Bicalutamide Explained

Verifiedfields:verified
Watchedfields:verified
Verifiedrevid:459978482
Width:250
Width2:250
Pronounce:Bicalutamide:
• [1]
•
Tradename:Casodex, Calutex, others
Dailymedid:Bicalutamide
Licence Us:Bicalutamide
Pregnancy Au:D
Routes Of Administration:By mouth
Class:Nonsteroidal antiandrogen
Atc Prefix:L02
Atc Suffix:BB03
Legal Au:S4
Legal Uk:POM
Legal Us:Rx-only
Legal Status:Rx-only
Bioavailability:Well-absorbed; absolute bioavailability unknown
Protein Bound:Racemate

96.1%
(R)-Isomer: 99.6%
(Mainly to albumin)

Metabolism:Liver (extensively):[2]
• Hydroxylation (CYP3A4)
• Glucuronidation (UGT1A9)
Metabolites:• Bicalutamide glucuronide
• Hydroxybicalutamide
• Hydroxybicalutamide
(All inactive)[3] [4] [5]
Onset:Unknown[6] -->
Elimination Half-Life:Single-dose: 5.8 days
Continuous: 7–10 days
Duration Of Action:Unknown -->
Excretion:Feces

43%
Urine: 34%

Cas Number:90357-06-5
Cas Supplemental:
113299-40-4 ((R)-isomer)
113299-38-0 ((S)-isomer)
Pubchem:2375
Iuphar Ligand:2863
Drugbank:DB01128
Chemspiderid:2284
Unii:A0Z3NAU9DP
Kegg:C08160
Chebi:91617
Chembl:409
Pdb Ligand:198
Synonyms:ICI-176,334; ZD-176,334
Iupac Name:(RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide
C:18
H:14
F:4
N:2
O:4
S:1
Chirality:Racemic mixture (of (R)- and (S)-enantiomers)
Smiles:CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Stdinchi:1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25)
Stdinchikey:LKJPYSCBVHEWIU-UHFFFAOYSA-N
Melting Point:191
Melting High:193
Melting Notes:(experimental)
Boiling Point:650
Boiling Notes:(predicted)
Solubility:0.005

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer.[7] It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC).[8] [7] [9] To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women,[10] [11] as a puberty blocker and component of feminizing hormone therapy for transgender girls and women,[12] to treat gonadotropin-independent early puberty in boys,[13] and to prevent overly long-lasting erections in men.[14] It is taken by mouth.

Common side effects of bicalutamide in men include breast growth, breast tenderness, and hot flashes. Other side effects in men include feminization and sexual dysfunction.[15] [16] Some side effects like breast changes and feminization are minimal when combined with castration.[17] While the medication appears to produce few side effects in women, its use in women is not explicitly approved by the Food and Drug Administration (FDA) at this time.[18] [7] Use during pregnancy may harm the baby. In men with early prostate cancer, bicalutamide monotherapy has been found to increase the likelihood of death from causes other than prostate cancer. Bicalutamide produces abnormal liver changes necessitating discontinuation in around 1% of people.[19] [20] Rarely, it has been associated with cases of serious liver damage, serious lung toxicity, and sensitivity to light.[21] [22] Although the risk of adverse liver changes is small, monitoring of liver function is recommended during treatment.

Bicalutamide is a member of the nonsteroidal antiandrogen (NSAA) group of medications.[23] It works by selectively blocking the androgen receptor (AR), the biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT).[24] It does not lower androgen levels. The medication can have some estrogen-like effects in men when used as a monotherapy due to increased estradiol levels.[25] Bicalutamide is well-absorbed, and its absorption is not affected by food. The elimination half-life of the medication is around one week. It shows peripheral selectivity in animals, but crosses the blood–brain barrier and affects both the body and brain in humans.

Bicalutamide was patented in 1982 and approved for medical use in 1995.[26] It is on the World Health Organization's List of Essential Medicines.[27] Bicalutamide is available as a generic medication.[28] The drug is sold in more than 80 countries, including most developed countries.[29] [30] [31] It was at one time the most widely used antiandrogen in the treatment of prostate cancer, with millions of men with the disease having been prescribed it.[32] [33] [34] Although bicalutamide is also used for other indications besides prostate cancer, the vast majority of prescriptions appear to be for treatment of prostate cancer.

Medical uses

See main article: Medical uses of bicalutamide.

Bicalutamide is approved for and mainly used in the following indications:

In Japan, bicalutamide is uniquely used at a dosage of 80 mg/day both in combination with castration and as a monotherapy in the treatment of prostate cancer.

Bicalutamide is also employed for the following off-label (non-approved) indications:

The medication has been suggested for but has uncertain effectiveness in the following indication:

For more information on these uses, see the medical uses of bicalutamide article.

Available forms

Bicalutamide is available for the treatment of prostate cancer in most developed countries,[65] [29] [66] including over 80 countries worldwide.[30] [31] It is available in 50 mg, 80 mg (in Japan),[67] and 150 mg tablets for oral administration.[68] [69] The drug is registered for use as a 150 mg/day monotherapy for the treatment of in at least 55 countries, with the being a notable exception where it is registered only for use at a dosage of 50 mg/day in combination with castration.[70] No other formulations or routes of administration are available or used. All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration. Due to the low water solubility of bicalutamide, bicalutamide in oral bicalutamide tablets is micronized to ensure small and consistent particle sizes and optimize oral bioavailability.[71]

A combined formulation of bicalutamide and the 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).[72] [73] [74]

Contraindications

Bicalutamide is pregnancy category X, or "contraindicated in pregnancy", in the, and pregnancy category D, the second most restricted rating, in Australia. As such, it 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 adequate contraception. It is unknown whether bicalutamide is excreted in breast milk, but many drugs are excreted in breast milk, and for this reason, bicalutamide treatment is similarly not recommended while breastfeeding.

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 as circulating levels of bicalutamide may be increased.[75] In severe hepatic impairment, the elimination half-life of the active (R)-enantiomer of bicalutamide is increased by about 1.75-fold (76% increase; elimination half-life of 5.9 and 10.4 days for normal and impaired patients, respectively).[76] [77] The elimination half-life of bicalutamide is unchanged in renal impairment.

Side effects

See main article: Side effects of bicalutamide.

The side effect profile of bicalutamide is highly dependent on sex; that is, on whether the person is male or female. In men, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia (breast development/enlargement) being the most common.[78] [79] Gynecomastia occurs in up to 80% of men treated with bicalutamide monotherapy, and is of mild-to-moderate severity in more than 90% of affected men.[80] In addition to breast changes, physical feminization and demasculinization in general, including reduced body hair growth, decreased muscle mass and strength, feminine changes in fat mass and distribution, reduced penile length, and decreased semen/ejaculate volume, may occur in men.[81] [82] Other side effects that have been observed in men and that are similarly related to androgen deprivation include hot flashes, sexual dysfunction (e.g., loss of libido, erectile dysfunction), depression, fatigue, weakness, and anemia.[83] [84] However, most men have preserved sexual function with bicalutamide monotherapy. In females, due to the minimal biological importance of androgens in this sex,[85] [86] the side effects of pure antiandrogens or are few, and bicalutamide has been found to be very well tolerated. However, bicalutamide has been found to increase levels of total and LDL cholesterol in women.[87] [88] The non-pharmacological side-effect profile of bicalutamide (i.e., side effects not related to its antiandrogenic activity) is said to be similar to that with placebo.[89] In any case, general side effects of bicalutamide that might occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.[90] [91] [92] [93] The drug is well-tolerated at higher dosages than 50 mg/day, up to 600mg/day, with rare additional side effects.[94] [95]

Bicalutamide has been associated with abnormal liver function tests such as elevated liver enzymes. In the Early Prostate Cancer (EPC) clinical programme of bicalutamide for and, the rate of abnormal liver function tests with bicalutamide monotherapy was 3.4% relative to 1.9% for placebo.[96] However, higher rates, up to 11%, have been seen in other studies. Hepatic changes that have necessitated discontinuation of bicalutamide, such as marked increases in liver enzymes or hepatitis, have occurred in 0.3 to 1.5% of men in clinical trials, or approximately 1% overall.[97] Elevated liver enzymes with bicalutamide usually occur within the first 3 to 6 months of treatment. Monitoring of liver function during treatment is recommended, particularly in the first few months. In men with early prostate cancer, bicalutamide monotherapy has been found to increase non-prostate cancer mortality.[98] [99] The reasons for the increase in mortality with bicalutamide in these men are unknown, but possible factors could include androgen deprivation or drug-related toxicity of bicalutamide.[100] [101]

There are 10 published case reports of liver toxicity associated with bicalutamide as of 2022.[102] [103] [104] [105] Death occurred in 2 of these cases.[106] [107] Hundreds of additional cases of liver complications in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database.[108] In all of the published case reports of liver toxicity with bicalutamide, the onset of symptoms was within the first 6 months of treatment. Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice. There are also published case reports of interstitial pneumonitis and eosinophilic lung disease associated with bicalutamide.[109] [110] [111] along with hundreds of additional instances in the FAERS database as well. Interstitial pneumonitis can potentially progress to pulmonary fibrosis and may be fatal. Symptoms that may indicate lung dysfunction include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat).[112] The exact incidence of liver toxicity and interstitial pneumonitis with bicalutamide are unknown, but both are said to be very rare events.[113] [114] A few cases of photosensitivity have been reported with bicalutamide. Hypersensitivity reactions (drug allergy) like angioedema and hives have also uncommonly been reported in association with bicalutamide.

Because it is an antiandrogen, bicalutamide has a theoretical risk of birth defects like ambiguous genitalia in male fetuses.[115] [116] [117] [118] Due to its teratogenic capacity, contraception should be used in women taking bicalutamide who are fertile and sexually active.[119]

Comparison

See also: Comparison of bicalutamide with other antiandrogens.

The side effect profile of bicalutamide in men and women differs from that of other antiandrogens and is considered favorable in comparison.[120] [121] [122] [123] Relative to analogues and the steroidal antiandrogen (SAA) cyproterone acetate (CPA), bicalutamide monotherapy has a much lower incidence and severity of hot flashes and sexual dysfunction.[124] In addition, unlike analogues and, bicalutamide monotherapy is not associated with decreased bone mineral density or osteoporosis. Conversely, bicalutamide monotherapy is associated with much higher rates of breast tenderness, gynecomastia, and feminization in men than analogues and . However, gynecomastia with bicalutamide is rarely severe and discontinuation rates due to this side effect are fairly low. These differences in side effects between bicalutamide monotherapy, analogues, and are attributed to the fact that whereas analogues and suppress estrogen production, bicalutamide monotherapy does not lower estrogen levels and in fact actually increases them.

Bicalutamide does not share the risk of neuropsychiatric side effects like fatigue as well as cardiovascular side effects like coagulation changes, blood clots, fluid retention, ischemic cardiomyopathy, and adverse serum lipid changes that has been associated with.[125] [126] [127] It has a much lower risk of hepatotoxicity than flutamide and and of interstitial pneumonitis than nilutamide.[128] [129] [130] [131] The drug also does not share the unique risks of diarrhea with flutamide and nausea, vomiting, visual disturbances, and alcohol intolerance with nilutamide. Unlike enzalutamide, bicalutamide is not associated with seizures or related central side effects like anxiety and insomnia.[132] [133] However, although the risk of adverse liver changes with bicalutamide is low, enzalutamide differs from bicalutamide in having no known risk of elevated liver enzymes or hepatotoxicity.[134] [135] In contrast to the spironolactone, bicalutamide does not have antimineralocorticoid effects,[136] and hence is not associated with hyperkalemia, urinary frequency, dehydration, hypotension, or other related side effects.[137] [138] [139] In women, unlike and spironolactone, bicalutamide does not produce menstrual irregularity or amenorrhea and does not interfere with ovulation or fertility.[38] [140]

Overdose

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.[141] Dosages of up to 600 mg/day have been well tolerated in clinical trials, 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. Overdose is considered unlikely to be life-threatening with bicalutamide or other first-generation (i.e., flutamide and nilutamide).[142] 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, symptoms, or toxicity.[143] There is no specific antidote for bicalutamide or overdose, and treatment should be based on symptoms, if any are present.

Interactions

Bicalutamide is almost exclusively metabolized by CYP3A4. As such, its levels in the body may be altered by inhibitors and inducers of CYP3A4.[144] (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.

In-vitro studies suggest that bicalutamide may be able to inhibit CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6. Conversely, animal studies suggest that bicalutamide may induce cytochrome P450 enzymes. In a clinical study, bicalutamide co-administered with the CYP3A4 substrate midazolam caused only a small and statistically non-significant increase in midazolam levels (+27%) presumably due to CYP3A4 inhibition. However, this was well below increases in midazolam exposure with potent CYP3A4 inhibitors like ketoconazole (+1500%), itraconazole (+1000%), and erythromycin (+350%), and is considered to not be clinically important. There is no indication of clinically significant enzyme inhibition or induction with bicalutamide at doses of 150mg/day or below.

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. This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments. 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.[145] [146] [147] 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.

Pharmacology

Pharmacodynamics

Antiandrogenic activity

Bicalutamide acts as a highly selective competitive silent antagonist of the (= 159–243 nM), the major biological target of the androgen sex hormones testosterone and, and hence is an antiandrogen.[148] [149] [150] The activity of bicalutamide lies in the (R)-isomer. Due to its selectivity for the, bicalutamide does not interact importantly with other steroid hormone receptors and hence has no clinically relevant off-target hormonal activity (e.g., progestogenic, estrogenic, glucocorticoid, antimineralocorticoid).[151] [152] [153] [154] However, it has been reported that bicalutamide has weak affinity for the progesterone receptor (PR), where it is an antagonist, and hence it could have some antiprogestogenic activity.[155] Bicalutamide does not inhibit 5α-reductase nor is known to inhibit other enzymes involved in androgen steroidogenesis (e.g., CYP17A1). Although it does not bind to the estrogen receptors (ERs), bicalutamide can increase estrogen levels secondarily to blockade when used as a monotherapy in males, and hence can have some indirect estrogenic effects in males.[156] Bicalutamide neither suppresses nor inhibits androgen production in the body (i.e., it does not act as an antigonadotropin or androgen steroidogenesis inhibitor or lower androgen levels) and hence exclusively mediates its antiandrogenic effects by antagonizing the . In addition to the classical nuclear, bicalutamide has been assessed at the membrane androgen receptors (mARs) and found to act as a potent antagonist of ZIP9 (= 66.3 nM), whereas it does not appear to interact with GPRC6A.[157] [158]

The affinity of bicalutamide for the is relatively low as it is approximately 30 to 100 times lower than that of, which is 2.5- to 10-fold as potent as an agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland.[159] [160] However, typical clinical dosages of bicalutamide result in circulating levels of the drug that are thousands of times higher than those of testosterone and, allowing it to powerfully prevent them from binding to and activating the receptor.[161] [162] [163] [164] This is especially true in the case of surgical or medical castration, in which testosterone levels in the circulation are approximately 95% reduced and levels in the prostate gland are about 50 to 60% reduced.[165] In women, levels of testosterone are substantially lower (20- to 40-fold) than in men,[166] so much smaller doses of bicalutamide (e.g., 25 mg/day in the hirsutism studies) are necessary.[167]

Blockade of the by bicalutamide in the pituitary gland and hypothalamus results in prevention of the negative feedback of androgens on the hypothalamic–pituitary–gonadal axis (HPG axis) in males and consequent disinhibition of pituitary luteinizing hormone (LH) secretion.[168] This, in turn, results in an increase in circulating levels and activation of the gonadal production of testosterone and by extension production of estradiol.[169] Levels of testosterone have been found to increase 1.5- to 2-fold (59–97% increase) and levels of estradiol about 1.5- to 2.5-fold (65–146% increase) in men treated with 150 mg/day bicalutamide monotherapy.[170] [171] In addition to testosterone and estradiol, there are smaller increases in concentrations of, sex hormone-binding globulin, and prolactin. Estradiol levels with bicalutamide monotherapy are similar to those in the low-normal premenopausal female range while testosterone levels generally remain in the high end of the normal male range.[172] Testosterone concentrations do not typically exceed the normal male range due to negative feedback on the axis by the increased concentrations of estradiol. Bicalutamide influences the axis and increases hormone levels only in men and not also in women.[173] [174] [175] This is due to the much lower levels of androgens in women and their lack of basal suppression of the axis in this sex. As evidenced by its effectiveness in the treatment of prostate cancer and other androgen-dependent conditions, the antiandrogenic actions of bicalutamide considerably exceed any impact of the increased levels of testosterone it results in. However, the elevated levels of estradiol remain unopposed by bicalutamide and are responsible for the gynecomastia and feminizing side effects it causes in men.[176] Although bicalutamide monotherapy increases gonadotropin and sex hormone levels in men, this will not occur if bicalutamide is combined with an antigonadotropin such as a analogue, estrogen, or progestogen, as these medications maintain negative feedback on the HPG axis.[177] [178] [179]

monotherapy, including with bicalutamide, shows a number of tolerability differences from methods of androgen deprivation therapy that incorporate surgical or medical castration. For example, the rates of hot flashes, depression, fatigue, and sexual dysfunction are all much higher with analogues than with monotherapy. It is thought that this is because analogues suppress estrogen production in addition to androgen production, resulting in estrogen deficiency.[180] [181] [182] In contrast, monotherapy does not decrease estrogen levels and in fact increases them, resulting in an excess of estrogens that compensates for androgen deficiency and allows for a preservation of mood, energy, and sexual function. Neurosteroids that are produced from testosterone like 3α-androstanediol and 3β-androstanediol, which are agonists and the former a potent GABAA receptor positive allosteric modulator, may also be involved.[183] [184] [185] [186] [187] [188] [189] In the specific case of sexual dysfunction, an additional possibility for the difference is that without concomitant suppression of androgen production, blockade of the by the bicalutamide in the brain is incomplete and insufficient to markedly influence sexual function.

Under normal circumstances, bicalutamide has no capacity to activate the .[190] [191] However, in prostate cancer, mutations and overexpression of the can accumulate in prostate gland cells which can convert bicalutamide from an antagonist of the into an agonist.[192] This can result in paradoxical stimulation of prostate cancer growth with bicalutamide and is responsible for the phenomenon of the antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of prostate cancer growth.

In transgender women, breast development is a desired effect of antiandrogen or estrogen treatment.[193] Breast development and gynecomastia induced by bicalutamide is thought to be mediated by increased activation of the secondary to blockade of the (resulting in disinhibition of the in breast tissue) and increased levels of estradiol.[194] [195] In addition to fat deposition, connective tissue growth, and ductal development, bicalutamide has been found to produce moderate lobuloalveolar development of the breasts.[196] [197] [198] However, full lobuloalveolar maturation necessary for lactation and breastfeeding will not occur without progestogen treatment.

Bicalutamide monotherapy seems to have minimal effect on testicular spermatogenesis, testicular ultrastructure, and certain aspects of male fertility.[199] [200] This seems to be because testosterone levels in the testes (where ~95% of testosterone in males is produced) are extremely high (up to 200-fold higher than circulating levels) and only a small fraction (less than 10%) of the normal levels of testosterone in the testes are actually necessary to maintain spermatogenesis.[201] [202] [203] As a result, bicalutamide appears to not be able to compete with testosterone in this sole part of the body to an extent sufficient to considerably interfere with androgen signaling and function. However, while bicalutamide does not seem to be able to adversely influence testicular spermatogenesis, it may interfere with -dependent sperm maturation and transport outside of the testes in the epididymides and vas deferens where androgen levels are far lower, and hence may still be able to impair male fertility.[204] In addition, the combination of bicalutamide with other medications, such as estrogens, progestogens, and analogues, can compromise spermatogenesis due to their own adverse effects on male fertility.[205] [206] [207] [208] [209] [210] These medications are able to strongly suppress gonadal androgen production, which can severely impair or abolish testicular spermatogenesis, and estrogens also appear to have direct and potentially long-lasting cytotoxic effects in the testes at sufficiently high concentrations.

Other activities

Bicalutamide has been found to act as an inhibitor or inducer of certain cytochrome P450 enzymes including CYP3A4, CYP2C9, CYP2C19, and CYP2D6 in preclinical research, but no evidence of this has been found in humans treated with up to 150 mg/day. It has also been identified in vitro as a strong inhibitor of CYP27A1 (cholesterol 27-hydroxylase) and as an inhibitor of CYP46A1 (cholesterol 24-hydroxylase), but this has yet to be assessed or confirmed in vivo or in humans and the clinical significance remains unknown.[211] [212] Bicalutamide has been found to be a P-glycoprotein (ABCB1) inhibitor.[213] [214] [215] Like other first-generation and enzalutamide, it has been found to act as a weak non-competitive inhibitor of GABAA receptor-mediated currents in vitro (= 5.2 μM).[216] [217] However, unlike enzalutamide, bicalutamide has not been found to be associated with seizures or other related adverse central effects, so the clinical relevance of this finding is uncertain.

Pharmacokinetics

Though its absolute bioavailability in humans is unknown, bicalutamide is known to be extensively and well-absorbed. Its absorption is not affected by food. The absorption of bicalutamide is linear at doses up to 150 mg/day and is saturable at doses above this, with no further increases in steady-state levels of bicalutamide occurring at doses above 300 mg/day.[218] [219] Whereas absorption of (R)-bicalutamide is slow, with levels peaking at 31 to 39 hours after a dose, (S)-bicalutamide is much more rapidly absorbed. Steady-state concentrations of the drug are reached after 4 to 12 weeks of treatment independently of dosage, with a 10- to 20-fold progressive accumulation in levels of (R)-bicalutamide.[220] [221] [222] The long time to steady-state levels is the result of bicalutamide's very long elimination half-life. There is wide interindividual variability in (R)-bicalutamide levels (up to 16-fold) with bicalutamide regardless of dosage.

The tissue distribution of bicalutamide is not well-characterized.[223] The amount of bicalutamide in semen that could potentially be transferred to a female partner during sexual intercourse is low and is not thought to be important. Based on animal studies with rats and dogs it was thought that bicalutamide could not cross the blood–brain barrier and hence could not enter the brain.[224] [225] [226] As such, it was initially thought to be a peripherally selective antiandrogen. However, subsequent clinical studies found that this was not also the case for humans, indicating species differences; bicalutamide crosses into the human brain and, in accordance, produces effects and side effects consistent with central antiandrogenic action.[227] [228] [229] In any case, there is indication that bicalutamide might have at least some peripheral selectivity in humans.[230] Bicalutamide is highly plasma protein bound (96.1% for racemic bicalutamide, 99.6% for (R)-bicalutamide) and is bound mainly to albumin, with negligible binding to and corticosteroid-binding globulin.[231]

Bicalutamide is metabolized in the liver. (R)-Bicalutamide is metabolized slowly and almost exclusively via hydroxylation by CYP3A4 into (R)-hydroxybicalutamide. This metabolite is then glucuronidated by UGT1A9.[232] In contrast to (R)-bicalutamide, (S)-bicalutamide is metabolized rapidly and mainly by glucuronidation (without hydroxylation). None of the metabolites of bicalutamide are known to be active and levels of the metabolites are low in plasma, where unchanged biclautamide predominates. Due to the stereoselective metabolism of bicalutamide, (R)-bicalutamide has a far longer terminal half-life than (S)-bicalutamide and its levels are about 10- to 20-fold higher in comparison following a single dose and 100-fold higher at steady-state.[233] [234] (R)-Bicalutamide has a relatively long elimination half-life of 5.8 days with a single dose and 7 to 10 days following repeated administration.[235]

Bicalutamide is eliminated in similar proportions in feces (43%) and urine (34%), while its metabolites are eliminated roughly equally in urine and bile.[236] [237] The drug is excreted to a substantial extent in unmetabolized form, and both bicalutamide and its metabolites are eliminated mainly as glucuronide conjugates. The glucuronide conjugates of bicalutamide and its metabolites are eliminated from the circulation rapidly, unlike unconjugated bicalutamide.[238]

The pharmacokinetics of bicalutamide are not affected by consumption of food, a person's age or body weight, renal impairment, or mild-to-moderate hepatic impairment. However, steady-state levels of bicalutamide are higher in Japanese individuals than in white people.

Chemistry

Bicalutamide is a racemic mixture consisting of equal proportions of enantiomers (R)-bicalutamide (dextrorotatory) and (S)-bicalutamide (levorotatory). Its systematic name () is (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide.[239] The compound has a chemical formula of C18H14F4N2O4S, a molecular weight of 430.373 g/mol, and is a fine white to off-white powder.[240]

The acid dissociation constant (pKa') of bicalutamide is approximately 12. It is a highly lipophilic compound (log P = 2.92).[241] 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). In organic solvents, it is slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and freely soluble in acetone and tetrahydrofuran.

Bicalutamide is a synthetic and nonsteroidal compound which was derived from flutamide. It is a bicyclic compound (has two rings) and can be classified as and has variously been referred to as an anilide (N-phenylamide) or aniline, a diarylpropionamide, and a toluidide.

Analogues

See also: Discovery and development of antiandrogens.

First-generation including bicalutamide, flutamide, and nilutamide are all synthetic, nonsteroidal anilide derivatives and structural analogues of each other.[242] Bicalutamide is a diarylpropionamide while flutamide is a monoarylpropionamide and nilutamide is a hydantoin. Bicalutamide and flutamide, though not nilutamide, can also be classified as toluidides. All three of the compounds share a common 3-trifluoromethylaniline moiety.[243] 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.[244] Topilutamide, also known as fluridil, is another that is closely related structurally to the first-generation, 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 pattern hair loss.[245] [246]

The second-generation enzalutamide and apalutamide were derived from and are analogues of the first-generation,[247] while another second-generation, darolutamide, is said to be structurally distinct and chemically unrelated to the other .[248] 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-thioxo imidazolidine 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.

The first nonsteroidal androgens, the arylpropionamides, were discovered via structural modification of bicalutamide.[249] Unlike bicalutamide (which is purely antiandrogenic), these compounds show tissue-selective androgenic effects and were classified as selective androgen receptor modulators (SARMs). Lead of this series included acetothiolutamide, enobosarm (ostarine; S-22), and andarine (acetamidoxolutamide or androxolutamide; S-4).[250] 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 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.[251]

A few radiolabeled derivatives of bicalutamide have been developed for potential use as radiotracers in medical imaging.[252] [253] They include [<sup>18</sup>F]bicalutamide, 4-[<sup>76</sup>Br]bromobicalutamide, and [<sup>76</sup>Br]bromo-thiobicalutamide. The latter two were found to have substantially increased affinity for the relative to that of bicautamide. However, none of these agents have been evaluated in humans.

5N-Bicalutamide, or 5-azabicalutamide, is a minor structural modification of bicalutamide which acts as a reversible covalent antagonist of the and has approximately 150-fold higher affinity for the and about 20-fold greater functional inhibition of the relative to bicalutamide.[254] [255] It is among the most potent antagonists to have been developed and is being researched for potential use in the treatment of antiandrogen-resistant prostate cancer.

Synthesis

A number of chemical syntheses of bicalutamide have been published in the literature.[256] [257] [258] [259] The procedure of the first published synthesis of bicalutamide can be seen below.

History

Bicalutamide as well as all of the other currently marketed were derived from structural modification of flutamide, which itself was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently and serendipitously found to possess antiandrogenic activity.[260] [261] [262] Bicalutamide was discovered by Tucker and colleagues at Imperial Chemical Industries (ICI) in the 1980s and was selected for development from a group of over 2,000 synthesized compounds.[263] [264] [265] It was first patented in 1982[266] and was first reported in the scientific literature in June 1987.[267]

Bicalutamide was first studied in a phase I clinical trial in 1987 and the results of the first phase II clinical trial in prostate cancer were published in 1990.[268] The pharmaceutical division of was split out into an independent company called Zeneca in 1993, and in April and May 1995, Zeneca (now AstraZeneca, after merging with Astra AB in 1999) began pre-approval marketing of bicalutamide for the treatment of prostate cancer in the .[269] It was first launched in the in May 1995,[270] and was subsequently approved by the on 4 October 1995, for the treatment of prostate cancer at a dosage of 50 mg/day in combination with a analogue.[271] [272]

Following its introduction for use in combination with a 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 late 1990s and early 2000s.[273] [274] This application of bicalutamide was also under review by the in the in 2002,[275] but ultimately was not approved in this country. In Japan, bicalutamide is licensed at a dosage of 80 mg/day alone or in combination with a analogue for prostate cancer.[67] 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.[276]

Subsequent to negative findings of bicalutamide monotherapy for in the clinical programme, approval of bicalutamide for use specifically in the treatment of was withdrawn in a number of countries[277] including the (in October or November 2003)[278] and several other European countries and Canada (in August 2003).[279] [280] In addition, the and Canada explicitly recommended against the use of 150 mg/day bicalutamide for this indication.[281] The drug is effective for, remains approved for, and continues to be used in the treatment of and, on the other hand.

The patent protection of bicalutamide expired in the in March 2009 and the drug has subsequently been available as a generic,[282] at greatly reduced cost.[283]

Bicalutamide was the fourth antiandrogen (and the third) to be introduced for the treatment of prostate cancer, following the in 1973[284] and the flutamide in 1983 (1989 in the)[285] and nilutamide in 1989 (1996 in the).[286] [287] It has been followed by abiraterone acetate in 2011, enzalutamide in 2012, apalutamide in 2018, and darolutamide in 2019, and may also be followed by in-development drugs such as proxalutamide and seviteronel.[288]

Society and culture

Generic names

Bicalutamide is the generic name of the drug in English and French and its,,,[289],,, and .[290] [291] It is also referred to as bicalutamidum in Latin, bicalutamida in Spanish and Portuguese, bicalutamid in German, and bikalutamid in Russian and other Slavic languages. The "bica-" prefix corresponds to the fact that bicalutamide is a bicyclic compound, while the "-lutamide" suffix is the standard suffix for .[292] [293] Bicalutamide is also known by its former developmental code name -176,334.

Brand names

Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries.[294] [295] It is also marketed under the brand names Bicadex, Bical, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries. 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. A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.

Cost and generics

Bicalutamide is off-patent and available as a generic.[282] Unlike bicalutamide, the newer enzalutamide is still on-patent, and for this reason, is considerably more expensive in comparison.[296]

The patent protection of all three of the first-generation has expired and flutamide and bicalutamide are both available as low-cost generics.[297] [298] 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

Bicalutamide is considerably less costly than analogues, which, in spite of some having been off-patent many years, have been reported (in 2013) to typically cost –$15,000 per year (or about per month) of treatment.[299] [300]

Sales and usage

Sales of bicalutamide (as Casodex) worldwide peaked at US$1.3 billion in 2007, and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection starting in 2007.[301] 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). Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca. Total worldwide sales of brand name Casodex were approximately US$13.4 billion as of the end of 2018.

Worldwide sales (millions,) of Casodex, 1995–2018
Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales
1995 ~$15m 1998 $245m 2001 $569m 2004 $1012m 2007* $1335m 2010 $579m 2013 $376m 2016 $247m
1996 $109m 1999 $340m 2002 $644m 2005 $1123m 2008 $1258m 2011 $550m 2014 $320m 2017 $215m
1997 $200m 2000 $433m 2003 $854m 2006 $1206m 2009 $844m 2012 $454m 2015 $267m 2018 $201m
Notes: First generic availability (*) was in 2007.[302] Total sales as of end 2018 were $13.4 billion. Sources:[303] <-- 1995 -->[304] [305] <-- 1999–2001 -->[306] [307] [308] <-- 2008–2010 -->[309] [310] [311] <-- 2017 -->[312]

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

Regulation

Bicalutamide is a prescription drug. It is not specifically a controlled substance in any country and therefore is not an illegal drug. However, the manufacture, sale, distribution, and possession of prescription drugs are all still subject to legal regulation throughout the world.[313] [314] [315]

Research

Bicalutamide has been studied in combination with the 5α-reductase inhibitors finasteride and dutasteride in prostate cancer.[316] [317] [318] [319] [320] [321] [322] It has also been studied in combination with raloxifene, a selective estrogen receptor modulator (SERM), for the treatment of prostate cancer.[323] [324] Bicalutamide has been tested for the treatment of -positive /-negative locally advanced and metastatic breast cancer in women in a phase II study for this indication.[325] [326] Enzalutamide is also being investigated for this type of cancer.[327] [328] Bicalutamide has also been studied in a phase II clinical trial for ovarian cancer in women.[329]

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.[330] [331] Prostate volume decreased by 26% in patients taking bicalutamide and urinary irritative symptom scores significantly decreased. Conversely, peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo. The decrease in prostate volume achieved with bicalutamide was comparable to that observed with the 5α-reductase inhibitor finasteride, which is approved for the treatment of BPH.[332] [333] Breast tenderness (93%), gynecomastia (54%), and sexual dysfunction (60%) were all reported as side effects of bicalutamide at the dosage used in the study, although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75% of patients.

A phase III clinical trial of bicalutamide in combination with an ethinylestradiol-containing combined oral contraceptive for the treatment of severe hirsutism in women with was completed in Italy in 2017 under supervision of the Italian Agency for Drugs (AIFA).[334]

Antiandrogens have been suggested for treating COVID-19 in men and as of May 2020 high-dose bicalutamide is in a phase II clinical trial for this purpose.[335] [336]

Veterinary use

Bicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary to hyperadrenocorticism (caused by excessive adrenal androgens) in male ferrets.[337] [338] [339] However, it has not been formally assessed in controlled studies for this purpose.[340]

See also

Further reading

Notes and References

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  3. Cockshott ID . Bicalutamide: clinical pharmacokinetics and metabolism . Clinical Pharmacokinetics . 43 . 13 . 855–878 . 2004 . 15509184 . 10.2165/00003088-200443130-00003. 29912565 .
  4. Dole EJ, Holdsworth MT . Nilutamide: an antiandrogen for the treatment of prostate cancer . The Annals of Pharmacotherapy . 31 . 1 . 65–75 . 1997 . 8997470 . 10.1177/106002809703100112 . 20347526 . page 67: Currently, information is not available regarding the activity of the major urinary metabolites of bicalutamide, bicalutamide glucuronide, and hydroxybicalutamide glucuronide..
  5. Schellhammer PF . An evaluation of bicalutamide in the treatment of prostate cancer . Expert Opinion on Pharmacotherapy . 3 . 9 . 1313–28 . September 2002 . 12186624 . 10.1517/14656566.3.9.1313 . 32216411 . The clearance of bicalutamide occurs pre- dominantly by hepatic metabolism and glucuronidation, with excretion of the resulting inactive metabolites in the urine and faces..
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  54. Reiter EO, Mauras N, McCormick K, Kulshreshtha B, Amrhein J, De Luca F, O'Brien S, Armstrong J, Melezinkova H . 6 . Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT) . Journal of Pediatric Endocrinology & Metabolism . 23 . 10 . 999–1009 . October 2010 . 21158211 . 10.1515/jpem.2010.161 . 110630 .
  55. Levey HR, Kutlu O, Bivalacqua TJ . Medical management of ischemic stuttering priapism: a contemporary review of the literature . Asian Journal of Andrology . 14 . 1 . 156–163 . January 2012 . 22057380 . 3753435 . 10.1038/aja.2011.114 .
  56. Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, Shamloul R . Priapism: pathogenesis, epidemiology, and management . The Journal of Sexual Medicine . 7 . 1 Pt 2 . 476–500 . January 2010 . 20092449 . 10.1111/j.1743-6109.2009.01625.x .
  57. Chow K, Payne S . The pharmacological management of intermittent priapismic states . BJU International . 102 . 11 . 1515–1521 . December 2008 . 18793304 . 10.1111/j.1464-410X.2008.07951.x . 35399393 . free .
  58. Dahm P, Rao DS, Donatucci CF . Antiandrogens in the treatment of priapism . Urology . 59 . 1 . 138 . January 2002 . 11796309 . 10.1016/S0090-4295(01)01492-3 .
  59. Gooren LJ . Clinical review: Ethical and medical considerations of androgen deprivation treatment of sex offenders . The Journal of Clinical Endocrinology & Metabolism . 96 . 12 . 3628–37 . 2011 . 21956411 . 10.1210/jc.2011-1540 . free .
  60. Giltay EJ, Gooren LJ . Potential side effects of androgen deprivation treatment in sex offenders . The Journal of the American Academy of Psychiatry and the Law . 37 . 1 . 53–8 . 2009 . 19297634 .
  61. Khan O, Mashru A . The efficacy, safety and ethics of the use of testosterone-suppressing agents in the management of sex offending . Current Opinion in Endocrinology, Diabetes and Obesity . 23 . 3 . 271–8 . 2016 . 27032060 . 10.1097/MED.0000000000000257 . 43286710 .
  62. Book: Dangerous Sex Offenders: A Task Force Report of the American Psychiatric Association . 1999 . American Psychiatric Pub . 978-0-89042-280-9 . 111–.
  63. Houts FW, Taller I, Tucker DE, Berlin FS . Androgen deprivation treatment of sexual behavior . Advances in Psychosomatic Medicine . 31 . 149–63 . 2011 . 22005210 . 10.1159/000330196 . 978-3-8055-9825-5 .
  64. Rousseau L, Couture M, Dupont A, Labrie F, Couture N . Effect of combined androgen blockade with an LHRH agonist and flutamide in one severe case of male exhibitionism . The Canadian Journal of Psychiatry . 35 . 4 . 338–41 . 1990 . 2189544 . 10.1177/070674379003500412 . 28970865 .
  65. Book: Swiss Pharmaceutical Society . Index Nominum 2000: International Drug Directory . January 2000 . Taylor & Francis . 978-3-88763-075-1 . 123–. live . https://web.archive.org/web/20160424054101/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA123 . 24 April 2016 . dmy-all.
  66. Book: Sweetman SC . Martindale: The Complete Drug Reference . 2011 . Pharmaceutical Press . 978-0-85369-933-0 . 750–751 . 27 September 2016 . 14 January 2023 . https://web.archive.org/web/20230114143130/https://books.google.com/books?id=r_qfcQAACAAJ . live .
  67. Suzuki H, Kamiya N, Imamoto T, Kawamura K, Yano M, Takano M, Utsumi T, Naya Y, Ichikawa T . Current topics and perspectives relating to hormone therapy for prostate cancer . International Journal of Clinical Oncology . 13 . 5 . 401–10 . October 2008 . 18946750 . 10.1007/s10147-008-0830-y. 32859879 .
  68. Book: White R, Bradnam V . Handbook of Drug Administration via Enteral Feeding Tubes . 3rd . 11 March 2015 . Pharmaceutical Press . 978-0-85711-162-3 . 133– . 27 September 2016 . 14 January 2023 . https://web.archive.org/web/20230114143141/https://books.google.com/books?id=yyikBwAAQBAJ&pg=PA133 . live .
  69. Book: Morton IK, Hall J . The Avery Complete Guide to Medicines . 2001 . Avery . 978-1-58333-105-7 . 105–106.
  70. Book: Chabner BA, Longo DL . Cancer Chemotherapy and Biotherapy: Principles and Practice . 8 November 2010 . Lippincott Williams & Wilkins . 978-1-60547-431-1 . 679–680 . From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used. . 27 September 2016 . 10 January 2023 . https://web.archive.org/web/20230110224032/https://books.google.com/books?id=WL4arNFsQa8C&pg=PA680 . live .
  71. Kolvenbag GJ, Furr BJ, Blackledge GR . Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity . Prostate Cancer Prostatic Dis . 1 . 6 . 307–314 . December 1998 . 12496872 . 10.1038/sj.pcan.4500262 . 33497597 . In addition, since bicalutamide has a low solubility, authentic Casodex® is micronised to ensure a small and consistent particle size to optimise bioavailability..
  72. Web site: Zolacos CP . Drugs.com . live . https://web.archive.org/web/20160920130215/https://www.drugs.com/international/zolacos-cp.html . 20 September 2016 . dmy-all.
  73. Web site: Zolacos CP . https://web.archive.org/web/20160917215734/https://www.betterhealth.vic.gov.au/~/media/bhc/files/medicine%20guides%20library/07/cmi7435.pdf . 17 September 2016 . dead . MIMS/myDr . April 2007.
  74. Web site: ZOLACOS CP . New Zealand Data Sheet . 25 July 2016 . live . https://web.archive.org/web/20160919034509/http://www.medsafe.govt.nz/profs/datasheet/z/ZolaCosCP.pdf . 19 September 2016 . dmy-all.
  75. Book: Skeel RT, Khleif SN . Handbook of Cancer Chemotherapy . 2011 . Lippincott Williams & Wilkins . 724–. live . https://web.archive.org/web/20160529144852/https://books.google.com/books?id=6Nz_87OLrtcC&pg=PA724 . 29 May 2016 . dmy-all. 9781608317820 .
  76. Book: Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs . 2001 . Mosby . 978-0-323-00629-3 . 289–290.
  77. Book: Duplay D . Physicians' Desk Reference . 2004 . Thomson PDR . 978-1-56363-471-0 . 27 September 2016 . 14 January 2023 . https://web.archive.org/web/20230114143131/https://books.google.com/books?id=_sf2G6ZPDKAC . live .
  78. Book: Lehne RA . Pharmacology for Nursing Care . 2013 . Elsevier Health Sciences . 978-1-4377-3582-6 . 1297– . 27 September 2016 . 10 January 2023 . https://web.archive.org/web/20230110224019/https://books.google.com/books?id=_4SwO2dHcAIC&pg=PA1297 . live .
  79. Wirth MP, Hakenberg OW, Froehner M . Antiandrogens in the treatment of prostate cancer . European Urology . 51 . 2 . 306–13; discussion 314 . February 2007 . 17007995 . 10.1016/j.eururo.2006.08.043.
  80. Wellington K, Keam SJ . Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer . Drugs . 66 . 6 . 837–50 . 2006 . 16706554 . 10.2165/00003495-200666060-00007. 46966712 .
  81. Higano CS . Side effects of androgen deprivation therapy: monitoring and minimizing toxicity . Urology . 61 . 2 Suppl 1 . 32–8 . February 2003 . 12667885 . 10.1016/S0090-4295(02)02397-X.
  82. Higano CS . Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer . Journal of Clinical Oncology . 30 . 30 . 3720–5 . 2012 . 23008326 . 10.1200/JCO.2012.41.8509 .
  83. Kolvenbag GJ, Blackledge GR . Worldwide activity and safety of bicalutamide: a summary review . Urology . 47 . 1A Suppl . 70–9; discussion 80–4 . January 1996 . 8560681 . 10.1016/s0090-4295(96)80012-4. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer..
  84. Book: Resnick MI, Thompson IM . Advanced Therapy of Prostate Disease . 2000 . PMPH-USA . 978-1-55009-102-1 . 379–. live . https://web.archive.org/web/20160610095331/https://books.google.com/books?id=9AKuf7rzfjcC&pg=PA379 . 10 June 2016 . dmy-all.
  85. Kathryn Korkidakis A, Reid RL . Testosterone in Women: Measurement and Therapeutic Use . Journal of Obstetrics and Gynaecology Canada . 39 . 3 . 124–130 . 2017 . 28343552 . 10.1016/j.jogc.2017.01.006 .
  86. Davis SR, Wahlin-Jacobsen S . Testosterone in women--the clinical significance . The Lancet Diabetes & Endocrinology . 3 . 12 . 980–92 . 2015 . 26358173 . 10.1016/S2213-8587(15)00284-3 .
  87. Cignarella A, Mioni R, Sabbadin C, Dassie F, Parolin M, Vettor R, Barbot M, Scaroni C . Pharmacological Approaches to Controlling Cardiometabolic Risk in Women with PCOS . Int J Mol Sci . 21 . 24 . December 2020 . 9554 . 33334002 . 7765466 . 10.3390/ijms21249554 . free .
  88. Luque-Ramírez M, Ortiz-Flores AE, Nattero-Chávez L, Escobar-Morreale HF . A safety evaluation of current medications for adult women with the polycystic ovarian syndrome not pursuing pregnancy . Expert Opin Drug Saf . 19 . 12 . 1559–1576 . December 2020 . 33070640 . 10.1080/14740338.2020.1839409 . 224784192 .
  89. Fourcade RO, McLeod D . Tolerability of Antiandrogens in the Treatment of Prostate Cancer . UroOncology . March 2004 . 4 . 1 . 5–13 . 1561-0950 . 10.1080/1561095042000191655 . Based on the available evidence, bicalutamide appears to have a better profile of non-pharmacological side effects than either flutamide or nilutamide; no specific nonpharmacological complications have yet been linked to this agent, while the incidence of the side effects such as diarrhoea and abnormal liver function appears to be lower than for the other two non-steroidal compounds. Furthermore, the recent data from the EPC programme suggest that the non-pharmacological side-effect profile of bicalutamide is not dissimilar to that of placebo (Table m [3]..
  90. Lunglmayr G . Efficacy and tolerability of Casodex in patients with advanced prostate cancer. International Casodex Study Group . Anti-Cancer Drugs . 6 . 4 . 508–13 . August 1995 . 7579554 . 10.1097/00001813-199508000-00003.
  91. McLeod DG . Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer . Oncologist . 2 . 1 . 18–27 . 1997 . 10388026 . 10.1634/theoncologist.2-1-18. free .
  92. Book: DeAngelis LM, Posner JB . Neurologic Complications of Cancer . 12 September 2008 . Oxford University Press, USA . 978-0-19-971055-3 . 479–. live . https://web.archive.org/web/20160507051525/https://books.google.com/books?id=mpZ8Dp2KdHMC&pg=PA479 . 7 May 2016 . dmy-all.
  93. Book: Jamnicky L, Nam R . Canadian Guide to Prostate Cancer . 5 November 2012 . John Wiley & Sons . 978-1-118-51565-5 . 177– . 27 September 2016 . 14 January 2023 . https://web.archive.org/web/20230114143131/https://books.google.com/books?id=EFJhvLJeWX4C&pg=PT177 . live .
  94. Tyrrell CJ, Denis L, Newling D, Soloway M, Channer K, Cockshott ID . Casodex 10-200 mg daily, used as monotherapy for the treatment of patients with advanced prostate cancer. An overview of the efficacy, tolerability and pharmacokinetics from three phase II dose-ranging studies. Casodex Study Group . Eur. Urol. . 33 . 1 . 39–53 . 1998 . 9471040 . 10.1159/000019526 . 71758492 . 13 April 2023 . 1 February 2022 . https://web.archive.org/web/20220201084113/https://www.karger.com/Article/Pdf/19526 . live .
  95. Tyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T . 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 . September 2006 . 16771791 . 10.1111/j.1464-410X.2006.06275.x. 41672303.
  96. See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, Chodak G, Montie J, Tyrrell C, Wallace DM, Delaere KP, Vaage S, Tammela TL, Lukkarinen O, Persson BE, Carroll K, Kolvenbag GJ . 6 . 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 . August 2002 . 12131282 . 10.1016/S0022-5347(05)64652-6.
  97. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G . Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy. Casodex Combination Study Group . Urology . 47 . 1A Suppl . 54–60; discussion 80–4 . January 1996 . 8560679 . 10.1016/s0090-4295(96)80010-0 .
  98. Jia AY, Spratt DE . Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer: A Non-Evidence-Based Alternative . Int J Radiat Oncol Biol Phys . 113 . 2 . 316–319 . June 2022 . 35569476 . 10.1016/j.ijrobp.2022.01.037 . 248765294 . Four other randomized trials using BICmono have also raised concerns about either lack of efficacy or even harm from this treatment approach compared with placebo or no hormone therapy. SPCG-6 randomized 1218 patients to either 150 mg of BICmono daily or placebo. In the subset of patients with LPCa managed with observation, survival was significantly worse with BIC than placebo (hazard ratio [HR], 1.47; 95% confidence interval, 1.06-2.03).10 Two other randomized trials were part of the early prostate cancer program,11 which conducted 3 randomized trials that were pooled together to determine the benefit of BICmono (SPCG-6 was one of the 3 trials). Overall, in the combined 8113 patient pooled cohort, after a median follow-up of 7 years, there was no improvement even in progression-free survival from the use of adjuvant BIC in LPCa, and there was a trend for worse overall survival (HR, 1.16; 95% confidence interval, 0.99-1.37; P = .07). [...] Although not in LPCa, NRG/RTOG 9601 demonstrated findings consistent with the prior trials.12 This trial randomized men to postprostatectomy salvage radiation therapy plus placebo versus 150 mg of BICmono daily for 2 years. After a median follow-up of 13 years, the trial showed that there were significantly more grade 3 to 5 cardiac events in the BICmono arm. In patients with less aggressive disease with lower PSAs (prostate-specific antigens; more analogous to LPCa), other-cause mortality was significantly higher in the BICmono arm. In patients with high PSAs >1.5 ng/mL (which with modern molecular positron emission tomography imaging would be expected to have high rates of regional and distant metastatic disease), a survival benefit from the addition of BIC was observed. This is consistent with results from the early prostate cancer studies that showed that only patients with more advanced disease derived benefit from BICmono.10 Thus, all the randomized evidence from 5 trials (Table 1) demonstrates that, in LPCa, BICmono had no clinically significant oncologic activity over placebo/no treatment, and consistent trends with long-term use resulted in worse survival..
  99. Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K . 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 . November 2004 . 15540741 . 10.1097/01.ju.0000139719.99825.54.
  100. Wellington K, Keam SJ . Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer . Drugs . 66 . 6 . 837–50 . 2006 . 16706554 . 10.2165/00003495-200666060-00007 . 46966712 .
  101. Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J . 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 . Scandinavian Journal of Urology and Nephrology . 40 . 6 . 441–52 . 2006 . 17130095 . 10.1080/00365590601017329 . 25862814 .
  102. Trüeb RM, Luu NC, Uribe NC, Régnier A . Comment on: Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know . J Cosmet Dermatol . 21 . 12 . 7200–7201 . December 2022 . 35332669 . 10.1111/jocd.14936 . 247677549 . Indeed, due to the minimal biological importance of androgens in women, the adverse effects of bicalutamide are few. And yet, bicalutamide has been associated with elevated liver enzymes, and as of 2021, there have been 10 case reports of liver toxicity associated with bicalutamide, with fatality occurring in 2 cases.2.
  103. Gretarsdottir HM, Bjornsdottir E, Bjornsson ES . Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect . Case Reports in Gastroenterology . 12 . 2 . 2018 . 266–70 . 1662-0631 . 10.1159/000485175. free . 20.500.11815/1492 . free .
  104. Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM . Bicalutamide-induced hepatotoxicity: A rare adverse effect . Am J Case Rep . 15 . 266–70 . 2014 . 24967002 . 4068966 . 10.12659/AJCR.890679 .
  105. Yun GY, Kim SH, Kim SW, Joo JS, Kim JS, Lee ES, Lee BS, Kang SH, Moon HS, Sung JK, Lee HY, Kim KH . Atypical onset of bicalutamide-induced liver injury . World J. Gastroenterol. . 22 . 15 . 4062–5 . April 2016 . 27099451 . 4823258 . 10.3748/wjg.v22.i15.4062 . free .
  106. O'Bryant CL, Flaig TW, Utz KJ . Bicalutamide-associated fulminant hepatotoxicity . Pharmacotherapy . 28 . 8 . 1071–5 . 2008 . 18657023 . 10.1592/phco.28.8.1071 . 20315801 .
  107. Castro Beza I, Sánchez Ruiz J, Peracaula Espino FJ, Villanego Beltrán MI . Drug-related hepatotoxicity and hepatic failure following combined androgen blockade . Clin Transl Oncol . 10 . 9 . 591–2 . September 2008 . 18796378 . 10.1007/s12094-008-0256-5 .
  108. FDA Adverse Event Reporting System (FAERS) Public Dashboard . FDA . 22 October 2021 . 15 February 2023 . 15 February 2023 . https://web.archive.org/web/20230215182941/https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard . live .
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  110. Masago T, Watanabe T, Nemoto R, Motoda K . Interstitial pneumonitis induced by bicalutamide given for prostate cancer . International Journal of Clinical Oncology . 16 . 6 . 763–5 . December 2011 . 21537882 . 10.1007/s10147-011-0239-x. 24068787 .
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  112. Daba MH, El-Tahir KE, Al-Arifi MN, Gubara OA . Drug-induced pulmonary fibrosis . Saudi Medical Journal . 25 . 6 . 700–6 . June 2004 . 15195196 .
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  114. Ricci F, Buzzatti G, Rubagotti A, Boccardo F . Safety of antiandrogen therapy for treating prostate cancer . Expert Opinion on Drug Safety . 13 . 11 . 1483–99 . November 2014 . 25270521 . 10.1517/14740338.2014.966686. 207488100 .
  115. Iswaran TJ, Imai M, Betton GR, Siddall RA . An overview of animal toxicology studies with bicalutamide (ICI 176,334) . The Journal of Toxicological Sciences . 22 . 2 . 75–88 . May 1997 . 9198005 . 10.2131/jts.22.2_75. free .
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  117. Book: Sex Differences in the Human Brain, their underpinnings and implications . 3 December 2010 . Elsevier . 978-0-444-53631-0 . 44–45 . live . https://web.archive.org/web/20160526221656/https://books.google.com/books?id=JFpq6hYQRhQC . 26 May 2016 . dmy-all.
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  128. Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A . Hepatotoxicity induced by antiandrogens: a review of the literature . Urol. Int. . 73 . 4 . 289–95 . 2004 . 15604569 . 10.1159/000081585 . 24799765 .
  129. Book: Craig JV, Furr BJ. Hormone Therapy in Breast and Prostate Cancer. 5 February 2010. Springer Science & Business Media. 978-1-59259-152-7. 356–. 27 September 2016. 14 January 2023. https://web.archive.org/web/20230114143135/https://books.google.com/books?id=dM0uvBnxiN0C&pg=PA356. live.
  130. Bennett CL, Raisch DW, Sartor O . Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect . Annals of Internal Medicine . 137 . 7 . 625 . October 2002 . 12353966 . 10.7326/0003-4819-137-7-200210010-00029 . An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period..
  131. Ricci F, Buzzatti G, Rubagotti A, Boccardo F . Safety of antiandrogen therapy for treating prostate cancer . Expert Opin Drug Saf . 13 . 11 . 1483–99 . 2014 . 25270521 . 10.1517/14740338.2014.966686 . 207488100 .
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  133. 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 . Enzalutamide in metastatic prostate cancer before chemotherapy . N. Engl. J. Med. . 371 . 5 . 424–33 . 2014 . 24881730 . 4418931 . 10.1056/NEJMoa1405095 .
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  136. Furr BJ, Tucker H . The preclinical development of bicalutamide: pharmacodynamics and mechanism of action . Urology . 47 . 1A Suppl . 13–25; discussion 29–32 . 1996 . 8560673 . 10.1016/S0090-4295(96)80003-3.
  137. Lenz AM, Shulman D, Eugster EA, Rahhal S, Fuqua JS, Pescovitz OH, Lewis KA . Bicalutamide and third-generation aromatase inhibitors in testotoxicosis . Pediatrics . 126 . 3 . e728-33 . September 2010 . 20713483 . 4096839 . 10.1542/peds.2010-0596.
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  140. Bahceci M, Tuzcu A, Canoruc N, Tuzun Y, Kidir V, Aslan C . 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 . 2004 . 15542929 . 10.1159/000081973. 46261843 .
  141. Book: Nurse Practitioner's Drug Handbook . 2000 . Springhouse Corp. . 9780874349979 . 27 September 2016 . 14 January 2023 . https://web.archive.org/web/20230114143136/https://books.google.com/books?id=I6Jt1THMB_4C . live .
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  143. Book: Genrx . 1999 Mosby's GenRx . 1999 . Mosby . 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..
  144. Book: Skidmore-Roth L . Mosby's 2014 Nursing Drug Reference – Elsevieron VitalSource . 17 April 2013 . Elsevier Health Sciences . 978-0-323-22267-9 . 193–194 . 27 September 2016 . 14 January 2023 . https://web.archive.org/web/20230114143136/https://books.google.com/books?id=ISYiAQAAQBAJ&pg=PA194 . live .
  145. Book: Weber GF . Molecular Therapies of Cancer . 22 July 2015 . Springer . 978-3-319-13278-5 . 318–. Compared to flutamide and nilutamide, bicalutamide has a 2-fold increased affinity for the Androgen Receptor, a longer half-life, and substantially reduced toxicities. Based on a more favorable safety profile relative to flutamide, bicalutamide is indicated for use in combination therapy with a Gonadotropin Releasing Hormone analog for the treatment of advanced metastatic prostate carcinoma..
  146. Book: Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs . 2001 . Mosby . 978-0-323-00629-3 . 290 . 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..
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  152. Furr BJ, Tucker H . The preclinical development of bicalutamide: pharmacodynamics and mechanism of action . Urology . 47 . 1A Suppl . 13–25; discussion 29–32 . January 1996 . 8560673 . 10.1016/S0090-4295(96)80003-3.
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  155. Ito Y, Sadar MD . Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens . Res Rep Urol . 10 . 23–32 . 2018 . 29497605 . 5818862 . 10.2147/RRU.S157116 . free .
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  157. Bulldan A, Malviya VN, Upmanyu N, Konrad L, Scheiner-Bobis G . Testosterone/bicalutamide antagonism at the predicted extracellular androgen binding site of ZIP9 . Biochim. Biophys. Acta . 1864 . 12 . 2402–2414 . 2017 . 28943399 . 10.1016/j.bbamcr.2017.09.012 . free .
  158. Pi M, Parrill AL, Quarles LD . GPRC6A mediates the non-genomic effects of steroids . J. Biol. Chem. . 285 . 51 . 39953–64 . 2010 . 20947496 . 3000977 . 10.1074/jbc.M110.158063 . free .
  159. Furr BJ . Research on reproductive medicine in the pharmaceutical industry . Human Fertility . 1 . 1 . 56–63 . 2009 . 11844311 . 10.1080/1464727982000198131.
  160. 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 . Development of a second-generation antiandrogen for treatment of advanced prostate cancer . Science . 324 . 5928 . 787–90 . 2009 . 19359544 . 2981508 . 10.1126/science.1168175 . 2009Sci...324..787T . [...] bicalutamide has relatively low affinity for AR (at least 30-fold reduced relative to the natural ligand dihydrotestosterone (DHT)) (7), [...].
  161. Furr BK . Relative potencies of flutamide and 'Casodex'. Endocrine-Related Cancer. 4. 2. 1997. 197–202. 1351-0088. 10.1677/erc.0.0040197.
  162. Book: Figg W, Chau CH, Small EJ . Drug Management of Prostate Cancer . 14 September 2010 . Springer Science & Business Media . 978-1-60327-829-4 . 56, 71–72, 75, 93 . 27 September 2016 . 14 January 2023 . https://web.archive.org/web/20230114143137/https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA56 . live .
  163. Furr BJ . The development of Casodex (bicalutamide): preclinical studies . European Urology . 29 . Suppl 2 . 83–95 . 1996 . 8717469 . 10.1159/000473846.
  164. Boccardo F, Rubagotti A, Conti G, Potenzoni D, Manganelli A, Del Monaco D . 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 . Cancer Chemotherapy and Pharmacology . 56 . 4 . 415–20 . 2005 . 15838655 . 10.1007/s00280-005-1016-1 . 23014567 . 11 December 2019 . 28 August 2021 . https://web.archive.org/web/20210828003250/https://www.researchgate.net/publication/7897958_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 . live .
  165. Luo S, Martel C, Chen C, Labrie C, Candas B, Singh SM, Labrie F . Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity . Urology . 50 . 6 . 913–9 . December 1997 . 9426723 . 10.1016/S0090-4295(97)00393-2.
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  167. Efficacy and Safety of Myo-Inositol Supplementation in the Treatment of Obese Hirsute PCOS Women: Comparative Evaluation with OCP+Bicalutamide Therapy . Moretti C, Guccione L, Di Giacinto P, Simonelli I, Exacoustos C, Toscano V, Motta C, De Leo V, Petraglia F, Lenzi A . 6 . April 2016 . ENDO 2016 . Boston, Massachusetts . 1 February 2020 . 1 February 2020 . https://web.archive.org/web/20200201071020/https://endo.confex.com/endo/2016endo/webprogram/Paper26631.html . dead .
  168. Iversen P, Melezinek I, Schmidt A . Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function . BJU International . 87 . 1 . 47–56 . January 2001 . 11121992 . 10.1046/j.1464-410x.2001.00988.x. 28215804 . free .
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  173. Book: Diamanti-Kandarakis E, Nestler JE, Pandas D, Pasquale R . Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation, and Treatment . 21 December 2009 . Springer Science & Business Media . 978-1-59745-310-3 . 75–. live . https://web.archive.org/web/20160519021821/https://books.google.com/books?id=7ej6ZgqiFEsC&pg=PA75 . 19 May 2016 . dmy-all.
  174. Book: Carrell DT, Peterson CW . Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice . 23 March 2010 . Springer Science & Business Media . 978-1-4419-1436-1 . 163–. live . https://web.archive.org/web/20140704201613/http://books.google.com/books?id=lcBEheiufVcC&pg=PA163 . 4 July 2014 . dmy-all.
  175. Book: Bouchard P, Caraty A . GnRH, GnRH Analogs, Gonadotropins and Gonadal Peptides . 15 November 1993 . CRC Press . 978-0-203-09205-7 . 455–456 . [...] 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]..
  176. Sieber PR . Treatment of bicalutamide-induced breast events . Expert Review of Anticancer Therapy . 7 . 12 . 1773–9 . December 2007 . 18062751 . 10.1586/14737140.7.12.1773. 40410461 .
  177. Book: Melmed S . Williams Textbook of Endocrinology. 1 January 2016. Elsevier Health Sciences. 978-0-323-29738-7. 752–. GnRH analogues, both agonists and antagonists, severely suppress endogenous gonadotropin and testosterone production [...] Administration of GnRH agonists (e.g., leuprolide, goserelin) produces an initial stimulation of gonadotropin and testosterone secretion (known as a "flare"), which is followed in 1 to 2 weeks by GnRH receptor downregulation and marked suppression of gonadotropins and testosterone to castration levels. [...] To prevent the potential complications associated with the testosterone flare, AR antagonists (e.g., bicalutamide) are usually coadministered with a GnRH agonist for men with metastatic prostate cancer.399.
  178. Asscheman H, Gooren LJ, Peereboom-Wynia JD . Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals—experiences with a novel androgen receptor blocker . Clinical and Experimental Dermatology . 14 . 5 . 361–3 . 1989 . 2612040 . 10.1111/j.1365-2230.1989.tb02585.x. 45303518 .
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  181. Motofei IG, Rowland DL, Popa F, Kreienkamp D, Paunica S . Preliminary study with bicalutamide in heterosexual and homosexual patients with prostate cancer: a possible implication of androgens in male homosexual arousal . BJU International . 108 . 1 . 110–5 . July 2011 . 20955264 . 10.1111/j.1464-410X.2010.09764.x. 45482984 .
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  185. Sánchez Montoya EL, Hernández L, Barreto-Estrada JL, Ortiz JG, Jorge JC . 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 . November 2010 . 20646182 . 4360968 . 10.1111/j.1743-6109.2010.01937.x.
  186. Book: Chedrese PJ . Reproductive Endocrinology: A Molecular Approach . 13 June 2009 . Springer Science & Business Media . 978-0-387-88186-7 . 233–. live . https://web.archive.org/web/20170905040216/https://books.google.com/books?id=3FJXUN6Vh44C . 5 September 2017 . dmy-all.
  187. Frye CA, Edinger KL, Lephart ED, Walf AA . 3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats . Frontiers in Aging Neuroscience . 2 . 15 . 2010 . 20552051 . 2874398 . 10.3389/fnagi.2010.00015. free .
  188. Huang Q, Zhu H, Fischer DF, Zhou JN . An estrogenic effect of 5alpha-androstane-3beta, 17beta-diol on the behavioral response to stress and on CRH regulation . Neuropharmacology . 54 . 8 . 1233–8 . June 2008 . 18457850 . 10.1016/j.neuropharm.2008.03.016. 9052079 .
  189. Frye CA, Koonce CJ, Edinger KL, Osborne DM, Walf AA . 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 . November 2008 . 18775724 . 3623974 . 10.1016/j.yhbeh.2008.07.013.
  190. Bambury RM, Scher HI . Enzalutamide: Development from bench to bedside . Urologic Oncology . 33 . 6 . 280–8 . June 2015 . 25797385 . 10.1016/j.urolonc.2014.12.017.
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  192. Pinto Á . Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer . Cancer Biology & Therapy . 15 . 2 . 149–55 . February 2014 . 24100689 . 3928129 . 10.4161/cbt.26724.
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  195. Book: Wilson CB, Nizet V, Maldonado Y, Klein JO, Remington JS . Remington and Klein's Infectious Diseases of the Fetus and Newborn Infant . 2015 . Elsevier Health Sciences . 978-0-323-24147-2 . 190–. live . https://web.archive.org/web/20170114165129/https://books.google.com/books?id=VuZ1BwAAQBAJ&pg=PA190 . 14 January 2017 . dmy-all.
  196. Kanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW . Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men . The American Journal of Surgical Pathology . 24 . 1 . 74–80 . January 2000 . 10632490 . 10.1097/00000478-200001000-00009 . 37752666 . free .
  197. Book: Meyer IH, Northridge ME . Mary Northridge . 2006 . Springer . New York . 978-0-387-28871-0 . Transgender Health Concerns . Lawrence AA . The Health of Sexual Minorities . 476 . 10.1007/978-0-387-31334-4_19.
  198. Book: Rosen PP . Rosen's Breast Pathology . 2009 . Lippincott Williams & Wilkins . Philadelphia . 978-0-7817-7137-5 . 31–. 3.
  199. Book: Mulhall JP . Fertility Preservation in Male Cancer Patients . 21 February 2013 . Cambridge University Press . 978-1-139-61952-3 . 84–. live . https://web.archive.org/web/20160429171718/https://books.google.com/books?id=97wgAwAAQBAJ&pg=PA84 . 29 April 2016 . dmy-all.
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  206. Jones CA, Reiter L, Greenblatt E . Fertility preservation in transgender patients . International Journal of Transgenderism . 17 . 2 . 2016 . 76–82 . 1553-2739 . 10.1080/15532739.2016.1153992 . 58849546 . 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..
  207. Book: Payne AH, Hardy MP . The Leydig Cell in Health and Disease . 28 October 2007 . Springer Science & Business Media . 978-1-59745-453-7 . 422–431 . 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..
  208. Book: Wakelin SH, Maibach HI, Archer CB . Systemic Drug Treatment in Dermatology: A Handbook . 1 June 2002 . CRC Press . 978-1-84076-013-2 . 32–. [Cyproterone acetate] inhibits spermatogenesis and produces reversible infertility (but is not a male contraceptive). . live . https://web.archive.org/web/20140725205131/http://books.google.com/books?id=F1ZiAgAAQBAJ&pg=PA32 . 25 July 2014 . dmy-all.
  209. Neumann F . The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research . Exp. Clin. Endocrinol. . 102 . 1 . 1–32 . 1994 . 8005205 . 10.1055/s-0029-1211261 . 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.. free .
  210. Book: Salam MA . Principles & Practice of Urology: A Comprehensive Text . 2003 . Universal-Publishers . 978-1-58112-412-5 . 684–. 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..
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