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Altered, Transcription of genes by AR leads to Reduced granulosa cell proliferation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Androgen receptor (AR) antagonism leading to decreased fertility in females||adjacent||Moderate||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|During development and at adulthood||High|
Key Event Relationship Description
Decreased transcription of genes that are downstream of AR activation leads to reduced granulosa cell proliferation of the early-stage gonadotropin-independent ovarian follicles. Therefore, the follicle growth to the antral stage is decreased.
Evidence Supporting this KER
AR is a ligand-activated nuclear transcription factor expressed in the ovaries across mammalian species, including humans(Gervásio et al., 2014). During the gonadotropin independent follicular stage, AR activation is hypothesized to promote follicle growth, whereas in later stages it has been shown to inhibit growth and induce apoptosis(Franks and Hardy, 2018; Harlow et al., 1988). In humans, both mRNA and protein of AR are present in the oocyte, stroma cells, theca cells, but most prominently in granulosa cells of small antral follicles(Gervásio et al., 2014; Jeppesen et al., 2012).
In the mouse ovary, AR mRNA and protein are present in the oocyte, theca, and granulosa cells(Gill et al., 2004; Hirai et al., 1994; Szoltys and Slomczynska, 2000; Tetsuka and Hillier, 1996; Tetsuka et al., 1995). In the cow and sheep ovary, AR mRNA is present in granulosa and theca cells, and most prominently in granulosa of antral and early antral follicles(Hampton et al., 2004; Juengel et al., 2006). In the pig ovary, AR mRNA is mainly expressed in the granulosa cells until the antral stage(Cárdenas and Pope, 2002; Slomczynska et al., 2001). In the monkey ovary, AR mRNA and protein are present in theca, but mainly granulosa cells of antral and early antral follicles(Hillier et al., 1997; Weil et al., 1998).
In human follicles, the expression of the AR transcript is observed after the primordial stage and is most pronounced during the small antral stage(Rice et al., 2007). Throughout early folliculogenesis, AR expression controls transcription of genes involved in promoting growth and differentiation of granulosa cells and formation of antrum(Gervásio et al., 2014). Genes under the control of AR that are involved in these processes include Kit ligand (KITL), Bone morphogenetic protein 15 (BMP15), and Hepatocyte growth factor (HGF)(Astapova et al., 2019; Prizant et al., 2014).
In the monkey ovary, high levels of AR mRNA correlates with high levels of granulosa cell proliferation(Vendola et al., 1998; Weil et al., 1998) Increased AR activation is associated with increased follicle growth and increased granulosa cell proliferation in small antral rat follicles, supporting the important role for AR during this developmental stage(Lim et al., 2017a).
AR may mediate early follicle growth through FSHR, supported by studies correlating mRNA levels of AR and FSHR in granulosa cells of small antral follicles(Nielsen et al., 2011,,Weil et al., 1999). In mice, FSH-mediated in vitro follicle growth is increased by androgens, suggesting that androgens through AR may act synergistically with FSHR, which in turn increases follicle growth to antral follicles(Sen et al., 2014).
It is also hypothesized that FSHR activation through AR leads to increased AMH expression in granulosa cells of primary to small antral follicles(Lin et al., 2021). In turn, elevated levels of AMH lead to inhibition of FSH-induced aromatase activity, resulting in higher androgen levels that inhibit further follicular growth.
AR activation has been associated with Insulin-like Growth Factor 1 (IGF1) and Insulin-like Growth Factor 1 Receptor (IGFR1) and other key factors of the IGF signaling pathway, which is essential for granulosa growth and differentiation(Baumgarten et al., 2014),(Vendola et al., 1999). In human granulosa cells of primordial and primary follicles, AR and IGF-related factors are highly enriched at the transcriptional level(Steffensen et al., 2018).
AR activation affects the level of connexins, proteins that form gap junctions between granulosa cells and the oocyte and hence regulate intracellular communication; a prerequisite for folliculogenesis(Kamal et al., 2020).
In humans, the importance of AR in follicular growth becomes evident with the beneficial effects of androgens in assisted reproductive technology outcomes(Bosdou et al., 2012; Casson et al., 2000; Fábregues et al., 2009; Kim et al., 2011, 2014; Nagels et al., 2015; Noventa et al., 2019; Petya Andreeva, Ivelina Oprova, Luboslava Valkova, Petya Chaveeva, Ivanka Dimova, 2020). Although the mechanism remains elusive, it has been suggested that androgen priming of women seeking fertility treatment promotes follicle growth resulting in an increase in the FSH-sensitive follicle pool(Hu et al., 2017). Gene expression studies in human small antral follicles reveal significant association of AR and FSHR levels, suggesting that the increase in follicle growth could be mediated through regulating AR transcription in granulosa cells(Hu et al., 2017; Nielsen et al., 2011). Epidemiological studies have shown that upon androgen pretreatment, increase in the number of antral follicles and mean follicular diameter were observed(Balasch et al., 2006; Kim et al., 2011). This increase supports the hypothesis that androgen receptor signaling is important for early follicle growth. Studies observing no effects upon androgen pre-treatment claim that dose and duration of the selected androgen might lead to contradicting results(Yeung et al., 2014).
Hypoandrogenism provides further evidence for an important role for androgen actions in human follicle development. Lower levels of DHEA or testosterone have been associated with women that have diminished ovarian reserve or premature ovarian aging(Gleicher et al., 2013). In the case of untreated primary adrenal insufficiency, the androgen deficient patient exhibit significantly reduced fertility(Erichsen et al., 2010).
Conclusions on the androgen significance can also be drawn from clinical evidence where women are exposed to an androgen excess. Hyperandrogenism in the case of congenital adrenal hyperplasia and exogenous androgen treatments in trans males lead to polycystic ovaries(Walters and Handelsman, 2018). This indicated that the androgens stimulate early follicle growth and inhibit further maturation(Walters and Handelsman, 2018). In polycystic ovarian syndrome, a syndrome characterized by accumulation of small antral follicles in the ovarian cortex, a plausible cause for this morphology is hyperandrogenaemia(Balen et al., 2003; Lebbe and Woodruff, 2013).
Uncertainties and Inconsistencies
Genomic and non-genomic effects are not distinguished in the studies included in the KER analysis. Hence, it cannot be concluded that all observations are solely due to directly perturbed transcription. However, since AR transcribes genes necessary for early folliculogenesis (KITLG, BMP15, HGF), it is reasonable to assume that genomic mechanisms are involved.
Other uncertainties to consider: different anti-androgenic compounds have different effects on the AR (e.g. different IC50, Cmax); compounds that are anti-androgenic may also affect other mechanisms/modalities; downstream effects of perturbed AR transcriptional function might depend on the duration of exposure as well as the developmental stage of the follicles. In humans, effects can be inconclusive since a part of the population can have androgen-related conditions such as polycystic ovary syndrome (PCOS)(Gleicher et al., 2011).
The nature of the response-response relationship between decreased AR activation and reduced granulosa cell proliferation in the early stage of follicular development is not clear. Some of the aforementioned studies claim the effects were dose-dependent; however, the limited number of concentrations tested prevents a solid conclusion(Murray et al., 1998; Wang et al., 2001; Yang and Fortune, 2006). Therefore, at present, the quantitative understanding of this KER is rated ‘low’.
Studies included in establishing this KER exhibit observed changes in vitro at 24h in pig granulosa cells, and in vivo studies after 48h in rats(Hickey et al., 2004, 2005; Kumari et al., 1978). The conclusion that can presently be drawn is that the approximate timescale of the changes in KEdownstream relative to changes in KEupstream is less than 48h. However, the species differences between the time scales of folliculogenesis need to be taken into consideration in order for human extrapolations to be made.
Known modulating factors
The E3 ubiquitin ligase protein Ring Finger Protein 6 (RNF6) regulates AR levels in granulosa cells through polyubiquitination and AR transcriptional activity for KITLG expression in small antral follicles(Lim et al., 2017b, 2017a).
Epidermal growth factor receptor (EGFR) may mediate the androgen-induced granulosa cell proliferation(Franks and Hardy, 2018).
Sixteen different mutations of the AR gene (Xq11.2-q12) that cause androgen insensitivity syndrome have been identified(Jiang et al., 2020).
The number of CAG repeats on the N-terminal domain of the AR has been associated with effects on fertility and ovarian reserve(Hickey et al., 2002; Lledo et al., 2014).
Known Feedforward/Feedback loops influencing this KER
Activated AR can transcriptionally regulate its own expression through a negative feedback loop(Gelmann, 2002). However, in granulosa cells of monkey ovaries, AR was shown to have the opposite effect, thus creating an autocrine positive feedback(Weil et al., 1998). More studies are needed to understand when AR regulation of its own expression is positive or negative.
During the early stages of folliculogenesis, mainly from the secondary to the small antral stage, activated AR can induce FSH activities in granulosa cells and promote granulosa cell differentiation and follicle maturation, even though follicles are still not gonadotropin-dependent(Gleicher et al., 2011). These activities include changes in androgen metabolism due to altered expression of steroidogenic enzymes. Therefore, it has been suggested that androgens can bind to the AR to establish a loop between activated AR and FSH action(Gleicher et al., 2011; Lenie and Smitz, 2009).
A positive feedback loop connecting activated AR and AMH through FSHR is also hypothesized. Activated AR could lead to increased expression of AMH through FSHR activation, resulting in inhibition of FSH-induced aromatase, ultimately increasing levels of androgens and AR activation(Dewailly et al., 2016). Typically, elevated levels of androgens, for instance in transgender males and PCOS patients, correlate with increased levels of AMH, however, contradictory results exist connecting elevated androgen or FSH levels to reduced AMH(Caanen et al., 2015; Li et al., 2011).
There is also evidence of an intra-follicular feedback loop that regulates steroidogenesis during the secondary follicle stage, causing downregulation of androgen synthesis upon exogenous androgen exposure and upregulation upon androgen receptor antagonism(Lebbe et al., 2017).
As mentioned, genes involved in early folliculogenesis like KITLG and HGF are under the control of AR. Those two genes have been shown to create a positive feedback loop in mice, by increasing the expression levels of each other(Guglielmo et al., 2011).
Domain of Applicability
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