By Aly | First published March 2, 2019 | Last modified June 13, 2022
Note also that this is older discussion and may be somewhat outdated.
As bicalutamide works exclusively as an androgen receptor antagonist and not by decreasing androgen levels, the potency and hence effective dosage of bicalutamide are fundamentally dependent on circulating androgen levels. There have been few clinical studies of bicalutamide in transfeminine people (only one, to be exact), and the proper dosage of bicalutamide for use as an antiandrogen in transfeminine people has not been well-characterized. In any case, a variety of pieces of information can guide dosage considerations for bicalutamide:
Gooren (2011) and Randolph (2018) recommend a dosage of bicalutamide of 50 mg/day in combination with testosterone suppression (via, e.g., estrogen therapy) in adult transfeminine people, while Fishman et al. (2019) recommend a dosage of 25 to 50 mg/day for this purpose. Neyman, Fuqua, and Eugster (2019) used a dosage of bicalutamide of 50 mg/day as a monotherapy puberty blocker in adolescent transgender girls. However, although this was clinically effective in producing the desired effects (including promotion of feminization and breast development and apparently preventing or reducing masculinization), the dosage of bicalutamide in Neyman, Fuqua, and Eugster (2019) was likely too low to be fully effective for such purposes (see section below).
Bicalutamide is used mainly to treat prostate cancer in men. The dosage of bicalutamide used in combined androgen blockade (CAB)—or combined GnRH modulator/orchiectomy and nonsteroidal antiandrogen therapy—is 50 mg/day. However, 50 mg/day bicalutamide is not maximally effective for this purpose; clinical studies suggest that dosages of 150 to 200 mg/day bicalutamide result in maximal effectiveness for this indication (Wiki; second to last paragraph). It is notable that although GnRH modulators/orchiectomy decrease circulating total testosterone levels by 95% (to about 15 ng/dL on average), they only decrease local DHT levels in the prostate gland to 40 to 50% of baseline on average (due to local transformation of circulating adrenal androgens like DHEA into DHT). (Note that about 90% of testosterone in the prostate gland is transformed into the ~3-fold more potent androgen DHT, so DHT is the relevant androgen in this part of the body.) The monotherapy dosage of bicalutamide in men with prostate cancer is 150 mg/day, and this has similar albeit slightly inferior effectiveness to GnRH modulators in the treatment of prostate cancer. Men with prostate cancer on bicalutamide monotherapy have total testosterone levels of 600 ng/dL on average. GnRH modulator monotherapy and 150 mg/day bicalutamide monotherapy are modestly significantly inferior in effectiveness for prostate cancer to CAB with 50 mg/day bicalutamide, and CAB with 50 mg/day bicalutamide is highly inferior to CAB with 160 mg/day enzalutamide (a much stronger antiandrogen than bicalutamide) (Wiki; second to last paragraph). There are major caveats to relating bicalutamide antiandrogenic efficacy in the prostate gland to its general antiandrogenic efficacy, but the data clearly show that very high doses of bicalutamide are needed to fully or near-fully neutralize androgen signaling in at least this part of the body.
In dose-ranging studies of bicalutamide monotherapy for prostate cancer in men, gynecomastia and breast tenderness rates increased linearly up to a maximum of about 80% at 100 mg/day, at which point no further increase in rates occurred. A dose-ranging study found that gynecomastia occurred with bicalutamide in 9% at 10 mg/day, 26% at 30 mg/day, 36% at 50 mg/day, 79% at 100 mg/day, 78% at 150 mg/day, and 79% at 200 mg/day (Table). The total testosterone levels of these men increased to about 400 to 600 ng/dL, or about 500 ng/dL on average, during bicalutamide therapy, and this was essentially regardless of dosage.
The dosage of bicalutamide that has been used to treat hirsutism (excessive body hair growth) in women is 25 mg/day. It has usually been combined with an ethinylestradiol-containing birth control pill, which notably suppresses total testosterone levels and further decreases free testosterone levels by 40 to 80% (via increased SHBG levels). Total testosterone levels in premenopausal women are 5 to 45 ng/dL, or 30 ng/dL on average, and the free testosterone fraction is about ~50% of that of men (due to ~2-fold higher SHBG levels in premenopausal women). As such, total and free testosterone levels are on average 20- and 40-fold lower in premenopausal women than in men, respectively. Hence, much lower doses of bicalutamide can be used in women than in men with high antiandrogenic effectiveness. This includes both cisgender women and transfeminine people in whom androgen levels have been markedly suppressed with, e.g., estrogen therapy. A recent phase III study of bicalutamide for women with hyperandrogenism due to polycystic ovary syndrome used a dosage of bicalutamide of 50 mg/day in combination with an ethinylestradiol-containing birth control pill.
Doses of flutamide of 125, 250, and 375 mg/day in combination with an ethinylestradiol-containing birth control pill have been found to have non-significantly different and hence equivalent effectiveness in the treatment of hirsutism in women with polycystic ovary syndrome. A “very low dose” of flutamide of 62.5 mg/day is effective and has been widely used in the treatment of hirsutism in women as well, although it has not been directly compared to the other doses. The CAB dosage of flutamide in prostate cancer in men is 750 mg/day. CAB with 750 mg/day flutamide has very similar albeit slightly non-significantly inferior effectiveness to CAB with 50 mg/day bicalutamide (Graph; Kolvenbag & Nash, 1999). This suggests that a dosage of as low as 8 mg/day bicalutamide, on the basis of extrapolation and calculation from flutamide (750 mg/day ÷ 125 mg/day = 6 → 50 mg/day ÷ 6 = 8 mg/day), might have maximal effectiveness in combination with an ethinylestradiol-containing birth control pill in the treatment of hirsutism in women with hyperandrogenism due to polycystic ovary syndrome. This suggests that bicalutamide at a dosage of say 50 mg/day may be being considerably overdosed in the treatment of hirsutism in women.
The dosage of bicalutamide that is typically used in boys with gonadotropin-independent precocious puberty (testotoxicosis) is 50 mg/day in combination with anastrozole, an aromatase inhibitor. However, it should be noted that these boys are very young, e.g. 3 years of age, and have much smaller bodies than adolescents and adults. Hence, bicalutamide may be more potent as an antiandrogen in such individuals, and the same doses may not result in equivalent antiandrogenic effects in adults. Surprisingly however, bicalutamide levels with an average dose of 50 mg/day have been found to be similar in these boys as in adults (Wiki).
The absorption of bicalutamide is linear up to a dosage of 150 to 200 mg/day, but becomes progressively less linear above this dosage, and little or no further absorption occurs at doses of 300 mg/day and above (Wiki; Graph; Graph). As such, there is a practical dosage limit of bicalutamide of about 200 to 300 mg/day.
Taken together, I would guess that doses of bicalutamide of 6.25 to 50 mg/day may be appropriate for use in the context of substantial suppression of testosterone levels (<200 ng/dL) in transfeminine people, whereas higher doses of bicalutamide of 150 to 300 mg/day may be appropriate for use as a monotherapy (i.e., without an estrogen or other antigonadotropin, for instance to block puberty) in the context of higher testosterone levels (e.g., >600 ng/dL). Note that, due to increased estradiol levels, considerable to full feminization will likely occur with bicalutamide monotherapy (at sufficiently high doses such that testosterone is adequately blocked). Hence, there isn’t really good basis for use of bicalutamide monotherapy in transfeminine people. It’s best to just combine it with at least some amount of an estrogen and/or progestogen, which will suppress testosterone levels and greatly reduce the required bicalutamide dosage (as well as associated cost).
A study was published of 50 mg/day bicalutamide monotherapy for use as a puberty blocker in adolescent transgender girls (Neyman, Fuqua, & Eugster, 2019). I believe that the dosage used in this study was too low to be a fully effective monotherapy for this purpose. A more appropriate dosage for such purposes would likely be 150 to 200 mg/day, but possibly up to 300 mg/day. It’s a better idea to just combine bicalutamide with an estrogen or progestogen to substantially lower testosterone levels and thereby reduce the required bicalutamide dosage though. This is particularly true in relation to estrogens, since bicalutamide monotherapy increases estradiol levels and will result in considerable feminization and breast development even without taking an estrogen in conjunction. In other words, bicalutamide doesn’t really “block puberty” so much as “convert” normal puberty from male to female. Hence, there isn’t much point in using bicalutamide without concomitant estrogen to “block” puberty. Conversely however, bicalutamide plus an adequately dosed progestogen would be more akin to puberty blockade.
I wrote a message on the topic of bicalutamide monotherapy dosage for puberty blockade in relation to Neyman, Fuqua, and Eugster (2019). Regarding my personal suggestions for bicalutamide monotherapy dosage, here is a summary of some of the key points from the message:
- Only 100 mg/day bicalutamide monotherapy was sufficient to allow for maximal incidences of breast pain and gynecomastia (~80%) in men with prostate cancer with post-treatment testosterone levels of about 600 ng/dL.
- A dosage of bicalutamide monotherapy of 150 mg/day is slightly but significantly inferior to GnRH agonist monotherapy in the treatment of prostate cancer per meta-analyses. Bicalutamide-treated men with prostate cancer typically have post-treatment testosterone levels of about 600 ng/dL. Conversely, GnRH agonists reduce testosterone levels to <20 ng/dL.
- The normal range for testosterone levels in males is about 250 to 1,100 ng/dL, and younger males have higher testosterone levels than men with prostate cancer (who are generally elderly)—testosterone levels that are about twice as high, to be exact.
- Bicalutamide monotherapy increases testosterone levels by 1.5- to 2-fold in men with prostate cancer and could potentially increase testosterone levels into the upper end of the normal male range in younger individuals.
- Testosterone levels reach near-adult levels (~550 ng/dL) by age 15 in adolescent males.
If we put all of this together, a 15-year-old pubertal transgender girl might on average have testosterone levels of about 550 ng/dL. Bicalutamide would increase her testosterone levels, potentially up to 1,100 ng/dL. Since 100 or 150 mg/day bicalutamide at minimum appears to be needed to fully or near-fully block 600 ng/dL testosterone, we’d want to roughly double this dosage to block testosterone levels of 1,100 ng/dL. Hence, 200 to 300 mg/day bicalutamide at minimum appears to be needed to fully or near-fully block testosterone levels of 1,100 ng/dL. (Actually the bioavailability of bicalutamide diminishes above 150 mg/day, so this complicates things even more.) If post-treatment testosterone levels were only 600 ng/dL (say in a younger pubertal transgender girl), then 100 or 150 mg/day bicalutamide at minimum might be able to fully or near-fully block such levels. I’d recommend 150 mg/day to be sure however. An adequate bicalutamide dosage is very important because even low excess levels of testosterone can result in irreversible masculinization, such as voice deepening. Hence, it’s critical to get the dosage right and ensure that this doesn’t happen.
As Neyman, Fuqua, and Eugster (2019) show, 50 mg/day bicalutamide will oppose masculinization and will increase estradiol levels and thereby induce feminization and breast development. But this does not mean that such a dosage is sufficient to ensure complete prevention of masculinization.
Antiandrogenic potency of bicalutamide in dose-ranging studies in men with prostate cancer:
Table 1: Antiandrogenic effects of bicalutamide in dose-ranging studies in men (Tyrrell et al., 1998):
|Effect||10 mg||30 mg||50 mg||100 mg||150 mg||200 mg|
|Improved prostate cancer1||63%||79%||85%||96%||98%||100%|
1 = In men with prostate cancer, percentage with partial regression or stable disease instead of objective progression.
Table 2: Potency of high-dose bicalutamide (Tyrrell et al., 2006):
|Effect||300 mg||450 mg||600 mg||Castration|
|Improved prostate cancer1||79%||77%||81%||–|
1 = In men with prostate cancer, percentage with partial regression or stable disease instead of objective progression.
Note that testosterone levels are typically around 400 ng/dL prior to introduction of bicalutamide and typically around 600 ng/dL after introduction of bicalutamide in men with prostate cancer (Wiki).