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Decrease, testosterone levels leads to Decrease, DHT level
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring||adjacent||Moderate||Low||Terje Svingen (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
|During development and at adulthood||High|
Key Event Relationship Description
Testosterone (T) and dihydrotestosterone (DHT) are androgens that are involved in numerous developmental and functional processes across animal taxa. In vertebrates, testosterone can be aromatized into estrogens catalyzed by the enzyme aromatase (CYP19) or be metabolized to DHT by the enzyme 5α-reductase (Azzouni et al., 2012; Naamneh Elzenaty et al., 2022; Swerdloff et al., 2017). Both T and DHT binds to the androgen receptor (AR), but with different affinities. DHT has a higher affinity for the AR than T. DHT also has a longer half-life and slower dissociation rate than T and cannot be aromatized into estrogens (Gerald & Raj, 2022; Naamneh Elzenaty et al., 2022; Swerdloff et al., 2017).
During mammalian development, T is primarily produced by the fetal testes and is needed for differentiation of the Wolffian ducts, the epididymis, and the ejaculatory duct. In pubertal and adult mammals, T is produced by the testes, the ovaries (although at a much lower level), and the adrenal glands (Ogino et al., 2011; Rey, 2021). In peripheral tissues (i.e. relative to the testes), DHT is converted from T by 5α-reductase to induce the differentiation of the urogenital sinus and genital tubercle to form the prostate, penis, scrotum and urethra (Swerdloff et al., 2017). Both androgens are essential for masculinization, sexual development, and fertility.
Evidence Collection Strategy
This KER is considered canonical knowledge and supporting literature was mainly sourced from key review articles from the open literature.
Evidence Supporting this KER
The biological plausibility for this KER is considered high
It is well established that DHT is synthesized from circulating T. 5α-reductase is the enzyme responsible for the conversion of T into DHT. Multiple isoforms of this enzyme are expressed in different tissues. Expression of 5α-reductase in peripheral tissues dictates where DHT will be formed from circulating T (Azzouni et al., 2012; Swerdloff et al., 2017).
Since T can be converted to DHT, it stands to reason that a lack of T can lead to a lack of DHT. Therefore, if there is a marked reduction in the availability of T, it can be surmised that DHT levels are consequently affected. However, to what extent T needs to be diminished in tissues before there is a functionally relevant decrease in DHT is largely unknown. In addition, the quantitative relationship between substrate (T) availability and levels of synthesized DHT is not well characterized in tissues in vivo. Notably, DHT can be produced via other steroid intermediates through the ‘backdoor pathway’ in mammals such as marsupials and humans (Renfree & Shaw 2023).
Uncertainties and Inconsistencies
The levels of T do not always reflect the levels of DHT. T is also converted to estradiol (Naamneh Elzenaty et al., 2022). Therefore, the decrease in T may lead to a decrease in estradiol while DHT levels remain unchanged.
Several studies have shown the existence of an alternative (‘backdoor’) pathway for DHT synthesis that is independent of T in marsupials and humans, but not in rodents (Marilyn B. Renfree et al., 1995). Instead of proceeding through the canonical pathway, progesterone or 17-OH progesterone, can be converted into allopregnanolone and 17OH-allopregnanolone. 17-OH allopregnanolone is then converted into androsterone leading to androstanediol that can finally be oxidized to produce DHT. Therefore, through this pathway, DHT can be synthesized without the presence of T (Auchus, 2004; Miller & Auchus, 2019).
Known modulating factors
The response-response relationship is not clearly established.
Different time scales have been observed in the studies above, the shortest one found being 48h. With Ibuprofen treatment, a decrease in both testosterone and DHT was observed after 48h in human fetal explant’s exposure media (Ben Maamar et al., 2017). However, it is not evident that this effect is direct and only due to a decrease in T.
Known Feedforward/Feedback loops influencing this KER
Activity of 5α-reductase type 1 and 2: The activity of this enzyme determines how much T is converted into DHT. There are two isomers, with type 2 being the primary isomer expressed in DHT target organs. In deficiencies of this enzyme, there are studies that observe maintained DHT levels. This indicates that the type 1 enzyme can take over if needed (Azzouni et al., 2012).
Conversion of T to estradiol (E2): Aromatase can convert T into estrogens. The activity of this enzyme may push towards a decrease of T levels and an increase in estrogen levels without necessarily affecting DHT levels (Naamneh Elzenaty et al., 2022).
Hypothalamus-pituitary-gonadal (HPG) axis: Like most sex steroids, T production is controlled by the HPG axis during puberty and adulthood, but also during certain periods of development. For humans, the HPG axis is active following birth between 1-3 months in both males and females. Increase of LH and FSH are observed in infants up to 4-6months old. This stage is also known as the minipuberty (Lanciotti et al., 2018; Renault et al., 2020). Once GnRH is released from the hypothalamus, the pituitary gland secretes LH in pulses, which then stimulates the cells in the testes to produce T. A negative feedback loop can then occur, where testosterone then inhibits the release of GnRH and LH, in turn slowing down T production (Gerald & Raj, 2022; Naamneh Elzenaty et al., 2022; Nef & Parada, 2000).
Domain of Applicability
T and DHT are androgens present in all vertebrates. They play a role in development and fertility in both males and females (Ogino et al., 2011; Prizant et al., 2014; Rey, 2021; Swerdloff et al., 2017). All tissues expressing 5α-reductase are applicable to this KER (Azzouni et al., 2012).
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