Clinical data
Pronunciation Bicalutamide:
Casodex: kay-SOH-dex[2]
Trade names Casodex, Cosudex, Calutide, Calumid, Kalumid, others
AHFS/ Monograph
MedlinePlus a697047
License data
  • AU: D
  • US: X (Contraindicated)
Routes of
ATC code L02BB03 (WHO)
QL02BB03 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Well-absorbed; absolute bioavailability unknown[4]
Protein binding Racemate: 96.1%[3]
(R)-Isomer: 99.6%[3]
(Mainly to albumin)[3]
Metabolism Hepatic (extensively):[5][6]
Hydroxylation (CYP3A4)
Glucuronidation (UGT1A9)
Metabolites • Bicalutamide glucuronide
• Hydroxybicalutamide
• Hydroxybicalutamide gluc.
(All inactive)[5][3][7][8]
Biological half-life Acute: 5.8 days[9]
Chronic: 7–10 days[10]
Excretion Feces: 43%[5]
Urine: 34%[5]
Synonyms ICI-176,334[11]
CAS Number 90357-06-5 YesY
113299-40-4 ((R)-isomer)
PubChem (CID) 2375
DrugBank DB01128 YesY
ChemSpider 2284 YesY
KEGG D00961 N
PDB ligand ID 198 (PDBe, RCSB PDB)
Chemical and physical data
Formula C18H14F4N2O4S
Molar mass 430.373 g/mol
3D model (Jmol) Interactive image
Chirality Racemic mixture
Melting point 191 to 193 °C (376 to 379 °F)
Solubility in water 0.005 mg/mL (20 °C)
 NYesY (what is this?)  (verify)

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen that is used primarily in the treatment of prostate cancer.[11][12][13][14][15] It is used alone or together with surgical or medical castration for this indication, and is able to significantly slow the course of the disease and extend life.[16][17][18] Bicalutamide is also used to treat hirsutism (excessive hair growth in women),[19] early-onset puberty in boys, as a component of hormone therapy for transgender women,[20] and in the treatment of other androgen-dependent conditions.[21][22][23]

Bicalutamide is a non-steroidal antiandrogen (NSAA) and acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).[24] It does not lower androgen levels,[4] instead acting purely by preventing androgens from mediating their effects in the body.[24][25][26] Bicalutamide is taken orally.[3] It is well-absorbed, and its absorption is not affected by food.[3] The drug has a long terminal half-life of 6 to 10 days.[3] It crosses the blood-brain-barrier.[3][27] The major side effects of bicalutamide in men are gynecomastia (breast development), breast tenderness, and feminization in general,[28][29][30][31] whereas the drug produces few side effects and is very well-tolerated in women.[32] Bicalutamide can cause elevated liver enzymes in around 1% of patients,[33][17][34] and has been associated with a few cases of liver damage[35][36] and lung toxicity in the medical literature.[37][38][39] Monitoring of liver enzymes is recommended during treatment with bicalutamide.[17][40]

Bicalutamide was developed and marketed by AstraZeneca (formerly as Imperial Chemical Industries (ICI)),[41] and was first approved in 1995.[16][17] It is the most widely used antiandrogen in the treatment of prostate cancer, as well as the most widely used NSAA, and has been prescribed to millions of men with the disease.[42][43][44][45] Prior to the introduction of the newer and improved NSAA enzalutamide in 2012,[46] bicalutamide was considered to be the standard-of-care antiandrogen in the treatment of prostate cancer.[47][46][48] Bicalutamide shows an improved profile of effectiveness, tolerability, and safety when compared to earlier antiandrogens like the steroidal antiandrogen (SAA) cyproterone acetate (CPA) and the NSAAs flutamide and nilutamide,[49][46][50][51] and has largely replaced them in the treatment of prostate cancer.[5][52][53][49][54][55][56]

Bicalutamide is available in most developed countries,[12][57][58] and is marketed in at least 70 countries throughout the world.[59] Its patent protection expired in 2009 and the drug has since been available in low-cost generic formulations.[60][61] Its cost is from $15.44 USD per month for a dosage of 50 mg per day.[62] Bicalutamide is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[63]

Medical uses

Prostate cancer

Bicalutamide is used primarily in the treatment of early and advanced prostate cancer.[64] It is approved at a dosage of 50 mg/day as a combination therapy with a gonadotropin-releasing hormone (GnRH) analogue or orchiectomy (that is, surgical or medical castration) in the treatment of stage D2 metastatic prostate cancer (mPC),[5][65] and as a monotherapy at a dosage of 150 mg/day for the treatment of stage C or D1 locally advanced prostate cancer (LAPC).[5][3][17][66] Although effective in mPC and LAPC, bicalutamide is no longer indicated for the treatment of localized prostate cancer (LPC) due to negative findings in the Early Prostate Cancer (EPC) trial (see below).[17]

Role of antiandrogens in prostate cancer

In 1941, Charles Huggins and Clarence Hodges discovered that growth of prostate cancer in men regressed with surgical castration or high-dose estrogen treatment, which were associated with very low levels of circulating testosterone, and accelerated with the administration of exogenous testosterone, findings for which they were later awarded the Nobel Prize.[67][68] It has since been elucidated that androgens like testosterone and 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.[69] As a result of the work of Huggins and Hodges, 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.[67] Although ADT can shrink or stabilize prostate tumors and hence significantly slow the course of prostate cancer and prolong life, it is, unfortunately, not generally curative.[70] 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 AR that result in the transformation of drugs like bicalutamide from AR antagonists to agonists.[71]

A few scientific observations form the basis of the reasoning behind combined androgen blockade (CAB), in which castration and an NSAA are combined.[72] 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.[73] Although castration ceases production of androgens by the gonads and reduces circulating testosterone levels by about 95%,[74] low levels of androgens continue to be produced by the adrenal glands, and this accounts for the residual levels of circulating testosterone.[75] Moreover, it has been found that intraprostatic levels of DHT, which is the major androgen in the prostate gland, remain at 40 to 50% of their initial values following castration.[75][76] This has been determined to be due to uptake of circulating weak adrenal androgens like dehydroepiandrosterone (DHEA) and androstenedione by the prostate and their de novo transformation into testosterone and then DHT.[75][76][77] As such, a significant amount of androgen signaling continues within the prostate gland even with castration.[75][76][77] Previously, surgical adrenalectomy or therapy with older androgen biosynthesis inhibitors like ketoconazole and aminoglutethimide were successfully employed in the treatment of castration-resistant prostate cancer.[74][67][78][79] However, adrenalectomy is a relatively invasive procedure with high morbidity and ketoconazole and aminoglutethimide are relatively toxic drugs, and both treatment modalities absolutely require supplementation of corticosteroids, making them in many ways unideal.[67][80][81][82] The development of CAB with NSAAs like bicalutamide and enzalutamide has since allowed for a non-invasive, convenient, and well-tolerated replacement.[79][83]

Subsequent clinical research has found that monotherapy with higher dosages of NSAAs than those used in CAB is slightly but non-significantly inferior or roughly equivalent to castration in extending life in men with prostate cancer.[49][67][84][85] Moreover, NSAA monotherapy is overall better tolerated and associated with greater quality of life than is castration,[15][86][87][88] 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.[87][88][89][90][91] For these reasons, NSAA monotherapy has become an important alternative to castration and CAB in the treatment of prostate cancer.[92][93][94]

Other uses

Excess hair and acne

Low-dose bicalutamide has been found to be effective in the treatment of hirsutism (excessive body and/or facial hair growth) in women in at least three clinical studies.[19][95][96][97] In one such study, the drug was well-tolerated, all of the patients experienced a visible decrease in hair density, and a highly significant clinical improvement was observed with the Ferriman–Gallwey score decreasing by 41.2% at 3 months and by 61.6% at 6 months.[98][32] According to a recent review, "Low dose bicalutamide (25 mg/day) was shown to be effective in the treatment of hirsutism related to IH and PCOS. It does not have any significant side effects [or lead] to irregular periods."[95]

In addition to hirsutism, bicalutamide can also be used in the treatment of acne in women.[21][99] Several studies have observed complete clearing of acne with flutamide in women, and similar or benefits would be expected with bicalutamide.[100]:712–717 Bicalutamide may also treat other androgen-dependent skin conditions, such as seborrhea and androgenic alopecia (pattern hair loss).[22] Flutamide has been found to produce a decrease of hirsutism score to normal and an 80% or greater decrease in scores of acne, seborrhea, and androgen-dependent hair loss.[24] Moreover, in combination with an oral contraceptive, flutamide treatment resulted in an increase in cosmetically acceptable scalp hair density in 6 of 7 women suffering from androgenic alopecia.[100]

Transgender hormone therapy

Bicalutamide is used as a component of hormone replacement therapy (HRT) in the endocrinological treatment of transgender women.[20][101][102][103][104] Beneficial or desired effects include breast development,[105][106][107] reduced male-pattern hair,[29] decreased muscle mass,[40] changes in fat distribution, lowered libido,[40] and loss of spontaneous erections.[108] Bicalutamide monotherapy increases estradiol levels in biological males and hence has indirect estrogenic effects in transgender women.[109][110] This is a property that can be considered to be desirable in transgender women, as it produces or contributes to feminization.[109][110]

Unlike the cases of the SAAs spironolactone and CPA and GnRH analogues,[111] no clinical studies assessing bicalutamide as an antiandrogen in the hormonal treatment of transgender women have been published. However, bicalutamide is effective as an antiandrogen in women (with hirsutism)[19][95][96] and in boys with precocious puberty,[112][113][114][115] and feminization is a well-documented effect of bicalutamide in men treated with it for prostate cancer (see below).[29][30][31] In addition, nilutamide, which is a closely related antiandrogen that possesses the same mechanism of action as bicalutamide, has been evaluated in transgender women in at least five small clinical studies.[109][116][117][118][119][120] In these studies, nilutamide monotherapy (i.e., without estrogen), employed at the same dosage at which it is used in prostate cancer (300 mg/day), induced observable signs of clinical feminization in young transgender women (age range 19–33 years) within 8 weeks,[117] including breast development, decreased male-pattern hair,[116] decreased morning erections and sex drive,[118] and positive psychological and emotional changes.[118][121] Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity,[120][117][118] and along with decreased hair growth, were the earliest sign of feminization.[117] The drug more than doubled luteinizing hormone (LH) and testosterone levels and tripled estradiol levels (see below),[116][117][119] and the addition of ethinyl estradiol (a potent estrogen) to nilutamide therapy after 8 weeks of treatment abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range.[116][117] Both nilutamide alone and particularly the combination of nilutamide and estrogen were regarded as effective in terms of antiandrogen action and producing feminization in transgender women.[116][117] However, use of nilutamide itself for prostate cancer and other conditions is now discouraged due to its unique adverse effects, most importantly a high incidence of interstitial pneumonitis (which can progress to pulmonary fibrosis and potentially be fatal),[69][122][123] and newer, safer NSAAs like bicalutamide and enzalutamide have largely replaced it and are used instead.[54][55][56]

According to Dr. Madeline Deutsch of the Center of Excellence for Transgender Health (a division of the University of California, San Francisco) in the Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People (2016), on the topic of bicalutamide in transgender women:[104]

In many countries, cyproterone acetate, a synthetic progestagen with strong anti-androgen activity is commonly used [as an antiandrogen in feminizing hormone therapy for transgender women]. Cyproterone [acetate] has been associated with uncommon episodes of fulminant hepatitis.[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.[104]

It is noteworthy, however, that CPA is widely used as an antiandrogen for the treatment of transgender women (and cisgender women with acne and hirsutism)[124] outside of the U.S. (a country where CPA is unavailable and spironolactone is generally used instead)[125][126][127] yet appears to have a much higher comparative risk of hepatotoxicity than does bicalutamide (see below).[128] Only five cases of hepatotoxicity have been associated with bicalutamide to date.[36]

Male early puberty

Bicalutamide (25–50 mg/day) is useful in combination with the aromatase inhibitor anastrozole as a puberty blocker in the treatment of male precocious puberty.[112][113][114] This is potentially a cost-effective alternative to GnRH analogues for the treatment of this condition, as GnRH analogues are very expensive.[129][130] Moreover, the combination is effective in gonadotropin-independent precocious puberty, namely familial male-limited precocious puberty (also known as testotoxicosis), where GnRH analogues notably are not effective.[113][114][131] Bicalutamide has been found to be superior to the SAA spironolactone (which has also been used, in combination with the aromatase inhibitor testolactone) for this indication; it has shown greater effectiveness and possesses fewer side effects in comparison.[113][132] For this reason, bicalutamide has replaced spironolactone in the treatment of the condition.[115]:2139


Antiandrogens can considerably relieve and prevent priapism (potentially painful penile erections that last more than four hours) via direct blockade of penile ARs.[133][134] 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,[135][136][137] and is used for this indication off-label.[4][9] 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.[135][136][137] Some gynecomastia and breast tenderness developed in one patient treated with 50 mg/day, but significantly improved upon the dosage being halved.[137] 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).[135][136] However, although successful and well-tolerated, very few cases have been reported.[23]

Available forms

Bicalutamide Teva 50 mg tablets.[138]

Bicalutamide is available in 50 mg, 80 mg (in Japan),[139] and 150 mg tablets for oral administration.[140][141] No other formulations or routes of administration are available or used.[140] All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration.[5]

A combined formulation of bicalutamide and the GnRH agonist goserelin in which goserelin is provided as a subcutaneous implant for injection and bicalutamide is included as 50 mg tablets for oral ingestion is marketed in Australia and New Zealand under the brand name ZolaCos CP (Zoladex-Cosudex Combination Pack).[58][142][143][144]


Hepatic impairment

In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution may be warranted in these patients.[3][145] In severe hepatic impairment, the terminal half-life of the active (R)-enantiomer of bicalutamide is increased by about 1.75-fold (76% increase; half-life of 5.9 and 10.4 days for normal and impaired patients, respectively).[17][146][147] The terminal half-life of bicalutamide is unchanged in renal impairment.[49]

Pregnancy and breastfeeding

Because bicalutamide blocks the AR, like all antiandrogens, it can interfere with the androgen-mediated sexual differentiation of the genitalia (and brain) during prenatal development.[148][149][150][151] In pregnant rats given bicalutamide at a dosage of 10 mg/kg/day (resulting in circulating drug levels approximately equivalent to two-thirds of human therapeutic concentrations) and above, feminization of male offspring, such as reduced anogenital distance and hypospadias, as well as impotence, were observed.[33] No other teratogenic effects were observed in rats or rabbits receiving up to very high dosages of bicalutamide (that corresponded to up to approximately two times human therapeutic levels), and no teratogenic effects of any sort were observed in female rat offspring at any dosage.[33] As such, bicalutamide is a reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.[148][149] For this reason, the drug is contraindicated in women during pregnancy, and women who are sexually active and who can or may become pregnant are strongly recommended to take bicalutamide only in combination with contraception.[148][149] It is unknown whether bicalutamide is excreted in breast milk, but many drugs are excreted in breast milk, and for this reason, breastfeeding is not recommended during bicalutamide treatment.[4][33]

Side effects

The side effect profile of bicalutamide is highly sex-dependent. In women, the side effects of pure antiandrogens/NSAAs are minimal, and bicalutamide has been found to be very well-tolerated.[32] In men however, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia being the most common[40][152] and others including physical feminization and demasculinization in general (e.g., reduced body hair growth/density, decreased muscle mass and strength, changes in fat mass and distribution, and reduced penile length),[40][29][30][31] hot flashes, sexual dysfunction (including loss of libido and erectile dysfunction), depression, fatigue, weakness, anemia, and decreased semen/ejaculate volume.[40][51][153] General side effects of bicalutamide that may occur in either sex may include diarrhea, constipation, abdominal pain, nausea, dry skin,[154] itching, and rash.[51][4][155][156][157] The drug is well-tolerated at higher dosages (than the 50 mg/day dosage), with rare additional side effects.[49]


Gynecomastia in a 60-year-old man treated with 150 mg/day bicalutamide for prostate cancer.[158]

The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia (Greek: gynaika: woman, mastos: breast, or "woman-like breasts").[159] These side effects may occur in up to more than 90% of men treated with bicalutamide monotherapy,[160] but gynecomastia is generally reported to occur in 70–80% of patients.[152] In the EPC trial, at a median follow-up of 7.4 years, breast pain and gynecomastia respectively occurred in 73.6% and 68.8% of men treated with 150 mg/day bicalutamide monotherapy.[17] In more than 90% of affected men, bicalutamide-related breast events are mild-to-moderate in severity.[28] It is only rarely and in severe or extreme cases of gynecomastia that the proportions of the male breasts become so marked that they are comparable to those of women.[161] In the EPC trial, 16.8% of bicalutamide patients relative to 0.7% of controls withdrew from the study due to breast pain and/or gynecomastia.[28] The incidence and severity of gynecomastia are higher with estrogens (e.g., diethylstilbestrol) than with NSAAs like bicalutamide in the treatment of men with prostate cancer.[162]


Severe gynecomastia in a 64-year-old man treated with 150 mg/day bicalutamide for prostate cancer. Before (A) and after (B) surgical breast reduction.[163]

Tamoxifen, a selective estrogen receptor modulator (SERM) with antiestrogenic actions in breast tissue and estrogenic actions in bone, has been found to be highly effective in preventing and reversing bicalutamide-induced gynecomastia in men.[164][165] Moreover, in contrast to GnRH analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis.[164][165] For reasons that are unclear, anastrozole, an aromatase inhibitor (or an inhibitor of estrogen biosynthesis), has been found to be much less effective in comparison to tamoxifen for treating bicalutamide-induced gynecomastia.[164][165] A systematic review of NSAA-induced gynecomastia and breast tenderness concluded that tamoxifen (10–20 mg/day) and radiotherapy could effectively manage the side effect without relevant adverse effects, though with tamoxifen showing superior effectiveness.[166] Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.[167]

Sexual dysfunction

Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction.[17] However, the rates of these side effects with bicalutamide monotherapy are very low.[17] In the EPC trial, at 7.4 years follow-up, the rates of decreased libido and impotence were only 3.6% and 9.3% in the 150 mg/day bicalutamide monotherapy group relative to 1.2% and 6.5% for placebo, respectively.[17] Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs.[159] In clinical trials, about two-thirds of men with advanced prostate cancer (and of almost invariably advanced age)[168] treated with bicalutamide monotherapy maintained sexual interest, while sexual function was slightly reduced by 18%.[92]

Reproductive changes

Bicalutamide reduces the size of the prostate gland and seminal vesicles,[169] though not of the testes.[170] Significantly reduced penile length is also a recognized adverse effect of ADT.[31][171] Reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur.[172][173] However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men (see below).[170] Due to the induction of chronic overproduction of LH and testosterone, there was concern that long-term bicalutamide monotherapy might induce Leydig cell hyperplasia and tumors (usually benign),[174] but the evidence indicates that Leydig cell hyperplasia does not occur to a significant extent.[51]

Other side effects


The incidence of diarrhea with bicalutamide monotherapy in the EPC trial was comparable to placebo (6.3% vs. 6.4%, respectively).[92] In phase III studies of bicalutamide monotherapy for LAPC, the rates of diarrhea for bicalutamide and castration were 6.4% and 12.5%, respectively, the rates of constipation were 13.7% and 14.4%, respectively, and the rates of abdominal pain were 10.5% and 5.6%, respectively.[175]

Hot flashes

In the EPC trial, at 7.4 years follow-up, the rate of hot flashes was 9.2% for bicalutamide relative to 5.4% for placebo, which was regarded as relatively low.[17] In the LAPC subgroup of the EPC trial, the rate of hot flashes with bicalutamide was 13.1% (relative to 50.0% for castration).[17][92]

Depression and asthenia

At 5.3 years follow-up, the incidence of depression was 5.5% for bicalutamide relative to 3.0% for placebo in the EPC trial, and the incidence of asthenia (weakness or fatigue) was 10.2% for bicalutamide relative to 5.1% for placebo.[176]


Androgens are known to stimulate the formation of red blood cells, and for this reason, whether via castration, NSAA monotherapy, or CAB, mild anemia is a common side effect of ADT in men.[51][177] The incidence of anemia with bicalutamide as a monotherapy or with castration was about 7.4% in clinical trials.[51] A decrease of hemoglobin levels of 1–2 g/dL after approximately six months of treatment may be observed.[177]

Skin changes

Androgens are involved in regulation of the skin (e.g., sebum production), and antiandrogens are known to be associated with skin changes.[51] Skin-related side effects, which included dry skin, itching, and rash, were reported at a rate of 12% in both monotherapy and CAB clinical studies of bicalutamide in men.[51]

With castration

Combination of bicalutamide with medical (i.e., a GnRH analogue) or surgical castration modifies the side effect profile of bicalutamide. Some of its side effects, including breast pain/tenderness and gynecomastia, are far less likely to occur when the drug is combined with a GnRH analogue,[178] while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,[179] occur much more frequently in combination with a GnRH analogue.[86][180][181] It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by GnRH analogues, as estrogen may compensate for various negative central effects of androgen deprivation.[86] If bicalutamide is combined with a GnRH analogue or surgical castration, the elevation of androgen and estrogen levels in men caused by bicalutamide will be prevented and the side effects of excessive estrogens, namely gynecomastia, will be reduced.[178] However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.[182]

Increased mortality

In the LPC group of the EPC study, although 150 mg/day bicalutamide monotherapy had reduced mortality due to prostate cancer relative to placebo, there was a trend toward significantly increased overall mortality for bicalutamide relative to placebo at 5.4-year follow-up (25.2% vs. 20.5%).[176][183][184] This was because more bicalutamide than placebo recipients had died due to causes unrelated to prostate cancer in this group (16.8% vs. 9.5% at 5.4-year follow-up; 10.2% vs. 9.2% at 7.4-year follow-up).[176][184][17] At 7.4-year follow-up, there were numerically more deaths from heart failure (1.2% vs. 0.6%; 49 vs. 25 patients) and gastrointestinal cancer (1.3% vs. 0.9%) in the bicalutamide group relative to placebo recipients, although cardiovascular morbidity was similar between the two groups and there was no consistent pattern suggestive of drug-related toxicity for bicalutamide.[17][185] In any case, although the reason for the increased overall mortality with 150 mg/day bicalutamide monotherapy has not been fully elucidated,[152] it has been said that the finding that heart failure was twice as frequent in the bicalutamide group warrants further investigation.[186] In this regard, it is notable that low testosterone levels in men have been associated in epidemiological studies with cardiovascular disease as well as with a variety of other disease states (including hypertension, hypercholesterolemia, diabetes, obesity, Alzheimer's disease, osteoporosis, and frailty).[187]

According to Iversen et al. (2006), the increased non-prostate cancer mortality with bicalutamide monotherapy in LPC patients has also been seen with castration (via orchiectomy or GnRH analogue monotherapy) and is likely a consequence of androgen deprivation in men rather than a specific drug toxicity of bicalutamide:[188]

The increased number of deaths in patients with localized disease receiving bicalutamide was meticulously investigated and they appeared to be due to a number of small imbalances rather than a specific cause. In addition, no direct toxic effect on any organ system could be identified. From this it may be speculated that the excess deaths in patients who are at low risk from prostate cancer mortality reflect the impact of endocrine therapy (rather than bicalutamide in particular). [...] The increased number of non-prostate cancer deaths in the early castration therapy arm [(via orchiectomy or GnRH monotherapy)] in the [Medical Research Council] study suggests that the trend towards an increased number of deaths in patients with localized disease in the present study is a reflection of early endocrine therapy as a concept rather than a bicalutamide-related phenomenon.[188]

Rare reactions

Liver toxicity

Bicalutamide may cause liver changes rarely, such as elevated transaminases (a marker of hepatotoxicity) and jaundice.[35] In the EPC study of 4,052 prostate cancer patients who received 150 mg/day bicalutamide as a monotherapy, the incidence of abnormal liver function tests was 3.4% for bicalutamide and 1.9% for standard care (a 1.5% difference potentially attributable to bicalutamide) at 3-year median follow-up.[17][189] For comparison, the incidences of abnormal liver function tests are 42–62% for flutamide, 2–3% for nilutamide,[35][190] and (dose-dependently) between 9.6% and 28.2% for CPA,[191][192][193] whereas there appears to be no risk with enzalutamide.[194][195] In the EPC trial, bicalutamide-induced liver changes were usually transient and rarely severe.[17] The drug was discontinued due to liver changes (manifested as hepatitis or marked increases in liver enzymes) in approximately 0.3% to 1% of patients treated with it for prostate cancer in clinical trials.[33][34]

The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended.[17][40] Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued.[196] Liver changes with bicalutamide usually occur within the first 3 or 4 months of treatment, and it is recommended that liver function be monitored regularly for the first 4 months of treatment and periodically thereafter.[33] Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.[33]

Out of millions of patient exposures,[45] a total of five cases of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been reported in the medical literature as of 2016.[35][36] One of these cases occurred after only two doses of bicalutamide, and has been regarded as much more likely to have been caused by prolonged prior exposure of the patient to flutamide and CPA.[35][190][197][198][199] In the five reported cases of bicalutamide-associated hepatotoxicity, the dosages of the drug were 50 mg/day (three), 100 mg/day (one), and 150 mg/day (one).[36] Relative to flutamide (which has an estimated incidence rate of 3 in every 10,000), hepatotoxicity or liver failure is far rarer with bicalutamide and nilutamide, and bicalutamide is regarded as having the lowest risk of the three drugs.[10][197][200] For comparison, by 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death.[191] Moreover, a 2002 review reported that there were 18 reports of hepatotoxicity associated with CPA in the medical literature, with 6 of the reported cases resulting in death, and the review also cited a report of an additional 96 instances of hepatotoxicity that were attributed to CPA, 33 of which resulted in death.[191]

From a theoretical standpoint (on the basis of structure-activity relationships), it has been suggested that flutamide, bicalutamide, and nilutamide, to varying extents, all have the potential to cause liver toxicity.[201] However, in contrast to flutamide, hydroxyflutamide, and nilutamide, bicalutamide exhibits much less or no mitochondrial toxicity and inhibition of enzymes in the electron transport chain such as respiratory complex I (NADH ubiquinone oxidoreductase), and this may be the reason for its much lower risk of hepatotoxicity in comparison.[202][203][204][205] The activity difference may be related to the fact that flutamide, hydroxyflutamide, and nilutamide all possess a nitroaromatic group, whereas in bicalutamide, a cyano group is present in place of this nitro group, potentially reducing toxicity.[197][202][205][206]

Lung toxicity

Several case reports of interstitial pneumonitis (which can progress to pulmonary fibrosis) in association with bicalutamide treatment have been published in the medical literature.[37][38][39] Interstitial pneumonitis with bicalutamide is said to be an extremely rare event,[207] and the risk is far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).[54]:81[38][208] In a very large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with NSAAs was 0.77% for nilutamide but only 0.04% for flutamide and 0.01% for bicalutamide.[209] An assessment done prior to the publication of the aforementioned study estimated the rates of pulmonary toxicity with flutamide, bicalutamide, and nilutamide as 1 case, 5 cases, and 303 cases per million, respectively.[210] In addition to interstitial pneumonitis, a single case report of eosinophilic lung disease in association with six months of 200 mg/day bicalutamide treatment exists.[4][211] Side effects associated with the rare potential pulmonary adverse reactions of bicalutamide may include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat).[212]


A few cases of photosensitivity (hypersensitivity to ultraviolet light-induced skin redness and/or lesions) associated with bicalutamide have been reported.[213][214][215] In one of the cases, bicalutamide was continued due to effectiveness in treating prostate cancer in the patient, and in combination with strict photoprotection (in the form of avoidance/prevention of ultraviolet light exposure), the symptoms disappeared and did not recur.[213] Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.[213][215]


Hypersensitivity reactions (i.e., drug allergy), including angioedema and hives, have uncommonly been reported with bicalutamide.[33]

Male breast cancer

A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published.[216] According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)."[216] It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men.[216][217] Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%,[218] the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years),[168][219] and millions of men have been treated with bicalutamide for prostate cancer,[45] all of which are potentially in support of the notion of chance co-occurrences.[216] In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."[216]


A single oral dose of bicalutamide in humans that results in symptoms of overdose or that is considered to be life-threatening has not been established.[33][220] Dosages of up to 600 mg/day have been well-tolerated in clinical trials,[221] and it is notable that there is a saturation of absorption with bicalutamide such that circulating levels of its active (R)-enantiomer do not further increase above a dosage of 300 mg/day.[3][221] Overdose is considered to be unlikely to be life-threatening with bicalutamide or other first-generation NSAAs (i.e., flutamide and nilutamide).[222] A massive overdose of nilutamide (13 grams, or 43 times the normal maximum 300 mg/day clinical dosage) in a 79-year-old man was uneventful, producing no clinical signs or symptoms or toxicity.[223] There is no specific antidote for bicalutamide or NSAA overdose, and treatment should be based on symptoms.[33][220]


Cytochrome P450 enzymes

Bicalutamide is almost exclusively metabolized by CYP3A4.[5] As such, its levels in the body may be altered by inhibitors and inducers of CYP3A4.[9] (For a list of CYP3A4 inhibitors and inducers, see here.) However, in spite of the fact bicalutamide is metabolized by CYP3A4, there is no evidence of clinically significant drug interactions when bicalutamide at a dosage of 150 mg/day or less is co-administered with drugs that inhibit or induce cytochrome P450 enzyme activity.[17]

Plasma binding proteins

Because bicalutamide circulates at relatively high concentrations and is highly protein-bound, it has the potential to displace other highly protein-bound drugs like warfarin, phenytoin, theophylline, and aspirin from plasma binding proteins.[152][51] This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments.[152] Bicalutamide has specifically been found to displace coumarin anticoagulants like warfarin from their plasma binding proteins (namely albumin) in vitro, potentially resulting in an increased anticoagulant effect, and for this reason, close monitoring of prothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs.[50][224][225] However, in spite of this, no conclusive evidence of an interaction between bicalutamide and other drugs was found in clinical trials of nearly 3,000 patients.[51]

Comparison with other antiandrogens

Since their introduction, bicalutamide and the other NSAAs have largely replaced CPA, an older drug and an SAA, in the treatment of prostate cancer.[5][52][53][49] Bicalutamide was the third NSAA to be marketed, with flutamide and nilutamide preceding, and followed by enzalutamide.[226][47] Relative to the earlier antiandrogens, bicalutamide has substantially reduced toxicity, and in contrast to them, is said to have an excellent and favorable safety profile.[49][46][50][51] For these reasons, as well as superior potency, tolerability, and pharmacokinetics, bicalutamide is preferred and has largely replaced flutamide and nilutamide in clinical practice.[54][55][56] In accordance, bicalutamide is the most widely used antiandrogen in the treatment of prostate cancer.[42][43][44] Between January 2007 and December 2009, it accounted in the U.S. for about 87.2% of NSAA prescriptions.[45] Prior to the 2012 approval of enzalutamide, a newer and improved NSAA with greater potency and efficacy,[46] bicalutamide was regarded as the standard-of-care antiandrogen in the treatment of the prostate cancer.[47][46][48]

First-generation NSAAs

Comparison of first-generation NSAAs[152][227]
Property Flutamide Nilutamide Bicalutamide
Half-life 5–6 hours ~2 days ~7 days
AR RBA 25% 20% 100%
Dosage 250 mg t.i.d. 100 mg t.i.d. 150 mg o.d.
Unique side
• Diarrhea
• Hepatotoxicity
• Photosensitivity
• Nausea and vomiting
• Visual disturbances
• Alcohol intolerance
• Interstitial pneumonitis
• None[159]

Flutamide and nilutamide are first-generation NSAAs, similarly to bicalutamide, and all three drugs possess the same core mechanism of action of being selective AR antagonists.[228] However, bicalutamide is the most potent of the three, with the highest affinity for the AR[153][229] and the longest half-life,[54] and is the safest, least toxic, and best-tolerated.[83] For these reasons, bicalutamide has largely replaced flutamide and nilutamide in clinical use,[201] and is by far the most widely used first-generation NSAA.[45]


In terms of binding to the AR, the active (R)-enantiomer of bicalutamide has 4-fold greater affinity relative to that of hydroxyflutamide, the active metabolite of flutamide (a prodrug),[230][231] and 5-fold higher affinity relative to that of nilutamide.[227] In addition, bicalutamide possesses the longest half-life of the three drugs,[54] with half-lives of 6–10 days for bicalutamide,[9][10] 5–6 hours for flutamide[49][54] and 8–9 hours for hydroxyflutamide,[49][232][69] and 23–87 hours (mean 56 hours) for nilutamide.[190] Due to the relatively short half-lives of flutamide and hydroxyflutamide, flutamide must be taken three times daily at 8-hour intervals, whereas bicalutamide and nilutamide may be taken once daily.[233] For this reason, dosing of bicalutamide (and nilutamide) is more convenient than with flutamide.[234] The greater AR affinity and longer half-life of bicalutamide allow it to be used at relatively low dosages in comparison to flutamide (750–1500 mg/day) and nilutamide (150–300 mg/day) in the treatment of prostate cancer.[190][25][93]

While it has not been directly compared to nilutamide,[92] the effectiveness of bicalutamide has been found to be at least equivalent to that of flutamide in the treatment of prostate cancer in a direct head-to-head comparison.[235][236] Moreover, indications of superior efficacy, including significantly greater relative decreases and increases in levels of prostate-specific antigen (PSA) and testosterone, respectively, were observed.[235][236]

It has been reported that hydroxyflutamide and nilutamide, in contrast to bicalutamide, have some ability to weakly activate the AR at high concentrations.[67]

Tolerability and safety

Tolerability of NSAAs based on clinical data (Buzzatti et al., 2014)[207]
Side effect Flutamide Nilutamide Bicalutamide Enzalutamide
Fatigue + ++
Hepatotoxicity +
Diarrhea ++ + +
Nausea + ++ +
Constipation + +
Gynecomastia[237] +++ +++ +++ ++
Breast pain[237] +++ +++ +++ ++
Hot flashes ++ + +
Seizures +
Hypertension +
Visual disturbances ++
Alcohol intolerance +
Back pain + +
–: Not reported; +: ≥ 1%, < 20%; ++: ≥ 20%, < 40%; +++: ≥ 40%

The core side effects of NSAAs such as gynecomastia, sexual dysfunction, and hot flashes occur at similar rates with the different drugs.[238][86] Conversely, bicalutamide is associated with a significantly lower rate of diarrhea compared to flutamide.[92][239] In fact, the incidence of diarrhea did not differ between the bicalutamide and placebo groups (6.3% vs. 6.4%, respectively) in the EPC trial,[15] whereas diarrhea occurs in up to 20% of patients treated with flutamide.[92][190] The rate of nausea and vomiting appears to be lower with bicalutamide and flutamide than with nilutamide (approximately 30% incidence of nausea with nilutamide, usually rated as mild-to-moderate).[122][240] In addition, bicalutamide (and flutamide) is not associated with alcohol intolerance, visual disturbances, or a high rate of interstitial pneumonitis.[92][239] In terms of toxicity and rare reactions, as described above, bicalutamide appears to have the lowest relative risks of hepatotoxicity and interstitial pneumonitis, with respective incidences far below those of flutamide and nilutamide.[10][197][200][209] In contrast to flutamide and nilutamide, no specific complications have been linked to bicalutamide.[159]


The patent protection of all three of the first-generation NSAAs has expired and flutamide and bicalutamide are both available as relatively inexpensive generics.[241][242] Nilutamide, on the other hand, has always been a poor third competitor to flutamide and bicalutamide and, in relation to this fact, has not been developed as a generic and is only available as brand name Nilandron, at least in the U.S.[241][242]

Second-generation NSAAs

Enzalutamide, along with the in-development apalutamide and darolutamide, are newer, second-generation NSAAs.[243] Similarly to bicalutamide and the other first-generation NSAAs, they possess the same core mechanism of action of selective AR antagonism, but are considerably more potent and efficacious in comparison.[243]


In comparison to bicaclutamide, enzalutamide has 5- to 8-fold higher affinity for the AR,[244][245][246][247] possesses mechanistic differences resulting in improved AR deactivation,[244][248] shows increased (though by no means complete) resistance to AR mutations in prostate cancer cells causing a switch from antagonist to agonist activity,[244][249] and has an even longer half-life (8–9 days versus ~6 days for bicalutamide).[250] In accordance, enzalutamide, at a dosage of 160 mg/day, has been found to produce similar increases in testosterone, estradiol, and LH levels relative to high-dosage bicalutamide (300 mg/day), and an almost two-fold higher increase in testosterone levels relative to 150 mg/day bicalutamide (114% versus 66%).[251][207] These findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison.[251][207] Moreover, the drug has demonstrated superior clinical effectiveness in the treatment of prostate cancer in a direct head-to-head comparison with bicalutamide.[252]

Tolerability and safety

In terms of tolerability, enzalutamide and bicalutamide appear comparable in most regards, with a similar moderate negative effect on sexual function and activity for instance.[251] However, enzalutamide has a risk of seizures and other central side effects such as anxiety and insomnia related to off-target GABAA receptor inhibition that bicalutamide does not appear to have.[250][253] On the other hand, unlike with all of the earlier NSAAs (flutamide, nilutamide, and bicalutamide), there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.[194][195] In addition to differences in adverse effects, enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19 and poses a high risk of major drug interactions (CYP3A4 alone being involved in the metabolism of approximately 50 to 60% of clinically important drugs),[254][255] whereas drug interactions are few and minimal with bicalutamide.[17][51]


Unlike bicalutamide, enzalutamide is still on-patent, and for this reason, is extremely expensive ($7,450 USD for a 30-day supply as of 2015).[256] In contrast, bicalutamide is off-patent and available as a generic, and its cost is very low in comparison (from $15.44 for a 30-day supply of once-daily 50 mg tablets).[62]

Steroidal antiandrogens

SAAs include CPA, megestrol acetate, chlormadinone acetate, and spironolactone.[257][258] These drugs are steroids, and similarly to NSAAs, act as competitive antagonists of the AR, reducing androgenic activity in the body.[67]:79 In contrast to NSAAs however, they are non-selective, also binding to other steroid hormone receptors, and exhibit a variety of other activities including progestogenic, antigonadotropic, glucocorticoid, and/or antimineralocorticoid.[257][258] In addition, they are not silent antagonists of the AR, but are rather weak partial agonists with the capacity for both antiandrogenic and androgenic actions.[67][24][259] Of the SAAs, CPA is the only one that has been widely used in the treatment of prostate cancer.[231]:488 As antiandrogens, the SAAs have largely been replaced by the NSAAs and are now rarely used in the treatment of prostate cancer, due to the superior selectivity, efficacy, and tolerability profiles of NSAAs.[5][52][53][49] However, some of them, namely CPA and spironolactone, are still commonly used in the management of certain androgen-dependent conditions (e.g., acne and hirsutism in women) and as the antiandrogen component of HRT for transgender women.[25]:1195–6[260]


In a large-scale clinical trial that compared 750 mg/day flutamide and 250 mg/day CPA monotherapies in the treatment of men with prostate cancer, the two drugs were found to have equivalent effectiveness on all endpoints.[84] In addition, contrarily to the case of men, flutamide has been found in various clinical studies to be more effective than CPA (and particularly spironolactone) in the treatment of androgen-dependent conditions such as acne and hirsutism in women.[261][262][263] This difference in effectiveness in men and women may be related to the fact that NSAAs like flutamide significantly increase androgen levels in men,[25] which counteracts their antiandrogen potency,[264] but do not increase androgen levels in women.[265] (In contrast to NSAAs, CPA, due to its progestogenic and hence antigonadotropic activity, does not increase and rather suppresses androgen levels in both sexes.)[25]

Bicalutamide has been found to be at least as effective as or more effective than flutamide in the treatment of prostate cancer,[235][236] and is considered to be the most powerful antiandrogen of the three first-generation NSAAs.[84] As such, although bicalutamide has not been compared head-to-head to CPA or spironolactone in the treatment of androgen-dependent conditions, flutamide has been found to be either equivalent or more effective than them in clinical studies, and the same would consequently be expected of bicalutamide. Accordingly, a study comparing the efficacy of 50 mg/day bicalutamide versus 300 mg/day CPA in preventing the PSA flare at the start of GnRH agonist therapy in men with prostate cancer found that the two regimens were equivalently effective.[266] There was evidence of a slight advantage in terms of speed of onset and magnitude for the CPA group, but the differences were small and did not reach statistical significance.[266] The differences may have been related to the antigonadotropic activity of CPA (which would directly counteract the GnRH agonist-induced increase in gonadal androgen production) and/or the fact that bicalutamide requires 4 to 12 weeks of administration to reach steady-state (maximal) levels.[17][266]

All medically used SAAs are weak partial agonists of the AR rather than silent antagonists, and for this reason, possess inherent androgenicity in addition to their predominantly antiandrogenic actions.[67][24][259] In accordance, although CPA produces feminization of and ambiguous genitalia in male fetuses when administered to pregnant animals,[267] it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals.[24] Additionally, all SAAs, including CPA and spironolactone, have been found to stimulate and significantly accelerate the growth of androgen-sensitive tumors in the absence of androgens, whereas NSAAs like flutamide have no effect and can in fact antagonize the stimulation caused by SAAs.[24][259][268] Accordingly, unlike NSAAs, the addition of CPA to castration has never been found in any controlled study to prolong survival in prostate cancer to a greater extent than castration alone.[24] In fact, a meta-analysis found that the addition of CPA to castration actually reduces the long-term effectiveness of ADT and causes an increase in mortality (mainly due to cardiovascular complications induced by CPA).[269] Also, there is a case report of spironolactone actually inducing progression of prostate cancer in a castrated man treated with it for heart failure, and for this reason, spironolactone has been regarded as contraindicated in patients with prostate cancer.[270] Because of their intrinsic capacity to activate the AR, SAAs are incapable of maximally depriving the body of androgen signaling, and will always maintain at least some degree of AR activation.[259][268]

Due to its progestogenic (and by extension antigonadotropic) activity, CPA is able to suppress circulating testosterone levels by 70–80% in men at high dosages.[83][271] In contrast, NSAAs increase testosterone levels by up to 2-fold via blockade of the AR, a difference that is due to their lack of concomitant antigonadotropic action.[110] However, in spite of the combined AR antagonism and marked suppression of androgen levels by CPA (and hence a sort of CAB profile of antiandrogen action), monotherapy with an NSAA, CPA, or a GnRH analogue/castration all have about the same effectiveness in the treatment of prostate cancer,[271][152] whereas CAB in the form of the addition of bicalutamide (but not of CPA) to castration has slightly but significantly greater comparative effectiveness in slowing the progression of prostate cancer and extending life.[24][152] These differences may be related to the inherent androgenicity of CPA, which likely serves to limit its clinical efficacy as an antiandrogen in prostate cancer.[67][24][259][272]

Tolerability and safety

Due to the different hormonal activities of NSAAs like bicalutamide and SAAs like CPA, they possess different profiles of adverse effects.[159] CPA is regarded as having an unfavorable side effect profile,[92] and the tolerability of bicalutamide is considered to be superior.[53][200] Due to its strong antigonadotropic effects and suppression of androgen and estrogen levels, CPA is associated with severe sexual dysfunction (including loss of libido and impotence) similar to that seen with castration[92][159][169] and osteoporosis,[273] whereas such side effects occur little or not at all with NSAAs like bicalutamide.[17][159] In addition, CPA is associated with coagulation changes[269] and thrombosis (5%),[24][169] fluid retention (4%),[169] cardiovascular side effects (e.g., ischemic cardiomyopathy) (4–40%),[274][34] and adverse effects on serum lipid profiles,[92][24][159] with severe cardiovascular complications (sometimes being fatal)[159] occurring in approximately 10% of patients.[122] In contrast, bicalutamide and other NSAAs are not associated with these adverse effects.[275] Moreover, CPA has a relatively high rate of generally severe and potentially fatal hepatotoxicity (see here),[92][276] whereas the risk of hepatotoxicity is far smaller and comparatively minimal with bicalutamide (though not necessarily with other NSAAs, namely flutamide) (see here).[277][278] CPA has also been associated with high rates of depression (20–30%) and other mental side effects such as fatigue, irritability, anxiety, and suicidal thoughts in both men and women, side effects which may be related to vitamin B12 deficiency.[279][280][281][282]

It has been said that the only advantage of CPA over castration is its relatively low incidence of hot flashes, a benefit that is mediated by its progestogenic activity.[169] Due to increased estrogen levels, bicalutamide and other NSAAs are similarly associated with low rates of hot flashes (9.2% for bicalutamide vs. 5.4% for placebo in the EPC trial).[17] One advantage of CPA over NSAAs is that, because it suppresses estrogen levels rather than increases them, it is associated with only a low rate of what is generally only slight gynecomastia (4–20%),[169][283][238] whereas NSAAs are associated with rates of gynecomastia of up to 80%.[284] Although NSAA monotherapy has many tolerability advantages in comparison to CPA, a few of these advantages, such as preservation of sexual function and interest and BMD (i.e., no increased incidence of osteoporosis) and low rates of hot flashes, are lost when NSAAs are combined with castration.[285] However, the risk and severity of gynecomastia with NSAAs are also greatly diminished in this context.[238][237]

Unlike spironolactone, bicalutamide has no antimineralocorticoid activity,[169] and for this reason, has no risk of hyperkalemia (which can, rarely/in severe cases, result in hospitalization and/or death)[286] or other antimineralocorticoid side effects such as urinary frequency, dehydration, hypotension, hyponatremia, metabolic acidosis, or decreased renal function that may occur with spironolactone treatment.[132][287][288]

In women, unlike CPA and spironolactone,[289] bicalutamide does not produce menstrual irregularity or amenorrhea, nor does it interfere with ovulation.[95][96][290]

Castration and GnRH analogues

Castration consists of either medical castration with a GnRH analogue or surgical castration via orchiectomy.[232] GnRH analogues include GnRH agonists like leuprorelin or goserelin and GnRH antagonists like cetrorelix.[232] They are powerful antigonadotropins and work by abolishing the GnRH-induced secretion of gonadotropins, in turn ceasing gonadal production of sex hormones.[232] Medical and surgical castration achieve essentially the same effect, decreasing circulating testosterone levels by approximately 95%.[232][291]


Bicalutamide monotherapy has overall been found to be equivalent in effectiveness compared to GnRH analogues and castration in the treatment of prostate cancer.[49][67][84] A meta-analysis concluded that there is a slight effectiveness advantage for GnRH analogues/castration, but the differences trend towards but do not reach statistical significance.[49][67][84][85] In mPC, the median survival time was found to be only 6 weeks shorter with bicalutamide monotherapy in comparison to GnRH analogue monotherapy.[292]

Tolerability and safety

Monotherapy with NSAAs including bicalutamide, flutamide, nilutamide, and enzalutamide shows a significantly lower risk of certain side effects, including hot flashes, depression, fatigue, loss of libido, and decreased sexual activity, relative to treatment with GnRH analogues, CAB (NSAA and GnRH analogue combination), CPA, or surgical castration in prostate cancer.[15][86][87][88] For example, 60% of men reported complete loss of libido with bicalutamide relative to 85% for CAB and 69% reported complete loss of erectile function relative to 93% for CAB.[15] Another large study reported a rate of impotence of only 9.3% with bicalutamide relative to 6.5% for standard care (the controls), a rate of decreased libido of only 3.6% with bicalutamide relative to 1.2% for standard care, and a rate of 9.2% with bicalutamide for hot flashes relative to 5.4% for standard care.[293] One other study reported decreased libido, impotence, and hot flashes in only 3.8%, 16.9%, and 3.1% of bicalutamide-treated patients, respectively, relative to 1.3%, 7.1%, and 3.6% for placebo.[176] It has been proposed that due to the lower relative effect of NSAAs on sexual interest and activity, with two-thirds of advanced mPC patients treated with them retaining sexual interest, these drugs may result in improved quality of life and thus be preferable for those who wish to retain sexual interest and function relative to other antiandrogen therapies in prostate cancer.[86] Also, bicalutamide differs from GnRH analogues (which decrease bone mineral density (BMD) and significantly increase the risk of fractures)[294] in that it has well-documented benefits on BMD, effects that are likely due to increased levels of estrogen.[85][295]


Bicalutamide is far less expensive than GnRH analogues, which, in spite of some having been off-patent many years, have been reported (in 2013) to typically cost $10,000 to $15,000 USD per year (or about $1,000 per month) of treatment.[129][130]



Bicalutamide acts as a highly selective competitive silent antagonist of the AR (IC50 = 159–243 nM).[24][247][296][75] It has no capacity to activate the AR under normal physiological circumstances (see below).[285] In addition to competitive antagonism of the AR, bicalutamide has been found to accelerate the degradation of the AR, and this action may also be involved in its activity as an antiandrogen.[297] The activity of bicalutamide lies in the (R)-isomer, which binds to the AR with an affinity that is about 30-fold higher than that of the (S)-isomer.[26] Levels of the (R)-isomer also notably are 100-fold higher than those of the (S)-isomer at steady-state.[232][298]

Owing to its selectivity for the AR, unlike SAAs such as CPA and megestrol acetate, bicalutamide does not bind to other steroid hormone receptors, and for this reason, has no additional, off-target hormonal activity (estrogenic or antiestrogenic, progestogenic or antiprogestogenic, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid);[25][169][26][64] nor does it inhibit 5α-reductase.[285] However, it significantly increases estrogen levels secondary to blockade of the AR in males, and for this reason, does have some indirect estrogenic effects in men.[299] Also in contrast to SAAs, bicalutamide neither inhibits nor suppresses androgen production in the body (i.e., it does not act as an antigonadotropin or steroidogenesis inhibitor),[4] and instead exclusively mediates its antiandrogen effects by blocking androgen binding and subsequent receptor activation at the level of the AR.[25][26]

Drug and androgen levels and efficacy

Although the affinity of bicalutamide for the AR is approximately 50 times lower than that of DHT (IC50 ≈ 3.8 nM),[229][75] the main endogenous ligand of the receptor in the prostate gland, sufficiently high relative concentrations of bicalutamide (1,000-fold excess)[67] are effective in preventing activation of the AR by androgens like DHT and testosterone and subsequent upregulation of the transcription of androgen-responsive genes.[169][300] At steady-state, relative to the normal adult male range for testosterone levels (300–1,000 ng/dL),[301] circulating concentrations of bicalutamide at 50 mg/day are 600 to 2,500 times higher and at 150 mg/day 1,500 to 8,000 times higher than circulating testosterone levels, while bicalutamide concentrations, relative to the mean testosterone levels present in men who have been surgically castrated (15 ng/dL),[302] are 42,000 times higher than testosterone levels at 50 mg/day.[33][303][304][17][305]

Whereas testosterone is the major circulating androgen, DHT is the major androgen in the prostate gland.[306] DHT levels in circulation are relatively low and only approximately 10% of those of circulating testosterone levels.[306] Conversely, local concentrations of DHT in the prostate gland are 5- to 10-fold higher than circulating levels of DHT.[307][25] This is due to high expression of 5α-reductase in the prostate gland, which very efficiently catalyzes the formation of DHT from testosterone[307] such that over 90% of intraprostatic testosterone is converted into DHT.[74][308] Relative to testosterone, DHT is 2.5- to 10-fold as potent as an AR agonist in bioassays, and hence, is a much stronger androgen in comparison.[309] As such, AR signaling is exceptionally high in the prostate gland, and the effectiveness of bicalutamide monotherapy in the treatment of prostate cancer, which is roughly equivalent to that of GnRH analogues,[49][67][84][85] is a reflection of its capacity to strongly and efficaciously antagonize the AR at clinically used dosages. On the other hand, GnRH analogues achieve only a 50 to 60% reduction in levels of DHT in the prostate gland,[75][76] and the combination of a GnRH analogue and bicalutamide is significantly more effective than either modality alone in the treatment of prostate cancer.[24][152]

In women, total testosterone levels are 20-fold and free testosterone levels 40-fold lower relative to men.[307] In addition, whereas bicalutamide monotherapy can increase testosterone levels by up to 2-fold in men,[85][310] the drug does not increase testosterone levels in women (see below).[265][311][312] For these reasons, much lower dosages of bicalutamide (e.g., 25 mg/day in the hirsutism studies) may be used in women with comparable antiandrogen effectiveness.[19][95][96][97][34]

Influences on hormone levels

In men, blockade of the AR by bicalutamide in the pituitary gland and hypothalamus suppresses the negative feedback of androgens on the release of LH, resulting in an elevation in LH levels.[86] Follicle-stimulating hormone (FSH) levels, in contrast, remain essentially unchanged.[313] The increase in LH levels leads to an increase in androgen and estrogen levels.[314] At a dosage of 150 mg/day, bicalutamide has been found to increase testosterone levels by about 1.5- to 2-fold (59–97% increase) and estradiol levels by about 1.5- to 2.5-fold (65–146% increase).[85][310][34] Levels of DHT are also increased to a lesser extent (by 25%), and concentrations of sex hormone-binding globulin (SHBG) and prolactin increase as well (by 8% and 40%, respectively) secondary to the increase in estradiol levels.[34] The estradiol concentrations produced by bicalutamide monotherapy in men are said to approximate the low-normal estradiol levels of a premenopausal woman,[310] while testosterone levels generally remain in the high end of the normal male range and rarely exceed it.[83][25] Dosages of bicalutamide of 10 mg, 30 mg, and 50 mg per day have been found to produce a "moderate" effect on sex hormone levels in men with prostate cancer (notably providing indication that the drug has clinically-relevant antiandrogen effects in males at a dosage as low as 10 mg/day).[315] It is important to note that bicalutamide increases androgen and estrogen levels only in men and not in women; this is because androgen levels are comparatively far lower in women and in turn exert little to no basal suppression of the hypothalamic-pituitary-gonadal (HPG) axis.[265][311][312]

The reason that testosterone levels are elevated but almost always remain in the normal male range with bicalutamide monotherapy is thought to be due to the concomitantly increased levels of estradiol, as estradiol is potently antigonadotropic and limits secretion of LH.[86] In fact, estradiol is a much stronger inhibitor of gonadotropin secretion than is testosterone, and even though circulating concentrations of estradiol are far lower than those of testosterone in men, it is said that estradiol is nonetheless likely the major feedback regulator of gonadotropin secretion in this sex.[110] In accordance, clomifene, a SERM with antiestrogenic activity, has been found to increase testosterone levels to as much as 250% of initial values in men with hypogonadism,[316] and a study of clomifene treatment in normal men observed increases in FSH and LH levels of 70–360% and 200–700%, respectively, with increases in testosterone levels that were similar to the increases seen with the gonadotropins.[317][318] In addition to systemic or circulating estradiol, local aromatization of testosterone into estradiol in the hypothalamus and pituitary gland may contribute to suppression of gonadotropin secretion.[110]

Bicalutamide more than blocks the effects of the increased testosterone levels that it induces in men, which is evidenced by the fact that monotherapy with the drug is about as effective as GnRH analogue therapy in the treatment of prostate cancer.[49] However, in contrast, the effects of the elevated estrogen levels remain unopposed by bicalutamide, and this is largely responsible for the feminizing side effects (e.g., gynecomastia) of the drug in men.[319]

Differences from castration

It has been proposed that the increase in estrogen levels caused by NSAAs like bicalutamide compensates for androgen blockade in the brain, which may explain differences in the side effect profiles of these drugs relative to GnRH analogues/castration, CAB, and CPA (which, in contrast, decrease both androgen and estrogen levels).[87][88][89] In the case of sexual interest and function, this notion is supported by a variety of findings including animal studies showing that estrogen deficiency results in diminished sexual behavior, treatment with tamoxifen resulting in significantly lowered libido in 30% of men receiving it for male breast cancer, and estrogen administration restoring libido and the frequency of sexual intercourse in men with congenital estrogen deficiency, among others.[87][88][89][320]

Several metabolites of testosterone and DHT, including estradiol, 3α-androstanediol, and 3β-androstanediol, are estrogens (mainly potent ERβ agonists in the cases of the latter two), and 3α-androstanediol is additionally a potent GABAA receptor-potentiating neurosteroid.[91][321] Due to the fact that bicalutamide does not lower testosterone levels, the levels of these metabolites would not be expected to be lowered either, unlike with therapies such as GnRH analogues. (Indeed, testosterone, DHT, and estradiol levels are actually raised by bicalutamide treatment, and for this reason, levels of 3α- and 3β-androstanediol might be elevated to some degree similarly.) These metabolites of testosterone have been found to have AR-independent positive effects on sexual motivation,[91][321][322][90] and may explain the preservation of sexual interest and function by bicalutamide and other NSAAs.[87] They also have antidepressant, anxiolytic, and cognitive-enhancing effects,[90][323][324][325] and may account for the lower incidence of depression with bicalutamide and other NSAAs relative to other antiandrogen therapies.

Induction of breast development

In transgender women, breast development is a desired effect of antiandrogen and/or estrogen treatment.[103][326] Bicalutamide induces breast development (or gynecomastia) in biologically male individuals by two mechanisms: 1) blocking androgen signaling in breast tissue; and 2) increasing estrogen levels.[115] Estrogen is responsible for the induction of breast development under normal circumstances, while androgens powerfully suppress estrogen-induced breast growth.[327][328] It has been found that very low levels of estrogen can induce breast development in the presence of low or no androgen signaling.[327][329][330] In accordance, bicalutamide not only induces gynecomastia at a high rate when given to men as a monotherapy,[115] it results in a higher incidence of gynecomastia in combination with a GnRH analogue relative to GnRH analogue treatment alone (in spite of the presence of only castrate levels of estrogen in both cases).[331]

A study of men treated with NSAA (flutamide or bicalutamide) monotherapy for prostate cancer found that NSAAs induced full ductal development and moderate lobuloalveolar development of the breasts from a histological standpoint.[107][332][333] The study also found that, in contrast, treatment of transgender women with estrogen and CPA (which is progestogenic in addition to antiandrogenic, unlike NSAAs) resulted in full lobuloalevolar development, as well as pregnancy-like breast hyperplasia in two of the subjects.[107][333] In addition, it was observed that the lobuloalveolar maturation reversed upon discontinuation of CPA after sex reassignment surgery (that is, surgical castration) in these individuals.[107] It was concluded that progestogen in addition to antiandrogen/estrogen treatment is required for the induction of full female-like histological breast development (i.e., that includes complete lobuloalveolar maturation), and that continued progestogen treatment is necessary to maintain such maturation.[107][332] It should be noted however that although these findings may have important implications in the contexts of lactation and breastfeeding, epithelial tissue accounts for approximately only 10% of breast volume (with the bulk of the breasts (80–90%) being represented by stromal or adipose tissue),[334][335][336][337] and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a form of epithelial tissue) contributes to breast size and/or shape.[103]

Effects on spermatogenesis and fertility

Spermatogenesis and male fertility are dependent on FSH, LH, and high levels of intratesticular testosterone.[307][338] LH does not seem to be involved in spermatogenesis outside of its role of inducing production of testosterone by the Leydig cells in the seminiferous tubules (which make up approximately 80%[339] of the bulk of the testes),[340] whereas this is not the case for FSH.[341][342] In accordance with the fact that the testes are the source of 95% of circulating testosterone in the body, levels of testosterone within the testes are extremely high, ranging from 20- to 200-fold higher than circulating concentrations.[343][308] High levels of intratesticular testosterone are required for spermatogenesis,[338] although only a small fraction (5–10%) of normal intratesticular levels of testosterone appears to actually be necessary for spermatogenesis.[308][344]

Unlike with antigonadotropic antiandrogens such as CPA and GnRH analogues, it has been reported that bicalutamide monotherapy (at 50 mg/day) has very little effect on the ultrastructure of the testes and on sperm maturation in humans even after long-term therapy (>4 years).[170] This may be explained by the extremely high local levels of testosterone in the testes, in that it is likely that systemic bicalutamide therapy is unable to produce intratesticular concentrations of the drug that are able to significantly block androgen action in this part of the body.[170] This is particularly so considering that bicalutamide increases circulating testosterone levels, and by extension testicular testosterone production, by up to two-fold in males,[314] and that only a small fraction of normal intratesticular testosterone levels, and by extension androgen action, appears to be necessary to maintain spermatogenesis.[308][344]

In contrast to bicalutamide and other pure antiandrogens/NSAAs, antigonadotropic antiandrogens suppress gonadotropin secretion, which in turn diminishes testosterone production by the testes as well as the maintenance of the testes by FSH, resulting in atrophy and loss of their function.[345] As such, bicalutamide and other NSAAs may uniquely have the potential to preserve testicular function and spermatogenesis and thus male fertility relative to alternative therapies.[170][346] In accordance with this notion, a study found that prolonged, high-dose bicalutamide treatment had minimal effects on fertility in male rats.[148] However, another study found that low-dose bicalutamide administration resulted in testicular atrophy and reduced the germ cell count in the testes of male rats by almost 50%, though the rate of successful fertilization and pregnancy following mating was not assessed.[347]

Treatment of men with exogenous testosterone or other anabolic-androgenic steroids results in suppression of gonadotropin secretion and gonadal testosterone production due to their antigonadotropic effects/activation of the AR in the pituitary gland, resulting in inhibition or abolition of spermatogenesis and fertility:[348]

Treatment of an infertile man with testosterone does [not] improve spermatogenesis, since exogenous administrated testosterone and its metabolite estrogen will suppress both GnRH production by the hypothalamus and luteinizing hormone production by the pituitary gland and subsequently suppress testicular testosterone production. Also, high levels of testosterone are needed inside the testis and this can never be accomplished by oral or parenteral administration of androgens. Suppression of testosterone production by the leydig cells will result in a deficient spermatogenesis, as can be seen in men taking anabolic-androgenic steroids.[348]

In contrast, pure AR antagonists would, in theory, result in the opposite (although reduced semen volume and sexual dysfunction may occur):[349]

It is theoretically a sound hypothesis that the spermatogenesis can be increased by indirectly stimulating FSH and LH secretions from the pituitary gland. However, for this to fructify, it requires the use of testosterone antagonist to nullify the negative feedback effect of circulating testosterone on the release of FSH and LH, thus augmenting the secretion of testosterone and spermatogenesis. Unfortunately, a testosterone antagonist will be unacceptable to males, as it may reduce secondary sexual functions including erection and ejaculation that is vital for the successful fertilization.[349]

Although bicalutamide alone would appear to have minimal detrimental effect on spermatogenesis and male fertility, other hormonal agents that bicalutamide may be combined with, including GnRH analogues and particularly estrogens (as in transgender hormone therapy), can have a considerable detrimental effect on fertility.[350][351] This is mainly or completely a consequence of their antigonadotropic activity.[351] Antigonadotropic agents like high-dose CPA,[352][353] high-dose androgens (e.g., testosterone esters), and GnRH antagonists (though notably not GnRH agonists) produce hypogonadism and high rates of severe or complete infertility (e.g., severe oligospermia or complete azoospermia) in men.[351] However, these effects are fully and often rapidly reversible with their discontinuation, even after prolonged treatment.[351][353] In contrast, while estrogens at sufficiently high dosages similarly are able to produce hypogonadism and to abolish or severely impair spermatogenesis,[350] this is not necessarily reversible in the case of estrogens and can be long-lasting after prolonged exposure.[351][354] The difference is attributed to an apparently unique, direct adverse effect of high concentrations of estrogens on the Leydig cells of the testes.[351][354]

Paradoxical AR activation in prostate cancer

Though a pure, or silent antagonist of the AR under normal circumstances, bicalutamide, as well as other earlier antiandrogens like flutamide and nilutamide, have been found to possess weak partial agonist properties in the setting of AR overexpression and agonist activity in the case of certain mutations in the ligand-binding domain of the AR.[355][356] As both of these circumstances can eventually occur in prostate cancer, resistance to bicalutamide usually develops and the drug has the potential to paradoxically stimulate tumor growth when this happens.[355][357] This is the mechanism of the phenomenon of antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of tumor growth.[357] The newer drug enzalutamide has been shown not to have agonistic properties in the context of overexpression of the AR, though certain mutations in the AR can still convert it from an antagonist to agonist.[355]

Other actions

Cytochrome P450 modulator

It has been reported that bicalutamide may have the potential to inhibit the enzymes CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6, based on in vitro research.[3] However, no relevant inhibition of CYP3A4 has been observed in vivo with bicalutamide at a dose of 150 mg (using midazolam as a specific marker of CYP3A4 activity).[3] In animals, bicalutamide has been found to be an inducer of certain cytochrome P450 enzymes.[3] However, dosages of 150 mg/day or less have shown no evidence of this in humans.[3]

Bicalutamide has been identified as a strong CYP27A1 (cholesterol 27-hydroxylase) inhibitor in vitro.[358] CYP27A1 converts cholesterol into 27-hydroxycholesterol, an oxysterol that has multiple biological functions including direct, tissue-specific activation of the estrogen receptor (ER) (it has been characterized as a selective estrogen receptor modulator) and the liver X receptor.[358] 27-Hydroxycholesterol has been found to increase ER-positive breast cancer cell growth via its estrogenic action, and hence, it has been proposed that bicalutamide and other CYP27A1 inhibitors may be effective as adjuvant therapies to aromatase inhibitors in the treatment of ER-positive breast cancer.[358]

Bicalutamide has also been found to bind to and inhibit CYP46A1 (cholesterol 24-hydroxylase) in vitro, but this has yet to be assessed and confirmed in vivo.[359]

P-Glycoprotein inhibitor

Bicalutamide, as well as enzalutamide, have been found to act as inhibitors of P-glycoprotein efflux and ATPase activity.[360][361][362] This action may reverse docetaxel resistance in prostate cancer cells by reducing transport of the drug out of these cells.[360][361][362]

GABAA receptor negative modulator

All of the NSAAs approved for the treatment of prostate cancer have been found to possess an off-target action of acting as weak non-competitive inhibitors of human GABAA receptor currents in vitro to varying extents.[253][363] The IC50 values are 44 μM for flutamide (as hydroxyflutamide), 21 μM for nilutamide, 5.2 μM for bicalutamide, and 3.6 μM for enzalutamide.[253] In addition, flutamide, nilutamide, and enzalutamide have been found to cause convulsions and/or death in mice at sufficiently high doses.[253] Bicalutamide was notably not found to do this, but this was likely simply due to the limited central nervous system penetration of bicalutamide in this species.[253] In any case, enzalutamide is the only approved NSAA that has been found to be associated with a significantly increased incidence of seizures and other associated side effects clinically, so the relevance of the aforementioned findings with regard to bicalutamide and the other NSAAs is unclear.[253]



Bicalutamide is extensively and well-absorbed following oral administration,[3] and its absorption is not affected by food.[4][50] The absolute bioavailability of bicalutamide in humans is unknown due to its very low water solubility and hence lack of an assessable intravenous formulation.[3][4] However, the absolute bioavailability of bicalutamide has been found to be high in animals at low doses (72% in rats at 1 mg/kg; 100% in dogs at 0.1 mg/kg), but diminishes with increasing doses such that the bioavailability of bicalutamide is low at high doses (10% in rats at 250 mg/kg; 31% in dogs at 100 mg/kg).[3] In accordance, absorption of (R)-bicalutamide in humans is slow and extensive but saturable,[17] with steady-state levels increasing linearly at a dosage of up to 50 mg/day and non-linearly at higher dosages.[3] At higher dosages of 100 to 200 mg/day, absorption of bicalutamide is approximately linear, with a small but increasing departure from linearity above 150 mg/day.[364] In terms of geometric mean steady-state concentrations of (R)-bicalutamide, the departures from linearity were 4%, 13%, 17%, and 32% with dosages of 100, 150, 200, and 300 mg/day, respectively.[3] There is a plateau in steady-state levels of (R)-bicalutamide with bicalutamide dosages above 300 mg/day, and, accordingly, dosages of bicalutamide of 300 to 600 mg/day result in similar circulating concentrations of (R)-bicalutamide and similar degrees clinically of efficacy, tolerability, and toxicity.[3][221] Relative to 150 mg/day bicalutamide, levels of (R)-bicalutamide are about 15% higher at a dosage of 200 mg/day and about 50% higher at a dosage of 300 mg/day.[221] In contrast to (R)-bicalutamide, the inactive enantiomer (S)-bicalutamide is much more rapidly absorbed (as well as cleared from circulation).[3]

Steady-state concentrations

Pharmacokinetic parameters for bicalut-
amide related to circulating concentrations
50 mg 150 mg
Cmax 0.77 μg/mL
(1.8 μmol/L)
1.4 μg/mL
(3.3 μmol/L)
tmax 31 hours 39 hours
Css 8.9 μg/mL
(21 μmol/L)
22–28.5 μg/mL
(51–66.3 μmol/L)
tss 4–12 weeks 4–12 weeks
All values are for (R)-bicalutamide

Steady-state concentrations of the drug are reached after 4 to 12 weeks of administration independently of dosage, with an approximate 10- to 20-fold progressive accumulation of circulating levels of (R)-bicalutamide.[17][239][313][304] In spite of the relatively long time to reach steady-state (which is a product of its long terminal half-life),[304] there is evidence that the achieved AR blockade of bicalutamide is equivalent to that of flutamide by the end of the first day of treatment.[239] With single 50 mg and 150 mg doses of bicalutamide, mean peak concentrations (Cmax) of (R)-bicalutamide are 0.77 μg/mL (1.8 μmol/L) (at 31 hours) and 1.4 μg/mL (3.3 μmol/L) (at 39 hours), respectively.[33][17] At steady-state, mean circulating concentrations (Css) of (R)-bicalutamide with 50 mg/day and 150 mg/day bicalutamide are 8.9 μg/mL (21 μmol/L) and 22 μg/mL (51 μmol/L), respectively.[33][303][304][17] In another 150 mg/day bicalutamide study, mean circulating concentrations of (R)-bicalutamide were 19.4 μg/mL (45.1 μmol/L) and 28.5 μg/mL (66.3 μmol/L) on days 28 and 84 (weeks 4 and 12) of treatment, respectively.[305]


The tissue distribution of bicalutamide is not well-characterized.[365] However, it has been reported that distribution studies with bicalutamide have shown that preferential (i.e., tissue-selective) accumulation in anabolic (e.g., muscle) tissues does not occur.[201] There are no available data on hepatic bicalutamide concentrations in humans, but a rat study found that oral bicalutamide treatment resulted in 4-fold higher concentrations of the drug in the liver relative to plasma (a common finding with orally administered drugs, due to transfer through the hepatic portal system prior to reaching circulation).[3][366] In men receiving 150 mg/day bicalutamide, concentrations of (R)-bicalutamide in semen were 4.9 μg/mL (11 μmol/L), and the amount of the drug that could potentially be delivered to a female partner during sexual intercourse is regarded as low (estimated at 0.3 μg/kg) and below the amount that is required to induce changes in the offspring of laboratory animals.[303] Bicalutamide is highly protein-bound (96.1% for racemic bicalutamide, 99.6% for (R)-bicalutamide), mainly to albumin.[5][3][365] It has negligible affinity for SHBG and no affinity for corticosteroid-binding globulin.[285]

Central penetration

Based on animal research, it was initially thought that bicalutamide was unable to cross the blood-brain-barrier into the central nervous system and hence would be a peripherally-selective antiandrogen in humans.[235][169] This conclusion was drawn from the finding that bicalutamide does not increase LH or testosterone levels in multiple animal species (including rats and dogs),[235][169][367][368] as antiandrogens like flutamide normally do this by blocking ARs in the pituitary gland and hypothalamus in the brain and thereby disinhibiting the HPG axis.[86] In humans however, bicalutamide has been found to increase LH and testosterone levels, and to a comparative extent relative to flutamide and nilutamide.[3][86][369][27] As such, it appears that there are species differences in the central penetration of bicalutamide and that the drug does indeed cross the blood-brain-barrier and affect central function in humans,[3][27] as supported by potential side effects, in spite of increased testosterone levels, like hot flashes and diminished sexual interest in men.[179] A newer NSAA, darolutamide, has been found to negligibly cross the blood-brain-barrier in both animals and humans, and in accordance, unlike bicalutamide, does not increase LH or testosterone levels in humans.[370]


The metabolism of bicalutamide is hepatic and stereoselective.[5][50] The inactive (S)-enantiomer is metabolized mainly by glucuronidation and is rapidly cleared from circulation, while the active (R)-isomer is slowly hydroxylated and glucuronidated.[50] In accordance, the active (R)-enantiomer has a far longer half-life than the (S)-isomer,[26] and circulating levels of (R)-bicalutamide are 10- to 20-fold[17] and 100-fold higher than those of (S)-bicalutamide after a single dose and at steady-state, respectively.[232][298] Bicalutamide is almost exclusively metabolized, via hydroxylation into hydroxybicalutamide,[5] by the cytochrome P450 enzyme CYP3A4.[3][232] It is also glucuronidated (via UDP-glucuronyltransferase, specifically UGT1A9)[6] into bicalutamide glucuronide,[3][7][8] and hydroxybicalutamide glucuronide is formed secondarily from hydroxybicalutamide.[3][7][8] Similarly to the inactive (S)-enantiomer of bicalutamide, (R)-hydroxybicalutamide is glucuronidated and rapidly cleared from circulation.[371] None of the metabolites of bicalutamide are known to be active.[5][7] Moreover, little, if any of the metabolites are present in circulation, where unchanged bicalutamide predominates.[3] (R)-Bicalutamide has a long terminal half-life of 5.8 days with a single dose,[9][83] and a terminal half-life of 7–10 days with repeated administration, which more than allows for convenient once-daily dosing of bicalutamide.[10]


Bicalutamide is eliminated in feces (43%) and urine (34%),[5][50] whereas its metabolites are eliminated in approximately equal proportions in urine and bile.[15][372] It is excreted to a substantial extent in its unmetabolized form, with both bicalutamide and its metabolites excreted mainly as glucuronide conjugates.[26]


The pharmacokinetics of bicalutamide are unaffected by food, age, body weight, renal impairment, and mild-to-moderate hepatic impairment.[3][304] However, it has been observed that steady-state concentrations of bicalutamide are higher in Japanese individuals than in Caucasians, indicating that ethnicity may be associated with differences in the pharmacokinetics of bicalutamide in some instances.[3]


Chemical properties

A space-filling model of bicalutamide.

Bicalutamide is a racemic mixture consisting of equal proportions of enantiomers (R)-bicalutamide and (S)-bicalutamide.[33] Its systematic name (IUPAC) is (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide.[41][373] It has a chemical formula of C18H14F4N2O4S, a molecular weight of 430.37, and is a fine white to off-white powder.[33][303] The pKa' of bicalutamide is approximately 12.[303] It is a highly lipophilic compound (log P = 2.92).[3][374] At 37 °C (98.6 °F), or normal human body temperature, bicalutamide is practically insoluble in water (4.6 mg/L), acid (4.6 mg/L at pH 1), and alkali (3.7 mg/L at pH 8).[33][303] In organic solvents, it is slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and freely soluble in acetone and tetrahydrofuran.[33][303]

Structure and analogues

First-generation NSAAs

First-generation NSAAs including bicalutamide, flutamide, and nilutamide are synthetic, non-steroidal anilide (N-phenylamide) derivatives and structural analogues of each other.[375] Bicalutamide is a diarylpropionamide, while flutamide is a monoarylpropionamide and nilutamide is a hydantoin.[375] Bicalutamide and flutamide, though not nilutamide, can also be classified as toluidides.[232] All three of the compounds share a common 3-trifluoromethylaniline moiety.[226] Bicalutamide is a modification of flutamide in which a 4-fluorophenylsulfonyl moiety has been added and the nitro group on the original phenyl ring has been replaced with a cyano group.[205] Topilutamide, also known as fluridil, is another NSAA that is closely related structurally to the first-generation NSAAs, but, in contrast to them, is not used in the treatment of prostate cancer and is instead used exclusively as a topical antiandrogen in the treatment of androgenic alopecia.[376][377][261]

Flutamide Nilutamide Bicalutamide Topilutamide

Second-generation NSAAs

The second-generation NSAAs enzalutamide and apalutamide were derived from and are analogues of the first-generation NSAAs,[50][378] while another second-generation NSAA, darolutamide, is said to be structurally distinct and chemically unrelated to the other NSAAs.[379] Enzalutamide is a modification of bicalutamide in which the inter-ring linking chain has been altered and cyclized into a 5,5-dimethyl-4-oxo-2-thioxoimidazolidine moiety. In apalutamide, the 5,5-dimethyl groups of the imidazolidine ring of enzalutamide are cyclized to form an accessory cyclobutane ring and one of its phenyl rings is replaced with a pyridine ring.

Enzalutamide Apalutamide Darolutamide

Arylpropionamide SARMs

In 1998, researchers discovered the first non-steroidal androgens (the arylpropionamides) via structural modification of bicalutamide.[380] Unlike bicalutamide (which is purely antiandrogenic), these compounds show tissue-selective androgenic effects and were classified as selective androgen receptor modulators (SARMs).[380] Lead SARMs of this series included acetothiolutamide, enobosarm (ostarine; S-22), and andarine (acetamidoxolutamide or androxolutamide; S-4).[375][380][381] They are very close to bicalutamide structurally, with the key differences being that the linker sulfone of bicalutamide has been replaced with an ether or thioether group to confer agonism of the AR and the 4-fluoro atom of the pertinent phenyl ring has been substituted with an acetamido or cyano group to eliminate reactivity at the position.[382]

Acetothiolutamide Enobosarm (ostarine) Andarine


A number of chemical syntheses of bicalutamide have been published in the literature.[41][383][384][385][386]

The first published chemical synthesis of bicalutamide (Tucker et al., 1988) proceeds as follows:[383]

Where the starting material is 4-cyano-3-(trifluoromethyl)aniline (also known as 4-amino-2-(trifluoromethyl)benzonitrile), DMA is dimethylacetamide, and mCPBA is meta-chloroperoxybenzoic acid.


All of the marketed NSAAs, including bicalutamide, were derived from flutamide, which was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently, and serendipitously, found to possess antiandrogen activity.[100][69][387] Bicalutamide was discovered by Tucker and colleagues at ICI in the mid-1980s and was selected for development from a group of over 1,000 synthesized compounds.[285][388] It was first reported in the scientific literature in June 1987,[389] was first studied in a phase I clinical trial in 1987,[51] and the results of the first phase II clinical trial in prostate cancer were published in 1990.[390] In April and May 1995, AstraZeneca began pre-approval marketing of bicalutamide for the treatment of prostate cancer,[391] and it was approved by the U.S. FDA on 4 October 1995 for the treatment of prostate cancer at a dosage of 50 mg/day in combination with a GnRH analogue.[16][392]

Subsequent to its introduction for use in combination with a GnRH analogue, bicalutamide was developed as a monotherapy at a dosage of 150 mg/day for the treatment of prostate cancer, and was approved for this indication in Europe, Canada, and a number of other countries in the early 2000s.[17][75][94][393] This application of bicalutamide was also under review by the FDA in the U.S. in 2002,[394] but ultimately was not approved in this country.[49] In Japan, bicalutamide is licensed at a dosage of 80 mg/day alone or in combination with a GnRH analogue for prostate cancer.[139] The unique 80 mg dosage of bicalutamide used in Japan was selected for development in this country on the basis of observed pharmacokinetic differences with bicalutamide in Japanese men.[395]

The patent protection of bicalutamide expired in the U.S. in March 2009 and the drug has subsequently been available as a generic,[60] at greatly reduced cost.[61]

Bicalutamide was the fourth antiandrogen (and the third NSAA) to be introduced for the treatment of prostate cancer, following the SAA CPA in 1973[396] and the NSAAs flutamide and nilutamide in 1975 (1989 in the U.S.)[397] and 1989 (1996 in the U.S.), respectively.[226][47][398] It has been followed by abiraterone acetate in 2011 and enzalutamide in 2012, and may also be followed by the in-development drugs apalutamide, darolutamide, galeterone, and seviteronel.[399]

Withdrawal for LPC

In 2003, the EPC trial, comprising over 8,000 patients, reported at 5.4-year follow-up that while 150 mg/day bicalutamide monotherapy increased overall survival in LAPC, it did not increase overall survival in an earlier stage of the disease, LPC (in which the risk of dying from prostate cancer is notably much lower in comparison),[176] and surprisingly, there was, in fact, a trend toward significantly reduced overall survival in this group (25.2% death rate for bicalutamide monotherapy versus 20.5% for placebo; hazard ratio = 1.23; 95% confidence interval, 1.00, 1.50).[176][183][184] Analyses revealed that bicalutamide monotherapy slightly decreased the rate of mortality due to prostate cancer in this group but accelerated the rate of non-prostate cancer deaths (16.8% for bicalutamide versus 9.5% for placebo).[176][184] Subsequently, approval for use of bicalutamide monotherapy in this patient population (i.e., LPC) was withdrawn in a number of countries,[184] including the U.K. (in October or November 2003)[183] and several other European countries and Canada (in August 2003),[17][400][401] and the U.S. and Canada recommended against the use of 150 mg/day bicalutamide for this indication.[402]

Society and culture

Generic name

Bicalutamide is the generic name of bicalutamide in English and the INN, USAN, USP,[403] BAN, DCF, and JAN of the drug.[57][11][12][13] It is also formally referred to as bicalutamidum in Latin, bicalutamida in Spanish and Portuguese, bicalutamid in German, and bikalutamid in Russian and other Slavic languages, whereas its generic name remains unchanged as bicalutamide in French.[57][12]

Bicalutamide is also known by its former developmental code name ICI-176,334.[11]

Brand names

Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries.[57][12][404][405] It is also marketed under the brand names Bicadex, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries.[57] The drug is sold under a large number of generic trade names such as Apo-Bicalutamide, Bicalutamide Accord, Bicalutamide Actavis, Bicalutamide Bluefish, Bicalutamide Kabi, Bicalutamide Sandoz, and Bicalutamide Teva as well.[57] A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.[58][142][143][144]


Bicalutamide is available for the treatment of prostate cancer in most developed countries,[12][57][58] and is available in at least 70 countries worldwide.[59] For an extensive list of countries in which bicalutamide is marketed along with its corresponding brand names, see here. The drug is registered for use as a 150 mg/day monotherapy for the treatment of LAPC in at least 55 countries,[3] with the U.S. being a notable exception (where it is registered only for use at a dosage of 50 mg/day in combination with castration).[49]

Legal status

Bicalutamide is a prescription drug.[141] The sale and distribution of prescription drugs is legally regulated throughout much of the world.[406][407][408]


Sales of bicalutamide (as Casodex) in the U.S. were $1.1 billion in 2005,[376] and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection.[44] In 2014, despite the introduction of abiraterone acetate in 2011 and enzalutamide in 2012, bicalutamide was still the most commonly prescribed drug in the treatment of metastatic castration-resistant prostate cancer (mCRPC).[44] Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca.[44]

Between January 2007 and December 2009 (a period of three years), 1,232,143 prescriptions were written for bicalutamide in the U.S., or about 400,000 prescriptions per year.[45] During that time, bicalutamide accounted for about 87.2% of the NSAA market, while flutamide accounted for 10.5% of it and nilutamide for 2.3% of it.[45] Approximately 96% of bicalutamide prescriptions were written for diagnosis codes that clearly indicated neoplasm.[45] About 1,200, or 0.1% of bicalutamide prescriptions were dispensed to pediatric patients (age 0–16).[45]


Prostate cancer

A phase II clinical trial of bicalutamide with everolimus in mCRPC has been conducted.[409]

Bicalutamide has been studied in combination with the 5α-reductase inhibitors finasteride and dutasteride in prostate cancer.[410][411][412][413][414][415][416]

Benign prostatic hyperplasia

Bicalutamide has been studied in the treatment of benign prostatic hyperplasia (BPH) in a 24-week trial of 15 patients at a dosage of 50 mg/day.[417][418] Prostate volume decreased by 26% in patients taking bicalutamide and urinary irritative symptom scores significantly decreased, but peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo.[417][418] Breast tenderness (93%), gynecomastia (54%), and sexual dysfunction (60%) were all reported as clinically significant side effects at this dosage in these patients, although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75% of patients.[418][51]

AR-positive breast cancer

Bicalutamide has been tested for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in a phase II study for this indication.[419][420][421] Enzalutamide may also hold some promise for this type of cancer.[422][423]

Ovarian cancer

Bicalutamide has been studied in a phase II clinical trial for ovarian cancer.[424]

Veterinary use

Bicalutamide is used to treat hyperandrogenism and associated prostatic hyperplasia secondary to hyperadrenocorticism (caused by excessive adrenal androgens) in male ferrets.[425][426][427] However, although used, it has not been formally assessed in controlled studies for this purpose.[427][428]


  1. Finkel R, Clark MA, Cubeddu LX (2009). Pharmacology. Lippincott Williams & Wilkins. pp. 481–. ISBN 978-0-7817-7155-9.
  2. Sifton DW, PDR Staff (2002). PDR Drug Guide for Mental Health Professionals. Thomson/PDR. ISBN 978-1-56363-457-4.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Cockshott ID (2004). "Bicalutamide: clinical pharmacokinetics and metabolism". Clinical Pharmacokinetics. 43 (13): 855–78. doi:10.2165/00003088-200443130-00003. PMID 15509184.
  4. 1 2 3 4 5 6 7 8 9 Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 497, 521. ISBN 978-0-7817-2845-4.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Lemke TL, Williams DA (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 121,1288,1290. ISBN 978-0-7817-6879-5.
  6. 1 2 Grosse L, Campeau AS, Caron S, Morin FA, Meunier K, Trottier J, Caron P, Verreault M, Barbier O (August 2013). "Enantiomer selective glucuronidation of the non-steroidal pure anti-androgen bicalutamide by human liver and kidney: role of the human UDP-glucuronosyltransferase (UGT)1A9 enzyme". Basic & Clinical Pharmacology & Toxicology. 113 (2): 92–102. doi:10.1111/bcpt.12071. PMC 3815647Freely accessible. PMID 23527766.
  7. 1 2 3 4 Dole EJ, Holdsworth MT (1997). "Nilutamide: an antiandrogen for the treatment of prostate cancer". The Annals of Pharmacotherapy. 31 (1): 65–75. doi:10.1177/106002809703100112. PMID 8997470. page 67: Currently, information is not available regarding the activity of the major urinary metabolites of bicalutamide, bicalutamide glucuronide, and hydroxybicalutamide glucumnide.
  8. 1 2 3 Schellhammer PF (September 2002). "An evaluation of bicalutamide in the treatment of prostate cancer". Expert Opinion on Pharmacotherapy. 3 (9): 1313–28. doi:10.1517/14656566.3.9.1313. PMID 12186624. The clearance of bicalutamide occurs pre- dominantly by hepatic metabolism and glucuronidation, with excretion of the resulting inactive metabolites in the urine and faces.
  9. 1 2 3 4 5 Skidmore-Roth L (17 April 2013). Mosby's 2014 Nursing Drug Reference - Elsevieron VitalSource. Elsevier Health Sciences. pp. 193–194. ISBN 978-0-323-22267-9.
  10. 1 2 3 4 5 Jordan VC, Furr BJ (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 350–. ISBN 978-1-59259-152-7.
  11. 1 2 3 4 Morton I, Hal JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 51–. ISBN 978-94-011-4439-1.
  12. 1 2 3 4 5 6 Swiss Pharmaceutical Society, ed. (January 2000). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 123–. ISBN 978-3-88763-075-1.
  13. 1 2 Ganellin C, Triggle DJ (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 570–. ISBN 978-0-412-46630-4.
  14. Schellhammer PF (September 2002). "An evaluation of bicalutamide in the treatment of prostate cancer". Expert Opinion on Pharmacotherapy. 3 (9): 1313–28. doi:10.1517/14656566.3.9.1313. PMID 12186624.
  15. 1 2 3 4 5 6 Fradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer". Expert Review of Anticancer Therapy. 4 (1): 37–48. doi:10.1586/14737140.4.1.37. PMID 14748655. In contrast, the incidence of diarrhea was comparable between the bicalutamide and placebo groups (6.3 vs. 6.4%, respectively) in the EPC program [71].
  16. 1 2 3 Klotz L (May 2006). "Combined androgen blockade: an update". The Urologic Clinics of North America. 33 (2): 161–6, v–vi. doi:10.1016/j.ucl.2005.12.001. PMID 16631454.
  17. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer" (PDF). Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554.
  18. Wass JA, Stewart PM (28 July 2011). Oxford Textbook of Endocrinology and Diabetes. OUP Oxford. pp. 1625–. ISBN 978-0-19-923529-2.
  19. 1 2 3 4 Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B (22 January 2009). Evidence-Based Dermatology. John Wiley & Sons. pp. 529–. ISBN 978-1-4443-0017-8.
  20. 1 2 Bockting W, Coleman E, De Cuypere G (June 2011). "Care of transsexual persons". The New England Journal of Medicine. 364 (26): 2559–60; author reply 2560. doi:10.1056/NEJMcp1008161. PMID 21714669.
  21. 1 2 Shaw JC (July 2002). "Hormonal therapies in acne". Expert Opinion on Pharmacotherapy. 3 (7): 865–74. doi:10.1517/14656566.3.7.865. PMID 12083987.
  22. 1 2 Lotti F, Maggi M (2015). "Hormonal Treatment for Skin Androgen-Related Disorders". European Handbook of Dermatological Treatments: 1451–1464. doi:10.1007/978-3-662-45139-7_142.
  23. 1 2 m Sternberg MH, Forget BG, Higgs DR, Weatherall DJ (17 August 2009). Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge University Press. pp. 476–. ISBN 978-1-139-48080-2.
  24. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Singh SM, Gauthier S, Labrie F (February 2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Current Medicinal Chemistry. 7 (2): 211–47. doi:10.2174/0929867003375371. PMID 10637363.
  25. 1 2 3 4 5 6 7 8 9 Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1119,1196,1208. ISBN 978-0-7817-1750-2.
  26. 1 2 3 4 5 6 Schellens JH, McLeod HL, Newell DR (5 May 2005). Cancer Clinical Pharmacology. OUP Oxford. pp. 229–230. ISBN 978-0-19-262966-1.
  27. 1 2 3 Gao W, Dalton JT (March 2007). "Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs)". Drug Discovery Today. 12 (5-6): 241–8. doi:10.1016/j.drudis.2007.01.003. PMC 2072879Freely accessible. PMID 17331889.
  28. 1 2 3 Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer". Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554.
  29. 1 2 3 4 Higano CS (February 2003). "Side effects of androgen deprivation therapy: monitoring and minimizing toxicity". Urology. 61 (2 Suppl 1): 32–8. doi:10.1016/S0090-4295(02)02397-X. PMID 12667885.
  30. 1 2 3 Elliott S, Latini DM, Walker LM, Wassersug R, Robinson JW (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. PMID 20626600.
  31. 1 2 3 4 Higano CS (2012). "Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 30 (30): 3720–5. doi:10.1200/JCO.2012.41.8509. PMID 23008326.
  32. 1 2 3 Shapiro J (12 November 2012). Hair Disorders: Current Concepts in Pathophysiology, Diagnosis and Management, An Issue of Dermatologic Clinics. Elsevier Health Sciences. pp. 187–. ISBN 1-4557-7169-4.
  33. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 "Casodex® (bicalutamide) Tablets" (PDF). FDA.
  34. 1 2 3 4 5 6 Mahler C, Verhelst J, Denis L (May 1998). "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer". Clinical Pharmacokinetics. 34 (5): 405–17. doi:10.2165/00003088-199834050-00005. PMID 9592622.
  35. 1 2 3 4 5 Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM (2014). "Bicalutamide-induced hepatotoxicity: A rare adverse effect". The American Journal of Case Reports. 15: 266–70. doi:10.12659/AJCR.890679. PMID 24967002.
  36. 1 2 3 4 Yun GY, Kim SH, Kim SW, Joo JS, Kim JS, Lee ES, Lee BS, Kang SH, Moon HS, Sung JK, Lee HY, Kim KH (April 2016). "Atypical onset of bicalutamide-induced liver injury". World Journal of Gastroenterology. 22 (15): 4062–5. doi:10.3748/wjg.v22.i15.4062. PMC 4823258Freely accessible. PMID 27099451.
  37. 1 2 Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 497–. ISBN 978-0-7817-2845-4.
  38. 1 2 3 Masago T, Watanabe T, Nemoto R, Motoda K (December 2011). "Interstitial pneumonitis induced by bicalutamide given for prostate cancer". International Journal of Clinical Oncology. 16 (6): 763–5. doi:10.1007/s10147-011-0239-x. PMID 21537882.
  39. 1 2 Aronson JK (4 March 2014). Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Newnes. pp. 740–. ISBN 978-0-444-62636-3.
  40. 1 2 3 4 5 6 7 Lehne RA (2013). Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 1297–. ISBN 1-4377-3582-7.
  41. 1 2 3 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Elsevier. pp. 627–. ISBN 978-0-8155-1856-3.
  42. 1 2 Mukherji D, Pezaro CJ, De-Bono JS (February 2012). "MDV3100 for the treatment of prostate cancer". Expert Opinion on Investigational Drugs. 21 (2): 227–33. doi:10.1517/13543784.2012.651125. PMID 22229405.
  43. 1 2 Pchejetski D, Alshaker H, Stebbing J (2014). "Castrate-resistant prostate cancer: the future of antiandrogens". Trends in Urology & Men's Health. 5 (1): 7–10. doi:10.1002/tre.371.
  44. 1 2 3 4 5 Campbell T (22 January 2014). "Slowing Sales for Johnson & Johnson's Zytiga May Be Good News for Medivation". The Motley Fool. Retrieved 20 July 2016. [...] the most commonly prescribed treatment for metastatic castration resistant prostate cancer: bicalutamide. That was sold as AstraZeneca's billion-dollar-a-year drug Casodex before losing patent protection in 2008. AstraZeneca still generates a few hundred million dollars in sales from Casodex, [...]
  45. 1 2 3 4 5 6 7 8 9 Chang S (10 March 2010), Bicalutamide BPCA Drug Use Review in the Pediatric Population (PDF), U.S. Department of Health and Human Service, retrieved 20 July 2016
  46. 1 2 3 4 5 6 Vogelzang NJ (September 2012). "Enzalutamide--a major advance in the treatment of metastatic prostate cancer". The New England Journal of Medicine. 367 (13): 1256–7. doi:10.1056/NEJMe1209041. PMID 23013078. 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.
  47. 1 2 3 4 Regitz-Zagrosek V (2 October 2012). Sex and Gender Differences in Pharmacology. Springer Science & Business Media. pp. 575–. ISBN 978-3-642-30725-6.
  48. 1 2 Horwich A (11 February 2010). Systemic Treatment of Prostate Cancer. OUP Oxford. pp. 44–. ISBN 978-0-19-956142-1.
  49. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Chabner BA, Longo DL (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 679–680. ISBN 978-1-60547-431-1. 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.
  50. 1 2 3 4 5 6 7 8 Weber GF (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 318–. ISBN 978-3-319-13278-5. 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.
  51. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Kolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9; discussion 80–4. PMID 8560681. 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.
  52. 1 2 3 Kaliks RA, Del Giglio A (2008). "Management of advanced prostate cancer" (PDF). Revista Da Associação Médica Brasileira. 54 (2): 178–82. doi:10.1590/S0104-42302008000200025. PMID 18506331.
  53. 1 2 3 4 Payen O, Top S, Vessières A, Brulé E, Lauzier A, Plamont M, McGlinchey MJ, Müller-Bunz H, Jaouen G (2011). "Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide" (PDF). 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].
  54. 1 2 3 4 5 6 7 Gulley JL (2011). Prostate Cancer. Demos Medical Publishing. pp. 81–. ISBN 978-1-935281-91-7.
  55. 1 2 3 Moser L (1 January 2008). Controversies in the Treatment of Prostate Cancer. Karger Medical and Scientific Publishers. pp. 41–42. ISBN 978-3-8055-8524-8.
  56. 1 2 3 Prostate Cancer. Demos Medical Publishing. 20 December 2011. pp. 505–. ISBN 978-1-935281-91-7.
  57. 1 2 3 4 5 6 7 "Bicalutamide - International Drug Names". Retrieved 13 August 2016.
  58. 1 2 3 4 Sweetman SC (2011). Martindale: The Complete Drug Reference. Pharmaceutical Press. pp. 750–751. ISBN 978-0-85369-933-0.
  59. 1 2 Akaza H (1999). "[A new anti-androgen, bicalutamide (Casodex), for the treatment of prostate cancer--basic clinical aspects]". Gan to Kagaku Ryoho. Cancer & Chemotherapy (in Japanese). 26 (8): 1201–7. PMID 10431591.
  60. 1 2 Moul JW (August 2009). "Twenty years of controversy surrounding combined androgen blockade for advanced prostate cancer". Cancer. 115 (15): 3376–8. doi:10.1002/cncr.24393. PMID 19484788.
  61. 1 2 Kampel LJ (20 March 2012). Dx/Rx: Prostate Cancer. Jones & Bartlett Publishers. pp. 178–. ISBN 978-0-7637-9453-8.
  62. 1 2 "Bicalutamide Prices, Coupons and Patient Assistance Programs". Retrieved 31 August 2015.
  63. "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  64. 1 2 Bagatelle C, Bremner WJ (27 May 2003). Androgens in Health and Disease. Springer Science & Business Media. pp. 25–. ISBN 978-1-59259-388-0.
  65. Klotz L, Schellhammer P (March 2005). "Combined androgen blockade: the case for bicalutamide". Clinical Prostate Cancer. 3 (4): 215–9. doi:10.3816/cgc.2005.n.002. PMID 15882477.
  66. Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ (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): 330–6. doi:10.1016/S0090-4295(97)00279-3. PMID 9301693.
  67. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Figg W, Chau CH, Small EJ (14 September 2010). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 56, 71–72, 75, 93. ISBN 978-1-60327-829-4.
  68. Kavoussi P, Costabile RA, Salonia A (17 October 2012). Clinical Urologic Endocrinology: Principles for Men’s Health. Springer Science & Business Media. pp. 7–. ISBN 978-1-4471-4404-5.
  69. 1 2 3 4 Denis LJ, Griffiths K, Kaisary AV, Murphy GP (1 March 1999). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 55,279–280. ISBN 978-1-85317-422-3.
  70. Munoz J, Wheler JJ, Kurzrock R (2015). "Androgen receptors beyond prostate cancer: an old marker as a new target". Oncotarget. 6 (2): 592–603. doi:10.18632/oncotarget.2831. PMC 4359241Freely accessible. PMID 25595907.
  71. 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. PMID 12231070.
  72. Sarosdy MF (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". Anticancer Drugs. 10 (9): 791–6. doi:10.1097/00001813-199910000-00001. PMID 10587288.
  73. Dasgupta P, Kirby RS (27 December 2011). ABC of Prostate Cancer. John Wiley & Sons. pp. 52–. ISBN 978-1-4443-3437-1.
  74. 1 2 3 Bruskewitz R (6 December 2012). Atlas of the Prostate. Springer Science & Business Media. pp. 5,190. ISBN 978-1-4615-6505-5.
  75. 1 2 3 4 5 6 7 8 Denis L (6 December 2012). Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment. Springer Science & Business Media. pp. 128,158, 203. ISBN 978-3-642-45745-6.
  76. 1 2 3 4 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): 913–9. doi:10.1016/S0090-4295(97)00393-2. PMID 9426723.
  77. 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. PMID 22449547.
  78. Lupulescu A (24 October 1990). Hormones and Vitamins in Cancer Treatment. CRC Press. pp. 113–. ISBN 978-0-8493-5973-6.
  79. 1 2 Petrovich Z, Baert L, Brady LW (6 December 2012). Carcinoma of the Prostate: Innovations in Management. Springer Science & Business Media. pp. 687–. ISBN 978-3-642-60956-5.
  80. Held-Warmkessel J (2006). Contemporary Issues in Prostate Cancer: A Nursing Perspective. Jones & Bartlett Learning. pp. 275–. ISBN 978-0-7637-3075-8.
  81. Steckler T, Kalin N, Reul J (25 February 2005). Handbook of Stress and the Brain Part 2: Stress: Integrative and Clinical Aspects. Elsevier. pp. 442–. ISBN 978-0-08-055331-3.
  82. Hong WK, Holland JF (2010). Holland-Frei Cancer Medicine 8. PMPH-USA. pp. 939–. ISBN 978-1-60795-014-1.
  83. 1 2 3 4 5 Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2938–2939,2946. ISBN 978-1-4160-6911-9.
  84. 1 2 3 4 5 6 Mydlo JH, Godec CJ (29 September 2015). Prostate Cancer: Science and Clinical Practice. Elsevier Science. pp. 516–521, 534–540. ISBN 978-0-12-800592-7.
  85. 1 2 3 4 5 6 Strauss III JF, Barbieri RL (28 August 2013). Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 688–. ISBN 978-1-4557-5972-9. 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.
  86. 1 2 3 4 5 6 7 8 9 10 Iversen P, Melezinek I, Schmidt A (January 2001). "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. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992.
  87. 1 2 3 4 5 6 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. PMID 21074215.
  88. 1 2 3 4 5 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): 110–5. doi:10.1111/j.1464-410X.2010.09764.x. PMID 20955264.
  89. 1 2 3 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): 224–38. doi:10.1016/j.critrevonc.2013.01.006. PMID 23484454.
  90. 1 2 3 Chedrese PJ (13 June 2009). Reproductive Endocrinology: A Molecular Approach. Springer Science & Business Media. pp. 233–. ISBN 978-0-387-88186-7.
  91. 1 2 3 King SR (2008). "Emerging roles for neurosteroids in sexual behavior and function". Journal of Andrology. 29 (5): 524–33. doi:10.2164/jandrol.108.005660. PMID 18567641.
  92. 1 2 3 4 5 6 7 8 9 10 11 12 Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU International. 91 (5): 455–61. doi:10.1046/j.1464-410X.2003.04026.x. PMID 12603397.
  93. 1 2 Boccardo F (August 2000). "Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy?". Critical Reviews in Oncology/Hematology. 35 (2): 121–32. doi:10.1016/S1040-8428(00)00051-2. PMID 10936469.
  94. 1 2 Kolvenbag GJ, Iversen P, Newling DW (2001). "Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer". Urology. 58 (2 Suppl 1): 16–23. PMID 11502439.
  95. 1 2 3 4 5 Erem C (2013). "Update on idiopathic hirsutism: diagnosis and treatment". Acta Clinica Belgica. 68 (4): 268–74. doi:10.2143/ACB.3267. PMID 24455796.
  96. 1 2 3 4 Müderris II, Bayram F, Ozçelik B, Güven M (February 2002). "New alternative treatment in hirsutism: bicalutamide 25 mg/day". Gynecological Endocrinology. 16 (1): 63–6. doi:10.1080/713602986. PMID 11915584.
  97. 1 2 Costanzo Giulio Moretti, Laura Guccione, Paola Di Giacinto, Amalia Cannuccia, Chiara Meleca, Giulia Lanzolla, Aikaterini Andreadi, Davide Lauro (2016), Efficacy and Safety of Myo-Inositol Supplementation in the Treatment of Obese Hirsute PCOS Women: Comparative Evaluation with OCP+Bicalutamide Therapy, doi:10.1210/endo-meetings.2016.RE.5.SUN-153
  98. Bigby M, Herxheimer A, Naldi L, et al. (5 June 2014). Evidence-Based Dermatology. Wiley. pp. 1904–. ISBN 978-1-118-35762-0.
  99. Ascenso A, Marques HC (January 2009). "Acne in the adult". Mini Reviews in Medicinal Chemistry. 9 (1): 1–10. doi:10.2174/138955709787001730. PMID 19149656.
  100. 1 2 3 Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–23. PMID 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].
  101. Bourgeois AL, Auriche P, Palmaro A, Montastruc JL, Bagheri H (February 2016). "Risk of hormonotherapy in transgender people: Literature review and data from the French Database of Pharmacovigilance". Annales d'Endocrinologie. 77 (1): 14–21. doi:10.1016/j.ando.2015.12.001. PMID 26830952. Drugs for cross-gender hormonal replacement therapy used in the male to female (MtoF) transsexual population. [...] Non-steroidal anti-androgens Bicalutamide, flutamide, nilutamide
  102. Ho CK (December 2011). "Testosterone testing in adult males". The Malaysian Journal of Pathology. 33 (2): 71–81. PMID 22299206. Anti-androgens such as flutamide, bicalutamide and cyproterone acetate are also used in patients with prostate cancer and sometimes in male-to-female transgender individuals [...]
  103. 1 2 3 Wierckx K, Gooren L, T'Sjoen G (May 2014). "Clinical review: Breast development in trans women receiving cross-sex hormones". The Journal of Sexual Medicine. 11 (5): 1240–7. doi:10.1111/jsm.12487. PMID 24618412. Other agents with anti-androgenic properties used [in the treatment of transgender women] are nonsteroidal androgen receptor blockers, such as flutamide and bicalutamide [...]
  104. 1 2 3 Deutsch M (17 June 2016), Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People (PDF) (2nd ed.), University of California, San Francisco: Center of Excellence for Transgender Health, p. 28
  105. Braunstein GD (September 2007). "Clinical practice. Gynecomastia". The New England Journal of Medicine. 357 (12): 1229–37. doi:10.1056/NEJMcp070677. PMID 17881754.
  106. Gentilini OD, Boccardo C (2015). "Male Breast Diseases". The Outpatient Breast Clinic: 431–446. doi:10.1007/978-3-319-15907-2_19.
  107. 1 2 3 4 5 Kanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW (January 2000). "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. doi:10.1097/00000478-200001000-00009. PMID 10632490.
  108. 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. PMID 12113064. At 2-year follow-up, loss of spontaneous erections and sexual function occurred in 80 vs. 92% and 78 vs. 88% in the flutamide versus CPA groups, respectively. This group of agents includes flutamide, nilutamide and bicalutamide.
  109. 1 2 3 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–. ISBN 978-1-4614-7441-8. 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.
  110. 1 2 3 4 5 Jameson JL, de Kretser DM, Marshall JC, De Groot LJ (7 May 2013). Endocrinology Adult and Pediatric: Reproductive Endocrinology. Elsevier Health Sciences. ISBN 978-0-323-22152-8. Nonsteroidal antiandrogens (e.g., flutamide and nilutamide) are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol.119 The latter is desirable in this context, as it has feminizing effects.
  111. Moore E, Wisniewski A, Dobs A (2003). "Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects". J. Clin. Endocrinol. Metab. 88 (8): 3467–73. doi:10.1210/jc.2002-021967. PMID 12915619.
  112. 1 2 Kliegman RM, Stanton B, St Geme J, Schor NF (17 April 2015). Nelson Textbook of Pediatrics. Elsevier Health Sciences. pp. 2661–. ISBN 978-0-323-26352-8.
  113. 1 2 3 4 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): 416–20. doi:10.1016/j.jpeds.2006.04.027. PMID 16939760.
  114. 1 2 3 Reiter EO, Mauras N, McCormick K, Kulshreshtha B, Amrhein J, De Luca F, O'Brien S, Armstrong J, Melezinkova H (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. PMID 21158211.
  115. 1 2 3 4 Jameson JL, De Groot LJ (25 February 2015). Edndocrinology: Adult and Pediatric. Elsevier Health Sciences. pp. 2425–2426. ISBN 978-0-323-32195-2.
  116. 1 2 3 4 5 Asscheman H, Gooren LJ, Peereboom-Wynia JD (1989). "Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals--experiences with a novel androgen receptor blocker". Clin. Exp. Dermatol. 14 (5): 361–3. doi:10.1111/j.1365-2230.1989.tb02585.x. PMID 2612040.
  117. 1 2 3 4 5 6 7 Rao BR, de Voogt HJ, Geldof AA, Gooren LJ, Bouman FG (1988). "Merits and considerations in the use of anti-androgen". J. Steroid Biochem. 31 (4B): 731–7. doi:10.1016/0022-4731(88)90024-6. PMID 3143862.
  118. 1 2 3 4 van Kemenade JF, Cohen-Kettenis PT, Cohen L, Gooren LJ (1989). "Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals". Arch Sex Behav. 18 (3): 217–28. doi:10.1007/BF01543196. PMID 2751416.
  119. 1 2 Gooren L, Spinder T, Spijkstra JJ, van Kessel H, Smals A, Rao BR, Hoogslag M (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". J. Clin. Endocrinol. Metab. 64 (4): 763–70. doi:10.1210/jcem-64-4-763. PMID 3102546.
  120. 1 2 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". Prostate. 11 (4): 305–11. doi:10.1002/pros.2990110403. PMID 2960959.
  121. Cohen-Kettenis, Peggy T.; Gooren, Louis J.G. (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. ISSN 0890-7064.
  122. 1 2 3 Chang C (22 March 2005). Prostate Cancer: Basic Mechanisms and Therapeutic Approaches. World Scientific. pp. 10–11. ISBN 978-981-4481-61-8.
  123. Vincent T. DeVita; Theodore S. Lawrence; Steven A. Rosenberg (18 March 2016). Prostate and Other Genitourinary Cancers: Cancer: Principles & Practice of Oncology. Wolters Kluwer Health. pp. 1006–. ISBN 978-1-4963-5421-1.
  124. Ricardo Azziz (8 November 2007). Androgen Excess Disorders in Women. Springer Science & Business Media. pp. 382–. ISBN 978-1-59745-179-6. Cyproterone acetate is an effective treatment for hirsutism and acne [in women] and is widely used throughout the world for this indication.
  125. Laura Erickson-Schroth (12 May 2014). Trans Bodies, Trans Selves: A Resource for the Transgender Community. Oxford University Press. pp. 258–. ISBN 978-0-19-932536-8. 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.
  126. Randi Ettner; Stan Monstrey; Eli Coleman (27 May 2016). Principles of Transgender Medicine and Surgery. Routledge. pp. 169–. ISBN 978-1-317-51460-2. In Europe, the most widely used drug [in the treatment of male-to-female patients] is cyproterone acetate [...]
  127. David L. Rowland; Luca Incrocci (2 May 2008). Handbook of Sexual and Gender Identity Disorders. John Wiley & Sons. pp. 444–. ISBN 978-0-470-25721-0. Spironolactone is the most commonly prescribed antiandrogen [for feminizing hormone therapy] in the United States.
  128. Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A (2004). "Hepatotoxicity induced by antiandrogens: a review of the literature". Urol. Int. 73 (4): 289–95. doi:10.1159/000081585. PMID 15604569.
  129. 1 2 Emans SJ, Laufer MR (5 January 2012). Emans, Laufer, Goldstein's Pediatric and Adolescent Gynecology. Lippincott Williams & Wilkins. pp. 365–. ISBN 978-1-4511-5406-1. Therapy with GnRH analogs is expensive and requires intramuscular injections of depot formulations, the insert of a subcutaneous implant yearly, or, much less commonly, daily subcutaneous injections.
  130. 1 2 Hillard PJ (29 March 2013). Practical Pediatric and Adolescent Gynecology. John Wiley & Sons. pp. 182–. ISBN 978-1-118-53857-9. Treatment is expensive, with costs typicall in the range of $10,000–$15,000 per year.
  131. Styne DM (25 April 2016). "Disorders of Puberty". Pediatric Endocrinology: A Clinical Handbook. Springer. pp. 197–. ISBN 978-3-319-18371-8. Antiandrogens are used [...] in conditions such as premature Leydig cell and germ cell maturation in boys to decrease androgen effects if the source of androgens cannot be removed.
  132. 1 2 Lenz AM, Shulman D, Eugster EA, Rahhal S, Fuqua JS, Pescovitz OH, Lewis KA (September 2010). "Bicalutamide and third-generation aromatase inhibitors in testotoxicosis". Pediatrics. 126 (3): e728–33. doi:10.1542/peds.2010-0596. PMC 4096839Freely accessible. PMID 20713483.
  133. Levey HR, Kutlu O, Bivalacqua TJ (2012). "Medical management of ischemic stuttering priapism: a contemporary review of the literature". Asian Journal of Andrology. 14 (1): 156–63. doi:10.1038/aja.2011.114. PMC 3753435Freely accessible. PMID 22057380.
  134. Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, Shamloul R (2010). "Priapism: pathogenesis, epidemiology, and management". The Journal of Sexual Medicine. 7 (1 Pt 2): 476–500. doi:10.1111/j.1743-6109.2009.01625.x. PMID 20092449.
  135. 1 2 3 Chow K, Payne S (2008). "The pharmacological management of intermittent priapismic states". BJU International. 102 (11): 1515–21. doi:10.1111/j.1464-410X.2008.07951.x. PMID 18793304.
  136. 1 2 3 Dahm P, Rao DS, Donatucci CF (2002). "Antiandrogens in the treatment of priapism". Urology. 59 (1): 138. doi:10.1016/S0090-4295(01)01492-3. PMID 11796309.
  137. 1 2 3 Yuan J, Desouza R, Westney OL, Wang R (2008). "Insights of priapism mechanism and rationale treatment for recurrent priapism". Asian Journal of Andrology. 10 (1): 88–101. doi:10.1111/j.1745-7262.2008.00314.x. PMID 18087648.
  139. 1 2 Suzuki H, Kamiya N, Imamoto T, Kawamura K, Yano M, Takano M, Utsumi T, Naya Y, Ichikawa T (October 2008). "Current topics and perspectives relating to hormone therapy for prostate cancer". International Journal of Clinical Oncology. 13 (5): 401–10. doi:10.1007/s10147-008-0830-y. PMID 18946750.
  140. 1 2 White R, Bradnam V (11 March 2015). Handbook of Drug Administration via Enteral Feeding Tubes (3rd ed.). Pharmaceutical Press. pp. 133–. ISBN 978-0-85711-162-3.
  141. 1 2 Morton I, Hall J (2001). The Avery Complete Guide to Medicines. Avery. pp. 105–106. ISBN 978-1-58333-105-7.
  142. 1 2
  143. 1 2
  144. 1 2
  145. Skeel RT, Khleif SN (2011). Handbook of Cancer Chemotherapy. Lippincott Williams & Wilkins. pp. 724–.
  146. Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs. Mosby. 2001. pp. 289–290. ISBN 978-0-323-00629-3.
  147. PDR T (2004). Physicians' Desk Reference. Thomson PDR. ISBN 978-1-56363-471-0.
  148. 1 2 3 4 Iswaran TJ, Imai M, Betton GR, Siddall RA (May 1997). "An overview of animal toxicology studies with bicalutamide (ICI 176,334)". The Journal of Toxicological Sciences. 22 (2): 75–88. doi:10.2131/jts.22.2_75. PMID 9198005.
  149. 1 2 3 Smith RE (4 April 2013). Medicinal Chemistry - Fusion of Traditional and Western Medicine. Bentham Science Publishers. pp. 306–. ISBN 978-1-60805-149-6.
  150. Sex Differences in the Human Brain, their underpinnings and implications. Elsevier. 3 December 2010. pp. 44–45. ISBN 978-0-444-53631-0.
  151. Paoletti R (6 December 2012). Chemistry and Brain Development: Proceedings of the Advanced Study Institute on “Chemistry of Brain Development,” held in Milan, Italy, September 9–19, 1970. Springer Science & Business Media. pp. 218–. ISBN 978-1-4684-7236-3.
  152. 1 2 3 4 5 6 7 8 9 Wirth MP, Hakenberg OW, Froehner M (February 2007). "Antiandrogens in the treatment of prostate cancer". European Urology. 51 (2): 306–13; discussion 314. doi:10.1016/j.eururo.2006.08.043. PMID 17007995.
  153. 1 2 Resnick MI, Thompson IM (2000). Advanced Therapy of Prostate Disease. PMPH-USA. pp. 379–. ISBN 978-1-55009-102-1.
  154. Jamnicky L, Nam R (5 November 2012). Canadian Guide to Prostate Cancer. John Wiley & Sons. pp. 177–. ISBN 978-1-118-51565-5.
  155. Lunglmayr G (August 1995). "Efficacy and tolerability of Casodex in patients with advanced prostate cancer. International Casodex Study Group". Anti-Cancer Drugs. 6 (4): 508–13. doi:10.1097/00001813-199508000-00003. PMID 7579554.
  156. McLeod DG (1997). "Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer". The Oncologist. 2 (1): 18–27. PMID 10388026.
  157. DeAngelis LM, Posner JB (12 September 2008). Neurologic Complications of Cancer. Oxford University Press, USA. pp. 479–. ISBN 978-0-19-971055-3.
  158. Michalopoulos NV, Keshtgar MR (2012). "Images in clinical medicine. Gynecomastia induced by prostate-cancer treatment". N. Engl. J. Med. 367 (15): 1449. doi:10.1056/NEJMicm1209166. PMID 23050528.
  159. 1 2 3 4 5 6 7 8 9 Aronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 150–152. ISBN 978-0-08-093292-7.
  160. Fradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S (2007). "Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study". European Urology. 52 (1): 106–14. doi:10.1016/j.eururo.2007.01.031. PMID 17270340.
  161. Brown JS, Rubenfeld S (1974). "Irradiation in preventing gynecomastia induced by estrogens". Urology. 3 (1): 51–3. doi:10.1016/s0090-4295(74)80060-9. PMID 4812899. Infrequently, the breast hypertrophy can become so marked that it attains proportions comparable to that in female breasts.
  162. Deepinder F, Braunstein GD (2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–95. doi:10.1517/14740338.2012.712109. PMID 22862307. Treatment with estrogen has the highest incidence of gynecomastia, at 40 – 80%, anti-androgens, including flutamide, bicalutamide and nilutamide, are next, with a 40 – 70% incidence, followed by GnRH analogs (goserelin, leuprorelin) and combined androgen deprivation, both with incidences of 13% each.
  163. Nakabayashi M, Bartlett RA, Oh WK (2006). "Treatment of bicalutamide-induced gynecomastia with breast-reduction surgery in prostate cancer" (PDF). J. Clin. Oncol. 24 (18): 2958–9. doi:10.1200/JCO.2005.03.8505. PMID 16782932.
  164. 1 2 3 Saltzstein D, Sieber P, Morris T, Gallo J (2005). "Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole". Prostate Cancer and Prostatic Diseases. 8 (1): 75–83. doi:10.1038/sj.pcan.4500782. PMID 15685254.
  165. 1 2 3 Boccardo F, Rubagotti A, Battaglia M, Di Tonno P, Selvaggi FP, Conti G, Comeri G, Bertaccini A, Martorana G, Galassi P, Zattoni F, Macchiarella A, Siragusa A, Muscas G, Durand F, Potenzoni D, Manganelli A, Ferraris V, Montefiore F (February 2005). "Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer". Journal of Clinical Oncology. 23 (4): 808–15. doi:10.1200/JCO.2005.12.013. PMID 15681525.
  166. Fagerlund A, Cormio L, Palangi L, Lewin R, Santanelli di Pompeo F, Elander A, Selvaggi G (2015). "Gynecomastia in Patients with Prostate Cancer: A Systematic Review". PloS One. 10 (8): e0136094. doi:10.1371/journal.pone.0136094. PMC 4550398Freely accessible. PMID 26308532.
  167. Di Lorenzo G, Autorino R, Perdonà S, De Placido S (2005). "Management of gynaecomastia in patients with prostate cancer: a systematic review". Lancet Oncol. 6 (12): 972–9. doi:10.1016/S1470-2045(05)70464-2. PMID 16321765.
  168. 1 2 Rahman HP, Hofland J, Foster PA (2016). "In touch with your feminine side: how oestrogen metabolism impacts prostate cancer". Endocrine-related Cancer. 23 (6): R249–66. doi:10.1530/ERC-16-0118. PMID 27194038. Prostate cancer primarily affects the elderly with 99.9% of patients diagnosed over the age of 50 and the mean age at diagnosis being 73 (Parkin, et al. 1997).
  169. 1 2 3 4 5 6 7 8 9 10 11 Furr BJ, Tucker H (January 1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action". Urology. 47 (1A Suppl): 13–25; discussion 29–32. doi:10.1016/S0090-4295(96)80003-3. PMID 8560673.
  170. 1 2 3 4 5 Morgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, Cardillo MR, Petrangeli E, Russo M, Di Silverio F (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. PMID 11260298.
  171. Nguyen PL, Alibhai SM, Basaria S, D'Amico AV, Kantoff PW, Keating NL, Penson DF, Rosario DJ, Tombal B, Smith MR (May 2015). "Adverse effects of androgen deprivation therapy and strategies to mitigate them". European Urology. 67 (5): 825–36. doi:10.1016/j.eururo.2014.07.010. PMID 25097095.
  172. Mazzola CR, Mulhall JP (March 2012). "Impact of androgen deprivation therapy on sexual function". Asian Journal of Andrology. 14 (2): 198–203. doi:10.1038/aja.2011.106. PMC 3735098Freely accessible. PMID 22231298.
  173. Mulcahy JJ (1 January 2001). Male Sexual Function. Springer Science & Business Media. pp. 3–. ISBN 978-1-59259-098-8.
  174. Scialli AR, Clegg ED (9 June 1992). Reversibility in Testicular Toxicity Assessment. CRC Press. pp. 107–. ISBN 978-0-8493-5980-4.
  175. Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, Chamberlain M, Carroll K, Melezinek I (2000). "Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup". J. Urol. 164 (5): 1579–82. doi:10.1016/s0022-5347(05)67032-2. PMID 11025708.
  176. 1 2 3 4 5 6 7 Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K (November 2004). "Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6". The Journal of Urology. 172 (5 Pt 1): 1871–6. doi:10.1097/01.ju.0000139719.99825.54. PMID 15540741.
  177. 1 2 Oh WK (2001). "Anemia Related to Hormonal Ablation Therapy for Prostate Cancer". The Prostate Journal. 3 (1): 14–17. doi:10.1046/j.1525-1411.2001.003001014.x.
  178. 1 2 Droz J, Audisio RA (2 October 2012). Management of Urological Cancers in Older People. Springer Science & Business Media. pp. 84–. ISBN 978-0-85729-986-4.
  179. 1 2 Mason M (August 2006). "What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care?". Journal of Cancer Research and Clinical Oncology. 132 Suppl 1: S27–35. doi:10.1007/s00432-006-0134-4. PMID 16896883.
  180. Cher ML, Honn KV, Raz A (11 April 2006). Prostate Cancer: New Horizons in Research and Treatment. Springer Science & Business Media. pp. 382–. ISBN 978-0-306-48143-7.
  181. Feldman D, Marcus R, Nelson D, Rosen CJ (8 November 2007). Osteoporosis. Academic Press. pp. 1354–. ISBN 978-0-08-055347-4.
  182. Vanderschueren D, Gaytant J, Boonen S, Venken K (June 2008). "Androgens and bone". Current Opinion in Endocrinology, Diabetes, and Obesity. 15 (3): 250–4. doi:10.1097/MED.0b013e3282fe6ca9. PMID 18438173.
  183. 1 2 3 Bowsher W, Carter A (15 April 2008). Challenges in Prostate Cancer. John Wiley & Sons. pp. 146–. ISBN 978-1-4051-7177-9.
  184. 1 2 3 4 5 Shahani R, Fleshner NE, Zlotta AR (2007). "Pharmacotherapy for prostate cancer: the role of hormonal treatment". Discov Med. 7 (39): 118–24. PMID 18093474.
  185. Pagliarulo V, Bracarda S, Eisenberger MA, Mottet N, Schröder FH, Sternberg CN, Studer UE (2012). "Contemporary role of androgen deprivation therapy for prostate cancer". European Urology. 61 (1): 11–25. doi:10.1016/j.eururo.2011.08.026. PMC 3483081Freely accessible. PMID 21871711.
  186. Sternberg CN (2006). "Adjuvant bicalutamide for early prostate cancer: an update". Nature Clinical Practice. Urology. 3 (8): 408–9. doi:10.1038/ncpuro0518. PMID 16902511.
  187. Stanworth RD, Jones TH (2008). "Testosterone for the aging male; current evidence and recommended practice". Clin Interv Aging. 3 (1): 25–44. PMC 2544367Freely accessible. PMID 18488876.
  188. 1 2 Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J (2006). "Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years". Scand. J. Urol. Nephrol. 40 (6): 441–52. doi:10.1080/00365590601017329. PMID 17130095.
  189. See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, et al. (August 2002). "Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program". The Journal of Urology. 168 (2): 429–35. doi:10.1016/S0022-5347(05)64652-6. PMID 12131282.
  190. 1 2 3 4 5 Craig JV, Furr B (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 356–. ISBN 978-1-59259-152-7. A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101).
  191. 1 2 3 Kaplowitz N (16 October 2002). Drug-Induced Liver Disease. CRC Press. pp. 618–. ISBN 978-0-203-90912-6.
  192. Kim JH, Yoo BW, Yang WJ (May 2014). "Hepatic failure induced by cyproterone acetate: A case report and literature review". Canadian Urological Association Journal = Journal De l'Association Des Urologues Du Canada. 8 (5-6): E458–61. doi:10.5489/cuaj.1753. PMC 4081269Freely accessible. PMID 25024808.
  193. Savidou I, Deutsch M, Soultati AS, Koudouras D, Kafiri G, Dourakis SP (December 2006). "Hepatotoxicity induced by cyproterone acetate: a report of three cases". World Journal of Gastroenterology. 12 (46): 7551–5. doi:10.3748/wjg.v12.i46.7551. PMC 4087608Freely accessible. PMID 17167851.
  194. 1 2 Keating GM (March 2015). "Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer". Drugs & Aging. 32 (3): 243–9. doi:10.1007/s40266-015-0248-y. PMID 25711765.
  195. 1 2 Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B (July 2014). "Enzalutamide in metastatic prostate cancer before chemotherapy". The New England Journal of Medicine. 371 (5): 424–33. doi:10.1056/NEJMoa1405095. PMC 4418931Freely accessible. PMID 24881730.
  196. Tripathi KD (30 September 2013). Essentials of Medical Pharmacology. JP Medical Ltd. pp. 302–. ISBN 978-93-5025-937-5.
  197. 1 2 3 4 Danseuse P, Snyder RR, Monks TJ, Jollow DJ, Sipes IG, Greim H, Gibson GG, Delaforge M (6 December 2012). Biological Reactive Intermediates Vi: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases. Springer Science & Business Media. pp. 37–. ISBN 978-1-4615-0667-6.
  198. Schellhammer PF (November 1997). "Fulminant hepatic failure associated with bicalutamide". Urology. 50 (5): 827. doi:10.1016/S0090-4295(97)80116-1. PMID 9372905.
  199. O'Bryant CL, Flaig TW, Utz KJ (August 2008). "Bicalutamide-associated fulminant hepatotoxicity". Pharmacotherapy. 28 (8): 1071–5. doi:10.1592/phco.28.8.1071. PMID 18657023. Finally, the patient did not receive enough bicalutamide doses to reach steady-state concentrations, and symptomatic hepatotoxicity after two doses of bicalutamide is unlikely. Hepatotoxicity induced by nonsteroidal antiandrogens follows a typical course of signs and symptoms.
  200. 1 2 3 Ramon J, Denis L (5 June 2007). Prostate Cancer. Springer Science & Business Media. pp. 256–. ISBN 978-3-540-40901-4.
  201. 1 2 3 Bunce CM, Campbell MJ (11 March 2010). Nuclear Receptors: Current Concepts and Future Challenges. Springer Science & Business Media. pp. 160, 167. ISBN 978-90-481-3303-1.
  202. 1 2 Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, Farin FM, Woodke L, Plymate SR, Fausto N, Nelson SD (September 2007). "Comparison of the cytotoxicity of the nitroaromatic drug flutamide to its cyano analogue in the hepatocyte cell line TAMH: evidence for complex I inhibition and mitochondrial dysfunction using toxicogenomic screening". Chemical Research in Toxicology. 20 (9): 1277–90. doi:10.1021/tx7001349. PMC 2802183Freely accessible. PMID 17702527.
  203. Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y (June 2007). "Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants". Toxicological Sciences. 97 (2): 539–47. doi:10.1093/toxsci/kfm052. PMID 17361016. Apoptosis induced by the androgen antagonist bicalutamide is receptor mediated (Lin et al., 2006), and hence a dominant effect at low concentrations, and hepatoxicity is a rare event (Dawson et al., 1997), in accord with its relative lack of toxicity to galactose-grown cells.
  204. Kashimshetty R, Desai VG, Kale VM, Lee T, Moland CL, Branham WS, New LS, Chan EC, Younis H, Boelsterli UA (July 2009). "Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity". Toxicology and Applied Pharmacology. 238 (2): 150–9. doi:10.1016/j.taap.2009.05.007. PMID 19442681.
  205. 1 2 3 Ball AL, Kamalian L, Alfirevic A, Lyon JJ, Chadwick AE (July 2016). "Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells". Toxicological Sciences: kfw126. doi:10.1093/toxsci/kfw126. PMID 27413113.
  206. Boelsterli UA, Ho HK, Zhou S, Leow KY (October 2006). "Bioactivation and hepatotoxicity of nitroaromatic drugs". Current Drug Metabolism. 7 (7): 715–27. doi:10.2174/138920006778520606. PMID 17073576.
  207. 1 2 3 4 Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety. 13 (11): 1483–99. doi:10.1517/14740338.2014.966686. PMID 25270521.
  208. Camus P, Rosenow III EC (29 October 2010). Drug-induced and Iatrogenic Respiratory Disease. CRC Press. pp. 235–. ISBN 978-1-4441-2869-7.
  209. 1 2 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. PMID 12353966. 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.
  210. Rodriguez EM, Staffa JA, Graham DJ (2001). "The role of databases in drug postmarketing surveillance". Pharmacoepidemiology and Drug Safety. 10 (5): 407–10. doi:10.1002/pds.615. PMID 11802586.
  211. Wong PW, Macris N, DiFabrizio L, Seriff NS (February 1998). "Eosinophilic lung disease induced by bicalutamide: a case report and review of the medical literature". Chest. 113 (2): 548–50. doi:10.1378/chest.113.2.548. PMID 9498983.
  212. Daba MH, El-Tahir KE, Al-Arifi MN, Gubara OA (June 2004). "Drug-induced pulmonary fibrosis". Saudi Medical Journal. 25 (6): 700–6. PMID 15195196.
  213. 1 2 3 Lee K, Oda Y, Sakaguchi M, Yamamoto A, Nishigori C (May 2016). "Drug-induced photosensitivity to bicalutamide - case report and review of the literature". Photodermatology, Photoimmunology & Photomedicine. 32 (3): 161–4. doi:10.1111/phpp.12230. PMID 26663090.
  214. Lee K, et al. (2016). "Drug-induced photosensitivity to bicalutamide - case report and review of the literature". Reactions Weekly. 1612 (1): 37–37. doi:10.1007/s40278-016-19790-1.
  215. 1 2 Sasada K, Sakabe J, Tamura A, Kasuya A, Shimauchi T, Ito T, Hirakawa S, Tokura Y (2012). "Photosensitive drug eruption induced by bicalutamide within the UVB action spectrum". European Journal of Dermatology. 22 (3): 402–3. doi:10.1684/ejd.2012.1719. PMID 22503957.
  216. 1 2 3 4 5 Aronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 155–. ISBN 978-0-08-093292-7.
  217. Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B (March 2014). "Gynecomastia: Clinical evaluation and management". Indian Journal of Endocrinology and Metabolism. 18 (2): 150–8. doi:10.4103/2230-8210.129104. PMC 3987263Freely accessible. PMID 24741509.
  218. Nussbaum RL, McInnes RR, Willard HF (21 May 2015). Thompson & Thompson Genetics in Medicine. Elsevier Health Sciences. pp. 319–. ISBN 978-1-4377-0696-3.
  219. Christopher Li (11 November 2009). Breast Cancer Epidemiology. Springer Science & Business Media. pp. 261–. ISBN 978-1-4419-0685-4.
  220. 1 2 Nurse Practitioner's Drug Handbook. Springhouse Corp. 2000.
  221. 1 2 3 4 Tyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T (September 2006). "Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration". BJU International. 98 (3): 563–72. doi:10.1111/j.1464-410X.2006.06275.x. PMID 16771791.
  222. Henry Winter Griffith (2008). Complete Guide to Prescription & Nonprescription Drugs 2009. HP Books. pp. 62–. ISBN 978-0-399-53463-8. Overdose unlikely to threaten life [with NSAAs].
  223. Genrx (1999). 1999 Mosby's GenRx. Mosby. ISBN 978-0-323-00625-5. A 79-year-old man attempted suicide by ingesting 13g of nilutamide (i.e., 43 times the maximum recommended dose). Despite immediate gastric lavage and oral administration of activated charcoal, plasma nilutamide levels peaked at 6 times the normal range 2 hours after ingestion. There were no clinical signs or symptoms or changes in parameters such as transaminases or chest x-ray. Maintenance treatment (150 mg/day) was resumed 30 days later.
  224. Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs. Mosby. 2001. p. 290. ISBN 978-0-323-00629-3. In vitro studies have shown bicalutamide can displace coumarin anticoagulants, such as warfarin, from their protein-binding sites. It is recommended that if bicalutamide is started in patients already receiving coumarin anticoagulants, prothrombin times should be closely monitored and adjustment of the anticoagulant dose may be necessary.
  225. Spratto G, Woods A (2 July 2008). 2009 Edition Delmar's Nurse's Drug Handbook. Cengage Learning. pp. 175–. ISBN 1-4283-6106-5.
  226. 1 2 3 Bégué J, Bonnet-Delpon D (2 June 2008). Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons. pp. 327–. ISBN 978-0-470-28187-1.
  227. 1 2 Gao W, Bohl CE, Dalton JT (September 2005). "Chemistry and structural biology of androgen receptor". Chemical Reviews. 105 (9): 3352–70. doi:10.1021/cr020456u. PMC 2096617Freely accessible. PMID 16159155. RBA (%): R-bicalutamide: 0.4%; Flutamide: 0.01%; Hydroxyflutamide: 0.1%; Nilutamide: 0.08%
  228. Saad F, Eisenberger MA (20 August 2014). Management of Castration Resistant Prostate Cancer. Springer. pp. 79–. ISBN 978-1-4939-1176-9.
  229. 1 2 Furr BJ (2009). "Research on reproductive medicine in the pharmaceutical industry". Human Fertility. 1 (1): 56–63. doi:10.1080/1464727982000198131. PMID 11844311.
  230. Wirth M, Altwein JE, Schmitz-Drager B, Kuptz S (1998). Molecular Biology of Prostate Cancer. Walter de Gruyter. pp. 92–. ISBN 978-3-11-016159-5.
  231. 1 2 Smith HJ, Williams H (10 October 2005). Smith and Williams' Introduction to the Principles of Drug Design and Action, Fourth Edition. CRC Press. pp. 489–. ISBN 978-0-203-30415-0.
  232. 1 2 3 4 5 6 7 8 9 Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1372–1373. ISBN 978-1-60913-345-0.
  233. Acosta WR (1 October 2009). LWW's Foundations in Pharmacology for Pharmacy Technicians. Lippincott Williams & Wilkins. pp. 300–. ISBN 978-0-7817-6624-1.
  234. Upfal J (2006). Australian Drug Guide. Black Inc. pp. 282–. ISBN 978-1-86395-174-6.
  235. 1 2 3 4 5 Helsen C, Van den Broeck T, Voet A, Prekovic S, Van Poppel H, Joniau S, Claessens F (August 2014). "Androgen receptor antagonists for prostate cancer therapy". Endocrine-Related Cancer. 21 (4): T105–18. doi:10.1530/ERC-13-0545. PMID 24639562.
  236. 1 2 3 Nakai Y, Tanaka N, Anai S, Miyake M, Tatsumi Y, Fujimoto K (August 2015). "A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide". Hormones & Cancer. 6 (4): 161–7. doi:10.1007/s12672-015-0226-1. PMID 26024831.
  237. 1 2 3 Bautista-Vidal C, Barnoiu O, García-Galisteo E, Gómez-Lechuga P, Baena-González V (2014). "Treatment of gynecomastia in patients with prostate cancer and androgen deprivation". Actas Urologicas EspañOlas. 38 (1): 34–40. doi:10.1016/j.acuro.2013.02.013. PMID 23850393. The frequency of occurrence of gynecomastia with the use of antiandrogens with gonadotrophin-releasing hormone agonists is about 15%, but the frequency of gynecomastia with antiandrogens in monotherapy is rather similar; thus, we found gynecomastia rates of around 43–76% with flutamide, 79% with nilutamide, and between 47 and 85% with bicalutamide.
  238. 1 2 3 Dicker AP (2003). "The safety and tolerability of low-dose irradiation for the management of gynaecomastia caused by antiandrogen monotherapy". The Lancet. Oncology. 4 (1): 30–6. doi:10.1016/s1470-2045(03)00958-6. PMID 12517537.
  239. 1 2 3 4 Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". Eur. Urol. 29 Suppl 2: 96–104. PMID 8717470. Casodex is associated with significantly less gastrointestinal effects (diarrhoea) than the nonsteroidal antiandrogen flutamide (Eulexin, Schering-Plough International). Casodex is not associated with alcohol intolerance, pneumonitis and ocular defects which have been seen with the antiandrogen nilutamide (Anandron, Roussel).
  240. Harris MG, Coleman SG, Faulds D, Chrisp P (1993). "Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer". Drugs & Aging. 3 (1): 9–25. doi:10.2165/00002512-199303010-00002. PMID 8453188.
  241. 1 2 Mary Ann Stuhan (2 April 2013). Understanding Pharmacology for Pharmacy Technicians. ASHP. pp. 268–. ISBN 978-1-58528-360-6.
  242. 1 2 Allan GF, Sui Z (2003). "Therapeutic androgen receptor ligands". Nucl Recept Signal. 1: e009. doi:10.1621/nrs.01009. PMC 1402218Freely accessible. PMID 16604181.
  243. 1 2 Rathkopf D, Scher HI (2013). "Androgen receptor antagonists in castration-resistant prostate cancer". Cancer Journal. 19 (1): 43–9. doi:10.1097/PPO.0b013e318282635a. PMC 3788593Freely accessible. PMID 23337756.
  244. 1 2 3 Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (May 2009). "Development of a second-generation antiandrogen for treatment of advanced prostate cancer". Science. 324 (5928): 787–90. doi:10.1126/science.1168175. PMC 2981508Freely accessible. PMID 19359544.
  245. Rodriguez-Vida A, Galazi M, Rudman S, Chowdhury S, Sternberg CN (2015). "Enzalutamide for the treatment of metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy. 9: 3325–39. doi:10.2147/DDDT.S69433. PMID 26170619.
  246. Annual Reports in Medicinal Chemistry. Elsevier Science. 13 September 2013. pp. 498–. ISBN 978-0-12-417151-0.
  247. 1 2 Balaj K (25 April 2016). Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer. pp. 24–25. ISBN 978-3-319-31341-2.
  248. Antonarakis ES (June 2013). "Enzalutamide: The emperor of all anti-androgens". Translational Andrology and Urology. 2 (2): 119–120. PMC 3785324Freely accessible. PMID 24076589.
  249. Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M, Maneval EC, Chen I, Darimont B, Hager JH (September 2013). "A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509". Cancer Discovery. 3 (9): 1020–9. doi:10.1158/2159-8290.CD-13-0226. PMID 23779130.
  250. 1 2 Litt JZ (25 January 2013). Litt's Drug Eruptions and Reactions Manual, 19th Edition. CRC Press. pp. 148–. ISBN 978-1-84214-599-9.
  251. 1 2 3 Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Hirmand M, Smith MR (May 2014). "Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study". The Lancet. Oncology. 15 (6): 592–600. doi:10.1016/S1470-2045(14)70129-9. PMID 24739897.
  252. Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Baron B, Hirmand M, Smith MR (November 2015). "Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results". European Urology. 68 (5): 787–94. doi:10.1016/j.eururo.2015.01.027. PMID 25687533.
  253. 1 2 3 4 5 6 Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (April 2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". The Prostate. 71 (5): 480–8. doi:10.1002/pros.21263. PMID 20878947.
  254. Richard J., Editor in Chief Hamilton FAAEM FACMT (4 December 2013). Tarascon Pocket Pharmacopoeia 2014 Deluxe Lab-Coat Edition. Jones & Bartlett Publishers. pp. 336–. ISBN 978-1-284-05399-9.
  255. McCutcheon SB (2013). "Enzalutamide: a new agent for the prostate cancer treatment armamentarium". J Adv Pract Oncol. 4 (3): 182–5. doi:10.6004/jadpro.2013.4.3.7. PMC 4093421Freely accessible. PMID 25031999.
  256. Ramadan WH, Kabbara WK, Al Basiouni Al Masri HS (2015). "Enzalutamide for patients with metastatic castration-resistant prostate cancer". OncoTargets and Therapy. 8: 871–6. doi:10.2147/OTT.S80488. PMID 25945058.
  257. 1 2 Advances in Clinical Chemistry. Academic Press. 11 October 2000. pp. 111–. ISBN 978-0-08-052230-2.
  258. 1 2 Thomas JA (12 March 1997). Endocrine Toxicology, Second Edition. CRC Press. pp. 152–. ISBN 978-1-4398-1048-4.
  259. 1 2 3 4 5 Poyet P, Labrie F (October 1985). "Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate". Molecular and Cellular Endocrinology. 42 (3): 283–8. doi:10.1016/0303-7207(85)90059-0. PMID 3930312.
  260. Ettner R, Monastery S, Eyler AE (1 February 2013). Principles of Transgender Medicine and Surgery. Routledge. pp. 76–. ISBN 978-1-136-76566-7.
  261. 1 2 Haber RS, Stough DB (2006). Hair Transplantation. Elsevier Health Sciences. pp. 6–7. ISBN 978-1-4160-3104-8. Retrieved 28 May 2012.
  262. Goroll AH, Mulley AG (27 January 2009). Primary Care Medicine: Office Evaluation and Management of the Adult Patient. Lippincott Williams & Wilkins. p. 1264. ISBN 978-0-7817-7513-7. Retrieved 28 May 2012.
  263. Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L (April 1996). "Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial". Gynecological Endocrinology. 10 (2): 119–23. doi:10.3109/09513599609097901. PMID 8701785.
  264. Pratt WB (1994). The Anticancer Drugs. Oxford University Press. pp. 219–220. ISBN 978-0-19-506739-2.
  265. 1 2 3 Diamanti-Kandarakis E, Nestler JE, Pandas D, Pasquale R (21 December 2009). Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation, and Treatment. Springer Science & Business Media. pp. 75–. ISBN 978-1-59745-310-3.
  266. 1 2 3 Sugiono M, Winkler MH, Okeke AA, Benney M, Gillatt DA (2005). "Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer--a pilot study". Prostate Cancer and Prostatic Diseases. 8 (1): 91–4. doi:10.1038/sj.pcan.4500784. PMID 15711607.
  267. James VH, Pasqualini JR (22 October 2013). Hormonal Steroids: Proceedings of the Sixth International Congress on Hormonal Steroids. Elsevier Science. pp. 391–. ISBN 978-1-4831-9067-9.
  268. 1 2 Luthy IA, Begin DJ, Labrie F (1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". Journal of Steroid Biochemistry. 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
  269. 1 2 Müller E (18 September 2003). Peptides and Non Peptides of Oncologic and Neuroendocrine Relevance: From Basic to Clinical Research. Springer Science & Business Media. pp. 171–. ISBN 978-88-470-0295-1. [CPA] induces relevant effects on the coagulative system. A recent meta-analysis relating to total androgenic blockade has shown that cyproterone acetate when combined with castration reduces the long-term efficacy of androgen-suppressive treatments. In fact, it causes an increase in treatment-related mortality, mainly due to cardiovascular complications (No authors, 2000).
  270. Sundar S, Dickinson PD (2012). "Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate". BMJ Case Rep. 2012: bcr1120115238. doi:10.1136/bcr.11.2011.5238. PMC 3291010Freely accessible. PMID 22665559.
  271. 1 2 Miyamoto H, Messing EM, Chang C (2004). "Androgen deprivation therapy for prostate cancer: current status and future prospects". The Prostate. 61 (4): 332–53. doi:10.1002/pros.20115. PMID 15389811.
  272. Caubet JF, Tosteson TD, Dong EW, Naylon EM, Whiting GW, Ernstoff MS, Ross SD (1997). "Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens". Urology. 49 (1): 71–8. doi:10.1016/S0090-4295(96)00325-1. PMID 9000189. Because steroidal antiandrogens such as cyproterone acetate have intrinsic androgenic activity and lower antiandrogenic activity than the NSAAs such as flutamide and nilutamide,39-43 it is not surprising that the two classes of antiandrogens may have different efficacies.
  273. Terrence Priestman (26 May 2012). Cancer Chemotherapy in Clinical Practice. Springer Science & Business Media. pp. 97–. ISBN 978-0-85729-727-3.
  274. Migliari R, Muscas G, Murru M, Verdacchi T, De Benedetto G, De Angelis M (1999). "Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer therapy". Archivio Italiano Di Urologia, Andrologia : Organo Ufficiale [Di] Società Italiana Di Ecografia Urologica E Nefrologica / Associazione Ricerche in Urologia. 71 (5): 293–302. PMID 10673793. The only advantage of cyproterone acetate on pure antiandrogens seems to be the low incidence of hot flushes; [...] However, hepatotoxicity associated with long term daily doses of 300 mg daily and the unacceptably high incidence of cardiovascular side effects (10%) should restrict its use to patients who are intolerant of pure antiandrogen compound. In contrast to steroidal compound nonsteroidal compounds let sexual potency to be retained, [...]
  275. Han M, Nelson JB (2000). "Non-steroidal anti-androgens in prostate cancer--current treatment practice". Expert Opinion on Pharmacotherapy. 1 (3): 443–9. doi:10.1517/14656566.1.3.443. PMID 11249529.
  276. Savidou I, Deutsch M, Soultati AS, Koudouras D, Kafiri G, Dourakis SP (2006). "Hepatotoxicity induced by cyproterone acetate: a report of three cases". World Journal of Gastroenterology. 12 (46): 7551–5. doi:10.3748/wjg.v12.i46.7551. PMC 4087608Freely accessible. PMID 17167851.
  277. Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A (2004). "Hepatotoxicity induced by antiandrogens: a review of the literature". Urologia Internationalis. 73 (4): 289–95. doi:10.1159/000081585. PMID 15604569.
  278. Manso G, Thole Z, Salgueiro E, Revuelta P, Hidalgo A (April 2006). "Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system". Pharmacoepidemiology and Drug Safety. 15 (4): 253–9. doi:10.1002/pds.1168. PMID 16294367.
  279. Blume-Peytavi U, Whiting DA, Trüeb RM (26 June 2008). Hair Growth and Disorders. Springer Science & Business Media. pp. 181–. ISBN 978-3-540-46911-7.
  280. James Barrett (2007). Transsexual and Other Disorders of Gender Identity: A Practical Guide to Management. Radcliffe Publishing. p. 174. ISBN 978-1-85775-719-4.
  281. Barth JH, Cherry CA, Wojnarowska F, Dawber RP (July 1991). "Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study". Clinical Endocrinology. 35 (1): 5–10. doi:10.1111/j.1365-2265.1991.tb03489.x. PMID 1832346.
  282. Rushton DH (July 2002). "Nutritional factors and hair loss". Clinical and Experimental Dermatology. 27 (5): 396–404. doi:10.1046/j.1365-2230.2002.01076.x. PMID 12190640.
  283. Neumann F, Kalmus J (1991). "Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience". Experimental and Clinical Endocrinology. 98 (2): 71–80. doi:10.1055/s-0029-1211103. PMID 1838080.
  284. Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Elsevier Science. 1 December 2014. pp. 629–. ISBN 978-0-444-63391-0.
  285. 1 2 3 4 5 Furr BJ (June 1995). "Casodex: preclinical studies and controversies". Annals of the New York Academy of Sciences. 761 (1): 79–96. doi:10.1111/j.1749-6632.1995.tb31371.x. PMID 7625752.
  286. Aronson JK (2 March 2009). Meyler's Side Effects of Cardiovascular Drugs. Elsevier. pp. 253–258. ISBN 978-0-08-093289-7.
  287. Greenblatt DJ, Koch-Weser J (July 1973). "Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program". JAMA. 225 (1): 40–3. doi:10.1001/jama.1973.03220280028007. PMID 4740303.
  288. Munoz R, da Cruz E, Vetterly CG, et al. (26 June 2014). Handbook of Pediatric Cardiovascular Drugs. Springer. pp. 224–. ISBN 978-1-4471-2464-1.
  289. Katsambas A, Lotti T, Dessinioti C, D'Erme AM (28 April 2015). European Handbook of Dermatological Treatments. Springer. pp. 1460–. ISBN 978-3-662-45139-7.
  290. Bahceci M, Tuzcu A, Canoruc N, Tuzun Y, Kidir V, Aslan C (2004). "Serum C-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance". Hormone Research. 62 (6): 283–7. doi:10.1159/000081973. PMID 15542929.
  291. Cassel CK, Leipzig R, Cohen HJ, Larson EB, Meier DE (29 May 2006). Geriatric Medicine: An Evidence-Based Approach. Springer Science & Business Media. pp. 460–. ISBN 978-0-387-22621-7.
  292. d'Ancona FC, Debruyne FM (2005). "Endocrine approaches in the therapy of prostate carcinoma". Hum. Reprod. Update. 11 (3): 309–17. doi:10.1093/humupd/dmi004. PMID 15790600.
  293. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP (February 2006). "Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer". BJU International. 97 (2): 247–54. doi:10.1111/j.1464-410X.2005.06051.x. PMID 16430622.
  294. Orwell ES, Bilezikian JP, Vanderschueren D (30 November 2009). Osteoporosis in Men: The Effects of Gender on Skeletal Health. Academic Press. pp. 324–. ISBN 978-0-08-092346-8.
  295. Hanna L, Crosby T, Macbeth F (19 November 2015). Practical Clinical Oncology. Cambridge University Press. pp. 37–. ISBN 978-1-107-68362-4.
  296. Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP (July 2002). "Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor". The Journal of Biological Chemistry. 277 (29): 26321–6. doi:10.1074/jbc.M203310200. PMID 12015321.
  297. Waller AS, Sharrard RM, Berthon P, Maitland NJ (June 2000). "Androgen receptor localisation and turnover in human prostate epithelium treated with the antiandrogen, casodex". Journal of Molecular Endocrinology. 24 (3): 339–51. doi:10.1677/jme.0.0240339. PMID 10828827.
  298. 1 2 Butler SK, Govindan R (25 October 2010). Essential Cancer Pharmacology: The Prescriber's Guide. Lippincott Williams & Wilkins. pp. 49–. ISBN 978-1-60913-704-5.
  299. Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR (2007). "Estrogenic side effects of androgen deprivation therapy". Reviews in Urology. 9 (4): 163–80. PMC 2213888Freely accessible. PMID 18231613.
  300. Furr BJ (1996). "The development of Casodex (bicalutamide): preclinical studies". European Urology. 29 Suppl 2: 83–95. PMID 8717469.
  301. Christopher R. Chapple; William D. Steers (10 May 2011). Practical Urology: Essential Principles and Practice: Essential Principles and Practice. Springer Science & Business Media. pp. 225–. ISBN 978-1-84882-034-0. Normal reference ranges for serum total testosterone in adult men is generally considered to be 300–1,000 ng/dL (10–35 nmol/L).
  302. Vincenzo Gentile; Valeria Panebianco; Alessandro Sciarra (11 April 2014). Multidisciplinary Management of Prostate Cancer: The Role of the Prostate Cancer Unit. Springer Science & Business Media. pp. 106–. ISBN 978-3-319-04385-2. The standard castrate level is <50 ng/dl. It was defined more than 40 years ago, when testosterone level testing was limited. However, current testing methods using chemiluminescence have found that the mean value of testosterone after surgical castration is 15 ng/dl.
  303. 1 2 3 4 5 6 7 "COSUDEX® (bicalutamide) 150 mg tablets". TGA.
  304. 1 2 3 4 5 Denis L, Mahler C (January 1996). "Pharmacodynamics and pharmacokinetics of bicalutamide: defining an active dosing regimen". Urology. 47 (1A Suppl): 26–8; discussion 29–32. doi:10.1016/S0090-4295(96)80004-5. PMID 8560674.
  305. 1 2 Boccardo F, Rubagotti A, Conti G, Potenzoni D, Manganelli A, Del Monaco D (2005). "Exploratory study of drug plasma levels during bicalutamide 150 mg therapy co-administered with tamoxifen or anastrozole for prophylaxis of gynecomastia and breast pain in men with prostate cancer" (PDF). Cancer Chemotherapy and Pharmacology. 56 (4): 415–20. doi:10.1007/s00280-005-1016-1. PMID 15838655.
  306. 1 2 Leland W. K. Chung; William B. Isaacs; Jonathan W. Simons (10 November 2007). Prostate Cancer: Biology, Genetics, and the New Therapeutics. Springer Science & Business Media. pp. 365–. ISBN 978-1-59745-224-3.
  307. 1 2 3 4 Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM (30 November 2015). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 704–708,711,1104. ISBN 978-0-323-29738-7.
  308. 1 2 3 4 Eberhard Nieschlag; Hermann M. Behre (6 December 2012). Testosterone: Action - Deficiency - Substitution. Springer Science & Business Media. pp. 130,276. ISBN 978-3-642-72185-4.
  309. Ashraf Mozayani; Lionel Raymon (18 September 2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science & Business Media. pp. 656–. ISBN 978-1-61779-222-9.
  310. 1 2 3 Marcus R, Feldman D, Nelson D, Rosen CJ (8 November 2007). Osteoporosis. Academic Press. pp. 1354–. ISBN 978-0-08-055347-4.
  311. 1 2 Carrell DT, Peterson CM (23 March 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer Science & Business Media. pp. 163–. ISBN 978-1-4419-1436-1.
  312. 1 2 Bouchard P, Caraty A (15 November 1993). GnRH, GnRH Analogs, Gonadotropins and Gonadal Peptides. CRC Press. pp. 455–456. ISBN 978-0-203-09205-7. [...] when male levels of androgens are achieved in plasma, their effects on gonadotropin secretion are similar in women and men. [...] administration of flutamide in a group of normally-cycling women produced a clinical improvement of acne and hirsutism without any significant hormonal change. [...] All these data emphasize that physiological levels of androgens have no action on the regulation of gonadotropins in normal women. [...] Androgens do not directly play a role in gonadotropin regulation [in women].
  313. 1 2 DeVita Jr VT, Lawrence TS, Rosenberg SA (7 January 2015). DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. Wolters Kluwer Health. pp. 1142–. ISBN 978-1-4698-9455-3.
  314. 1 2 Eri LM, Haug E, Tveter KJ (March 1995). "Effects on the endocrine system of long-term treatment with the non-steroidal anti-androgen Casodex in patients with benign prostatic hyperplasia". British Journal of Urology. 75 (3): 335–40. doi:10.1111/j.1464-410X.1995.tb07345.x. PMID 7537602.
  315. Lunglmayr G (1989). "Casodex (ICI 176,334), a new, non-steroidal anti-androgen. Early clinical results". Hormone Research. 32 Suppl 1: 77–81. doi:10.1159/000181316. PMID 2515147.
  316. Bach, Phil Vu; Najari, Bobby B.; Kashanian, James A. (2016). "Adjunct Management of Male Hypogonadism". Current Sexual Health Reports. doi:10.1007/s11930-016-0089-7. ISSN 1548-3584.
  317. Santen RJ, Leonard JM, Sherins RJ, Gandy HM, Paulsen CA (1971). "Short- and long-term effects of clomiphene citrate on the pituitary-testicular axis". J. Clin. Endocrinol. Metab. 33 (6): 970–9. doi:10.1210/jcem-33-6-970. PMID 5135636. Increase in serum LH levels ranged from 200–700% during the initial 21 days of clomiphene administration but then plateaued. Serum FSH levels exhibited a similar plateau after 35 days, with maximum titers 70–360% over control. - See more at: The range in serum testosterone increments after 7 and 51 days of clomiphene administration was similar to that observed in serum gonadotrophin levels.
  318. Luciano Martini (2 December 2012). Clinical Neuroendocrinology. Elsevier. p. 239. ISBN 978-0-323-14429-2. From the studies of Santen et al. (1971), it seems that a longer period of administration (51 days in their study) would cause an even greater rise in FSH and LH (70–360% and 200–700%, respectively).
  319. Sieber PR (December 2007). "Treatment of bicalutamide-induced breast events". Expert Review of Anticancer Therapy. 7 (12): 1773–9. doi:10.1586/14737140.7.12.1773. PMID 18062751.
  320. Simpson ER, Jones ME (2007). "Of mice and men: the many guises of estrogens". Ernst Schering Foundation Symposium Proceedings. 2006/1 (1): 45–67. doi:10.1007/2789_2006_016. PMID 17824171.
  321. 1 2 Morali G, Oropeza MV, Lemus AE, Perez-Palacios G (September 1994). "Mechanisms regulating male sexual behavior in the rat: role of 3 alpha- and 3 beta-androstanediols". Biology of Reproduction. 51 (3): 562–71. doi:10.1095/biolreprod51.3.562. PMID 7803627.
  322. Sánchez Montoya EL, Hernández L, Barreto-Estrada JL, Ortiz JG, Jorge JC (November 2010). "The testosterone metabolite 3α-diol enhances female rat sexual motivation when infused in the nucleus accumbens shell". The Journal of Sexual Medicine. 7 (11): 3598–609. doi:10.1111/j.1743-6109.2010.01937.x. PMC 4360968Freely accessible. PMID 20646182.
  323. Frye CA, Edinger KL, Lephart ED, Walf AA (2010). "3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats". Frontiers in Aging Neuroscience. 2: 15. doi:10.3389/fnagi.2010.00015. PMC 2874398Freely accessible. PMID 20552051.
  324. Huang Q, Zhu H, Fischer DF, Zhou JN (June 2008). "An estrogenic effect of 5alpha-androstane-3beta, 17beta-diol on the behavioral response to stress and on CRH regulation". Neuropharmacology. 54 (8): 1233–8. doi:10.1016/j.neuropharm.2008.03.016. PMID 18457850.
  325. Frye CA, Koonce CJ, Edinger KL, Osborne DM, Walf AA (November 2008). "Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice". Hormones and Behavior. 54 (5): 726–34. doi:10.1016/j.yhbeh.2008.07.013. PMC 3623974Freely accessible. PMID 18775724.
  326. Orentreich N, Durr NP (1974). "Mammogenesis in Transsexuals". Journal of Investigative Dermatology. 63 (1): 142–6. doi:10.1111/1523-1747.ep12678272.
  327. 1 2 Strauss III JF, Barbieri RL (13 September 2013). Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. pp. 236–237. ISBN 978-1-4557-2758-2.
  328. Wilson CB, Nizet V, Maldonado Y, Klein JO, Remington JS (2015). Remington and Klein's Infectious Diseases of the Fetus and Newborn Infant. Elsevier Health Sciences. pp. 190–. ISBN 978-0-323-24147-2.
  329. Yen SS, Jaffe RB, Barbieri RL (2001). Endocrinología de la reproducción: fisiología, fisiopatología y manejo clínico. Ed. Medic Panamericana. pp. 303–. ISBN 978-950-06-2538-8.
  330. Pinsky L, Ericsson RP, Schimke RN (1999). Genetic Disorders of Human Sexual Development. Oxford University Press. pp. 215–. ISBN 978-0-19-510907-8.
  331. Wassersug RJ, Oliffe JL (April 2009). "The social context for psychological distress from iatrogenic gynecomastia with suggestions for its management". The Journal of Sexual Medicine. 6 (4): 989–1000. doi:10.1111/j.1743-6109.2008.01053.x. PMID 19175864. By themselves, the LH-RH agonists do not produce much gynecomastia (ie, estimates as low as 4.4%) [13], but in conjunction with the typically prescribed antiandrogens (flutamide, bicalutamide, and nilutamide), gynecomastia is more common (49–68%) [13].
  332. 1 2 Lawrence AA (2006). "Transgender Health Concerns". In Meyer IH, Northridge ME. The Health of Sexual Minorities Public Health Perspectives on Lesbian, Gay, Bisexual and Transgender Populations. New York: Springer. p. 476. doi:10.1007/978-0-387-31334-4_19. ISBN 978-0-387-28871-0.
  333. 1 2 Rosen PP (2009). Rosen's Breast Pathology (3 ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 31–. ISBN 978-0-7817-7137-5.
  334. Lorincz AM, Sukumar S (2006). "Molecular links between obesity and breast cancer". Endocrine-related Cancer. 13 (2): 279–92. doi:10.1677/erc.1.00729. PMID 16728564. Adipocytes make up the bulk of the human breast, with epithelial cells accounting for only approximately 10% of human breast volume.
  335. Howard BA, Gusterson BA (2000). "Human breast development". Journal of Mammary Gland Biology and Neoplasia. 5 (2): 119–37. PMID 11149569. In the stroma, there is an increase in the amount of fibrous and fatty tissue, with the adult nonlactating breast consisting of 80% or more of stroma.
  336. Sperling MA (10 April 2014). Pediatric Endocrinology. Elsevier Health Sciences. pp. 598–. ISBN 978-1-4557-5973-6. Estrogen stimulates the nipples to grow, mammary terminal duct branching to progress to the stage at which ductules are formed, and fatty stromal growth to increase until it constitutes about 85% of the mass of the breast. [...] Lobulation appears around menarche, when multiple blind saccular buds form by branching of the terminal ducts. These effects are due to the presence of progesterone. [...] Full alveolar development normally only occurs during pregnancy under the influence of additional progesterone and prolactin.
  337. Hagisawa S, Shimura N, Arisaka O (2012). "Effect of excess estrogen on breast and external genitalia development in growth hormone deficiency". Journal of Pediatric and Adolescent Gynecology. 25 (3): e61–3. doi:10.1016/j.jpag.2011.11.005. PMID 22206682. Estrogen stimulates growth of the nipples, progression of mammary duct branching to the stage at which ductiles are formed, and fatty stromal growth until it constitutes about 85% of the mass of the breast.
  338. 1 2 J. Aiman (6 December 2012). Infertility: Diagnosis and Management. Springer Science & Business Media. pp. 182–. ISBN 978-1-4613-8265-2.
  339. Kroemer RW (2009). The Reproductive System. Infobase Publishing. pp. 51–. ISBN 978-1-4381-3083-5.
  340. Fody EP, Walker EM (1985). "Effects of drugs on the male and female reproductive systems". Ann. Clin. Lab. Sci. 15 (6): 451–8. PMID 4062226.
  341. Liu YX (2005). "Control of spermatogenesis in primate and prospect of male contraception". Arch. Androl. 51 (2): 77–92. doi:10.1080/01485010490485768. PMID 15804862.
  342. Cheng CY, Wong EW, Yan HH, Mruk DD (2010). "Regulation of spermatogenesis in the microenvironment of the seminiferous epithelium: new insights and advances". Mol. Cell. Endocrinol. 315 (1-2): 49–56. doi:10.1016/j.mce.2009.08.004. PMC 3516447Freely accessible. PMID 19682538.
  343. Schill W, Comhaire FH, Hargreave TB (26 August 2006). Andrology for the Clinician. Springer Science & Business Media. pp. 76–. ISBN 978-3-540-33713-3.
  344. 1 2 Cheng C (24 October 2009). Molecular Mechanisms in Spermatogenesis. Springer Science & Business Media. pp. 258–. ISBN 978-0-387-09597-4.
  345. Johnson LR (14 October 2003). Essential Medical Physiology. Academic Press. pp. 731–. ISBN 978-0-08-047270-6.
  346. Mulhall JP (21 February 2013). Fertility Preservation in Male Cancer Patients. Cambridge University Press. pp. 84–. ISBN 978-1-139-61952-3.
  347. Khursheed A, Minhas LA, Diaz WA (September 2011). "Histomorphometric study of effects of bicalutamide on spermatogenesis in male rats" (PDF). Pakistan Armed Forces Medical Journal (3).
  348. 1 2 Dohle GR, Smit M, Weber RF (November 2003). "Androgens and male fertility". World Journal of Urology. 21 (5): 341–5. doi:10.1007/s00345-003-0365-9. PMID 14566423.
  349. 1 2 Basu SC (15 December 2011). Male Reproductive Dysfunction. Jaypee Brothers Medical Publishers Pvt. Ltd. pp. 323–. ISBN 978-93-5025-703-6.
  350. 1 2 Jones, C. A.; Reiter, L.; Greenblatt, E. (2016). "Fertility preservation in transgender patients". International Journal of Transgenderism. 17 (2): 76–82. doi:10.1080/15532739.2016.1153992. ISSN 1553-2739. Traditionally, patients have been advised to cryopreserve sperm prior to starting cross-sex hormone therapy as there is a potential for a decline in sperm motility with high-dose estrogen therapy over time (Lubbert et al., 1992). However, this decline in fertility due to estrogen therapy is controversial due to limited studies.
  351. 1 2 3 4 5 6 Anita H. Payne; Matthew P. Hardy (28 October 2007). The Leydig Cell in Health and Disease. Springer Science & Business Media. pp. 422–431. ISBN 978-1-59745-453-7. Estrogens are highly efficient inhibitors of the hypothalamic-hypophyseal-testicular axis (212–214). Aside from their negative feedback action at the level of the hypothalamus and pituitary, direct inhibitory effects on the testis are likely (215,216). [...] The histology of the testes [with estrogen treatment] showed disorganization of the seminiferous tubules, vacuolization and absence of lumen, and compartmentalization of spermatogenesis.
  352. Sarah H. Wakelin; Howard I. Maibach; Clive B. Archer (1 June 2002). Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. pp. 32–. ISBN 978-1-84076-013-2. [Cyproterone acetate] inhibits spermatogenesis and produces reversible infertility (but is not a male contraceptive).
  353. 1 2 Neumann F (1994). "The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research". Exp. Clin. Endocrinol. 102 (1): 1–32. doi:10.1055/s-0029-1211261. PMID 8005205. Spermatogenesis is also androgen-dependent and is inhibited by CPA, meaning that patients treated with high doses of CPA are sterile (Figure 23). All the effects of CPA are fully reversible.
  354. 1 2 Muhammad A. Salam (2003). Principles & Practice of Urology: A Comprehensive Text. Universal-Publishers. pp. 684–. ISBN 978-1-58112-412-5. Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce LH secretion and testicular androgen synthesis. [...] Interestingly, if the treatment with estrogens is discontinued after 3 yr. of uninterrupted exposure, serum testosterone may remain at castration levels for up to another 3 yr. This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells.
  355. 1 2 3 Bambury RM, Scher HI (June 2015). "Enzalutamide: Development from bench to bedside". Urologic Oncology. 33 (6): 280–8. doi:10.1016/j.urolonc.2014.12.017. PMID 25797385.
  356. Bambury RM, Rathkopf DE (August 2016). "Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide". Urologic Oncology. 34 (8): 348–55. doi:10.1016/j.urolonc.2015.05.025. PMID 26162486.
  357. 1 2 Pinto Á (February 2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biology & Therapy. 15 (2): 149–55. doi:10.4161/cbt.26724. PMC 3928129Freely accessible. PMID 24100689.
  358. 1 2 3 Mast N, Lin JB, Pikuleva IA (September 2015). "Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy". Molecular Pharmacology. 88 (3): 428–36. doi:10.1124/mol.115.099598. PMID 26082378.
  359. Mast N, Zheng W, Stout CD, Pikuleva IA (February 2013). "Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response". The Journal of Biological Chemistry. 288 (7): 4613–24. doi:10.1074/jbc.M112.438754. PMC 3576067Freely accessible. PMID 23288837.
  360. 1 2 Zhu Y, Liu C, Armstrong C, Lou W, Sandher A, Gao AC (September 2015). "Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer". Clinical Cancer Research. 21 (18): 4133–42. doi:10.1158/1078-0432.CCR-15-0269. PMID 25995342.
  361. 1 2 Fenner A (July 2015). "Prostate cancer: Antiandrogens reverse docetaxel resistance via ABCB1 inhibition". Nature Reviews. Urology. 12 (7): 361. doi:10.1038/nrurol.2015.135. PMID 26057062.
  362. 1 2 Armstrong CM, Gao AC (2015). "Drug resistance in castration resistant prostate cancer: resistance mechanisms and emerging treatment strategies". American Journal of Clinical and Experimental Urology. 3 (2): 64–76. PMC 4539108Freely accessible. PMID 26309896.
  363. Barrish J, Carter P, Cheng P (2010). Accounts in Drug Discovery: Case Studies in Medicinal Chemistry. Royal Society of Chemistry. pp. 127–. ISBN 978-1-84973-126-3.
  364. Kolvenbag GJ, Blackledge GR, Gotting-Smith K (January 1998). "Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development". The Prostate. 34 (1): 61–72. doi:10.1002/(SICI)1097-0045(19980101)34:1<61::AID-PROS8>3.0.CO;2-N. PMID 9428389.
  365. 1 2 Chu E, DeVita Jr VT (28 December 2012). Physicians' Cancer Chemotherapy Drug Manual 2013. Jones & Bartlett Publishers. pp. 51–. ISBN 978-1-284-04039-5.
  366. Beale C, Collins P (15 May 1996). The Cardioprotective Role of HRT: A Clinical Update. CRC Press. pp. 14–. ISBN 978-1-85070-740-0.
  367. Furr BJ (1989). ""Casodex" (ICI 176,334)--a new, pure, peripherally-selective anti-androgen: preclinical studies". Hormone Research. 32 Suppl 1 (1): 69–76. doi:10.1159/000181315. PMID 2533159.
  368. Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". The Journal of Endocrinology. 113 (3): R7–9. doi:10.1677/joe.0.113R007. PMID 3625091.
  369. Soloway MS, Schellhammer PF, Smith JA, Chodak GW, Vogelzang NJ, Kennealey GT (December 1995). "Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II noncomparative multicenter trial evaluating safety, efficacy and long-term endocrine effects of monotherapy". The Journal of Urology. 154 (6): 2110–4. doi:10.1016/S0022-5347(01)66709-0. PMID 7500470.
  370. Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Scientific Reports. 5: 12007. doi:10.1038/srep12007. PMC 4490394Freely accessible. PMID 26137992.
  371. Anderson PO, Knoben JE, Troutman WG (22 August 2001). Handbook of Clinical Drug Data. McGraw Hill Professional. p. 245. ISBN 978-0-07-138942-6. With an oral dose of 50 mg/day, bicalutamide attains a peak serum level of 8.9 mg/L (21 μmol/L) 31 hr after a dose at steady state. CI of (R)-bicalutamide is 0.32 L/hr. The active (R)-enantiomer of bicalutamide is oxidized to an inactive metabolite, which, like the inactive (S)-enantiomer, is glucuronidated and cleared rapidly by elimination in the urine and feces.165
  372. Sharma K, Pawar GV, Giri S, Rajagopal S, Mullangi R (2012). "Development and validation of a highly sensitive LC-MS/MS-ESI method for the determination of bicalutamide in mouse plasma: application to a pharmacokinetic study". Biomedical Chromatography : BMC. 26 (12): 1589–95. doi:10.1002/bmc.2736. PMID 22495777.
  373. Lukasz Komsta; Monika Waksmundzka-Hajnos; Joseph Sherma (20 December 2013). Thin Layer Chromatography in Drug Analysis. CRC Press. pp. 652–. ISBN 978-1-4665-0715-9.
  374. Sancheti PP, Vyas VM, Shah M, Karekar P, Pore YV (2008). "Spectrophotometric estimation of bicalutamide in tablets". Indian Journal of Pharmaceutical Sciences. 70 (6): 810–2. doi:10.4103/0250-474X.49131. PMC 3040883Freely accessible. PMID 21369450.
  375. 1 2 3 Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD (June 2009). "Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit". Journal of Medicinal Chemistry. 52 (12): 3597–617. doi:10.1021/jm900280m. PMID 19432422. [C]linically relevant antiandrogens currently are nonsteroidal anilide derivatives. Antiandrogens used for prostate cancer include the monoarylpropionamide flutamide (1) (a prodrug of hydroxyflutamide (2)),29-31 the hydantoin nilutamide(3),32-34 and the diarylpropionamide bicalutamide (4) (Chart1).35-37
  376. 1 2 Hermkens PH, Kamp S, Lusher S, Veeneman GH (July 2006). "Non-steroidal steroid receptor modulators". IDrugs. 9 (7): 488–94. PMID 16821162.
  377. Marc R. Avram; Nicole E. Rogers (30 November 2009). Hair Transplantation. Cambridge University Press. pp. 11–. ISBN 978-1-139-48339-1.
  378. Kawahara T, Minamoto H (2014). "Androgen Receptor Antagonists in the Treatment of Prostate Cancer". Clinical Immunology, Endocrine & Metabolic Drugs. 1 (1): 11–19. doi:10.2174/22127070114019990002.
  379. Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Sci Rep. 5: 12007. doi:10.1038/srep12007. PMC 4490394Freely accessible. PMID 26137992.
  380. 1 2 3 Segal S, Narayanan R, Dalton JT (April 2006). "Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery". Expert Opinion on Investigational Drugs. 15 (4): 377–87. doi:10.1517/13543784.15.4.377. PMID 16548787. Structural modifications of bicalutamide led to the discovery of the first nonsteroidal androgens (the aryl propionamides) in 1998. Lead compounds in this class (denoted S1 and S4 in published literature) not only bind to the AR with high affinity (low nanomolar range), but also demonstrate tissue selectivity in animal models [46,50].
  381. Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT (March 2003). "Pharmacodynamics of selective androgen receptor modulators". The Journal of Pharmacology and Experimental Therapeutics. 304 (3): 1334–40. doi:10.1124/jpet.102.040840. PMC 2040238Freely accessible. PMID 12604714.
  382. Eckhard Ottow; Hilmar Weinmann (8 September 2008). Nuclear Receptors as Drug Targets. John Wiley & Sons. pp. 257–258. ISBN 978-3-527-62330-3.
  383. 1 2 Tucker H, Crook JW, Chesterson GJ (1988). "Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides". Journal of Medicinal Chemistry. 31 (5): 954–9. doi:10.1021/jm00400a011. PMID 3361581.
  384. James KD, Ekwuribe NN (2002). "A Two-step Synthesis of the Anti-cancer Drug (R,S)-Bicalutamide". Synthesis. 2002 (7): 850–2. doi:10.1055/s-2002-28508.
  385. US application 2006/0041161, Pizzetti E, Vigano E, Lussana M, Landonio E, "Procedure for the synthesis of bicalutamide", published 23 February 2006
  386. Chand M, Shukla AK (2012). "Novel Synthesis of Bicalutamide Drug Substance and their Impurities using Imidazolium Type of Ionic Liquid". SSRN Electronic Journal. doi:10.2139/ssrn.2160199.
  387. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 573–. ISBN 978-1-4757-2085-3.
  388. Cadilla R, Turnbull P (2006). "Selective androgen receptor modulators in drug discovery: medicinal chemistry and therapeutic potential". Curr Top Med Chem. 6 (3): 245–70. doi:10.2174/156802606776173456. PMID 16515480.
  389. Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". The Journal of Endocrinology. 113 (3): R7–9. doi:10.1677/joe.0.113r007. PMID 3625091.
  390. Newling DW (1990). "The response of advanced prostatic cancer to a new non-steroidal antiandrogen: results of a multicenter open phase II study of Casodex. European/Australian Co-operative Group". European Urology. 18 Suppl 3: 18–21. PMID 2094607.
  391. The United States Patents Quarterly. Associated Industry Publications. 1997.
  392. Gohil K (August 2015). "Exciting Therapies Ahead in Prostate Cancer". P & T. 40 (8): 530–1. PMC 4517537Freely accessible. PMID 26236143.
  393. Carswell CI, Figgitt DP (2002). "Bicalutamide: in early-stage prostate cancer". Drugs. 62 (17): 2471–79; discussion 2480–1. doi:10.2165/00003495-200262170-00006. PMID 12421104.