Androgen-induced epigenetic modulations in the ovary

In recent years, androgens have emerged as critical regulators of female reproduction and women’s health in general. While high levels of androgens in women are associated with polycystic ovary syndrome (PCOS), recent evidence suggests that a certain amount of direct androgen action through androgen receptor is also essential for normal ovarian function. Moreover, prenatal androgen exposure has been reported to cause developmental reprogramming of the fetus that manifests into adult pathologies, supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis. Therefore, it has become imperative to understand the underlying mechanism of androgen actions and its downstream effects under normal and pathophysiological conditions. Over the years, there has been a lot of studies on androgen receptor function as a transcriptional regulator in the nucleus as well as androgen-induced rapid extra-nuclear signaling. Conversely, new evidence suggests that androgen actions may also be mediated through epigenetic modulation involving both the nuclear and extra-nuclear androgen signaling. This review focuses on androgen-induced epigenetic modifications in female reproduction, specifically in the ovary, and discusses emerging concepts, latest perceptions, and highlight the areas that need further investigation.

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Subfertility in androgen-insensitive female mice is rescued by transgenic FSH

Reproduction Fertility and Development ◽

10.1071/rd16022 ◽

2017 ◽

Vol 29 (7) ◽

pp. 1426 ◽

Cited By ~ 2

Author(s):

K. A. Walters ◽

M. C. Edwards ◽

M. Jimenez ◽

D. J. Handelsman ◽

C. M. Allan

Keyword(s):

Androgen Receptor ◽

Litter Size ◽

Ovarian Function ◽

Reproductive Function ◽

Antral Follicle ◽

Female Fertility ◽

Wild Type ◽

Female Reproduction ◽

Androgen Insensitivity ◽

Female Mice

Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.

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Evolutionary origins of polycystic ovary syndrome: An environmental mismatch disorder

Evolution Medicine and Public Health ◽

10.1093/emph/eoz011 ◽

2019 ◽

Vol 2019 (1) ◽

pp. 50-63 ◽

Cited By ~ 5

Author(s):

Mia A Charifson ◽

Benjamin C Trumble

Keyword(s):

Polycystic Ovary Syndrome ◽

Ovarian Function ◽

Polycystic Ovary ◽

Severe Form ◽

Urban Environments ◽

Future Research ◽

Female Reproduction ◽

Ovary Syndrome ◽

High Prevalence ◽

Obesogenic Environments

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder and has important evolutionary implications for female reproduction and health. PCOS presents an interesting paradox, as it results in significant anovulation and potential sub-fecundity in industrialized populations, yet it has a surprisingly high prevalence and has a high heritability. In this review, we discuss an overview of PCOS, current diagnostic criteria, associated hormonal pathways and a review of proposed evolutionary hypotheses for the disorder. With a multifactorial etiology that includes ovarian function, metabolism, insulin signaling and multiple genetic risk alleles, PCOS is a complex disorder. We propose that PCOS is a mismatch between previously neutral genetic variants that evolved in physically active subsistence settings that have the potential to become harmful in sedentary industrialized environments. Sedentary obesogenic environments did not exist in ancestral times and exacerbate many of these pathways, resulting in the high prevalence and severity of PCOS today. Overall, the negative impacts of PCOS on reproductive success would likely have been minimal during most of human evolution and unlikely to generate strong selection. Future research and preventative measures should focus on these gene-environment interactions as a form of evolutionary mismatch, particularly in populations that are disproportionately affected by obesity and metabolic disorders. Lay Summary The most severe form of polycystic ovary syndrome (PCOS) is likely a result of interactions between genetic predispositions for PCOS and modern obesogenic environments. PCOS would likely have been less severe ancestrally and the fitness reducing effects of PCOS seen today are likely a novel product of sedentary, urban environments.

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IGF-1 Inhibits Apoptosis of Porcine Primary Granulosa Cell by Targeting Degradation of BimEL

International Journal of Molecular Sciences ◽

10.3390/ijms20215356 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5356 ◽

Cited By ~ 1

Author(s):

Ying Han ◽

Shumin Wang ◽

Yingzheng Wang ◽

Shenming Zeng

Keyword(s):

Growth Factor ◽

Granulosa Cell ◽

Granulosa Cells ◽

Ovarian Function ◽

Polycystic Ovary ◽

Annexin V ◽

Underlying Mechanism ◽

Ovary Syndrome ◽

Autophagy Flux ◽

Ovarian Dysplasia

Insulin-like growth factor-1 (IGF-1) is an intra-ovarian growth factor that plays important endocrine or paracrine roles during ovarian development. IGF-1 affects ovarian function and female fertility through reducing apoptosis of granulosa cells, yet the underlying mechanism remains poorly characterized. Here, we aimed to address these knowledge gaps using porcine primary granulosa cells and examining the anti-apoptotic mechanisms of IGF-1. IGF-1 prevented the granulosa cell from apoptosis, as shown by TUNEL and Annexin V/PI detection, and gained the anti-apoptotic index, the ratio of Bcl-2/Bax. This process was partly mediated by reducing the pro-apoptotic BimEL (Bcl-2 Interacting Mediator of Cell Death-Extra Long) protein level. Western blotting showed that IGF-1 promoted BimEL phosphorylation through activating p-ERK1/2, and that the proteasome system was responsible for degradation of phosphorylated BimEL. Meanwhile, IGF-1 enhanced the Beclin1 level and the rate of LC3 II/LC3 I, indicating that autophagy was induced by IGF-1. By blocking the proteolysis processes of both proteasome and autophagy flux with MG132 and chloroquine, respectively, the BimEL did not reduce and the phosphorylated BimEL protein accumulated, thereby indicating that both proteasome and autophagy pathways were involved in the degradation of BimEL stimulated by IGF-1. In conclusion, IGF-1 inhibited porcine primary granulosa cell apoptosis via degradation of pro-apoptotic BimEL. This study is critical for us to further understand the mechanisms of follicular survival and atresia regulated by IGF-1. Moreover, it provides a direction for the treatment of infertility caused by ovarian dysplasia, such as polycystic ovary syndrome and the improvement of assisted reproductive technology.

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AGEs-related dysfunctions in PCOS: evidence from animal and clinical research

Journal of Endocrinology ◽

10.1530/joe-21-0143 ◽

2021 ◽

Vol 251 (2) ◽

pp. R1-R9

Author(s):

Carla Tatone ◽

Giovanna Di Emidio ◽

Martina Placidi ◽

Giulia Rossi ◽

Stefania Ruggieri ◽

...

Keyword(s):

Polycystic Ovary ◽

Underlying Mechanism ◽

Experimental Models ◽

Reproductive Age ◽

Ovary Syndrome ◽

Innovative Strategies ◽

Downstream Effects ◽

Glycation End Products ◽

By Products

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder in women in their reproductive age. In recent years, the role of advanced glycation end products (AGEs) in PCOS has gained great attention. AGEs are highly reactive molecules that can be assumed by diet or endogenously synthesized as by-products of metabolic processes. AGE deposition increases with aging, hyperglycemia, insulin resistance, and glycotoxin-rich diet. Therefore, it has become imperative to understand the underlying mechanism of AGEs actions and its downstream effects in PCOS pathophysiology. By integrating evidence from human studies and experimental models, the present review points out that altered AGE deposition is a common feature in all PCOS phenotypes. Searching for possible mechanisms involved in the adaptive response against glycation injury in oocytes and ovaries, the role of SIRT1, the main member of the mammalian sirtuin family, has also recently emerged. Therefore, further studies based on anti-AGE interventions could be helpful in creating innovative strategies for counteracting PCOS and its effects on fertility.

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