Medical uses of bicalutamide
The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Such indications include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.
Bicalutamide is used primarily in the treatment of early and advanced prostate cancer. It is approved at a dosage of 50 mg/day as a combination therapy with a gonadotropin-releasing hormone analogue (GnRH analogue) or orchiectomy (that is, surgical or medical castration) in the treatment of stage D2 metastatic prostate cancer (mPC), and as a monotherapy at a dosage of 150 mg/day for the treatment of stage C or D1 locally advanced prostate cancer (LAPC). Although effective in mPC and LAPC, bicalutamide is no longer indicated for the treatment of localized prostate cancer (LPC) due to negative findings in the Early Prostate Cancer (EPC) trial. Prior to the introduction of the newer NSAA enzalutamide in 2012, bicalutamide was considered to be the standard-of-care antiandrogen in the treatment of prostate cancer, and still remains widely used for this indication. Compared to earlier antiandrogens like the steroidal antiandrogen (SAA) cyproterone acetate (CPA) and the NSAAs flutamide and nilutamide, bicalutamide shows an improved profile of effectiveness, tolerability, and safety, and for this reason has largely replaced them in the treatment of prostate cancer.
In the early 1940s, it was discovered that growth of prostate cancer in men regressed with surgical castration or high-dose estrogen therapy, which produced very low levels of circulating testosterone, and accelerated with the administration of exogenous testosterone. It has since been elucidated that androgens like testosterone and dihydrotestosterone (DHT) function as trophic factors for the prostate gland, stimulating cell division and proliferation and producing tissue growth and glandular enlargement, which, in the context of prostate cancer, results in stimulation of tumors and a considerable acceleration of disease progression. As a result of these discoveries, androgen deprivation therapy (ADT), via a variety of modalities including surgical castration, high-dose estrogens, SAAs, GnRH analogues, NSAAs, and androgen biosynthesis inhibitors (e.g., abiraterone acetate), has become the mainstay of treatment for prostate cancer. Although ADT can shrink or stabilize prostate tumors and hence significantly slow the course of prostate cancer and prolong life, it is, unfortunately, not generally curative. While effective in slowing the progression of the disease initially, most advanced prostate cancer patients eventually become resistant to ADT and prostate cancer growth starts to accelerate again, in part due to progressive mutations in the androgen receptor (AR) that result in the transformation of drugs like bicalutamide from AR antagonists to agonists.
A few observations form the basis of the reasoning behind combined androgen blockade (CAB), in which castration and an NSAA are combined. It has been found that very low levels of androgens, as in castration, are able to significantly stimulate growth of prostate cancer cells and accelerate disease progression. Although castration ceases production of androgens by the gonads and reduces circulating testosterone levels by about 95%, low levels of androgens continue to be produced by the adrenal glands, and this accounts for the residual levels of circulating testosterone. Moreover, it has been found that prostate gland levels of DHT, which is the major androgen in the prostate, remain at 40 to 50% of their initial values following castration. This has been determined to be due to uptake of circulating weak adrenal androgens like dehydroepiandrosterone (DHEA) and androstenedione (A4) by the prostate and their de novo transformation into testosterone and DHT. As such, a considerable amount of androgen signaling continues within the prostate gland even with castration.
In the past, surgical adrenalectomy and early androgen biosynthesis inhibitors like ketoconazole and aminoglutethimide were successfully employed in the treatment of castration-resistant prostate cancer. However, adrenalectomy is an invasive procedure with high morbidity, ketoconazole and aminoglutethimide have relatively high toxicity, and both treatment modalities require supplementation with corticosteroids, making them in many ways unideal. The development of CAB with NSAAs like bicalutamide and enzalutamide and with newer and more tolerable androgen biosynthesis inhibitors like abiraterone acetate has since allowed for non-invasive, convenient, and well-tolerated therapies that have replaced the earlier modalities.
Subsequent clinical research has found that monotherapy with higher dosages of NSAAs than those used in CAB is roughly equivalent to castration in extending life in men with prostate cancer. Moreover, NSAA monotherapy is overall better tolerated and associated with greater quality of life than is castration, which is thought to be related to the fact that testosterone levels do not decrease with NSAA monotherapy and hence by extension that levels of biologically active and beneficial metabolites of testosterone such as estrogens and neurosteroids are preserved. For these reasons, NSAA monotherapy has become an important alternative to castration and CAB in the treatment of prostate cancer.
Skin and hair conditions
Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and pattern hair loss (androgenic alopecia). In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair. Moreover, men with congenital 5α-reductase type II deficiency, 5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male pattern hair loss. Conversely, hyperandrogenism in women, for instance due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general. In accordance with the preceding, antiandrogens have been found to be highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.
Low-dose bicalutamide has been found to be effective in the treatment of hirsutism in women in clinical studies. In one of the studies, the drug was well-tolerated, all of the patients experienced a visible decrease in hair density, and a highly significant clinical improvement was observed with the Ferriman–Gallwey score decreasing by 41.2% at 3 months and by 61.6% at 6 months. According to a 2013 review, "Low dose bicalutamide (25 mg/day) was shown to be effective in the treatment of hirsutism related to IH and PCOS. It does not have any significant side effects [or lead] to irregular periods."
In addition to hirsutism, bicalutamide can also be used in the treatment of acne in women. Several studies have observed complete clearing of acne with flutamide in women, and similar benefits would be expected with bicalutamide.:712–717 Bicalutamide may also treat other androgen-dependent skin and hair conditions like seborrhea and pattern hair loss. Flutamide has been found to produce a decrease of hirsutism score to normal and an 80% or greater decrease in scores of acne, seborrhea, and androgen-dependent hair loss. Moreover, in combination with an oral contraceptive, flutamide treatment resulted in an increase in cosmetically acceptable scalp hair density in 6 of 7 women suffering from pattern hair loss.
Antiandrogens like flutamide and bicalutamide are male-specific teratogens which can feminize male fetuses due to their antiandrogen effects, and for this reason, are not recommended by the U.S. Food and Drug Administration for use in women. Because of this risk, it is strongly recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception. Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose. Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.
Transgender hormone therapy
Bicalutamide is used as a component of feminizing hormone therapy for transgender women. Beneficial or desired effects consist of demasculinization and feminization, and include breast development, reduced male-pattern hair, decreased muscle mass, feminine changes in fat distribution, lowered libido, and loss of spontaneous erections. Unlike various other antiandrogens, bicalutamide significantly increases testosterone and estradiol levels in biological males when used as a monotherapy, and hence can have indirect estrogenic effects in transgender women. This can be considered to be desirable in transgender women, as it can produce or contribute to feminization. It should be noted that bicalutamide does not increase sex hormone levels if combined with an antigonadotropin such as a GnRH analogue, an estrogen, or a progestogen, due to negative feedback of these agents on sex hormone production. Because bicalutamide does not lower androgen levels, it may be a favorable option for transgender women who wish to preserve sex drive and fertility.
Unlike the SAAs CPA and spironolactone, as well as GnRH analogues, few clinical studies assessing bicalutamide as an antiandrogen in transgender women have been conducted to date. In any case, bicalutamide is clinically effective as an antiandrogen in women with hirsutism and in boys with precocious puberty, and demasculinization and feminization are well-documented effects of bicalutamide in men treated with it for prostate cancer. In addition, nilutamide, a closely related antiandrogen that possesses the same mechanism of action as bicalutamide, has been evaluated in transgender women in at least five small clinical studies. It was given at a high dosage of 300 mg/day, the same dosage in which it has been used as a monotherapy in the treatment of prostate cancer. The corresponding monotherapy dosage of bicalutamide in the treatment of prostate cancer is 150 mg/day.
In the clinical studies of nilutamide for transgender hormone therapy, the drug, without being combined with estrogen, induced observable signs of clinical feminization in young transgender women (age range 19–33 years) within 8 weeks, including breast development, decreased male-pattern hair, decreased spontaneous erections and sex drive, and positive psychological and emotional changes. Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity; along with decreased hair growth, these changes were the earliest signs of feminization. The drug more than doubled luteinizing hormone (LH) and testosterone levels and tripled estradiol levels, and the addition of ethinylestradiol, a potent estrogen, to nilutamide therapy after 8 weeks of treatment abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range. On the basis of these results, both nilutamide alone, and particularly the combination of nilutamide and an estrogen, were regarded as effective in terms of producing antiandrogen effects and feminization in transgender women.
Although nilutamide has been found to be effective for transgender hormone therapy, the use of nilutamide in the treatment of prostate cancer and particularly for other indications that are of a less dire nature is now discouraged due to the unique adverse effects of the medication, most importantly a high incidence of interstitial pneumonitis. This is an adverse effect that can progress to pulmonary fibrosis and can potentially be fatal. For this reason, newer, safer NSAAs like bicalutamide have largely replaced nilutamide and are now used for such indications instead.
Madeline Deutsch of the Center of Excellence for Transgender Health at the University of California, San Francisco, in her Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People (2016), has said the following on the topic of bicalutamide in transgender women:
In many countries, cyproterone acetate, a synthetic progestagen with strong anti-androgen activity is commonly used [as an antiandrogen in feminizing hormone therapy for transgender women]. Cyproterone [acetate] has been associated with uncommon episodes of fulminant hepatitis. Bicalutamide, a direct anti-androgen used for the treatment of prostate cancer, also has a small but not fully quantified risk of liver function abnormalities (including several cases of fulminant hepatitis); while such risks are acceptable when considering the benefits of bicalutamide in the management of prostate cancer, such risks are less justified in the context of gender-affirming treatment. No evidence at present exists to inform such an analysis.
In spite of its risk of hepatotoxicity, CPA is the most widely used antiandrogen in Europe and elsewhere in the world for hormone therapy in transgender women. In addition, it is widely used in cisgender women for the treatment of acne and hirsutism. In the U.S., one of the only countries where CPA has not been approved for medical use, the relatively weak agent spironolactone is the antiandrogen most commonly used in transgender and cisgender women instead. Although both CPA and bicalutamide have been associated with hepatotoxicity (while spironolactone is not usually associated with such), bicalutamide has a far lower and only small risk of both elevated liver enzymes and hepatotoxicity; whereas CPA has been associated with over 100 reports of hepatotoxicity, five cases of hepatotoxicity, out of millions of patient exposures, have been associated with bicalutamide to date.
In 2017, the first clinical study of bicalutamide in transgender females was published.:477 The study specifically assessed bicalutamide as a puberty blocker to prevent puberty in adolescent transgender girls alone or in combination with an estrogen. The subjects were 14 transgender girls with a mean age of 15.8 years (range 12 to 18.4 years) who were treated with 50 mg/day bicalutamide between 2013 and 2017, of whom seven returned for follow-up. In addition to showing effectiveness as an antiandrogen in the subjects, bicalutamide monotherapy increased estradiol levels and promoted feminization as a secondary effect. This included breast development to Tanner stage II and III in 86% of the subjects after an average of 5.7 months of treatment, with the seventh girl showing Tanner stage III breast development at her second follow-up at 12.5 months. Testosterone levels were 524 to 619 ng/dL and estradiol levels were 26 to 61 pg/mL in the subjects. Liver function tests were unremarkable. Although GnRH analogues are the first-line treatment to prevent puberty in transgender adolescents, they are very expensive and are often denied by medical insurance. According to the researchers, bicalutamide represents a potential alternative to GnRH analogues as a puberty blocker in transgender girls. However, they expressed that additional studies are necessary to further evaluate the potential of bicalutamide for this use.
Male early puberty
Bicalutamide (25–50 mg/day) is useful in combination with the aromatase inhibitor anastrozole as a puberty blocker in the treatment of male precocious puberty. This is potentially a cost-effective alternative to GnRH analogues for the treatment of this condition, as GnRH analogues are very expensive. Moreover, the combination is effective in gonadotropin-independent precocious puberty, namely familial male-limited precocious puberty (also known as testotoxicosis), where GnRH analogues notably are not effective. Bicalutamide has been found to be superior to the SAA spironolactone (which has also been used, in combination with the aromatase inhibitor testolactone) for this indication; it has shown greater effectiveness and possesses fewer side effects in comparison. For this reason, bicalutamide has replaced spironolactone in the treatment of the condition.:2139
Antiandrogens can considerably relieve and prevent priapism (potentially painful penile erections that last more than four hours) via direct blockade of penile ARs. In accordance, bicalutamide, at low dosages (50 mg every other day or as little as once or twice weekly), has been found in a series of case reports to completely resolve recurrent priapism in men without producing significant side effects, and is used for this indication off-label. In the reported cases, libido, rigid erections, the potential for sexual intercourse, orgasm, and subjective ejaculatory volume have all remained intact or unchanged, and gynecomastia has not developed when bicalutamide is administered at a total dosage of 25 mg/day or less. Some gynecomastia and breast tenderness developed in one patient treated with 50 mg/day, but significantly improved upon the dosage being halved. The observed tolerability profile of bicalutamide in these subjects has been regarded as significantly more favorable than that of GnRH analogues and estrogens (which are also used in the treatment of this condition). However, although successful and well-tolerated, very few cases have been reported.
Paraphilias and hypersexuality
The antigonadotropic antiandrogens CPA, medroxyprogesterone acetate (MPA), and GnRH analogues have all been widely used to treat paraphilias (e.g., pedophilia) and hypersexuality in men. They suppress androgen levels to castrate or near-castrate levels and are highly effective in reducing sexual urges, arousal, and behaviors. In addition, they are used to treat sex offenders as a means of chemical castration for the purpose of reducing the likelihood of recidivism.
Although they have not been studied in the treatment of paraphilias and hypersexuality, NSAAs like flutamide and bicalutamide have been suggested as potential medications for these indications and may have superior tolerability and safety relative to antigonadotropic antiandrogens. As an example, because NSAAs do not reduce estrogen levels, unlike antigonadotropic antiandrogens, they preserve bone mineral density (BMD) and have little or no risk of osteoporosis and associated bone fractures. However, due to unopposed estrogen signaling, a substantial incidence of gynecomastia is associated with NSAAs. In addition to potential monotherapy use, NSAAs have been advocated for temporarily suppressing sex drive during the start of GnRH agonist treatment via prevention of the increased androgen signaling associated with the initial testosterone flare.
Though treatment of paraphilias and hypersexuality with selective AR antagonists is a seemingly sound strategy, this may not be true in practice. Surprisingly, little or no sexual dysfunction, including loss of sex drive and decreased sexual activity, has been observed in clinical studies of NSAA monotherapy. The explanation for this is that NSAAs do not lower androgen levels, and metabolites of testosterone like estrogens and neurosteroids may be of critical importance for maintenance of sex drive and function in males. In accordance, testosterone is locally aromatized into estradiol widely throughout the brain and estradiol appears to be the mediator of many of the central actions of testosterone. For these reasons, unlike antigonadotropic antiandrogens, NSAA monotherapy may have limited usefulness in the management of paraphilias and hypersexuality. The addition of NSAAs to antigonadotropic antiandrogens like GnRH analogues may have some usefulness however, particularly in severe cases. In any case, insufficient evidence is available at this time, and further research is thus warranted.
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GnRH analogues, both agonists and antagonists, severely suppress endogenous gonadotropin and testosterone production [...] Administration of GnRH agonists (e.g., leuprolide, goserelin) produces an initial stimulation of gonadotropin and testosterone secretion (known as a "flare"), which is followed in 1 to 2 weeks by GnRH receptor downregulation and marked suppression of gonadotropins and testosterone to castration levels. [...] To prevent the potential complications associated with the testosterone flare, AR antagonists (e.g., bicalutamide) are usually coadministered with a GnRH agonist for men with metastatic prostate cancer.399
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Drugs for cross-gender hormonal replacement therapy used in the male to female (MtoF) transsexual population. [...] Non-steroidal anti-androgens Bicalutamide, flutamide, nilutamide
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Anti-androgens such as flutamide, bicalutamide and cyproterone acetate are also used in patients with prostate cancer and sometimes in male-to-female transgender individuals [...]
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Other agents with anti-androgenic properties used [in the treatment of transgender women] are nonsteroidal androgen receptor blockers, such as flutamide and bicalutamide [...]
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Abstract. Objectives: GnRH analogs are first-line treatment for halting pubertal development in gender variant youth. However, this medication is often denied by third party payors. The pure androgen receptor blocker bicalutamide represents a potential alternative approach to blocking puberty in natal males. Here, we describe the use of bicalutamide in MTF transgender patients. Methods: Medical records for patients with gender dysphoria (GD) followed in the pediatric endocrine clinic at Riley Hospital for Children were reviewed. All MTF transgender patients treated with bicalutamide were included. Variables evaluated comprised age, duration of follow up, timing of estrogen initiation, laboratory studies and physical exam findings including change in breast Tanner stage during treatment. Results: Of 77 patients with GD identified, 29 were MTF, of whom 14 (48%) aged 15.8 ± 1.9 years (range 12-18.4yr) were treated with bicalutamide 50 mg daily between 2013 and 2017. Of these, 3 were started on estrogen concurrently whereas 11 received bicalutamide alone, 7 of whom have returned for follow up thus far. After an average of 5.7±1.5 months, 86% of the patients (n=6) had breast development consisting of Tanner stage III in 4, Tanner stage II in 1, and Tanner stage III/11 of the right and left breast in 1. The 7th patient was noted to have Tanner Ill breasts at her 2nd follow-up clinic visit 12.5 months after starting bicalutamide. LFTs were obtained on 4 patients, estradiol on 3 patients and testosterone on 2 patients while exclusively taking bicalutamide. LFTs were unremarkable and concentrations of estradiol and testosterone were 26-61 pg/mL and 524-619 ng/dL, respectively. Conclusions: Bicalutamide is used in rare forms of precocious puberty in males and has a known side effect of gynecomastia. Here, we report the novel use of bicalutamide as a puberty blocker in MTF patients with GD in whom it also results in feminization by causing breast development. Additional studies are needed to further evaluate the potential role of bicalutamide in the therapeutic armamentarium for the treatment of transgender MTF adolescents.
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