Medical uses of bicalutamide explained

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. Indications for bicalutamide 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.

Prostate cancer

Bicalutamide is used primarily in the treatment of early and advanced prostate cancer.[1] 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),[2] and as a monotherapy at a dosage of 150 mg/day for the treatment of stage C or D1 locally advanced prostate cancer (LAPC).[3] [4] [5] Although effective in and, bicalutamide is no longer indicated for the treatment of localized prostate cancer (LPC) due to negative findings in the Early Prostate Cancer (EPC) clinical trial programme. Prior to the introduction of the newer 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.[6] [7] Compared to earlier antiandrogens like the steroidal antiandrogen (SAA) cyproterone acetate (CPA) and the flutamide and nilutamide, bicalutamide shows an improved profile of effectiveness, tolerability, and safety,[8] [9] [10] [11] and for this reason has largely replaced them in the treatment of prostate cancer.[12] [13] [14] [15] [16] [17]

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.[18] [19] 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.[20] As a result of these discoveries, androgen deprivation therapy (ADT), via a variety of modalities including surgical castration, high-dose estrogens,, analogues,, and androgen biosynthesis inhibitors (e.g., abiraterone acetate), has become the mainstay of treatment for prostate cancer. Although can shrink or stabilize prostate tumors and hence significantly slow the course of prostate cancer and prolong life, it is not generally curative. While effective in slowing the progression of the disease initially, most advanced prostate cancer patients eventually become resistant to 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 antagonists to agonists.[21]

A few observations form the basis of the reasoning behind combined androgen blockade (CAB), in which castration and an are combined.[22] 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.[23] Although castration ceases production of androgens by the gonads and reduces circulating testosterone levels by about 95%,[24] low levels of androgens continue to be produced by the adrenal glands, and this accounts for the residual levels of circulating testosterone.[25] Moreover, it has been found that prostate gland levels of, which is the major androgen in the prostate, remain at 40 to 50% of their initial values following castration.[26] 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 .[27] 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.[28] [29] 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.[30] [31] [32] The development of with 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.[33]

Subsequent clinical research has found that monotherapy with higher dosages of than those used in is roughly equivalent to castration in extending life in men with prostate cancer.[34] [35] Moreover, monotherapy is overall better tolerated and associated with greater quality of life than is castration,[36] [37] [38] which is thought to be related to the fact that testosterone levels do not decrease with monotherapy and hence by extension that levels of biologically active and beneficial metabolites of testosterone such as estrogens and neurosteroids are preserved.[39] [40] [41] For these reasons, monotherapy has become an important alternative to castration and in the treatment of prostate cancer.[42] [43] [44]

Bicalutamide may be used to reduce the effects of the testosterone flare at the initiation of agonist therapy.[45] [46]

The combination of bicalutamide with an estrogen such as ethinylestradiol sulfonate has been used as a form of and as an alternative to the combination of bicalutamide with surgical or medical castration.[47]

Skin and hair conditions

Androgens like testosterone and 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).[48] 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.[49] [50] 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.[51] [52] [53] [54] [55] 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.[56] [57]

Low-dose bicalutamide has been found to be effective in the treatment of hirsutism in women in clinical studies.[58] [59] [60] [61] [62] [63] [64] In one of the studies, the medication 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 (from 22.0 ± 5.1 to 8.6 ± 3.5).[65] [66] According to a 2013 review, "Low dose bicalutamide (25 mg/day) was shown to be effective in the treatment of hirsutism related to and . It does not have any significant side effects [or lead] to irregular periods." In 2017, the combination of bicalutamide with a combined birth control pill was evaluated in a phase III clinical trial for the treatment of severe hirsutism in women with, and was found to be significantly more effective than a combined birth control pill alone.[67] [68] [62] In addition, bicalutamide was shown to be safe and to produce no side effects, except for a significant increase in total cholesterol and low-density lipoprotein levels. Studies have reported bicalutamide to be effective in the treatment of scalp hair loss in women.[69] [70] [71]

In addition to hirsutism, bicalutamide can be used in the treatment of acne in women.[72] [73] [74] Flutamide has generally been found to reduce symptoms of acne by 80 or 90% even at low doses, with several studies showing complete acne clearance.[75] [76] [77] In one study, it decreased acne scores by 80% within 3 months, whereas the spironolactone decreased symptoms by only 40% in the same time period.[78] [79] Bicalutamide has an antiandrogenic efficacy that is comparable to or greater than that of flutamide, and would be expected to produce similar therapeutic benefits.[80] [81] Other androgen-dependent skin and hair conditions, such as seborrhea and pattern hair loss, may also be treated by bicalutamide.[82] In addition to acne, flutamide has been found to produce an 80% or greater decrease in scores of seborrhea and androgen-dependent scalp hair loss.[83] Moreover, in combination with a combined birth control pill, flutamide treatment resulted in an increase in cosmetically acceptable scalp hair density in almost all women suffering from pattern hair loss in one small study. Bicalutamide is an appealing alternative to flutamide for the treatment of androgen-dependent skin and hair conditions in women because flutamide has a considerable risk of serious liver toxicity,[84] [85] which bicalutamide does not share.[74] [86] [87]

Antiandrogens like flutamide and bicalutamide are male-specific teratogens which can feminize male fetuses due to their antiandrogen effects.[88] [89] For this reason, they are not recommended by the Food and Drug Administration for use in women.[90] 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. Birth control pills, which contain an estrogen and a progestin, are typically used for this purpose. Moreover, birth control pills themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions; hence, they can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.[91]

Transgender hormone therapy

Bicalutamide is used as an antiandrogen in feminizing hormone therapy for transgender women and as a puberty blocker in adolescent transgender girls.[92] [93] [94] [95] [96] [97] [98] It can be used in transgender females both in combination with an estrogen and alone. The medication directly blocks the effects of androgens like testosterone and dihydrotestosterone in the body, and, when used by itself, also induces a significant increase in estradiol levels. As a result, bicalutamide causes demasculinization, and can additionally promote feminization, even without concomitant use of estrogen. This is analogous to what occurs in women with a defective due to complete androgen insensitivity syndrome.[99] Demasculinizing and feminizing effects of bicalutamide in those assigned male at birth include breast development,[100] [101] [102] reduced male-pattern hair,[103] decreased muscle mass,[104] feminine changes in fat distribution, decreased sex drive, and reduced spontaneous erections.[105] Dosages of bicalutamide of 25 to 50mg/day have been used and recommended in transgender females.[106] Lower doses may also be effective.

Unlike various other antiandrogens, bicalutamide when used as a monotherapy significantly increases testosterone and estradiol levels in individuals assigned male at birth, and hence can have indirect estrogenic effects in transgender women.[107] This is desirable in transgender women, as it can help promote feminization. However, bicalutamide does not increase sex hormone levels if combined with adequate doses of an antigonadotropin such as a modulator, estrogen, or progestogen, due to the negative feedback effects of these medications on sex-hormone production.[45] Because bicalutamide does not lower androgen levels, it may be a particularly favorable antiandrogen for transgender women who wish to help preserve sex drive, sexual function, and/or fertility, as antiandrogens that strongly suppress levels of testosterone and its metabolites, such as and modulators, can greatly disrupt these functions.[108] [36] [109] Although bicalutamide has the potential to increase testosterone levels, there is no effect of this testosterone due to the blockade of the by bicalutamide.

Neyman and colleagues in 2019 published a study on bicalutamide as a puberty blocker in adolescent transgender girls. It was employed both alone (n=17) and in combination with estrogen (n=6) at a dose of 50mg/day in 23transgender girls (mean age of 16years, range 12 to 18.4years) between 2013 and 2018. Of the girls who were treated exclusively with bicalutamide alone, 13 returned for follow-up and were analyzed. In addition to apparently showing effectiveness as an antiandrogen and puberty blocker, bicalutamide alone increased estradiol levels and promoted feminization as a secondary effect. This included breast development to Tanner stages 2 to 5 in 85% of the patients at the first follow-up visit at 6.3months of treatment. Of the two who did not show breast development, one had only been on bicalutamide for 2months and the other progressed to Tanner stage 3 at the second follow-up at 12.5months after starting bicalutamide. Testosterone levels (n=5) were 524 to 823ng/dL and estradiol levels (n=6) were <20 to 61pg/mL in the patients. Liver function tests were performed and were all normal. Although modulators 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 modulators as a puberty blocker in transgender girls.

Studies assessing bicalutamide as an antiandrogen in transgender women are very limited.[110] [111] In any case, besides the study of bicalutamide as a puberty blocker in transgender girls, it has been found to be effective as an antiandrogen in women with hirsutism due to hyperandrogenism and in boys with gonadotropin-independent precocious puberty, and demasculinization and feminization are well-documented effects of bicalutamide in men treated with it for prostate cancer.[112] [113] In addition, nilutamide, a closely related antiandrogen with the same mechanism of action as bicalutamide, has been evaluated in transgender women in at least five small published clinical studies by the same group of researchers.[114] [115] [116] [117] [118] It was given at a relatively high dosage of 300mg/day, the same dosage at 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 150mg/day. Flutamide has also been employed as an antiandrogen in transgender women, with at least two treatment centers at one point reporting its frequent use.[119]

In the studies of nilutamide for transgender hormone therapy, the medication, given alone and not in combination with estrogen, induced observable signs of feminization in young transgender women (ages 19–33 years) within 8 weeks. These changes included breast development, decreased male-pattern hair, decreased spontaneous erections and sex drive, and positive psychological and emotional changes.[120] Signs of breast development, such as increased nipple sensitivity, were, along with decreased male-pattern hair, the earliest indications of feminization, and occurred in all subjects within 6 weeks. Nilutamide by itself more than doubled luteinizing hormone (LH) and testosterone levels and tripled estradiol levels. The addition of 100 μg/day oral ethinylestradiol to nilutamide therapy after 8 weeks abolished the increase in, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the female or castrate range. On the basis of these results, both nilutamide alone, and particularly the combination of nilutamide and estrogen, were regarded as effective for producing antiandrogenic 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 clinically serious nature, is now discouraged due to the unique adverse effects of the medication, most importantly a high incidence of interstitial pneumonitis.[121] [122] This is an adverse effect that can progress to pulmonary fibrosis and can potentially be fatal.[123] Flutamide is also no longer recommended due to excessive risk of hepatotoxicity and liver failure in men with prostate cancer.[124] [125] For these reasons, newer and safer like bicalutamide have largely replaced flutamide and nilutamide, and are now used for relevant indications instead. As selective antagonists, flutamide, nilutamide, and bicalutamide have the same mechanism of action, and bicalutamide has similar or greater efficacy to flutamide and nilutamide as an antiandrogen.[126]

Bicalutamide is known to have a small risk of elevated liver enzymes and serious liver toxicity.[87] [127] As a result, it is recommended that liver function tests (LFTs) periodically be performed.[128] One protocol that has been recommended is to check LFTs at baseline, at one month, at two months, and then every 6months thereafter. The risk of elevated liver enzymes and liver failure with bicalutamide appears to be much smaller than with high doses of, which is the most widely used antiandrogen in transgender women in Europe and elsewhere in the world.[129] [130] However, only low doses of are now recommended for use in transgender women. In the United States, one of the only countries where has not been approved for medical use,[131] [132] spironolactone is commonly used in transgender women instead.[133] [134] [135] Bicalutamide has certain favorable properties as a potential alternative option to these antiandrogens in transgender females. For example, it is much more potent and selective as an antagonist than and spironolactone.[136] However, may be a more potent antiandrogen than bicalutamide in the context of male levels of testosterone, due to its additional action of substantially suppressing testosterone levels at low doses.[137] [138] In transgender women who do not achieve their desired results or are unable to tolerate the side effects of other antiandrogens, switching to bicalutamide may be useful.

The World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8), released in September 2022, recommends against the routine use of bicalutamide in transfeminine people due to lack of study and data on it in this population and safety concerns such as liver toxicity.[139] Instead, the SOC8 recommends other more established and better-studied antiandrogens, like spironolactone,, and modulators. Other less prominent transgender health guidelines are mixed in recommending against use of bicalutamide (guidelines),[140] cautiously allowing it (Fenway Health guidelines),[141] and recommending it over other antiandrogens (Southern African HIV Clinicians' Society guidelines).[142]

Male early puberty

Bicalutamide is used in combination with an aromatase inhibitor such as anastrozole or letrozole in the treatment of peripheral precocious puberty in young boys.[143] [144] [145] [146] The combination has specifically been used to treat male peripheral precocious puberty due to familial male-limited precocious puberty (FMPP, otherwise known as testotoxicosis) and, to a lesser extent, McCune–Albright syndrome.[147] Whereas antigonadotropic medications such as modulators and progestogens like cyproterone acetate and medroxyprogesterone acetate are normally used to treat central precocious puberty, these medications are less or not at all effective in peripheral precocious puberty, as this type of precocious puberty is independent of gonadotropin secretion. Instead, androgens and estrogens must be more directly inhibited in peripheral precocious puberty via the use of sex-hormone receptor antagonists and synthesis inhibitors. A dosage of bicalutamide of 2 mg/kg (or about 40 to 60 mg in boys that are 20 to 30 kg or 45 to 65 lbs) once daily is recommended for use in male peripheral precocious puberty. Bicalutamide is used to block the actions of androgens in the condition, while the aromatase inhibitor is used to decrease levels of estrogens. The goal of treatment is to prevent further development of secondary sexual characteristics, and particularly to slow the rate of growth and improve final adult height.

Due to the rare nature of peripheral precocious puberty, medications used in the treatment of the condition have only been studied limitedly in small numbers of patients.[148] The largest and sole study employing bicalutamide, an industry-sponsored, phase II, multicenter, international, open-label, single-arm clinical trial known as the icalutamide and nastrozole of estotoxicosis (BATT) study, assessed the combination of 12.5 to 100 mg/day bicalutamide and 0.5 to 1 mg/day anastrozole over a period of 12 months in 14 young boys with .[149] [150] [151] The mean age of the boys was 4 ± 2 years, with a range of 2 to 9 years of age. At baseline, the boys weighed 23 ± 6 kg (52 ± 12 lbs) on average, with a range 17 to 35 kg (37 to 77 lbs). Mean total levels of testosterone in the boys were 277 ± 208 ng/dL at baseline and increased to 523 ± 258 ng/dL at 6 months and 427 ± 243 ng/dL at 12 months. Mean total levels of estradiol in the boys were 3.8 pg/mL at baseline and were relatively unchanged at 6 and 12 months (2.5 pg/mL and 3.5 pg/mL, respectively). The dosage of bicalutamide was initiated at 12.5 mg/day and was then increased, with adjustment as necessary to maintain trough circulating (R)-bicalutamide concentrations within a target range of 5 to 15 μg/mL. This range is similar to (R)-bicalutamide levels achieved with approximately 30 to 100 mg/day bicalutamide in adult men with prostate cancer. The mean final dosage of bicalutamide in the boys at 12 months was 60 ± 29 mg/day, with 86% of the boys on either 50 or 100 mg/day bicalutamide. Levels of (R)-bicalutamide were proportional to dosage and did not appear to be related to the age or weight of the boys.

In the trial, growth velocity was decreased, bone age advancement was slowed, aggressiveness was decreased, and masculinization, measured via Tanner staging of pubic hair and genitals, did not appear to further progress.[152] [153] However, the decrease in growth rate was modest and fell just short of reaching statistical significance (p = 0.053). Conversely, although the decrease in rate of bone maturation was described as modest similarly, the ratio of bone age to chronological age was significantly reduced (p < 0.0001). Linear growth and skeletal maturation during normal puberty is mainly due to estradiol and not testosterone in both boys and girls, and hence inhibition of these processes with the combination of bicalutamide and anastrozole in precocious puberty would in theory be mostly dependent on the aromatase inhibitor rather than on bicalutamide.[154] [155] Testicular volume increased mildly over the year that the boys were observed. A New Drug Application of bicalutamide for in the United States was submitted on the basis of the trial data.[156] However, the application was not approved by the Food and Drug Administration, which cited insufficient evidence of effectiveness. Although indication of bicalutamide for the use was not granted, the bicalutamide medication label was updated to include the findings of the study. In terms of side effects, the combination of bicalutamide and anastrozole in the study was described as well tolerated with no safety concerns.[157] However, gynecomastia, attributed to bicalutamide, was observed in almost half of the boys. In addition, one case of mildly elevated liver enzymes (1 of 14; 7%), possibly related to bicalutamide, was observed but resolved spontaneously without discontinuation of therapy.

Additional research is necessary to more clearly determine the true effectiveness and safety of bicalutamide and anastrozole in the treatment of . No long-term results for the study have been published as of yet, but a 5-year follow-up of two of the boys in the study was published and reported continued effectiveness.[158] It is intended that the study will continue until all of the boys reach adult final height, with an additional publication planned in the future. In addition to the study, a variety of case reports and series of bicalutamide in combination with an aromatase inhibitor in male peripheral precocious puberty have been published.[159] [160] [161] [162] [163] [164] [165] [166] [167] [168] These case reports have described similar results as those of the study.[169]

Alternatives to bicalutamide in the treatment of male peripheral precocious puberty include spironolactone, cyproterone acetate, and ketoconazole. Bicalutamide with anastrozole is considered to be superior to the combination of spironolactone and testolactone in peripheral precocious puberty, with greater efficacy and fewer side effects. This corresponds to the fact that bicalutamide is a much more potent and selective antiandrogen than spironolactone. Additionally, dosing is easier with bicalutamide, as it requires administration only once daily as opposed to twice daily at 12-hour intervals with spironolactone. For these reasons, bicalutamide has replaced spironolactone in the treatment of the condition. For comparison to bicalutamide, a higher dosage of spironolactone of 5 mg/kg (or about 100 to 150 mg in boys that are 20 to 30 kg or 45 to 65 lbs) once daily is recommended for use in male peripheral precocious puberty.

Long-lasting erections

Antiandrogens can considerably relieve and prevent priapism (potentially painful penile erections that last more than four hours) via direct blockade of penile .[170] [171] 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,[172] [173] [174] and is used for this indication off-label.[175] [176] 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 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.[177] Despite the apparent efficacy of bicalutamide for priapism, a small clinical study found that bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer.[178]

Sexual deviance

The antigonadotropic antiandrogens, medroxyprogesterone acetate (MPA), and analogues have all been widely used to treat paraphilias (e.g., pedophilia) and hypersexuality in men.[179] [180] 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, like flutamide and bicalutamide have been suggested as potential medications for these indications and may have superior tolerability and safety relative to antigonadotropic antiandrogens.[181] [182] [183] As an example, because 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.[184] However, due to unopposed estrogen signaling, a substantial incidence of gynecomastia is associated with . In addition to potential monotherapy use, have been advocated for temporarily suppressing sex drive during the start of agonist treatment via prevention of the increased androgen signaling associated with the initial testosterone flare.

Though treatment of paraphilias and hypersexuality with selective 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 monotherapy. The explanation for this is that 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, monotherapy may have limited usefulness in the management of paraphilias and hypersexuality. The addition of to antigonadotropic antiandrogens like analogues may have some usefulness however, particularly in severe cases.[185] In any case, insufficient evidence is available at this time, and further research is thus warranted.

Notes and References

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  5. Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ . 6 . Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group . Urology . 50 . 3 . 330–336 . September 1997 . 9301693 . 10.1016/S0090-4295(97)00279-3 .
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  8. Book: Bruce A. . Chabner . Dan L. . Longo . vanc . Cancer Chemotherapy and Biotherapy: Principles and Practice . 8 November 2010 . Lippincott Williams & Wilkins . 978-1-60547-431-1 . 679–680 . From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used..
  9. Vogelzang NJ . Enzalutamide--a major advance in the treatment of metastatic prostate cancer . The New England Journal of Medicine . 367 . 13 . 1256–1257 . September 2012 . 23013078 . 10.1056/NEJMe1209041 . The first nonsteroidal antiandrogen agents — flutamide, nilutamide, and bicalutamide2 — were shown to be less effective than castration in cases of metastatic castration-resistant prostate cancer, but bicalutamide is still widely used as a moderately effective secondary hormone therapy because of an excellent safety profile. . 32314622 .
  10. Book: Weber, Georg F. . vanc . Molecular Therapies of Cancer . 22 July 2015 . Springer . 978-3-319-13278-5 . 318– . Compared to flutamide and nilutamide, bicalutamide has a 2-fold increased affinity for the Androgen Receptor, a longer half-life, and substantially reduced toxicities. Based on a more favorable safety profile relative to flutamide, bicalutamide is indicated for use in combination therapy with a Gonadotropin Releasing Hormone analog for the treatment of advanced metastatic prostate carcinoma..
  11. Kolvenbag GJ, Blackledge GR . Worldwide activity and safety of bicalutamide: a summary review . Urology . 47 . 1A Suppl . 70–9; discussion 80–4 . January 1996 . 8560681 . 10.1016/s0090-4295(96)80012-4 . Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer. .
  12. Book: Thomas L. . Lemke . David A. . Williams. vanc . Foye's Principles of Medicinal Chemistry . 2008 . Lippincott Williams & Wilkins . 978-0-7817-6879-5 . 121, 1288, 1290 . live . https://web.archive.org/web/20170908145128/https://books.google.com/books?id=R0W1ErpsQpkC . 8 September 2017 . dmy-all.
  13. Kaliks RA, Del Giglio A . Management of advanced prostate cancer . Revista da Associação Médica Brasileira . 54 . 2 . 178–182 . 2008 . 18506331 . 10.1590/S0104-42302008000200025 . live . dmy-all . https://web.archive.org/web/20170510112152/http://www.scielo.br/pdf/ramb/v54n2/a25v54n2.pdf . 10 May 2017 .
  14. Payen O, Top S, Vessières A, Brulé E, Lauzier A, Plamont MA, McGlinchey MJ, Müller-Bunz H, Jaouen G . 6 . Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide . Journal of Organometallic Chemistry . 696 . 5 . 2011 . 1049–1056 . 10.1016/j.jorganchem.2010.10.051 . Cyproterone acetate was one of the first steroidal antiandrogen clinically used but its side-effects, especially the interaction with the progestin and glucocorticoid receptor, made this drug less popular than the nonsteroidal antiandrogens such as nilutamide [3,4], flutamide [5–7] and bicalutamide [8]..
  15. Book: James Leonard . Gulley . vanc . Prostate Cancer . 2011 . Demos Medical Publishing . 978-1-935281-91-7 . 81– . live . https://web.archive.org/web/20160425141102/https://books.google.com/books?id=WJkjgbRJe3EC&pg=PT81 . 25 April 2016 . dmy-all.
  16. Book: Lutz . Moser . vanc . Controversies in the Treatment of Prostate Cancer . 1 January 2008 . Karger Medical and Scientific Publishers . 978-3-8055-8524-8 . 41–42 . live . https://web.archive.org/web/20160516112448/https://books.google.com/books?id=4J4OCRyHWRYC&pg=PA41 . 16 May 2016 . dmy-all.
  17. Book: Gulley, James L. . vanc . Prostate Cancer . 20 December 2011 . Demos Medical Publishing . 978-1-935281-91-7 . 505–.
  18. Book: William . Figg . Cindy H. . Chau . Eric J. . Small . vanc . Drug Management of Prostate Cancer . 14 September 2010 . Springer Science & Business Media . 978-1-60327-829-4 . 56, 71–72, 75, 93.
  19. Book: Parviz . Kavoussi . Raymond A. . Costabile . Andrea . Salonia . vanc . Clinical Urologic Endocrinology: Principles for Men's Health . 17 October 2012 . Springer Science & Business Media . 978-1-4471-4404-5 . 7–.
  20. Book: Louis J . Denis . Keith . Griffiths . Amir V . Kaisary . Gerald P . Murphy . vanc . Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment . 1 March 1999 . CRC Press . 978-1-85317-422-3 . 55,279–280 . live . https://web.archive.org/web/20160603180141/https://books.google.com/books?id=GreZlojD-tYC&pg=PA280 . 3 June 2016 . dmy-all.
  21. Balk SP . Androgen receptor as a target in androgen-independent prostate cancer . Urology . 60 . 3 Suppl 1 . 132–8; discussion 138–9 . September 2002 . 12231070 . 10.1016/S0090-4295(02)01593-5 .
  22. Sarosdy MF . Which is the optimal antiandrogen for use in combined androgen blockade of advanced prostate cancer? The transition from a first- to second-generation antiandrogen . Anti-Cancer Drugs . 10 . 9 . 791–796 . October 1999 . 10587288 . 10.1097/00001813-199910000-00001 .
  23. Book: Prokar . Dasgupta . Roger S. . Kirby . vanc . ABC of Prostate Cancer . 27 December 2011 . John Wiley & Sons . 978-1-4443-3437-1 . 52–.
  24. Book: Bruskewitz, Reginald . vanc . Atlas of the Prostate . 6 December 2012 . Springer Science & Business Media . 978-1-4615-6505-5 . 5,190.
  25. Book: Denis, Louis . vanc . Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment . 6 December 2012 . Springer Science & Business Media . 978-3-642-45745-6 . 128, 158, 203.
  26. Luo S, Martel C, Chen C, Labrie C, Candas B, Singh SM, Labrie F . Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity . Urology . 50 . 6 . 913–919 . December 1997 . 9426723 . 10.1016/S0090-4295(97)00393-2 .
  27. Gauthier S, Martel C, Labrie F . Steroid derivatives as pure antagonists of the androgen receptor . The Journal of Steroid Biochemistry and Molecular Biology . 132 . 1–2 . 93–104 . October 2012 . 22449547 . 10.1016/j.jsbmb.2012.02.006 . 28982450 .
  28. Book: Lupulescu, Aurel . vanc . Hormones and Vitamins in Cancer Treatment . 24 October 1990 . CRC Press . 978-0-8493-5973-6 . 113–.
  29. Book: Zbigniew . Petrovich . Luc . Baert . Luther W. . Brady . vanc . Carcinoma of the Prostate: Innovations in Management . 6 December 2012 . Springer Science & Business Media . 978-3-642-60956-5 . 687–.
  30. Book: Held-Warmkessel, Jeanne . vanc . Contemporary Issues in Prostate Cancer: A Nursing Perspective . 2006 . Jones & Bartlett Learning . 978-0-7637-3075-8 . 275–.
  31. Book: Thomas . Steckler . N.H. . Kalin . J.M.H.M. . Reul . vanc . Handbook of Stress and the Brain Part 2: Stress: Integrative and Clinical Aspects . 25 February 2005 . Elsevier . 978-0-08-055331-3 . 442–.
  32. Book: Waun Ki . Hong . James F. . Holland . vanc . Holland-Frei Cancer Medicine 8 . 2010 . PMPH-USA . 978-1-60795-014-1 . 939–.
  33. Book: Alan J. . Wein . Louis R. . Kavoussi . Andrew C. . Novick . Alan W. . Partin . Craig A. . Peters . vanc . Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set . 25 August 2011 . Elsevier Health Sciences . 978-1-4160-6911-9 . 2938–2939, 2946 . live . https://web.archive.org/web/20160505225217/https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2939 . 5 May 2016 . dmy-all.
  34. Book: Jack H. . Mydlo . Ciril J. . Godec . vanc . Prostate Cancer: Science and Clinical Practice . 29 September 2015 . Elsevier Science . 978-0-12-800592-7 . 516–521, 534–540 . live . https://web.archive.org/web/20170908222331/https://books.google.com/books?id=292cBAAAQBAJ&pg=PA530 . 8 September 2017 . dmy-all.
  35. Book: Jerome F. . Strauss III . Robert L. . Barbieri . vanc . Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management . 28 August 2013 . Elsevier Health Sciences . 978-1-4557-5972-9 . 688– . Bone density improves in men receiving bicalutamide, most likely secondary to the 146% increase in estradiol and the fact that estradiol is the major mediator of bone density in men..
  36. Iversen P, Melezinek I, Schmidt A . Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function . BJU International . 87 . 1 . 47–56 . January 2001 . 11121992 . 10.1046/j.1464-410x.2001.00988.x . 28215804 . free .
  37. Wibowo E, Schellhammer P, Wassersug RJ . Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy . The Journal of Urology . 185 . 1 . 17–23 . January 2011 . 21074215 . 10.1016/j.juro.2010.08.094 .
  38. Motofei IG, Rowland DL, Popa F, Kreienkamp D, Paunica S . Preliminary study with bicalutamide in heterosexual and homosexual patients with prostate cancer: a possible implication of androgens in male homosexual arousal . BJU International . 108 . 1 . 110–115 . July 2011 . 20955264 . 10.1111/j.1464-410X.2010.09764.x . 45482984 .
  39. Wibowo E, Wassersug RJ . The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy . Critical Reviews in Oncology/Hematology . 87 . 3 . 224–238 . September 2013 . 23484454 . 10.1016/j.critrevonc.2013.01.006 .
  40. Book: Chedrese, P. Jorge . vanc . Reproductive Endocrinology: A Molecular Approach . 13 June 2009 . Springer Science & Business Media . 978-0-387-88186-7 . 233– . live . https://web.archive.org/web/20170905040216/https://books.google.com/books?id=3FJXUN6Vh44C . 5 September 2017 . dmy-all.
  41. King SR . Emerging roles for neurosteroids in sexual behavior and function . Journal of Andrology . 29 . 5 . 524–533 . 2008 . 18567641 . 10.2164/jandrol.108.005660 . 8834769 . free .
  42. Anderson J . The role of antiandrogen monotherapy in the treatment of prostate cancer . BJU International . 91 . 5 . 455–461 . March 2003 . 12603397 . 10.1046/j.1464-410X.2003.04026.x . 8639102 . free .
  43. Boccardo F . Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy? . Critical Reviews in Oncology/Hematology . 35 . 2 . 121–132 . August 2000 . 10936469 . 10.1016/S1040-8428(00)00051-2 .
  44. Kolvenbag GJ, Iversen P, Newling DW . Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer . Urology . 58 . 2 Suppl 1 . 16–23 . August 2001 . 11502439 . 10.1016/s0090-4295(01)01237-7 .
  45. Book: Shlomo Melmed. Williams Textbook of Endocrinology. 1 January 2016. Elsevier Health Sciences. 978-0-323-29738-7. 752–. 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.
  46. Sugiono M, Winkler MH, Okeke AA, Benney M, Gillatt DA . Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer--a pilot study . Prostate Cancer and Prostatic Diseases . 8 . 1 . 91–94 . 2005 . 15711607 . 10.1038/sj.pcan.4500784 . 9151853 . free .
  47. Book: Wolfgang Hinkelbein. Kurt Miller. Thomas Wiegel. Prostatakarzinom — urologische und strahlentherapeutische Aspekte: urologische und strahlentherapeutische Aspekte. Prostate carcinoma — urological and radiotherapeutic aspects: urological and radiotherapeutic aspects. 7 March 2013. Springer-Verlag. 978-3-642-60064-7. 99–.
  48. Zouboulis CC, Degitz K . Androgen action on human skin -- from basic research to clinical significance . Experimental Dermatology . 13 . Suppl 4 . 5–10 . 2004 . 15507105 . 10.1111/j.1600-0625.2004.00255.x . 34863608 .
  49. Book: Alan R. . Shalita . James Q. . Del Rosso . Guy . Webster . vanc . Acne Vulgaris . 21 March 2011 . CRC Press . 978-1-61631-009-7 . 33– . live . https://web.archive.org/web/20161209210819/https://books.google.com/books?id=CIPOBQAAQBAJ&pg=PA33 . 9 December 2016 . dmy-all.
  50. Book: Christos C. . Zouboulis . Andreas D. . Katsambas . Albert M. . Kligman . vanc . Pathogenesis and Treatment of Acne and Rosacea . 28 July 2014 . Springer . 978-3-540-69375-8 . 121– . live . https://web.archive.org/web/20161210040108/https://books.google.com/books?id=vnQqBAAAQBAJ&pg=PA121 . 10 December 2016 . dmy-all.
  51. Marks LS . 5alpha-reductase: history and clinical importance . Reviews in Urology . 6 . Suppl 9 . S11–S21 . 2004 . 16985920 . 1472916 .
  52. Book: Ethel . Sloane . vanc . Biology of Women . 2002 . Cengage Learning . 0-7668-1142-5 . 160–.
  53. Book: Philip M . Hanno . Thomas J. . Guzzo . S. Bruce . Malkowicz . Alan J. . Wein . vanc . Penn Clinical Manual of Urology E-Book: Expert Consult - Online . 26 January 2014 . Elsevier Health Sciences . 978-0-323-24466-4 . 782–.
  54. Book: Catherine . Harper . vanc . Intersex . 1 August 2007 . Berg . 978-1-84788-339-1 . 123–.
  55. Book: Ulrik . Blume-Peytavi . David A. . Whiting . Ralph M. . Trüeb . vanc . Hair Growth and Disorders . 26 June 2008 . Springer Science & Business Media . 978-3-540-46911-7 . 161–162, 181.
  56. Diamanti-Kandarakis E, Tolis G, Duleba AJ . Androgens and therapeutic aspects of antiandrogens in women . Journal of the Society for Gynecologic Investigation . 2 . 4 . 577–592 . 1995 . 9420861 . 10.1177/107155769500200401 . Androgen receptors have been detected in many areas including the cortex, pituitary, hypothalamus, preoptic area, septum, amygdala, thalamus, and brain stem.79,80 These receptors appear to be identical to other ARs and may be activated by both testosterone and 5α-DHT. In the cortex and pituitary, androgens do not undergo significant aromatization, and it appears that the effects of androgens on these tissues are mediated by ARs. In contrast, most of the effects of androgens on the hypothalamus and limbic system are thought to be mediated by estrogen receptors rather than AR.78 This concept, the aromatization hypothesis, has been validated in studies of the brain of the female subhuman primate. . 32242838 .
  57. Katsambas AD, Dessinioti C . Hormonal therapy for acne: why not as first line therapy? facts and controversies . Clinics in Dermatology . 28 . 1 . 17–23 . 2010 . 20082945 . 10.1016/j.clindermatol.2009.03.006 .
  58. Book: Hywel . Williams . Michael . Bigby . Thomas . Diepgen . Andrew . Herxheimer . Luigi . Naldi . Berthold . Rzany . vanc . Evidence-Based Dermatology . 22 January 2009 . John Wiley & Sons . 978-1-4443-0017-8 . 529– . live . https://web.archive.org/web/20160502212533/https://books.google.com/books?id=SbsQij5xkfYC&pg=PA529 . 2 May 2016 . dmy-all.
  59. Erem C . Update on idiopathic hirsutism: diagnosis and treatment . Acta Clinica Belgica . 68 . 4 . 268–274 . 2013 . 24455796 . 10.2143/ACB.3267 . 39120534 .
  60. Rabe T, Albring C, Blume-Peytavi U, Egarter C, Geisthövel F, König K, Kuhl H, Merkle E, Mueck AO, Reisch N, Schüring A, Stute P, Toth B, Wildt L, Zouboulis CC . Hirsutismus – Medikamentöse Therapie Gemeinsame Stellungnahme der Deutschen Gesellschaft für Gynäkologische Endokrinologie und Fortpflanzungsmedizin e.V. und des Berufsverbands der Frauenärzte e.V. . Hirsutism – Medicinal treatment. Joint statement of the German Society of Gynaecological Endocrinology and Reproductive Medicine and the Professional Association of Gynaecologists . Journal für Reproduktionsmedizin und Endokrinologie . 2015 . 12 . 3 . 102–149 . de . 1810-2107 .
  61. Müderris II, Bayram F, Ozçelik B, Güven M . New alternative treatment in hirsutism: bicalutamide 25 mg/day . Gynecological Endocrinology . 16 . 1 . 63–66 . February 2002 . 11915584 . 10.1080/gye.16.1.63.66 . 6942048 .
  62. Moretti C, Guccione L, Di Giacinto P, Simonelli I, Exacoustos C, Toscano V, Motta C, De Leo V, Petraglia F, Lenzi A . 6 . Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial . The Journal of Clinical Endocrinology and Metabolism . 103 . 3 . 824–838 . March 2018 . 29211888 . 10.1210/jc.2017-01186 . 3784055 . free .
  63. Müderris II, Öner G . Hirsutizm Tedavisinde Flutamid ve Bikalutamid Kullanımı . Flutamide and Bicalutamide Treatment in Hirsutism . Turkiye Klinikleri Journal of Endocrinology-Special Topics . 2 . 2 . 2009 . 110–2 . tr . 1304-0529 .
  64. Efficacy and Safety of Myo-Inositol Supplementation in the Treatment of Obese Hirsute PCOS Women: Comparative Evaluation with OCP+Bicalutamide Therapy . Moretti CG, Guccione L, Di Giacinto P, Cannuccia A, Meleca C, Lanzolla G, Andreadi A, Lauro D . Endocrine Reviews . 2016 . 1325–1326 . https://web.archive.org/web/20200201071020/https://endo.confex.com/endo/2016endo/webprogram/Paper26631.html . dead . 2020-02-01 .
  65. Book: Michael . Bigby . Andrew . Herxheimer . Luigi . Naldi . Berthold . Rzany . Robert . Dellavalle . Yuping . Ran . Masutaka . Furue . vanc . 3 . Evidence-Based Dermatology . 5 June 2014 . Wiley . 978-1-118-35762-0 . 1904–.
  66. Book: Shapiro, Jerry . vanc . Hair Disorders: Current Concepts in Pathophysiology, Diagnosis and Management, An Issue of Dermatologic Clinics . 12 November 2012 . Elsevier Health Sciences . 978-1-4557-7169-1 . 187–.
  67. Sarrafzadeh Y, Sarrafzadeh S, Sheibani A . Clinical Gynecologic Endocrinology and Infertility: A Literature Review . Journal of Research in Medical and Dental Science . 2018 . 6 . 3 . 220–225 . 2347-2545 . 10.24896/jrmds.20186334 . 31 January 2024 .
  68. Neven AC, Laven J, Teede HJ, Boyle JA . A Summary on Polycystic Ovary Syndrome: Diagnostic Criteria, Prevalence, Clinical Manifestations, and Management According to the Latest International Guidelines . Seminars in Reproductive Medicine . 36 . 1 . 5–12 . January 2018 . 30189445 . 10.1055/s-0038-1668085 . free .
  69. Carvalho RM, Santos LD, Ramos PM, Machado CJ, Acioly P, Frattini SC, Barcaui CB, Donda AL, Melo DF . 6 . Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know . Journal of Cosmetic Dermatology . 21. 10. January 2022 . 4171–4175 . 35032336 . 10.1111/jocd.14773 . 253239337 .
  70. Meyer-Gonzalez T, Bacqueville D, Grimalt R, Mengeaud V, Piraccini BM, Rudnicka L, Saceda-Corralo D, Vogt A, Vano-Galvan S . 6 . Current controversies in trichology: a European expert consensus statement . Journal of the European Academy of Dermatology and Venereology . 35 . Suppl 2 . 3–11 . November 2021 . 34668238 . 10.1111/jdv.17601 . 239029062 . 11585/863826 . free .
  71. Nestor MS, Ablon G, Gade A, Han H, Fischer DL . Treatment options for androgenetic alopecia: Efficacy, side effects, compliance, financial considerations, and ethics . Journal of Cosmetic Dermatology . 20 . 12 . 3759–3781 . December 2021 . 34741573 . 10.1111/jocd.14537 . 9298335 . 243801494 .
  72. Ascenso A, Marques HC . Acne in the adult . Mini Reviews in Medicinal Chemistry . 9 . 1 . 1–10 . January 2009 . 19149656 . 10.2174/138955709787001730 .
  73. Hassoun LA, Chahal DS, Sivamani RK, Larsen LN . The use of hormonal agents in the treatment of acne . Seminars in Cutaneous Medicine and Surgery . 35 . 2 . 68–73 . June 2016 . 27416311 . 10.12788/j.sder.2016.027 .
  74. Azarchi S, Bienenfeld A, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR . Androgens in women: Hormone-modulating therapies for skin disease . Journal of the American Academy of Dermatology . 80 . 6 . 1509–1521 . June 2019 . 30312645 . 10.1016/j.jaad.2018.08.061 . 52973096 .
  75. Bettoli V, Zauli S, Virgili A . Is hormonal treatment still an option in acne today? . The British Journal of Dermatology . 172 . Suppl 1 . 37–46 . July 2015 . 25627824 . 10.1111/bjd.13681 . 35615492 . free .
  76. Nguyen HL, Tollefson MM . Endocrine disorders and hormonal therapy for adolescent acne . Current Opinion in Pediatrics . 29 . 4 . 455–465 . August 2017 . 28562419 . 10.1097/MOP.0000000000000515 . 4640778 .
  77. Diamanti-Kandarakis E . Current aspects of antiandrogen therapy in women . Current Pharmaceutical Design . 5 . 9 . 707–723 . September 1999 . 10.2174/1381612805666230111201150 . 10495361 . Several trials demonstrated complete clearing of acne with flutamide [62,77]. Flutamide used in combination with an [oral contraceptive], at a dose of 500mg/d, flutamide caused a dramatic decrease (80%) in total acne, seborrhea and hair loss score after only 3 months of therapy [53]. When used as a monotherapy in lean and obese PCOS, it significantly improves the signs of hyperandrogenism, hirsutism and particularly acne [48]. [...] flutamide 500mg/d combined with an [oral contraceptive] caused an increase in cosmetically acceptable hair density, in sex of seven women suffering from diffuse androgenetic alopecia [53]. .
  78. Book: Walter Brown Shelley. E. Dorinda Shelley. Advanced Dermatologic Therapy II. 2001. W. B. Saunders. 978-0-7216-8258-7.
  79. Book: Adam Balen. Stephen Franks. Roy Homburg. Sean Kehoe. Current Management of Polycystic Ovary Syndrome. October 2010. Cambridge University Press. 978-1-906985-41-7. 132–.
  80. Blackledge GR . Clinical progress with a new antiandrogen, Casodex (bicalutamide) . European Urology . 29 . Suppl 2 . 96–104 . 1996 . 8717470 . 10.1159/000473847 .
  81. Fradet Y . Bicalutamide (Casodex) in the treatment of prostate cancer . Expert Review of Anticancer Therapy . 4 . 1 . 37–48 . February 2004 . 14748655 . 10.1586/14737140.4.1.37 . 34153031 .
  82. Book: Lotti . Francesco . Maggi . Mario . European Handbook of Dermatological Treatments . Hormonal Treatment for Skin Androgen-Related Disorders . vanc . 2015 . 1451–1464 . 10.1007/978-3-662-45139-7_142 . 978-3-662-45138-0 .
  83. Singh SM, Gauthier S, Labrie F . Androgen receptor antagonists (antiandrogens): structure-activity relationships . Current Medicinal Chemistry . 7 . 2 . 211–247 . February 2000 . 10637363 . 10.2174/0929867003375371 . 20732899 .
  84. Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A . Flutamide-induced hepatotoxicity: ethical and scientific issues . European Review for Medical and Pharmacological Sciences . 21 . 1 Suppl . 69–77 . March 2017 . 28379593 .
  85. Shaw JC . Hormonal therapies in acne . Expert Opinion on Pharmacotherapy . 3 . 7 . 865–874 . July 2002 . 12083987 . 10.1517/14656566.3.7.865 . 44388601 .
  86. Kaur S, Verma P, Sangwan A, Dayal S, Jain VK . Etiopathogenesis and Therapeutic Approach to Adult Onset Acne . Indian Journal of Dermatology . 61 . 4 . 403–407 . 2016 . 27512185 . 4966398 . 10.4103/0019-5154.185703 . free .
  87. Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A . Hepatotoxicity induced by antiandrogens: a review of the literature . Urologia Internationalis . 73 . 4 . 289–295 . 2004 . 15604569 . 10.1159/000081585 . 24799765 .
  88. Iswaran TJ, Imai M, Betton GR, Siddall RA . An overview of animal toxicology studies with bicalutamide (ICI 176,334) . The Journal of Toxicological Sciences . 22 . 2 . 75–88 . May 1997 . 9198005 . 10.2131/jts.22.2_75 . free .
  89. Book: Robert E. . Smith . vanc . Medicinal Chemistry – Fusion of Traditional and Western Medicine . 4 April 2013 . Bentham Science Publishers . 978-1-60805-149-6 . 306– . live . https://web.archive.org/web/20160529034219/https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 . 29 May 2016 . dmy-all.
  90. Web site: Bicalutamide . The American Society of Health-System Pharmacists . 8 December 2016 . live . https://web.archive.org/web/20161229173027/https://www.drugs.com/monograph/bicalutamide.html . 29 December 2016 . dmy-all.
  91. Book: Adam Ostrzenski . Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy . 2002 . Lippincott Williams & Wilkins . 978-0-7817-2761-7 . 86–.
  92. Randolph JF . Gender-Affirming Hormone Therapy for Transgender Females . Clinical Obstetrics and Gynecology . 61 . 4 . 705–721 . December 2018 . 30256230 . 10.1097/GRF.0000000000000396 . ANDROGEN RECEPTOR BLOCKERS: Androgen receptor blockers bind directly to the androgen receptor and either competitively inhibit binding by testosterone or DHT, or irreversibly bind and induce variable antagonist/agonist effects. The prototype drug in this class is flutamide, a competitive inhibitor of the androgen receptor infrequently used clinically today due to complications including liver failure and death. Bicalutamide is a safer, longer acting alternative with a more favorable safety profile, although a small percentage of users will show elevated liver enzymes and rare cases of liver failure have been reported. Bicalutamide is approved for use in prostate cancer at an oral dose of 50 mg daily, but has been used in the treatment of hirsutism, polycystic ovary syndrome, precocious puberty, persistent erections, and in sex offenders. Studies in transwomen are quite limited, but bicalutamide appears to be effective and induces an actual increase in serum estradiol levels, a welcome adjunct effect in transwomen (Table 4). [...] TABLE 4. Available Antiandrogens/Androgen Suppressors and Routes of Administration: [...] Bicalutamide Oral 50 mg daily. . 52821192 .
  93. Book: Fishman. Sarah L.. Transgender Medicine. Paliou. Maria. Poretsky. Leonid. Hembree. Wylie C.. Endocrine Care of Transgender Adults. 2019. 143–163. 2523-3785. 10.1007/978-3-030-05683-4_8. Non-steroidal selective androgen receptor antagonists, developed as a treatment for androgen-sensitive prostate cancer, are occasionally used in transgender females who do not achieve their desired results or do not tolerate alternative drugs [52]. There are isolated reports of successful outcomes with flutamide (Eulexin), though reportedly not as effective as cyproterone acetate in reducing testosterone levels [12]. Both flutamide and bicalutamide (Casodex), in conjunction with oral contraceptive pills, have shown significant improvements in hirsutism in natal females with polycystic ovarian syndrome (PCOS) [53, 54, 55, 56, 57]. The use of these agents as antiandrogens in transgender patients has been limited by concerns of hepatotoxicity. However, at low doses, these agents have shown to be both well tolerated and effective when used for the treatment of hirsutism [57]. [...] Table 8.2: Antiandrogens: [...] Androgen receptor blocker: [...] Type: Bicalutamide. Route: Oral. Dose: 25–50 mg/day.. Contemporary Endocrinology. 978-3-030-05682-7. 86772102.
  94. Neyman A, Fuqua JS, Eugster EA . Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents . The Journal of Adolescent Health . 64 . 4 . 544–546 . April 2019 . 30612811 . 6431559 . 10.1016/j.jadohealth.2018.10.296 .
  95. Book: Courtney Finlayson. Pubertal Suppression in Transgender Youth. 3 August 2018. Elsevier Health Sciences. 978-0-323-56964-4. 81, 98. As a class, the antiandrogens (bicalutamide, flutamide, and nilutamide bind directly to the androgen receptor, thereby inhibiting its availability and increasing the receptors' degradation.50 The primary indication is for metastatic prostate cancer, although it has been used in the transfeminine population.52 These three agents differ primarily by pharmacokinetics, bicalutamide having the longest duration of action. While on the medication, testosterone levels are expected to rise dramatically but do not have an effect. Gynecomastia is a recognized side effect and could be desired in the transfeminine population. There are cases of fulminant hepatitis described, and it is recommended that transaminase levels are checked prior to initiation and then at 4-month intervals.53 The use of antiandrogens has not been rigorously studied in the gender nonconforming population, but its use is recommended for consideration in some transgender-health related publications.54-56 (p. 98) [...] Spironolactone, a weak androgen receptor antagonist, can also be used in [adolescent transgender girls] if GnRH agonists are not used. The medication, prescribed at dosing ranging from 100 to 300 mg/day orally,7 blunts the effect of androgens and can be helpful at slowing development of unwanted facial and body hair, or other masculinizing effects of male puberty. Other medications that suppress androgen action, including cyproterone acetate, flutamide, nilutamide, and bicalutamide, have been reported for use in transgender women as well.38 (p. 81).
  96. Book: Benjamin Vincent. Transgender Health: A Practitioner's Guide to Binary and Non-Binary Trans Patient Care. 21 June 2018. Jessica Kingsley Publishers. 978-1-78450-475-5. 158–. Bicalutamide (Casodex®): This antiandrogen is used by some clinicians in the United States, it is not used in the UK. Its primary use is in the treatment of prostate cancer, but may effectively block testosterone production at much lower doses than are given in that context. Bicalutamide is associated with some risk of liver function abnormalities (Kolvenbag and Blackledge 1996), which are deemed acceptable in the context of prostate cancer but less so in gender affirming medical intervention because of the range of other options available (Deutsch 2017). (pp. 158–159) [...] There has been specific publication of a case of prostate cancer in a transgender woman, 41 years after accessing HRT (Miksad et al. 2006). In this case, oral bicalutamide and dutasteride were prescribed, which were effective in their antiandrogenic functions while also being maintainable with the patient's estrogen regimen. Indeed, bicalutamide may be an option as part of transfeminine HRT due to its antiandrogenic properties, such that synergy may be obtained in specific treatment circumstances. (p. 115–116).
  97. Gooren LJ . Clinical practice. Care of transsexual persons . The New England Journal of Medicine . 364 . 13 . 1251–1257 . March 2011 . 21449788 . 10.1056/nejmcp1008161 . Male-to-Female Transsexuals: Hormonal therapy is prescribed for male-to-female transsexuals to induce breast formation and a more female distribution of fat and to reduce male-pattern hair growth.19 To achieve these goals, the biologic action of androgens must be almost completely neutralized. Administration of estrogens suppresses gonadotropin output and therefore androgen production, but combining this treatment with a progestational agent, a gonadotropin-releasing-hormone (GnRH) analogue,20 or other medications that suppress androgen action (e.g., cyproterone acetate, flutamide, nilutamide, or bicalutamide) appears to be more effective.21 [...] Supplemental Table 1. Cross-sex hormone administration to transsexuals: Male-to-female transsexuals: 1) Drugs suppressing testosterone levels and/or testosterone action: Non-steroidal pure antiandrogens: flutamide 250 mg twice daily, nilutamide 150 mg twice daily, or the more recent bicalutamide 50 mg once daily (fewer side effects). .
  98. Book: J. Larry . Jameson . Leslie J. . De Groot . vanc . Edndocrinology: Adult and Pediatric . 25 February 2015 . Elsevier Health Sciences . 978-0-323-32195-2 . 2139, 2172, 2425–2426 . Male-to-Female Transsexual Treatment. [...] For suppression of androgen secretion/action, several agents are available. In Europe, the most widely used drug is cyproterone acetate (usually 50 mg twice daily), a progestational compound with antiandrogenic properties. If not available, medroxyprogesterone acetate, 5 to 10 mg/day, is a less-effective alternative. Nonsteroidal anti-androgens, such as flutamide and nilutamide [and bicalutamide], are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol. The latter is desirable in this context, as it has feminizing effects. Spironolactone (up to 100 mg twice daily), a diuretic with antiandrogenic properties, has similar effects and is widely available..
  99. Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A . Androgen insensitivity syndrome: clinical features and molecular defects . Hormones . 7 . 3 . 217–229 . 2008 . 18694860 . 10.14310/horm.2002.1201 . 8232293 . free .
  100. Braunstein GD . Clinical practice. Gynecomastia . The New England Journal of Medicine . 357 . 12 . 1229–1237 . September 2007 . 17881754 . 10.1056/NEJMcp070677 .
  101. Book: Gentilini . Oreste D. . Boccardo . Chiara . The Outpatient Breast Clinic . Male Breast Diseases . vanc . 2015 . 431–446 . 10.1007/978-3-319-15907-2_19 . 978-3-319-15906-5 .
  102. Kanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW . Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men . The American Journal of Surgical Pathology . 24 . 1 . 74–80 . January 2000 . 10632490 . 10.1097/00000478-200001000-00009 . 37752666 . free .
  103. Higano CS . Side effects of androgen deprivation therapy: monitoring and minimizing toxicity . Urology . 61 . 2 Suppl 1 . 32–38 . February 2003 . 12667885 . 10.1016/S0090-4295(02)02397-X .
  104. Book: Lehne, Richard A. . vanc . Pharmacology for Nursing Care . 2013 . Elsevier Health Sciences . 978-1-4377-3582-6 . 1297–.
  105. el-Rayes BF, Hussain MH . Hormonal therapy for prostate cancer: past, present and future . Expert Review of Anticancer Therapy . 2 . 1 . 37–47 . February 2002 . 12113064 . 10.1586/14737140.2.1.37 . At 2-year follow-up, loss of spontaneous erections and sexual function occurred in 80 vs. 92% and 78 vs. 88% in the [flutamide, nilutamide and bicalutamide] versus CPA groups, respectively. . 6869320 .
  106. Libby V, Lee M, Liu JH . Transgender health: Hormonal management at 50 years and beyond . Maturitas . 126 . 34–37 . August 2019 . 31239115 . 10.1016/j.maturitas.2019.04.220 . 155768314 .
  107. Book: Baudewijntje P.C. . Kreukels . Thomas D. . Steensma . Annelou L.C. . de Vries . vanc . Gender Dysphoria and Disorders of Sex Development: Progress in Care and Knowledge . 1 July 2013 . Springer Science & Business Media . 978-1-4614-7441-8 . 280– . Nonsteroidal antiandrogens, such as flutamide (50–75 mg/day) and nilutamide (150 mg/day), are also used, but they increase gonadotropin output with a rise of testosterone and estradiol; the rise of estradiol is a desirable effect in this context..
  108. Gao Y, Maurer T, Mirmirani P . Understanding and Addressing Hair Disorders in Transgender Individuals . American Journal of Clinical Dermatology . 19 . 4 . 517–527 . August 2018 . 29352423 . 10.1007/s40257-018-0343-z . Non-steroidal antiandrogens include flutamide, nilutamide, and bicalutamide, which do not lower androgen levels and may be favorable for individuals who want to preserve sex drive and fertility [9]. . 6467968 .
  109. Morgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, Cardillo MR, Petrangeli E, Russo M, Di Silverio F . 6 . Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study . Histopathology . 38 . 3 . 195–201 . March 2001 . 11260298 . 10.1046/j.1365-2559.2001.01077.x . 11573/387981 . 36892099 .
  110. Web site: Search query: "bicalutamide" OR "bicalutamid" OR "bikalutamid" OR "bicalutamida" OR "casodex" "transgender" OR "transsexual" OR "transsexuals" OR "trans girls" OR "transgirls" OR "trans women" OR "transwomen" OR "male-to-female" - Google Scholar . 2019-03-28 .
  111. 10th Individual Abstracts for International Meeting of Pediatric Endocrinology: Free Communication and Poster Sessions, Abstracts . Hormone Research in Paediatrics . 88 . Suppl 1 . 1–628 . December 2017 . 28968603 . 10.1159/000481424 . 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. . free .
  112. Elliott S, Latini DM, Walker LM, Wassersug R, Robinson JW . Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life . The Journal of Sexual Medicine . 7 . 9 . 2996–3010 . September 2010 . 20626600 . 10.1111/j.1743-6109.2010.01902.x .
  113. Higano CS . Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer . Journal of Clinical Oncology . 30 . 30 . 3720–3725 . October 2012 . 23008326 . 10.1200/JCO.2012.41.8509 .
  114. Asscheman H, Gooren LJ, Peereboom-Wynia JD . Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals--experiences with a novel androgen receptor blocker . Clinical and Experimental Dermatology . 14 . 5 . 361–363 . September 1989 . 2612040 . 10.1111/j.1365-2230.1989.tb02585.x . 45303518 .
  115. Rao BR, de Voogt HJ, Geldof AA, Gooren LJ, Bouman FG . Merits and considerations in the use of anti-androgen . Journal of Steroid Biochemistry . 31 . 4B . 731–737 . October 1988 . 3143862 . 10.1016/0022-4731(88)90024-6 .
  116. van Kemenade JF, Cohen-Kettenis PT, Cohen L, Gooren LJ . Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals . Archives of Sexual Behavior . 18 . 3 . 217–228 . June 1989 . 2751416 . 10.1007/BF01543196 . 44664956 .
  117. Gooren L, Spinder T, Spijkstra JJ, van Kessel H, Smals A, Rao BR, Hoogslag M . Sex steroids and pulsatile luteinizing hormone release in men. Studies in estrogen-treated agonadal subjects and eugonadal subjects treated with a novel nonsteroidal antiandrogen . The Journal of Clinical Endocrinology and Metabolism . 64 . 4 . 763–770 . April 1987 . 3102546 . 10.1210/jcem-64-4-763 .
  118. de Voogt HJ, Rao BR, Geldof AA, Gooren LJ, Bouman FG . Androgen action blockade does not result in reduction in size but changes histology of the normal human prostate . The Prostate . 11 . 4 . 305–311 . 1987 . 2960959 . 10.1002/pros.2990110403 . 84632739 .
  119. Web site: Dahl . M . Feldman . JL . Goldberg . J . Jaberi . A . Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines . . 2015 . 15 August 2018 .
  120. Cohen-Kettenis . Peggy T. . Gooren . Louis J.G. . vanc . The Influence of Hormone Treatment on Psychological Functioning of Transsexuals . Journal of Psychology & Human Sexuality . 5 . 4 . 1993 . 55–67 . 0890-7064 . 10.1300/J056v05n04_04. 145237890 .
  121. Book: Chang, Chawnshang . vanc . Prostate Cancer: Basic Mechanisms and Therapeutic Approaches . 22 March 2005 . World Scientific . 978-981-4481-61-8 . 10–11 . live . https://web.archive.org/web/20170908222331/https://books.google.com/books?id=xPLICgAAQBAJ&pg=PA10 . 8 September 2017 . dmy-all.
  122. Book: Vincent T. . DeVita . Theodore S. . Lawrence . Steven A. . Rosenberg . vanc . Prostate and Other Genitourinary Cancers: Cancer: Principles & Practice of Oncology . 18 March 2016 . Wolters Kluwer Health . 978-1-4963-5421-1 . 1006–.
  123. Bennett CL, Raisch DW, Sartor O . Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect . Annals of Internal Medicine . 137 . 7 . 625 . October 2002 . 12353966 . 10.7326/0003-4819-137-7-200210010-00029 . An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period. .
  124. Book: J. . Ramon . L.J. . Denis . vanc . Prostate Cancer. 5 June 2007. Springer Science & Business Media. 978-3-540-40901-4. 256–.
  125. Dahl. Marshall. Feldman. Jamie L.. Goldberg. Joshua M.. Jaberi. Afshin. Physical Aspects of Transgender Endocrine Therapy. International Journal of Transgenderism. 9. 3–4. 2006. 111–134. 1553-2739. 10.1300/J485v09n03_06. 146232471. Flutamide use (750 mg po qd) has been reported by some clinicians (Israel & Tarver, 1997; Levy et al., 2003). Hepatotoxicity has been reported in men receiving comparable doses of flutamide for treatment of prostate cancer (Wysowski, Freiman, Tourtelot, & Horton, 1993), and for this reason we do not recommend flutamide as part of MTF feminization..
  126. Kolvenbag GJ, Furr BJ, Blackledge GR . Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity . Prostate Cancer and Prostatic Diseases . 1 . 6 . 307–314 . December 1998 . 12496872 . 10.1038/sj.pcan.4500262 . 33497597 . free .
  127. Gretarsdottir . Helga M. . Bjornsdottir . Elin . Bjornsson . Einar S. . Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect . Case Reports in Gastroenterology . 12 . 2 . 2018 . 266–270 . 1662-0631 . 10.1159/000485175. 81661015 . free . 20.500.11815/1492 . free .
  128. Web site: TransLine . Gender Affirming Hormone Therapy Guidelines . 5 April 2019 . 11 January 2019 . https://web.archive.org/web/20200111175811/https://static1.squarespace.com/static/5ac6a3e825bf0250fa23d6cb/t/5cafe0c415fcc05709d4a452/1555030213716/TransLine+HRT+Guidelines+FINAL.pdf . 2020-01-11 .
  129. Book: Randi . Ettner . Stan . Monstrey . Eli . Coleman . vanc . Principles of Transgender Medicine and Surgery . 27 May 2016 . Routledge . 978-1-317-51460-2 . 169– . In Europe, the most widely used drug [in the treatment of male-to-female patients] is cyproterone acetate [...].
  130. Book: Erickson-Schroth, Laura . vanc . Trans Bodies, Trans Selves: A Resource for the Transgender Community . 12 May 2014 . Oxford University Press . 978-0-19-932536-8 . 258– . Cyproterone [acetate] is widely used outside the United States as the primary testosterone blocker in transgender women. Cyproterone, however, is not authorized for sale in the United States for any condition and has been associated with liver problems. . live . https://web.archive.org/web/20160624162616/https://books.google.com/books?id=oZeAAwAAQBAJ . 24 June 2016 . dmy-all.
  131. Book: F. William Danby . Acne: Causes and Practical Management . 27 January 2015 . John Wiley & Sons . 978-1-118-23277-4 . 142–.
  132. Book: Loren S Schechter . Surgical Management of the Transgender Patient . 22 September 2016 . Elsevier Health Sciences . 978-0-323-48408-4 . 26–.
  133. Book: H.J.T. Coelingh Benni . H.M. Vemer . Chronic Hyperandrogenic Anovulation . 15 December 1990 . CRC Press . 978-1-85070-322-8 . 152– . CPA is not available in the United States. Thus, spironolactone is currently used. [...] In our opinion, [spironolactone] has a weak antiandrogenic activity..
  134. Book: Tommaso Falcone . William Hurd . Clinical Reproductive Medicine and Surgery E-Book . 26 April 2007 . Elsevier Health Sciences . 978-0-323-07659-3 . 285– . [Flutamide] is also more effective than spironolactone in treating hirsutism, with reduction in hirsutism scores to almost normal after 6 months of therapy with flutamide versus only a 30% reduction in women treated with spironolactone.151.
  135. Book: David L. . Rowland . Luca . Incrocci . vanc . Handbook of Sexual and Gender Identity Disorders . 2 May 2008 . John Wiley & Sons . 978-0-470-25721-0 . 444– . Spironolactone is the most commonly prescribed antiandrogen [for feminizing hormone therapy] in the United States..
  136. Snyder BW, Winneker RC, Batzold FH . Endocrine profile of Win 49596 in the rat: a novel androgen receptor antagonist . Journal of Steroid Biochemistry . 33 . 6 . 1127–1132 . December 1989 . 2615357 . 10.1016/0022-4731(89)90419-6 .
  137. Book: Neumann. Friedmund. Antiandrogens in Prostate Cancer. Pharmacology of Cyproterone Acetate — A Short Review. 1996. 31–44. 10.1007/978-3-642-45745-6_3. 978-3-642-45747-0.
  138. Book: Schröder . Fritz H. . Radlmaier . Albert . Steroidal Antiandrogens . 325–346 . 10.1007/978-1-59259-152-7_15 . Hormone Therapy in Breast and Prostate Cancer . V. Craig Jordan . Barrington J. A. Furr . 2009 . Humana Press . 978-1-60761-471-5.
  139. Coleman . E. . Radix . A. E. . Bouman . W. P. . Brown . G. R. . de Vries . A. L. C. . Deutsch . M. B. . Ettner . R. . Fraser . L. . Goodman . M. . Green . J. . Hancock . A. B. . Johnson . T. W. . Karasic . D. H. . Knudson . G. A. . Leibowitz . S. F. . Meyer-Bahlburg . H. F. L. . Monstrey . S. J. . Motmans . J. . Nahata . L. . Nieder . T. O. . Reisner . S. L. . Richards . C. . Schechter . L. S. . Tangpricha . V. . Tishelman . A. C. . Van Trotsenburg . M. A. A. . Winter . S. . Ducheny . K. . Adams . N. J. . Adrián . T. M. . Allen . L. R. . Azul . D. . Bagga . H. . Başar . K. . Bathory . D. S. . Belinky . J. J. . Berg . D. R. . Berli . J. U. . Bluebond-Langner . R. O. . Bouman . M.-B. . Bowers . M. L. . Brassard . P. J. . Byrne . J. . Capitán . L. . Cargill . C. J. . Carswell . J. M. . Chang . S. C. . Chelvakumar . G. . Corneil . T. . Dalke . K. B. . De Cuypere . G. . de Vries . E. . Den Heijer . M. . Devor . A. H. . Dhejne . C. . D’Marco . A. . Edmiston . E. K. . Edwards-Leeper . L. . Ehrbar . R. . Ehrensaft . D. . Eisfeld . J. . Elaut . E. . Erickson-Schroth . L. . Feldman . J. L. . Fisher . A. D. . Garcia . M. M. . Gijs . L. . Green . S. E. . Hall . B. P. . Hardy . T. L. D. . Irwig . M. S. . Jacobs . L. A. . Janssen . A. C. . Johnson . K. . Klink . D. T. . Kreukels . B. P. C. . Kuper . L. E. . Kvach . E. J. . Malouf . M. A. . Massey . R. . Mazur . T. . McLachlan . C. . Morrison . S. D. . Mosser . S. W. . Neira . P. M. . Nygren . U. . Oates . J. M. . Obedin-Maliver . J. . Pagkalos . G. . Patton . J. . Phanuphak . N. . Rachlin . K. . Reed . T. . Rider . G. N. . Ristori . J. . Robbins-Cherry . S. . Roberts . S. A. . Rodriguez-Wallberg . K. A. . Rosenthal . S. M. . 1 . Sabir . K. . Safer . J. D. . Scheim . A. I. . Seal . L. J. . Sehoole . T. J. . Spencer . K. . St. Amand . C. . Steensma . T. D. . Strang . J. F. . Taylor . G. B. . Tilleman . K. . T’Sjoen . G. G. . Vala . L. N. . Van Mello . N. M. . Veale . J. F. . Vencill . J. A. . Vincent . B. . Wesp . L. M. . West . M. A. . Arcelus . J. . Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 . . 19 August 2022 . 23 . sup1 . S1–S259 . 2689-5269 . 10.1080/26895269.2022.2100644 . free . 36238954. 9553112 .
  140. Book: Deutsch, Madeline . vanc . Overview of feminizing hormone therapy . Deutsch . Madeline . Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People . 17 June 2016 . 2nd . Center of Excellence for Transgender Health . University of California, San Francisco . 26–48 . In many countries, cyproterone acetate, a synthetic progestagen with strong anti-androgen activity is commonly used. Cyproterone has been associated with uncommon episodes of fulminant hepatitis.[12] 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.[13] No evidence at present exists to inform such an analysis..
  141. Web site: Thompson J, Hopwood RA, deNormand S, Cavanaugh T . Medical Care of Trans and Gender Diverse Adults . 13 July 2021 . Boston . Fenway Health .
  142. Tomson A, McLachlan C, Wattrus C, Adams K, Addinall R, Bothma R, Jankelowitz L, Kotze E, Luvuno Z, Madlala N, Matyila S, Padavatan A, Pillay M, Rakumakoe MD, Tomson-Myburgh M, Venter WD, de Vries E . Southern African HIV Clinicians' Society gender-affirming healthcare guideline for South Africa . South Afr J HIV Med . 22 . 1 . 1299 . 2021 . 34691772 . 8517808 . 10.4102/sajhivmed.v22i1.1299 .
  143. Web site: Casodex® (bicalutamide) Tablets . FDA . live . https://web.archive.org/web/20190730062812/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020498s028lbl.pdf . 30 July 2019 . dmy-all.
  144. Book: Schoelwer. Melissa. Puberty from Bench to Clinic. Eugster. Erica A.. Treatment of Peripheral Precocious Puberty. 29. 2015. 230–239. 1421-7082. 10.1159/000438895. 26680582. 5345994. Endocrine Development. 978-3-318-02788-4.
  145. Book: Zacharin. Margaret. Pediatric Pharmacotherapy. Disorders of Puberty: Pharmacotherapeutic Strategies for Management. 2019. 0171-2004. 31144045. 10.1007/164_2019_208. Handbook of Experimental Pharmacology. 261. 507–538. 978-3-030-50493-9. 169040406.
  146. Book: Robert M. . Kliegman . Bonita . Stanton . Joseph . St. Geme . Nina F . Schor . vanc . Nelson Textbook of Pediatrics . 17 April 2015 . Elsevier Health Sciences . 978-0-323-26352-8 . 2661–.
  147. Neyman A, Eugster EA . Treatment of Girls and Boys with McCune-Albright Syndrome with Precocious Puberty - Update 2017 . Pediatric Endocrinology Reviews . 15 . 2 . 136–141 . December 2017 . 29292624 . 5808444 . 10.17458/per.vol15.2017.nau.treatmentgirlsboys .
  148. Web site: AstraZeneca Pharmaceuticals . Clinical Review NDA 22-310/S-001 Casodex (bicalutamide) for Testotoxicosis . . 2008-12-15 . 2019-07-29 . PDF . https://web.archive.org/web/20190730023433/https://www.fda.gov/media/75809/download . 2019-07-30 .
  149. Book: Haddad. Nadine G.. Handbook of Growth and Growth Monitoring in Health and Disease. Eugster. Erica A.. Peripheral Precocious Puberty: Interventions to Improve Growth. 2012. 1199–1212. 10.1007/978-1-4419-1795-9_71. 978-1-4419-1794-2.
  150. Diaz-Thomas A, Shulman D . Use of aromatase inhibitors in children and adolescents: what's new? . Current Opinion in Pediatrics . 22 . 4 . 501–507 . August 2010 . 20489637 . 10.1097/MOP.0b013e32833ab888 . 23933791 .
  151. Reiter EO, Mauras N, McCormick K, Kulshreshtha B, Amrhein J, De Luca F, O'Brien S, Armstrong J, Melezinkova H . 6 . Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT) . Journal of Pediatric Endocrinology & Metabolism . 23 . 10 . 999–1009 . October 2010 . 21158211 . 10.1515/jpem.2010.161 . 110630 .
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