By Aly W. | First published December 16, 2018 | Last modified October 5, 2020
We don’t really know. Dose-ranging studies of bicalutamide haven’t been conducted outside of prostate cancer so we’re not really sure what the appropriate dosages are for transfeminine people. Based on its mechanism of action as a competitive androgen receptor blocker though, the dosage of bicalutamide can be assumed to be fundamentally dependent on testosterone levels. But we don’t really know how much bicalutamide is needed to block a given amount of testosterone. In any case, a common dosage of bicalutamide in transfeminine people is 50 mg/day. This dosage is commonly recommended for transfeminine people in the literature and was notably used in this study of bicalutamide monotherapy as a puberty blocker in adolescent transgender girls. There is indication that this dosage of bicalutamide is too low to be fully effective for use as a monotherapy however. If I had to make an educated guess, I would assume that 12.5 to 50 mg/day bicalutamide would be appropriate for transfeminine people in the context of low testosterone levels (<200 ng/dL) whereas 150 to 300 mg/day bicalutamide would be appropriate as a monotherapy in the context of high testosterone levels (>600 ng/dL). (Note that these testosterone levels are for post-introduction of bicalutamide.) See the article here for some additional although somewhat dated discussion on bicalutamide dosage.
Q2: Is Bicalutamide a Stronger Antiandrogen than Spironolactone or Cyproterone Acetate? What are the Equivalent Dosages Between Them?
Yes, although the answer is somewhat nuanced. The available data from both animal and human studies indicate that bicalutamide is a significantly more potent androgen receptor blocker than cyproterone acetate and a substantially more potent androgen receptor blocker than spironolactone. Whereas spironolactone is suitable for blocking the low androgen levels in women (e.g., ≤50 ng/dL), bicalutamide can block much higher male-range testosterone levels (e.g., >300 ng/dL) at sufficient doses. However, cyproterone acetate works as an antiandrogen not only by blocking the androgen receptor but also by suppressing testosterone production by the gonads. In fact, this is its main or sole mechanism of action at the low doses that are taken by many transfeminine people today (Aly W., 2019). The strong testosterone suppression that occurs with estrogen plus cyproterone acetate makes cyproterone acetate a more potent antiandrogen than bicalutamide. Studies are mixed as to whether spironolactone decreases testosterone levels or not, with some finding that it does and others finding that it doesn’t (Aly W., 2018; Aly W., 2020). Due to a lack of comparative studies and comparable measured data in humans, we don’t know what the precise equivalent dosages of bicalutamide, spironolactone, and cyproterone acetate are in terms of androgen receptor blockade or general antiandrogenic strength.
Bicalutamide has a very long half-life of about 6 days after a single dose and of about 7 to 10 days after a dose following continuous administration. In other words, it takes 6 to 10 days for bicalutamide levels to decrease by 50%. Because of this, bicalutamide does not necessarily have to be taken every day, and can be taken as little as once every few days or even as little as once a week depending on the particular circumstances. However, if bicalutamide is taken less often than once a day, the dose per intake should be increased accordingly to compensate for the less frequent administration and hence to maintain the same total dosage. Clinical dosages of bicalutamide have already taken into account the long half-life of the medication and were selected to be the lowest effective dosages.
Yes and no. Because of its very long half-life, bicalutamide slowly and gradually builds up in the system upon initiation of treatment. Steady-state levels of bicalutamide in which no further increase in concentrations occurs are achieved after 4 to 12 weeks of continuous daily administration. However, progression towards steady-state levels is a logarithmic curve. In other words, levels increase very rapidly at first and slowly later on. Studies have found that roughly 50% of steady state levels are reached after just 1 week of administration and around 80 to 90% of steady state levels after 3 to 4 weeks of administration. See this graph.
Bicalutamide acts as a selective antagonist of the androgen receptor (AR), the main biological target of androgens like testosterone and dihydrotestosterone (DHT). It works by directly binding to the AR without causing activation of the receptor, thereby displacing androgens from the receptor and preventing them from activating it. Unlike certain other antiandrogens, such as spironolactone and cyproterone acetate, bicalutamide does not interact with other steroid-hormonal targets, which makes it a safer medication with fewer side effects. It does not work by lowering testosterone levels, which is also in contrast to other antiandrogens.
Yes, bicalutamide blocks both testosterone and dihydrotestosterone (DHT). They are both androgens, and hence are agonists of the same biological target, the androgen receptor. DHT is just several-fold more potent as an agonist of the androgen receptor than testosterone. Bicalutamide binds to the androgen receptor and blocks both testosterone and DHT from exerting their actions and hence producing their androgenic effects.
Bicalutamide given alone increases testosterone levels in gonadally intact cisgender men and transfeminine people. This is due to loss of negative feedback by androgens via the androgen receptor on the hypothalamic–pituitary–gonadal (HPG) axis and hence on the testes. The body attempts to upregulate testosterone production to compensate for the low androgen receptor signaling. Bicalutamide maximally increases testosterone levels by about 1.5- to 2-fold at sufficiently high doses. In men with prostate cancer with baseline testosterone levels of 400 ng/dL, bicalutamide monotherapy usually increases testosterone levels to around 600 ng/dL.
The increase in testosterone levels caused by bicalutamide does not occur in cisgender women, in gonadectomized cisgender men and transfeminine people, in those taking a GnRH agonist or antagonist, or, most relevantly, in anyone taking sufficient doses of an estrogen and/or progestogen. The reason for this in the case of GnRH modulators, estrogens, and progestogens is because they’re antigonadotropins and substitute for androgens in maintaining negative feedback on the HPG axis. Since most transfeminine people take an estrogen, increased testosterone levels with bicalutamide will not occur and should not be of concern (it takes only a small amount of estrogen to provide a high degree of negative feedback on the HPG axis). Bicalutamide has no influence on levels of adrenally derived androgens regardless of gonadal status. See here for more information on the effects and mechanics of bicalutamide on hormone levels.
The increase in testosterone levels with bicalutamide monotherapy will never exceed the antiandrogenic actions of bicalutamide in terms of androgen receptor activation, as upregulation of testosterone production is merely a compensatory/homeostatic effect to make up for an apparent deficit. In other words, bicalutamide will not increase testosterone levels more than it can block them. The same applies to DHT. See here for some discussion on this topic.
Estradiol is synthesized in the body from testosterone via an enzyme known as aromatase. Because bicalutamide increases testosterone levels when used by itself in gonadally intact people assigned male at birth, it also increases estradiol levels in this context. Estradiol levels are increased with bicalutamide monotherapy by up to 1.5- to 2.5-fold. In men with prostate cancer and testosterone levels of 600 ng/dL on bicalutamide monotherapy, estradiol levels range from 30 to 50 pg/mL. They may be higher in younger individuals with higher testosterone levels.
As a result of increased estradiol levels and blockade of androgens, bicalutamide monotherapy has feminizing effects in addition to demasculinizing effects and can produce breast development as well as all other aspects of feminization. This is analogous to women with complete androgen insensitivity syndrome (CAIS), who have a defective androgen receptor with similarly increased testosterone and estradiol levels and experience complete feminization and breast development.
Bicalutamide readily crosses the blood–brain barrier and blocks the androgen receptor in the brain, and by extension inhibits the mental/cognitive effects of androgens. It was originally thought that this was not the case, based on animal studies, but clinical studies revealed differences between the animal species studied and humans in that bicalutamide demonstrates prominent and measurable central effects in humans even at low doses (e.g., a significant increase in luteinizing hormone and testosterone levels at a dosage as low as 10 mg/day). It should be noted that bicalutamide given alone has minimal effects on sex drive/function in both women and men, but that this is not due to a failure of bicalutamide to enter the brain or block androgen-receptor signaling in this part of the body. See here for more information on the topic of bicalutamide and brain entry; second paragraph.
Bicalutamide and other selective androgen receptor antagonists given by themselves have minimal to no influence on sexual desire or function even at high dosages, both in men and in women. This is in spite of the fact that these antiandrogens readily cross into the brain and block the androgen receptor in this part of the body. The reasons for the minimal influence on sexual desire and function of selective androgen receptor antagonists have not been fully elucidated. However, it appears that it may be at least partially because metabolites of androgens such as estrogens and/or neurosteroids are involved in the stimulatory effects of androgens on sexual desire and function. Since bicalutamide and related antiandrogens by themselves do not lower testosterone levels, they do not lower levels of these metabolites, and this may contribute to the preservation of sexual desire and function by such antiandrogens. In any case, most transfeminine people also take an estrogen and/or a progestogen, and these medications strongly suppress testosterone levels. Suppression of testosterone levels (e.g., with cyproterone acetate, other progestogens, GnRH modulators, and estrogens) is well-known to markedly impair sexual desire and function, so sexual desire and function will usually be diminished in transfeminine people regardless of whether they are taking bicalutamide or not. See here and here for more information on the topic of bicalutamide and sexual desire and function.
Bicalutamide and other selective androgen receptor antagonists given by themselves appear to have minimal or no influence on spermatogenesis in the testes and hence on fertility. In animals given such antiandrogens, only minimal or partial reduction in sperm quality is observed. In addition, testicular morphology and spermatogenesis are normal in men treated with bicalutamide alone even at high doses for years. This appears to be because selective androgen receptor antagonists do not suppress gonadal testosterone production, and because testosterone levels in the testes are extremely high (up to 200-fold greater than in the circulation); it is thought that these antiandrogens are unable to effectively compete for and block the androgen receptor in this sole part of the body, thereby preserving spermatogenesis. However, actual ejaculated sperm quality and fertility have never been assessed in humans with bicalutamide; it is possible that bicalutamide could interfere with late sperm maturation and transport in the epididymides and/or vas deferens, which are extratesticular and where androgen levels are far lower (indeed, this might account for the minimal to partial reduction in sperm quality observed in animals). In addition, estrogens, progestogens, and GnRH modulators all strongly suppress gonadal testosterone production and markedly impair spermatogenesis and fertility, so fertility will usually be diminished or abolished in transfeminine people regardless of whether they are taking bicalutamide or not. See here for more information on the topic of bicalutamide and fertility.
Yes, it is still useful. Bicalutamide does not suppress testosterone levels and instead actually increases them when it is used by itself. As such, testosterone levels cannot be used as a way of gauging the antiandrogenic effects of bicalutamide on its own, similarly to spironolactone but in contrast to cyproterone acetate, other progestogens, and estrogens (which all act in large part by decreasing testosterone levels). However, the antiandrogenic effectiveness of bicalutamide is dependent on circulating testosterone levels. Because of this, it is useful to know what one’s testosterone levels are so that the correct dosage of bicalutamide can be more appropriately determined. In addition, estrogens, progestogens, and GnRH modulators all strongly suppress testosterone levels, so blood work will be useful in monitoring the effectiveness of hormone therapy in people taking these medications regardless of whether they are also taking bicalutamide or not.