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Darolutamide (Nubeqa) is an antiandrogen. Like bicalutamide and enzalutamide, it is a nonsteroidal full androgen receptor antagonist (NSAA). Unlike other NSAAs, it does not cross the blood-brain barrier, and thus does not increase testosterone levels or cause seizues (a side-effect of enzalutamide).
Most NSAAs increase testosterone levels, including bicalutamide and enzalutamide. This is because they block the negative feedback of androgens in the hypothalamus and pituitary gland, resulting in increased LH and FSH production in the pituitary gland and thus increased testosterone production in the testes (see HPG axis for more details). Because darolutamide does not cross the blood-brain barrier, it does not block androgens from binding to androgen receptors in the hypothalamus and pituitary gland, so negative feedback is maintained, resulting in no increase in testosterone (and presumably no increase in LH or FSH).
Potential applications to trans health
PLEASE DON'T TRY THIS AT HOME! This is highly experimental and incredibly dangerous stuff.
Simpler dosing than bicalutamide when taken without estradiol (AMAB)
Some trans women and non-binary people dislike spironolactone and cyproterone acetate due to their side effects. As a result, some people are starting to use bicalutamide instead. However, this comes with a downside: in those taking bicalutamide without estradiol or taking it with a SERM, testosterone levels are greatly increased, making it difficult to choose the correct dose and potentially unsafe (see bicalutamide and raloxifene for details on that combination). As darolutamide does not increase testosterone levels, this would likely not be a concern for darolutamide.
Erectile function (AMAB)
Some AMAB trans people have reported that they maintained erectile function while on bicalutamide, but not on spironolactone or cyproterone acetate. While erectile function is not desired by all trans people, it is desirable to some. Because darolutamide does not cross the blood-brain barrier and has a similar mechanism of action as bicalutamide, it is plausible that people taking darolutamide would maintain erectile function.
Mental effects of testosterone without physical changes (AFAB)
Testosterone and its metabolites are responsible for certain behavioural/mental changes, such as increased libido. Someone who desires these mental effects without masculinizing their body might choose to take darolutamide with testosterone. Testosterone would provide the desired mental effects while darolutamide would prevent testosterone from masculinizing the body. Note that this regimen may result in osteoporosis and other side effects of sex hormone deprivation. Those could potentially be remedied with a SERM.
Demasculinization without mental changes (AMAB)
A general discomfort that is not attributable to the body/physical appearance or social treatment is sometimes called mental dysphoria. Some trans people report that this form of gender dysphoria is alleviated by hormone replacement therapy even before it causes any changes to physical appearance. It is unclear if this is placebo or if it is a real effect (e.g., due to changes in neurosteroid levels). Some trans people do not experience mental dysphoria, and therefore wish to avoid medications that may alter their mental state. Darolutamide could be a suitable choice for them, as it does not cross the blood-brain barrier or cause changes in hormone levels.
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