Bicalutamide

Bicalutamide is an anti-androgen which is used mainly in the treatment of prostate cancer but can also be used to treat hirsutism, or as a component of hormone therapy in feminizing HRT, among other uses. It is nonsteroidal anti-androgen and a selective/pure antagonist of the androgen receptor. It has no other hormonal activity and does not lower androgen levels. Bicalutamide crosses the blood-brain barrier and blocks the effects of testosterone and dihydrotestosterone (DHT) both in the body and in the brain. While it has been observed that bicalutamide does not cross the blood-brain barrier in rats and dogs, this was found not to be the case in humans.

Transgender studies
Bicalutamide is used as an antiandrogen in hormone therapy for transgender women and this has been mentioned in a number of secondary sources,    Moreover, feminization and demasculinization are very well-documented side effects of bicalutamide in men treated with it for prostate cancer (50-150 mg/day) and bicalutamide has been used in the treatment of hirsutism in women in at least five clinical studies (25-50 mg/day; dates 1999, 2002, 2004, 2016, 2017; a review in 2009). It has also been assessed as a puberty blocker (in combination with an aromatase inhibitor like anastrozole or letrozole) in boys with gonadotropin-independent precocious puberty in a number of reports and studies. However, until very recently there were no published studies specifically evaluating bicalutamide in transgender women.

In 2017, the first study of bicalutamide for male-to-female hormone therapy was published. Bicalutamide was used as a puberty blocker at a dosage of 50 mg/day as an alternative to GnRH analogues in 14 adolescent transgender girls of mean age 15.8 years (range 12 to 18.4 years) between 2013 and 2017. Of the girls, three received estrogen concurrently while 11 received only bicalutamide. Seven of the girls returned for follow-up by the time that the report was published. After a mean of about 5.7 months, 86% (6 of 7) of the girls showed breast development; the degree was Tanner stage III in four (57%), Tanner stage II in one (14%), and mixed Tanner stage III/II of the right and left breast in one (14%). The one patient that did not show breast development at that follow-up did show breast development at her second follow-up at 12.5 months; she had Tanner stage III breast development at that time. Liver function tests were obtained in four of the girls and were unremarkable. Estradiol levels were obtained in three of the girls and were 26 to 61 pg/mL while testosterone levels were obtained in two and were 524 to 619 ng/dL. The researchers concluded that bicalutamide is useful as an antiandrogen and puberty blocker in adolescent transgender girls and that it has a secondary benefit of promoting feminization and breast development in such subjects. They called for further studies to evaluate the potential role of bicalutamide in the therapeutic armamentarium for the treatment of transgender girls and women.

While bicalutamide has only recently been assessed in transgender females in one study, nilutamide has been assessed in transgender women in five studies/publications between 1987 and 1989. It was found to be effective as an antiandrogen and in promoting feminization in these studies both alone and in combination with ethinylestradiol. The dosage of nilutamide used in these studies was the prostate cancer monotherapy dosage of 300 mg/day, which is roughly equivalent to a bicalutamide dosage of 150 mg/day. Nilutamide itself is rarely used nowadays both for prostate cancer and for other indications due to a high risk of lung toxicity that can potentially result in death and hence is no longer recommended for use as an antiandrogen in general. Bicalutamide can be used instead of nilutamide and would be anticipated to have the same if not greater benefits due to its greater potency and efficacy as an antiandrogen (same mechanism of action – selective androgen receptor antagonist – but higher affinity for the androgen receptor and longer elimination half-life).

Hormone levels
Bicalutamide on its own increases testosterone levels in men and transgender women who have intact gonads. This is because androgens exert negative feedback on the hypothalamic–pituitary–gonadal axis via activation of androgen receptors in the pituitary gland and hypothalamus, and by blocking these receptors, this negative feedback is lost and disinhibition of the axis occurs. More specifically, blockade of androgen receptors in the pituitary gland and hypothalamus causes disinhibition of the secretion of luteinizing hormone from the pituitary gland, which in turn results in increased levels of luteinizing hormone in the blood. This luteinizing hormone then travels through the bloodstream to the gonads and activates production of sex hormones in the gonads.

Although bicalutamide blocks the androgen receptor, disinhibits the hypothalamic–pituitary–gonadal axis, and thereby increases testosterone levels in men and transgender women, this will not happen if bicalutamide is taken in combination with a sufficiently high dosage of an antigonadotropin like an estrogen, progestogen, or GnRH analogue. This is because these drugs suppress the hypothalamic–pituitary–gonadal axis by exerting positive feedback on it and therefore the loss of testosterone-mediated negative feedback caused by bicalutamide is rendered inconsequential. Studies have found that whereas 300 mg/day treatment with nilutamide on its own increased testosterone levels in transgender women by more than 2-fold, the addition of ethinylestradiol to nilutamide therapy abolished the increase and suppressed testosterone levels into the female/castrate range.

In clinical studies of men treated with bicalutamide on its own for the treatment of prostate cancer, dosages of bicalutamide ranging from 10 mg/day to 200 mg/day were assessed and found to increase testosterone levels. The 10 mg/day dosage increased testosterone levels by about 20 to 30% and the 30 mg/day dosage by about 55 to 75%. Dosages above 30 mg/day showed no further increase in testosterone levels, suggesting that a plateau in the effect is reached by 30 mg/day.

Bicalutamide increases testosterone levels to the high end of the male range and they do not generally exceed the normal male range. This is because estradiol is produced from testosterone and hence estradiol levels are also increased by bicalutamide. Estradiol, unlike the case of testosterone, is not opposed or blocked by bicalutamide, so estradiol exerts negative feedback on the hypothalamic–pituitary–gonadal axis and stops testosterone levels from further increasing. The maximal estradiol levels produced by bicalutamide approximate those of the low-normal female range.

Bicalutamide does not increase testosterone levels in cisgender women. This is because testosterone levels are low in cisgender women and so exert little or no basal negative feedback on the hypothalamic–pituitary–gonadal axis.

Comparison with other antiandrogens
Unlike steroidal antiandrogens like cyproterone acetate and spironolactone, bicalutamide does not lower androgen levels and has no off-target hormone activity (e.g., progestogenic activity, glucocorticoid activity, or antimineralocorticoid activity). It has a much better tolerability profile than cyproterone acetate and spironolactone and a much better safety profile than cyproterone acetate, whereas the safety profiles of bicalutamide and spironolactone are more comparable. Clinical studies suggest that bicalutamide and other nonsteroidal antiandrogens are more effective antiandrogens than cyproterone acetate and spironolactone both for the treatment of prostate cancer and in the treatment of androgen-dependent conditions in women like acne and hirsutism.

With spironolactone
Both bicalutamide and spironolactone have been studied in the treatment of benign prostatic hyperplasia (otherwise known as enlarged prostate) in men. This condition is androgen-dependent and so antiandrogens can treat it. Bicalutamide at a dosage of 50 mg/day decreased prostate volume by 26%. Breast tenderness was reported in 93% and gynecomastia was reported in 54% of the men. In contrast, spironolactone at a dosage of 100 mg/day failed to affect prostate volume and caused gynecomastia in only 5% of men. Another study has, however, found a rate of gynecomastia of 7% with 25 to 50 mg/day spironolactone and a rate of 52% with doses of spironolactone of 150 mg/day or higher. In another study of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100 mg/day, in 5 of 8 (62.5%) at 200 mg/day, and in 6 of 9 (66.7%) at 400 mg/day. In comparison, 150 mg/day bicalutamide was found to cause gynecomastia at a rate of 69% in a large study. Taken together, these findings suggest that bicalutamide may be a more efficacious antiandrogen than spironolactone.

Related Papers

 * (January 2019) Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents.


 * Testosterone/bicalutamide (December 2017) antagonism at the predicted extracellular androgen binding site of ZIP9.


 * (December 2017) Development of 5N-Bicalutamide, a High-Affinity Reversible Covalent Antiandrogen.


 * (July 2016) Efficacy of Immediate Switching from Bicalutamide to Flutamide as Second-Line Combined Androgen Blockade.


 * (December 2015) Interaction mechanism exploration of R-bicalutamide/S-1 with WT/W741L AR using molecular dynamics simulations.


 * (August 2015) A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide.


 * (January 2015) Effects of the ABCG2 and ABCB1 drug transporter polymorphisms on the pharmacokinetics of bicalutamide in humans.


 * (February 2015) Binding of a Cyano- and Fluoro-containing Drug Bicalutamide to Cytochrome P450 46A1.


 * (February 2015) Species-dependent binding of new synthesized bicalutamide analogues to albumin by optical biosensor analysis.


 * (July 2014) Optical biosensor analysis in studying new synthesized bicalutamide analogs binding to androgen receptor.


 * (January 2012) The relative bioavailability study and fasting and fed states pharmacokinetics of bicalutamide 50-mg tablets in healthy Chinese volunteers.


 * (February 2011) Formation of bicalutamide nanodispersion for dissolution rate enhancement.


 * (May 2010) Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity.


 * (February 2009) Mechanistic studies on the synthesis of bicalutamide.


 * (September 2007) Activity of Androgen Receptor Antagonist Bicalutamide in Prostate Cancer Cells Is Independent of NCoR and SMRT Corepressors.


 * (May 2002) Bicalutamide Functions as an Androgen Receptor Antagonist by Assembly of a Transcriptionally Inactive Receptor.