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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||Terje Svingen (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 Do not cite|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 to androgen receptor activation leads to reduced granulosa cell proliferation of the gonadotropin-independent ovarian follicles. Therefore, the follicle growth to the antral stage is attenuated.
Evidence Supporting this KER
AR is a ligand-activated nuclear transcription factor expressed in the ovaries across mammalian species, including humans (Gervásio, Bernuci, Silva-de-Sá, & Rosa-e-Silva, 2014). In humans, both mRNA and protein of AR are present in the oocyte, stroma cells, theca cells, but most prominently in granulosa cells of preantral follicles (Gervásio et al., 2014).
In the rodent ovary, AR mRNA and protein are present in the oocyte, theca and granulosa cells (Gill, Jamnongjit, & Hammes, 2004; Hirai, Hirata, Osada, Hagihara, & Kato, 1994; Szoltys & Slomczynska, 2000; Tetsuka & Hillier, 1996; Tetsuka et al., 1995). In the bovine and ovine ovary, AR mRNA is present in granulosa and theca cells, and most prominently in granulosa of preantral and antral follicles (Hampton, Manikkam, Lubahn, Smith, & Garverick, 2004; Juengel, Heath, Quirke, & McNatty, 2006). In the porcine ovary, AR mRNA is mainly expressed in the granulosa cells until the antral stage (Cárdenas & Pope, 2002; Slomczynska, Duda, & Sl zak, 2001). In the non-human primate ovary, AR mRNA and protein is present in theca, but mainly granulosa cells of preantral and antral follicles (Hillier, Tetsuka, & Fraser, 1997; S. J. 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 preantral stage (Rice, Ojha, Whitehead, & Mason, 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, Minor, & Hammes, 2019; Prizant, Gleicher, & Sen, 2014).
In the monkey ovary, high levels of AR mRNA correlates with high levels of granulosa cell proliferation (K. A. Vendola, Zhou, Adesanya, Weil, & Bondy, 1998; S. J. Weil et al., 1998) Increased AR activation is associated with increased follicle growth and increased granulosa cell proliferation in preantral rat follicles (Lim, Han, Lee, & Tsang, 2017), supporting the important role for AR during this developmental stage.
AR may mediate preantral 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; S. Weil, Vendola, Zhou, & Bondy, 1999). In mice, FSH-mediated in vitro follicle growth is increased by androgens (Sen et al., 2014), suggesting that androgens through AR may act synergistically with FSHR, which in turn increases preantral follicle growth.
AR activation has been associated with IGF-1 and IGFR-1 and other key factors of the IGF signaling pathway, which is essential for granulosa growth and differentiation (Baumgarten et al., 2014; K. 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, Ernst, Amoushahi, Ernst, & Lykke-Hartmann, 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, Ibrahim, & Mokhtar, 2020).
In humans, the importance of AR in follicular growth becomes evident with the beneficial effects of androgens in IVF outcomes (Bosdou et al., 2012; Casson, Lindsay, Pisarska, Carson, & Buster, 2000; Fábregues et al., 2009; C.-H. Kim et al., 2014; C. H. Kim, Howles, & Lee, 2011; 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 a significant association of AR and FSHR levels, suggesting that the increase in follicle growth could be mediated through regulating androgen receptor 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; C. H. 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).
Further human evidence that supports the importance of androgen actions in follicle development are cases of hypoandrogenism. Lower levels of DHEA or TT have been associated with women that have diminished ovarian reserve or premature ovarian aging (Gleicher et al., 2013). In the case of primary adrenal insufficiency, androgen deficient patients exhibit significantly reduced fertility (Erichsen, Husebye, Michelsen, Dahl, & Løvås, 2010).
Conclusions on the androgen significance can also be drawn from clinical evidence where women are exposed to androgen excess. Hyperandrogenism in the case of congenital adrenal hyperplasia and exogenous androgen treatments in trans males leads to polycystic ovaries (K. A. Walters & Handelsman, 2018). This indicated that the androgens stimulate early follicle growth and inhibit further maturation (K. A. Walters & 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, Laven, Tan, & Dewailly, 2003; Lebbe & 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 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 affect also 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, Weghofer, & Barad, 2011).
The nature of the response-response relationship between decreased AR activation and reduced granulosa cell proliferation 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 & Fortune, 2006). Therefore, at present, the quantitative understanding of this KER is rated as low.
In vitro studies included in establishing this KER in the present report exhibit observed changes at 24h, and in vivo studies after 48h (T. E. Hickey et al., 2005, 2004; Kumari et al., 1978). The conclusion that can be drawn at present is that the approximate timescale of the changes in KEdownstream relative to changes in KEupstream is less than 48h.
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 preantral follicles (Lim, Han, et al., 2017; Lim, Lima, Salehi, Lee, & Tsang, 2017). Epidermal growth factor receptor (EGFR) may mediate the androgen-induced granulosa cell proliferation (Franks & 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 gene has been associated with effects on fertility and ovarian reserve (T. Hickey, Chandy, & Norman, 2002; Lledo et al., 2014).
Known Feedforward/Feedback loops influencing this KER
Regulations in the endocrine system are characterized by many positive and negative feedback loops. 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 (S. J. Weil et al., 1998). More studies are needed to understand when AR regulation of its own expression is positive and negative.
During the early stages of folliculogenesis, mainly from the preantral 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 & Smitz, 2009).
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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