A Hyperandrogenic Environment Causes Intrinsic Defects That Are Detrimental to Follicular Dynamics in a PCOS Mouse Model

Bertoldo, Michael J.; Caldwell, Aimee S L; Riepsamen, Angelique H; Lin, Dianliang; Gonzalez, Macarena B; Robker, Rebecca L.; Ledger, William; Gilchrist, Robert B.; Handelsman, David J.; Walters, Kirsty A

doi:10.1210/en.2018-00966

Cited by 40 publications

(23 citation statements)

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“…Our data show that the PCOS traits of acyclicity and anovulation can be rescued by a specific dietary macronutrient balance, supporting the use of dietary manipulation as a potential viable strategy to be used to assist in restoration of ovulatory dysfunction in women with PCOS. In agreement with previous studies 25,26,34 , ovulatory function is aberrant in the hyperandrogenic mouse model of PCOS as corpora lutea populations are diminished. However, ovulatory function was restored in PCOS females on a tightly defined intake range of protein, carbohydrate and fat, indicated by the presence of corpora lutea in their ovaries (8/35), which conclusively confirms the occurrence of recent ovulations.…”

Section: Discussionsupporting

confidence: 92%

“…The pattern of PCOS females being unable to regulate adiponectin and cholesterol across various diets, also extended to their inability to regulate serum glucose levels. In our study, as per our previous publications 26 , 34 , impaired glucose homeostasis was observed in PCOS females. This finding is consistent with studies in humans where women with PCOS have increased levels of steady state plasma glucose and fasting glucose compared to non-PCOS women 32 .…”

Section: Discussionsupporting

confidence: 90%

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Defining the impact of dietary macronutrient balance on PCOS traits

et al. 2020

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Lifestyle, mainly dietary, interventions are first-line treatment for women with polycystic ovary syndrome (PCOS), but the optimal diet remains undefined. We combined a hyperandrogenized PCOS mouse model with a systematic macronutrient approach, to elucidate the impact of dietary macronutrients on the development of PCOS. We identify that an optimum dietary macronutrient balance of a low protein, medium carbohydrate and fat diet can ameliorate key PCOS reproductive traits. However, PCOS mice display a hindered ability for their metabolic system to respond to diet variations, and varying macronutrient balance did not have a beneficial effect on the development of metabolic PCOS traits. We reveal that PCOS traits in a hyperandrogenic PCOS mouse model are ameliorated selectively by diet, with reproductive traits displaying greater sensitivity than metabolic traits to dietary macronutrient balance. Hence, providing evidence to support the development of evidence-based dietary interventions as a promising strategy for the treatment of PCOS, especially reproductive traits.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Defining the impact of dietary macronutrient balance on PCOS traits

et al. 2020

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“…While this model has been reported to not have a strong metabolic PCOS phenotype and may be most representative of the lean PCOS phenotype, it has been reported that adipocyte hypertrophy and impaired glucose tolerance are still present, inferring that metabolic function is still aberrant (Roland et al 2010, Caldwell et al 2014. Early postnatal DHT exposure induces a robust mouse PCOS model with a wide range of PCOS traits including irregular cycles, ovulatory dysfunction, PCOM, adiposity, adipocyte hypertrophy, dyslipidemia, hepatic steatosis and altered glucose and insulin homeostasis (Caldwell et al 2014, Bertoldo et al 2019. In sheep and nonhuman primate PCOS models, prenatal exposure to testosterone generates the closest simulation to the clinical features of PCOS, with both models also displaying a breadth of endocrine, reproductive and metabolic PCOS traits, including irregular cycles, oligo-or anovulation, PCOM, LH hypersecretion, lipid abnormalities and insulin resistance (Padmanabhan & Veiga-Lopez 2013, Abbott et al 2016.…”

Section: Evidence From Hyperandrogenized Preclinical Animal Pcos Modementioning

confidence: 99%

Androgens and ovarian function: translation from basic discovery research to clinical impact

Walters

Paris

Aflatounian

et al. 2019

Journal of Endocrinology

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In the last decade, it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar-knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.

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“…The different effects observed between treatments are summarised in Figure 1. However, interventions that reduce levels of excess androgens may still not be effective in patients desiring children as it appears hyperandrogenism may impart adverse legacies on fertility, even after follicles and oocytes have been removed from the hyperandrogenic environment [31].…”

Section: Clinical Targeting Of Androgen Excess—potential For Mitigmentioning

confidence: 99%

The Mechanism of Androgen Actions in PCOS Etiology

Paris

Bertoldo

2019

Medical Sciences

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Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-age women. By comprising reproductive, endocrine, metabolic and psychological features—the cause of PCOS is still unknown. Consequently, there is no cure, and management is persistently suboptimal as it depends on the ad hoc management of symptoms only. Recently it has been revealed that androgens have an important role in regulating female fertility. Androgen actions are facilitated via the androgen receptor (AR) and transgenic Ar knockout mouse models have established that AR-mediated androgen actions have a part in regulating female fertility and ovarian function. Considerable evidence from human and animal studies currently reinforces the hypothesis that androgens in excess, working via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). Identifying and confirming the locations of AR-mediated actions and the molecular mechanisms involved in the development of PCOS is critical to provide the knowledge required for the future development of innovative, mechanism-based interventions for the treatment of PCOS. This review summarises fundamental scientific discoveries that have improved our knowledge of androgen actions in PCOS etiology and how this may form the future development of effective methods to reduce symptoms in patients with PCOS.

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A Hyperandrogenic Environment Causes Intrinsic Defects That Are Detrimental to Follicular Dynamics in a PCOS Mouse Model

Cited by 40 publications

References 60 publications

Defining the impact of dietary macronutrient balance on PCOS traits

Defining the impact of dietary macronutrient balance on PCOS traits

Androgens and ovarian function: translation from basic discovery research to clinical impact

The Mechanism of Androgen Actions in PCOS Etiology

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