Altered, Transcription of genes by AR leads to Reduced granulosa cell proliferation

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, C_max); 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.

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).