ovarian syndrome (PCOS) models. Sixty adult female Wistar rats were divided into four groups: L (0.2 mg letrozole/0.5 ml carboxymethyl cellulose (CMC), daily for 30 days), the control group C L , EV (one i.m. injection of 5 mg EV/0.5 ml sesame oil) and its corresponding control group C EV . After 30 days, ovarian morphology was assessed through ultrasound, serum free testosterone was determined, and an oral glucose tolerance test was performed. Blood, muscle, liver and periovarian adipose tissue (POAT) were collected for oxidative/antioxidative and inflammatory status evaluation. Free testosterone was increased only in the L group, while fasting glycemia was higher in the EV group. Both L and EV led to a significantly decreased level of muscle malondialehyde (MDA) and liver glutathione peroxidase (GPx) activity, while in POAT, MDA level diminished and GPx activity increased. The only difference between the two protocols was in muscle, where after L administration, GPx activity was significantly lower. Implementation of both protocols resulted in an increased expression of pNFKB in muscle, liver and POAT. The expression of monocyte chemoattractant protein 1 (MCP1) increased in liver and POATafter L administration, while in the EV group, MCP1 and STAT3 decreased in POAT. Our study shows that both protocols are characterized by an inflammatory environment in the usually insulin resistant tissues of human PCOS, without generating oxidative stress. In addition, EV has mild metabolic effects and unexpected interference with MCP1 expression in POAT, which require further investigation.

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Rodent Models of Polycystic Ovary Syndrome: Phenotypic Presentation, Pathophysiology, and the Effects of Different Interventions

Cited by 55 publications

References 96 publications

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Effect of maternal PCOS and PCOS-like phenotype on the offspring's health

Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment

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