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 exogenoustestosterone.[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, SAAs, GnRH analogues, NSAAs, and androgen biosynthesis inhibitors (e.g., abiraterone acetate), has become the mainstay of treatment for prostate cancer.[18] Although ADT 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 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.[21]
A few observations form the basis of the reasoning behind combined androgen blockade (CAB), in which castration and an NSAA 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 DHT, which is the major androgen in the prostate, remain at 40 to 50% of their initial values following castration.[25][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 DHT.[25][26][27] As such, a considerable amount of androgen signaling continues within the prostate gland even with castration.[25][26][27]
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.[24][18][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.[18][30][31][32] 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.[29][33]
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.[10][18][34][35] Moreover, NSAA monotherapy is overall better tolerated and associated with greater quality of life than is castration,[36][37][38][39] 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.[38][39][40][41][42] For these reasons, NSAA monotherapy has become an important alternative to castration and CAB in the treatment of prostate cancer.[43][44][45]
Bicalutamide may be used to reduce the effects of the testosterone flare at the initiation of GnRH agonist therapy.[46][47]
The combination of bicalutamide with an estrogen such as ethinylestradiol sulfonate has been used as a form of CAB and as an alternative to the combination of bicalutamide with surgical or medical castration.[48]
Improvement in scalp hair density in a 37-year-old woman treated with 25mg/day bicalutamide monotherapy. Left is before treatment and right is after 6months of therapy.
Low-dose bicalutamide has been found to be effective in the treatment of hirsutism in women in clinical studies.[60][61][62][63][64][65][66] 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 3months and by 61.6% at 6months (from 22.0 ± 5.1 to 8.6 ± 3.5).[67][68][62] According to a 2013 review, "Low dose bicalutamide (25mg/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."[61] In 2017, the combination of bicalutamide with a combined birth control pill was evaluated in a phase IIIclinical trial for the treatment of severe hirsutism in women with PCOS, and was found to be significantly more effective than a combined birth control pill alone.[69][70][64] 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.[64] Studies have reported bicalutamide to be effective in the treatment of scalp hair loss in women.[71][72][73]
In addition to hirsutism, bicalutamide can be used in the treatment of acne in women.[74][75][76][77] 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.[78][79][80] In one study, it decreased acne scores by 80% within 3months, whereas the SAA spironolactone decreased symptoms by only 40% in the same time period.[80][81][82] Bicalutamide has an antiandrogenic efficacy that is comparable to or greater than that of flutamide, and would be expected to produce similar therapeutic benefits.[83][36] Other androgen-dependent skin and hair conditions, such as seborrhea and pattern hair loss, may also be treated by bicalutamide.[84] 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.[85] 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.[80] 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,[86][87] which bicalutamide does not share.[77][75][88]
Antiandrogens like flutamide and bicalutamide are male-specific teratogens which can feminize male fetuses due to their antiandrogen effects.[57][89][90] For this reason, they are not recommended by the U.S.Tooltip United StatesFood and Drug Administration for use in women.[91] 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.[57][89][90] Birth control pills, which contain an estrogen and a progestin, are typically used for this purpose.[57] 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.[57][92]
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.[93][110][100] This is desirable in transgender women, as it can help promote feminization.[93][110][95][101] However, bicalutamide does not increase sex hormone levels if combined with adequate doses of an antigonadotropin such as a GnRH modulator, estrogen, or progestogen, due to the negative feedback effects of these medications on sex-hormone production.[46][111][112] 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 CPA and GnRH modulators, can greatly disrupt these functions.[113][37][114] Although bicalutamide has the potential to increase testosterone levels, there is no effect of this testosterone due to the blockade of the AR by bicalutamide.[96]
Neyman and colleagues in 2019 published a study on bicalutamide as a puberty blocker in adolescent transgender girls.[95][101]:477 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.[95][101] Of the girls who were treated exclusively with bicalutamide alone, 13 returned for follow-up and were analyzed.[95][101] In addition to apparently showing effectiveness as an antiandrogen and puberty blocker, bicalutamide alone increased estradiol levels and promoted feminization as a secondary effect.[95][101] 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.[95][101] 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.[95][101] Testosterone levels (n=5) were 524 to 823ng/dL and estradiol levels (n=6) were <20 to 61pg/mL in the patients.[95][101]Liver function tests were performed and were all normal.[95][101] Although GnRH modulators are the first-line treatment to prevent puberty in transgender adolescents, they are very expensive and are often denied by medical insurance.[95][101] According to the researchers, bicalutamide represents a potential alternative to GnRH modulators as a puberty blocker in transgender girls.[95][101]
Studies assessing bicalutamide as an antiandrogen in transgender women are very limited.[93][115][95][101] 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[60][61][64] and in boys with gonadotropin-independent precocious puberty,[116][117][118][100] and demasculinization and feminization are well-documented effects of bicalutamide in men treated with it for prostate cancer.[106][119][120] 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.[110][111][112][121][122][123] 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.[110][111][112][121][122][123] The corresponding monotherapy dosage of bicalutamide in the treatment of prostate cancer is 150mg/day.[2][4][5] Flutamide has also been employed as an antiandrogen in transgender women, with at least two treatment centers at one point reporting its frequent use.[94][110][124]
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 19–33years) within 8weeks.[112] These changes included breast development, decreased male-pattern hair,[111] decreased spontaneous erections and sex drive,[121] and positive psychological and emotional changes.[121][125] 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 6weeks.[123][112][121] Nilutamide by itself more than doubled luteinizing hormone (LH) and testosterone levels and tripled estradiol levels.[111][112][122] The addition of 100μg/day oralethinylestradiol to nilutamide therapy after 8weeks abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the female or castrate range.[111][112] 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.[111][112]
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.[20][126][127] This is an adverse effect that can progress to pulmonary fibrosis and can potentially be fatal.[128] Flutamide is also no longer recommended due to excessive risk of hepatotoxicity and liver failure in men with prostate cancer.[129][124][86][130] For these reasons, newer and safer NSAAs like bicalutamide have largely replaced flutamide and nilutamide, and are now used for relevant indications instead.[15][16][17] As selective AR 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.[131]
Bicalutamide is known to have a small risk of elevated liver enzymes and serious liver toxicity.[93][96][61][88][132] As a result, it is recommended that liver function tests (LFTs) periodically be performed.[96][109][133] One protocol that has been recommended is to check LFTs at baseline, at one month, at two months, and then every 6months thereafter.[133] The risk of elevated liver enzymes and liver failure with bicalutamide appears to be much smaller than with high doses of CPA,[88] which is the most widely used antiandrogen in transgender women in Europe and elsewhere in the world.[110][134][135] However, only low doses of CPA are now recommended for use in transgender women.[136] In the United States, one of the only countries where CPA has not been approved for medical use,[137][138] spironolactone is commonly used in transgender women instead.[139][140][141] Bicalutamide has certain favorable properties as a potential alternative option to these antiandrogens in transgender females.[93][96][94] For example, it is much more potent and selective as an AR antagonist than CPA and spironolactone.[95][142] However, CPA 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.[143][144] 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.[94][95]
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.[136] Instead, the SOC8 recommends other more established and better-studied antiandrogens, like spironolactone, CPA, and GnRH modulators.[136] Other less prominent transgender health guidelines are mixed in recommending against use of bicalutamide (UCSFTooltip University of California, San Francisco guidelines),[98] cautiously allowing it (Fenway Health guidelines),[145] and recommending it over other antiandrogens (Southern African HIV Clinicians' Society guidelines).[146]
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.[149][148][151] The largest and sole study employing bicalutamide, an industry-sponsored, phase II, multicenter, international, open-label, single-arm clinical trial known as the Bicalutamide and Anastrozole Treatment of Testotoxicosis (BATT) study, assessed the combination of 12.5 to 100mg/day bicalutamide and 0.5 to 1mg/day anastrozole over a period of 12months in 14young boys with FMPP.[147][152][148][153][154][118][151] The mean age of the boys was 4 ± 2years, with a range of 2 to 9years of age.[147][118][151] At baseline, the boys weighed 23 ± 6kg (52 ± 12lbs) on average, with a range 17 to 35kg (37 to 77lbs).[151] Mean total levels of testosterone in the boys were 277 ± 208ng/dL at baseline and increased to 523 ± 258ng/dL at 6months and 427 ± 243ng/dL at 12months.[147][118][151] Mean total levels of estradiol in the boys were 3.8pg/mL at baseline and were relatively unchanged at 6 and 12months (2.5pg/mL and 3.5pg/mL, respectively).[147][118][151] The dosage of bicalutamide was initiated at 12.5mg/day and was then increased, with adjustment as necessary to maintain trough circulating (R)-bicalutamide concentrations within a target range of 5 to 15μg/mL.[155][147][118][151] This range is similar to (R)-bicalutamide levels achieved with approximately 30 to 100mg/day bicalutamide in adult men with prostate cancer.[151][147][4] The mean final dosage of bicalutamide in the boys at 12months was 60 ± 29mg/day, with 86% of the boys on either 50 or 100mg/day bicalutamide.[118] Levels of (R)-bicalutamide were proportional to dosage and did not appear to be related to the age or weight of the boys.[118]
In the BATT 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.[148][156][157][118][151] However, the decrease in growth rate was modest and fell just short of reaching statistical significance (p = 0.053).[148][152][118][151] 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).[148][152][118][151] 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.[158][159]Testicular volume increased mildly over the year that the boys were observed.[118] A New Drug Application of bicalutamide for FMPP in the United States was submitted on the basis of the BATT trial data.[147][151][160] However, the application was not approved by the Food and Drug Administration, which cited insufficient evidence of effectiveness.[147][151][160] Although indication of bicalutamide for the use was not granted, the bicalutamide medication label was updated to include the findings of the study.[147][151] In terms of side effects, the combination of bicalutamide and anastrozole in the study was described as well tolerated with no safety concerns.[155] However, gynecomastia, attributed to bicalutamide, was observed in almost half of the boys.[148][156][118][151] 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.[147][151]
Additional research is necessary to more clearly determine the true effectiveness and safety of bicalutamide and anastrozole in the treatment of FMPP.[152] No long-term results for the BATT 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.[148][156][157][161][154] 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.[154][148] In addition to the BATT study, a variety of case reports and series of bicalutamide in combination with an aromatase inhibitor in male peripheral precocious puberty have been published.[117][162][163][161][164][165][166][167][168][169] These case reports have described similar results as those of the BATT study.[170][161]
Alternatives to bicalutamide in the treatment of male peripheral precocious puberty include spironolactone, cyproterone acetate, and ketoconazole.[148][149] 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.[117][161] This corresponds to the fact that bicalutamide is a much more potent and selective antiandrogen than spironolactone.[118][161][95] Additionally, dosing is easier with bicalutamide, as it requires administration only once daily as opposed to twice daily at 12-hour intervals with spironolactone.[152][148][161] For these reasons, bicalutamide has replaced spironolactone in the treatment of the condition.[100]:2139 For comparison to bicalutamide, a higher dosage of spironolactone of 5mg/kg (or about 100 to 150mg in boys that are 20 to 30kg or 45 to 65lbs) once daily is recommended for use in male peripheral precocious puberty.[149]
Long-lasting erections
Antiandrogens can considerably relieve and prevent priapism (potentially painful penileerections that last more than four hours) via direct blockade of penile ARs.[171][172] In accordance, bicalutamide, at low dosages (50mg 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,[173][174][175] and is used for this indication off-label.[176][177] 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 25mg/day or less.[173][174][175] Some gynecomastia and breast tenderness developed in one patient treated with 50mg/day, but significantly improved upon the dosage being halved.[175] 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).[173][174] However, although successful and well tolerated, very few cases have been reported.[178] Despite the apparent efficacy of bicalutamide for priapism, a small clinical study found that bicalutamide monotherapy at a dosage of 50mg/day had no effect on nocturnal erections in men with prostate cancer.[37][179]
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.[180][182][183][184] 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.[180][182][185] However, due to unopposed estrogen signaling, a substantial incidence of gynecomastia is associated with NSAAs.[180] 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.[181]
Though treatment of paraphilias and hypersexuality with selective AR antagonists is a seemingly sound strategy, this may not be true in practice.[37] Surprisingly, little or no sexual dysfunction, including loss of sex drive and decreased sexual activity, has been observed in clinical studies of NSAA monotherapy.[37][5] 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.[38][39][40][41][42] 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.[57] For these reasons, unlike antigonadotropic antiandrogens, NSAA monotherapy may have limited usefulness in the management of paraphilias and hypersexuality.[37] The addition of NSAAs to antigonadotropic antiandrogens like GnRH analogues may have some usefulness however, particularly in severe cases.[181][186] In any case, insufficient evidence is available at this time, and further research is thus warranted.[182]
Related Research Articles
Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.
Spironolactone, sold under the brand name Aldactone among others, is a diuretic medication primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, and low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women. Spironolactone is taken by mouth.
Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.
Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.
Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.
A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.
Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.
Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.
The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.
Sexual motivation is influenced by hormones such as testosterone, estrogen, progesterone, oxytocin, and vasopressin. In most mammalian species, sex hormones control the ability and motivation to engage in sexual behaviours.
Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender individuals, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.
A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.
Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer. It is an androgen receptor inhibitor. It is taken by mouth.
Trimethyltrienolone (TMT), also known by its developmental code name R-2956 or RU-2956, is an antiandrogen medication which was never introduced for medical use but has been used in scientific research.
A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.
The side effects of bicalutamide, a nonsteroidal antiandrogen (NSAA), including its frequent and rare side effects, have been well-studied and characterized. The most common side effects of bicalutamide monotherapy in men include breast tenderness, breast growth, feminization, demasculinization, and hot flashes. Less common side effects of bicalutamide monotherapy in men include sexual dysfunction, depression, fatigue, weakness, and anemia. Bicalutamide is well tolerated and has few side effects in women. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.
Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.
The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.
The pharmacology of cyproterone acetate (CPA) concerns the pharmacology of the steroidal antiandrogen and progestin medication cyproterone acetate.
The side effects of cyproterone acetate (CPA), a steroidal antiandrogen and progestin, including its frequent and rare side effects, have been studied and characterized. It is generally well-tolerated and has a mild side-effect profile, regardless of dosage, when it used as a progestin or antiandrogen in combination with an estrogen such as ethinylestradiol or estradiol valerate in women. Side effects of CPA include hypogonadism and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis; breast changes such as breast tenderness, enlargement, and gynecomastia; emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes. Weight gain can occur with CPA when it is used at high doses. Some of the side effects of CPA can be improved or fully prevented if it is combined with an estrogen to prevent estrogen deficiency. Few quantitative data are available on many of the potential side effects of CPA. Pooled tolerability data for CPA is not available in the literature.
↑ Klotz L, Schellhammer P (March 2005). "Combined androgen blockade: the case for bicalutamide". Clinical Prostate Cancer. 3 (4): 215–219. doi:10.3816/cgc.2005.n.002. PMID15882477.
1 2 3 Cockshott ID (2004). "Bicalutamide: clinical pharmacokinetics and metabolism". Clinical Pharmacokinetics. 43 (13): 855–878. doi:10.2165/00003088-200443130-00003. PMID15509184. These data indicate that direct glucuronidation is the main metabolic pathway for the rapidly cleared (S)-bicalutamide, whereas hydroxylation followed by glucuronidation is a major metabolic pathway for the slowly cleared (R)-bicalutamide.
↑ Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, etal. (September 1997). "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. doi:10.1016/S0090-4295(97)00279-3. PMID9301693.
1 2 3 Vogelzang NJ (September 2012). "Enzalutamide--a major advance in the treatment of metastatic prostate cancer". The New England Journal of Medicine. 367 (13): 1256–1257. doi:10.1056/NEJMe1209041. PMID23013078. S2CID32314622. 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.
1 2 3 Chabner BA, Longo DL (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp.679–680. ISBN978-1-60547-431-1. 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.
↑ Weber GF (22 July 2015). Molecular Therapies of Cancer. Springer. pp.318–. ISBN978-3-319-13278-5. 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.
↑ Kolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9, discussion 80–4. doi:10.1016/s0090-4295(96)80012-4. PMID8560681. 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.
↑ Payen O, Top S, Vessières A, Brulé E, Lauzier A, Plamont MA, etal. (2011). "Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide". Journal of Organometallic Chemistry. 696 (5): 1049–1056. doi: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].
↑ Balk SP (September 2002). "Androgen receptor as a target in androgen-independent prostate cancer". Urology. 60 (3 Suppl 1): 132–8, discussion 138–9. doi:10.1016/S0090-4295(02)01593-5. PMID12231070.
↑ Sarosdy MF (October 1999). "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. doi:10.1097/00001813-199910000-00001. PMID10587288.
1 2 3 Luo S, Martel C, Chen C, Labrie C, Candas B, Singh SM, Labrie F (December 1997). "Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity". Urology. 50 (6): 913–919. doi:10.1016/S0090-4295(97)00393-2. PMID9426723.
1 2 Gauthier S, Martel C, Labrie F (October 2012). "Steroid derivatives as pure antagonists of the androgen receptor". The Journal of Steroid Biochemistry and Molecular Biology. 132 (1–2): 93–104. doi:10.1016/j.jsbmb.2012.02.006. PMID22449547. S2CID28982450.
1 2 3 Wibowo E, Schellhammer P, Wassersug RJ (January 2011). "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. doi:10.1016/j.juro.2010.08.094. PMID21074215.
1 2 3 Motofei IG, Rowland DL, Popa F, Kreienkamp D, Paunica S (July 2011). "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. doi:10.1111/j.1464-410X.2010.09764.x. PMID20955264. S2CID45482984.
1 2 Wibowo E, Wassersug RJ (September 2013). "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. doi:10.1016/j.critrevonc.2013.01.006. PMID23484454.
↑ Boccardo F (August 2000). "Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy?". Critical Reviews in Oncology/Hematology. 35 (2): 121–132. doi:10.1016/S1040-8428(00)00051-2. PMID10936469.
↑ Kolvenbag GJ, Iversen P, Newling DW (August 2001). "Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer". Urology. 58 (2 Suppl 1): 16–23. doi:10.1016/s0090-4295(01)01237-7. PMID11502439.
1 2 Shlomo Melmed (1 January 2016). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp.752–. ISBN978-0-323-29738-7. 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
1 2 3 4 5 6 Diamanti-Kandarakis E, Tolis G, Duleba AJ (1995). "Androgens and therapeutic aspects of antiandrogens in women". Journal of the Society for Gynecologic Investigation. 2 (4): 577–592. doi:10.1177/107155769500200401. PMID9420861. S2CID32242838. 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.
↑ Katsambas AD, Dessinioti C (2010). "Hormonal therapy for acne: why not as first line therapy? facts and controversies". Clinics in Dermatology. 28 (1): 17–23. doi:10.1016/j.clindermatol.2009.03.006. PMID20082945.
↑ Müderris II, Bayram F, Ozçelik B, Güven M (February 2002). "New alternative treatment in hirsutism: bicalutamide 25 mg/day". Gynecological Endocrinology. 16 (1): 63–66. doi:10.1080/gye.16.1.63.66. PMID11915584. S2CID6942048.
↑ Carvalho RM, Santos LD, Ramos PM, Machado CJ, Acioly P, Frattini SC, etal. (January 2022). "Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know". Journal of Cosmetic Dermatology. 21 (10): 4171–4175. doi:10.1111/jocd.14773. PMID35032336. S2CID253239337.
↑ Meyer-Gonzalez T, Bacqueville D, Grimalt R, Mengeaud V, Piraccini BM, Rudnicka L, etal. (November 2021). "Current controversies in trichology: a European expert consensus statement". Journal of the European Academy of Dermatology and Venereology. 35 (Suppl 2): 3–11. doi:10.1111/jdv.17601. hdl:11585/863826. PMID34668238. S2CID239029062.
↑ Hassoun LA, Chahal DS, Sivamani RK, Larsen LN (June 2016). "The use of hormonal agents in the treatment of acne". Seminars in Cutaneous Medicine and Surgery. 35 (2): 68–73. doi:10.12788/j.sder.2016.027 (inactive 1 November 2024). PMID27416311.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
1 2 Azarchi S, Bienenfeld A, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR (June 2019). "Androgens in women: Hormone-modulating therapies for skin disease". Journal of the American Academy of Dermatology. 80 (6): 1509–1521. doi:10.1016/j.jaad.2018.08.061. PMID30312645. S2CID52973096.
1 2 3 Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–723. doi:10.2174/1381612805666230111201150. PMID10495361. 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].
↑ Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". European Urology. 29 (Suppl 2): 96–104. doi:10.1159/000473847. PMID8717470.
1 2 Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (March 2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". European Review for Medical and Pharmacological Sciences. 21 (1 Suppl): 69–77. PMID28379593.
1 2 3 4 5 6 7 8 9 10 Randolph JF (December 2018). "Gender-Affirming Hormone Therapy for Transgender Females". Clinical Obstetrics and Gynecology. 61 (4): 705–721. doi:10.1097/GRF.0000000000000396. PMID30256230. S2CID52821192. 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.
1 2 3 4 5 Fishman, Sarah L.; Paliou, Maria; Poretsky, Leonid; Hembree, Wylie C. (2019). "Endocrine Care of Transgender Adults". Transgender Medicine. Contemporary Endocrinology. pp.143–163. doi:10.1007/978-3-030-05683-4_8. ISBN978-3-030-05682-7. ISSN2523-3785. S2CID86772102. 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.
1 2 3 4 5 Courtney Finlayson (3 August 2018). Pubertal Suppression in Transgender Youth. Elsevier Health Sciences. pp.81, 98. ISBN978-0-323-56964-4. 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)
1 2 Benjamin Vincent (21 June 2018). Transgender Health: A Practitioner's Guide to Binary and Non-Binary Trans Patient Care. Jessica Kingsley Publishers. pp.158–. ISBN978-1-78450-475-5. 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)
1 2 Deutsch M (17 June 2016). "Overview of feminizing hormone therapy". In Deutsch M (ed.). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People(PDF) (2nded.). University of California, San Francisco: Center of Excellence for Transgender Health. pp.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.
1 2 Gooren LJ (March 2011). "Clinical practice. Care of transsexual persons". The New England Journal of Medicine. 364 (13): 1251–1257. doi:10.1056/nejmcp1008161. PMID21449788. 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).
1 2 3 4 5 Jameson JL, De Groot LJ (25 February 2015). Edndocrinology: Adult and Pediatric. Elsevier Health Sciences. pp.2139, 2172, 2425–2426. ISBN978-0-323-32195-2. 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.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "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. doi:10.1159/000481424. PMID28968603. 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.
↑ Braunstein GD (September 2007). "Clinical practice. Gynecomastia". The New England Journal of Medicine. 357 (12): 1229–1237. doi:10.1056/NEJMcp070677. PMID17881754.
↑ el-Rayes BF, Hussain MH (February 2002). "Hormonal therapy for prostate cancer: past, present and future". Expert Review of Anticancer Therapy. 2 (1): 37–47. doi:10.1586/14737140.2.1.37. PMID12113064. S2CID6869320. 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.
1 2 3 4 5 6 Kreukels BP, Steensma TD, de Vries AL (1 July 2013). Gender Dysphoria and Disorders of Sex Development: Progress in Care and Knowledge. Springer Science & Business Media. pp.280–. ISBN978-1-4614-7441-8. 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.
1 2 3 4 5 6 7 Asscheman H, Gooren LJ, Peereboom-Wynia JD (September 1989). "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. doi:10.1111/j.1365-2230.1989.tb02585.x. PMID2612040. S2CID45303518.
1 2 3 4 5 6 7 8 Rao BR, de Voogt HJ, Geldof AA, Gooren LJ, Bouman FG (October 1988). "Merits and considerations in the use of anti-androgen". Journal of Steroid Biochemistry. 31 (4B): 731–737. doi:10.1016/0022-4731(88)90024-6. PMID3143862.
↑ Gao Y, Maurer T, Mirmirani P (August 2018). "Understanding and Addressing Hair Disorders in Transgender Individuals". American Journal of Clinical Dermatology. 19 (4): 517–527. doi:10.1007/s40257-018-0343-z. PMID29352423. S2CID6467968. 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].
↑ Morgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, etal. (March 2001). "Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study". Histopathology. 38 (3): 195–201. doi:10.1046/j.1365-2559.2001.01077.x. hdl:11573/387981. PMID11260298. S2CID36892099.
1 2 3 Kreher NC, Pescovitz OH, Delameter P, Tiulpakov A, Hochberg Z (September 2006). "Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole". The Journal of Pediatrics. 149 (3): 416–420. doi:10.1016/j.jpeds.2006.04.027. PMID16939760.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Reiter EO, Mauras N, McCormick K, Kulshreshtha B, Amrhein J, De Luca F, etal. (October 2010). "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. doi:10.1515/jpem.2010.161. PMID21158211. S2CID110630.
↑ Elliott S, Latini DM, Walker LM, Wassersug R, Robinson JW (September 2010). "Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life". The Journal of Sexual Medicine. 7 (9): 2996–3010. doi:10.1111/j.1743-6109.2010.01902.x. PMID20626600.
↑ Higano CS (October 2012). "Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer". Journal of Clinical Oncology. 30 (30): 3720–3725. doi:10.1200/JCO.2012.41.8509. PMID23008326.
1 2 3 4 5 van Kemenade JF, Cohen-Kettenis PT, Cohen L, Gooren LJ (June 1989). "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. doi:10.1007/BF01543196. PMID2751416. S2CID44664956.
1 2 3 Gooren L, Spinder T, Spijkstra JJ, van Kessel H, Smals A, Rao BR, Hoogslag M (April 1987). "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. doi:10.1210/jcem-64-4-763. PMID3102546.
1 2 3 de Voogt HJ, Rao BR, Geldof AA, Gooren LJ, Bouman FG (1987). "Androgen action blockade does not result in reduction in size but changes histology of the normal human prostate". The Prostate. 11 (4): 305–311. doi:10.1002/pros.2990110403. PMID2960959. S2CID84632739.
↑ Cohen-Kettenis PT, Gooren LJ (1993). "The Influence of Hormone Treatment on Psychological Functioning of Transsexuals". Journal of Psychology & Human Sexuality. 5 (4): 55–67. doi:10.1300/J056v05n04_04. ISSN0890-7064. S2CID145237890.
↑ Bennett CL, Raisch DW, Sartor O (October 2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect". Annals of Internal Medicine. 137 (7): 625. doi:10.7326/0003-4819-137-7-200210010-00029. PMID12353966. 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.
↑ Dahl, Marshall; Feldman, Jamie L.; Goldberg, Joshua M.; Jaberi, Afshin (2006). "Physical Aspects of Transgender Endocrine Therapy". International Journal of Transgenderism. 9 (3–4): 111–134. doi:10.1300/J485v09n03_06. ISSN1553-2739. S2CID146232471. 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.
↑ Erickson-Schroth L (12 May 2014). Trans Bodies, Trans Selves: A Resource for the Transgender Community. Oxford University Press. pp.258–. ISBN978-0-19-932536-8. Archived from the original on 24 June 2016. 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.
↑ H.J.T. Coelingh Benni; H.M. Vemer (15 December 1990). Chronic Hyperandrogenic Anovulation. CRC Press. pp.152–. ISBN978-1-85070-322-8. CPA is not available in the United States. Thus, spironolactone is currently used. [...] In our opinion, [spironolactone] has a weak antiandrogenic activity.
↑ Tommaso Falcone; William Hurd (26 April 2007). Clinical Reproductive Medicine and Surgery E-Book. Elsevier Health Sciences. pp.285–. ISBN978-0-323-07659-3. [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
↑ Schröder, Fritz H.; Radlmaier, Albert (2009). "Steroidal Antiandrogens". In V. Craig Jordan; Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp.325–346. doi:10.1007/978-1-59259-152-7_15. ISBN978-1-60761-471-5.
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↑ Lewis, K. A., Lenz, A., Eugster, E. A., Fuqua, J. S., Pescovitz, O. H., Rahhal, S., & Shulman, D. (2009, January). Long term bicalutamide and 3 (rd) generation aromatase inhibitor therapy in two boys with testotoxicosis. In Hormone Research (Vol. 72, pp. 266–267).
↑ Mitre N, Lteif A (December 2009). "Treatment of familial male-limited precocious puberty (testotoxicosis) with anastrozole and bicalutamide in a boy with a novel mutation in the luteinizing hormone receptor". Journal of Pediatric Endocrinology & Metabolism. 22 (12): 1163–1167. doi:10.1515/JPEM.2009.22.12.1163. PMID20333877. S2CID297301.
↑ Kor Y (June 2018). "Central precocious puberty in a case of late-diagnosed familial testotoxicosis and long-term treatment monitoring". Hormones. 17 (2): 275–278. doi:10.1007/s42000-018-0029-1. PMID29858851. S2CID46923277.
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↑ Khan O, Mashru A (June 2016). "The efficacy, safety and ethics of the use of testosterone-suppressing agents in the management of sex offending". Current Opinion in Endocrinology, Diabetes, and Obesity. 23 (3): 271–278. doi:10.1097/MED.0000000000000257. PMID27032060. S2CID43286710.
↑ Wadhwa VK, Weston R, Parr NJ (June 2011). "Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer". BJU International. 107 (12): 1923–1929. doi:10.1111/j.1464-410X.2010.09726.x. PMID20950306. S2CID205543615.
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