Nilutamide

Nilutamide
Names
Pronunciationnye-LOO-tah-mide[1]
Trade namesNilandron, Anandron
Other namesRU-23908
IUPAC name
  • 5,5-Dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione
Clinical data
Drug classNonsteroidal antiandrogen (NSAA)[2]
Main usesProstate cancer[3]
Side effectsHot flushes, poor ability to see in darkness, nausea, constipation, trouble sleeping, breat enlargement, pneumonitis[4]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: C (Risk not ruled out)[5]
    Routes of
    use    		By mouth[6]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa697044
    Legal
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    BioavailabilityGood[6]
    Protein binding80–84%[7]
    MetabolismLiver (CYP2C19, FMO)[6][7]
    MetabolitesAt least 5, some active[7][8]
    Elimination half-lifeMean: 56 hours (~2 days)[9]
    Range: 23–87 hours[9]
    ExcretionUrine: 62%[6][7]
    Feces: <10%[6][7]
    Chemical and physical data
    FormulaC12H10F3N3O4
    Molar mass317.224 g·mol−1
    3D model (JSmol)
    Melting point149 °C (300 °F)
    SMILES
    • CC1(C(=O)N(C(=O)N1)C2=CC(=C(C=C2)[N+](=O)[O-])C(F)(F)F)C
    InChI
    • InChI=1S/C12H10F3N3O4/c1-11(2)9(19)17(10(20)16-11)6-3-4-8(18(21)22)7(5-6)12(13,14)15/h3-5H,1-2H3,(H,16,20) checkY
    • Key:XWXYUMMDTVBTOU-UHFFFAOYSA-N checkY

    Nilutamide, sold under the brand names Nilandron and Anandron, is a medication used to treat prostate cancer.[3] It has also been used as a component of feminizing hormone therapy for transgender women.[10] It is taken by mouth[3]

    Common side effects may include hot flushes, poor ability to see in darkness, nausea, constipation, trouble sleeping, and breat enlargement.[4] Other side effects may include sexual dysfunction, osteoporosis, alcohol intolerance[4][3] Rarely, it can cause pneumonitis and liver damage.[3] These unfavorable side effects have limited it use.[11]

    Nilutamide is a nonsteroidal antiandrogen (NSAA) which acts as a selective antagonist of the androgen receptor (AR), preventing the effects of androgens.[2] As prostate cancer rely on these hormones for growth and survival, it can slow the progression of the disease.[3]

    Nilutamide was discovered in 1977 and was approved for medical use in 1987.[12][13] It was approved in the United States in 1996.[3] It is on the World Health Organization's List of Essential Medicines as an alternative to bicalutamide.[14] It is available as a generic medication.[15] In the United States 30 tablets of 150 mg costs about 1,600 USD as of 2021.[15]

    Medical uses

    Prostate cancer

    Nilutamide is used in prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue at a dosage of 300 mg/day (150 mg twice daily) for the first 4 weeks of treatment, and 150 mg/day thereafter.[16][17] It is not indicated as a monotherapy in prostate cancer.[16] Only one small non-comparative study has assessed nilutamide as a monotherapy in prostate cancer.[18]

    Nilutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.[19][20][21]

    Transgender hormone therapy

    Nilutamide has been studied for use as a component of feminizing hormone therapy for transgender women.[22][10] It has been assessed in at least five small clinical studies for this purpose in treatment-naive subjects.[10][23][24][25][26][27] In these studies, nilutamide monotherapy at a dosage of 300 mg/day, induced observable signs of clinical feminization in young transgender women (age range 19–33 years) within 8 weeks,[24] including breast development, decreased body hair (though not facial hair),[23] decreased morning erections and sex drive,[25] and positive psychological and emotional changes.[25][28] Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity,[27][24][25] and along with decreased hair growth, were the earliest sign of feminization.[24]

    Nilutamide did not change the size of the prostate gland (which is the same as with high-dosage cyproterone acetate and ethinylestradiol treatment for as long as 18 months), but was found to alter its histology, including increased stromal tissue with a significant reduction in acini and atrophic epithelial cells, indicating glandular atrophy.[26][27][29] In addition, readily apparent histological changes were observed in the testes, including a reduction in tubular and interstitial cells.[26]

    Nilutamide was found to more than double luteinizing hormone (LH) and testosterone levels and to triple estradiol levels.[23][24][26] In contrast, follicle-stimulating hormone levels remained unchanged.[24][26] A slight but significant increase in prolactin levels was observed, and levels of sex hormone-binding globulin increased as well.[24][26] The addition of ethinylestradiol to nilutamide therapy after 8 weeks abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range.[23][24] Both nilutamide alone and the combination of nilutamide and estrogen were regarded as resulting in effective and favorable antiandrogen action and feminization in transgender women.[23][24]

    Skin conditions

    Nilutamide has been assessed in the treatment of acne and seborrhea in women in at least one small clinical study.[30][31] The dosage used was 200 mg/day, and in the study, "seborrhea and acne decreased markedly within the first month and practically disappeared after 2 months of [nilutamide] treatment."[30][31]

    Available forms

    Nilutamide is available in the form of 50 and 150 mg oral tablets.[32]

    Side effects

    General side effects of NSAAs, including nilutamide, include gynecomastia, breast pain/tenderness, hot flashes (67%), depression, fatigue, sexual dysfunction (including loss of libido and erectile dysfunction), decreased muscle mass, and decreased bone mass with an associated increase in fractures.[33][34][4] Also, nausea (24–27%), vomiting, constipation (20%), and insomnia (16%) may occur with nilutamide.[4] Nilutamide monotherapy is known to eventually induce gynecomastia in 40 to 80% of men treated with it for prostate cancer, usually within 6 to 9 months of treatment initiation.[35][36][37][38]

    Relative to other NSAAs, nilutamide has been uniquely associated with mild and reversible visual disturbances (31–58%) including delayed ocular adaptation to darkness and impaired color vision,[39] a disulfiram-like[33] alcohol intolerance (19%), interstitial pneumonitis (0.77–2.4%)[40][41][42] (which can result in dyspnea (1%) as a secondary effect and can progress to pulmonary fibrosis),[43] and hepatitis (1%), and has a higher incidence of nausea and vomiting compared to other NSAAs.[44][16][4][45] The incidence of interstitial pneumonitis with nilutamide has been found to be much higher in Japanese patients (12.6%), warranting particular caution in Asian individuals.[46][47] There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient.[48]

    There is also a risk of hepatoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide.[9][49] The incidence of abnormal liver function tests (e.g., elevated liver enzymes) has been variously reported as 2 to 33% with nilutamide.[50][1] For comparison, the risk of elevated liver enzymes has been reported as 4 to 62% in the case of flutamide.[50][51][9] The risk of hepatotoxicity with nilutamide has been described as far less than with flutamide.[1] Fulminant hepatic failure has been reported for nilutamide, with fatal outcome.[9][52][53][54] Between 1986 and 2003, the numbers of published cases of hepatotoxicity for antiandrogens totaled 46 for flutamide, 21 for cyproterone acetate, 4 for nilutamide, and 1 for bicalutamide.[55] Similarly to flutamide, nilutamide exhibits mitochondrial toxicity in hepatocytes by inhibiting respiratory complex I (NADH ubiquinone oxidoreductase) (though not respiratory complexes II, III, or IV) in the electron transport chain, resulting in reduced ATP and glutathione production and thus decreased hepatocyte survival.[54][56][57] The nitro group of nilutamide has been theorized to be involved in both its hepatotoxicity and its pulmonary toxicity.[57][58]

    Side effects of combined androgen blockade with nilutamide and surgical castration
    ClassSide effectNilutamide 150 mg/day +
    orchiectomy (n = 225) (%)a,b    		Placebo + orchi-
    ectomy     (n = 232) (%)a,b
    Cardiovascular systemHypertension5.32.6
    Digestive systemNausea9.86.0
    Constipation7.13.9
    Endocrine systemHot flashes28.422.4
    Metabolic and nutritional systemIncreased aspartate transaminase8.03.9
    Increased alanine transaminase7.64.3
    Nervous systemDizziness7.13.4
    Respiratory systemDyspnea6.27.3
    Special sensesImpaired adaptation to darkness12.91.3
    Abnormal vision6.71.7
    Urogenital systemUrinary tract infection8.09.1
    Overall8681
    Footnotes: a = Phase III studies of combined androgen blockade (nilutamide + orchiectomy) in men with advanced prostate cancer. b = Incidence ≥5% regardless of causality. Sources: See template.
    Side effects of combined androgen blockade with nilutamide and a GnRH agonist
    ClassSide effectNilutamide 150 mg/day +
    leuprorelin (n = 209) (%)a,b    		Placebo + leupro-
    relin     (n = 202) (%)a,b
    Body as a wholePain26.827.7
    Headache13.910.4
    Asthenia19.120.8
    Back pain11.516.8
    Abdominal pain10.05.4
    Chest pain7.24.5
    Flu syndrome7.23.0
    Fever5.36.4
    Cardiovascular systemHypertension9.19.9
    Digestive systemNausea23.98.4
    Constipation19.616.8
    Anorexia11.06.4
    Dyspepsia6.74.5
    Vomiting5.74.0
    Endocrine systemHot flashes66.559.4
    Erectile dysfunction11.012.9
    Decreased libido11.04.5
    Hemic and lymphatic systemAnemia7.26.4
    Metabolic and nutritional systemIncreased aspartate transaminase12.913.9
    Peripheral edema12.417.3
    Increased alanine transaminase9.18.9
    Musculoskeletal systemBone pain6.25.0
    Nervous systemInsomnia16.315.8
    Dizziness10.011.4
    Depression8.67.4
    Hypesthesia5.32.0
    Respiratory systemDyspnea10.57.4
    Upper respiratory infection8.110.9
    Pneumonia5.33.5
    Skin and appendagesSweating6.23.0
    Decreased body hair5.70.5
    Dry skin5.32.5
    Rash5.34.0
    Special sensesImpaired adaptation to darkness56.95.4
    Chromatopsia8.60.0
    Impaired adaptation to light7.71.0
    Abnormal vision6.24.5
    Urogenital systemTesticular atrophy16.312.4
    Gynecomastia10.511.9
    Urinary tract infection8.621.3
    Hematuria8.17.9
    Urinary tract disorder7.210.4
    Nocturia6.76.4
    Overall99.598.5
    Footnotes: a = Phase III studies of combined androgen blockade (nilutamide + GnRH agonist) in men with advanced prostate cancer. b = Incidence ≥5% regardless of causality. Sources: See template.

    Pharmacology

    Pharmacodynamics

    Antiandrogenic activity

    Affinities[lower-alpha 1][59]
    Compound RBA[lower-alpha 2]
    Metribolone 100
    Dihydrotestosterone 85
    Cyproterone acetate 7.8
    Bicalutamide 1.4
    Nilutamide 0.9
    Hydroxyflutamide 0.57
    Flutamide <0.0057
    Notes:
    1. ↑ At androgen receptors; measured in human prostate tissue.
    2. ↑ Relative to Metribolone, which is by definition 100%

    Nilutamide acts as a selective competitive silent antagonist of the AR (IC50 = 412 nM),[60] which prevents androgens like testosterone and DHT from activating the receptor.[22] The affinity of nilutamide for the AR is about 1 to 4% of that of testosterone and is similar to that of bicalutamide and 2-hydroxyflutamide.[61][62][63] Similarly to 2-hydroxyflutamide, but unlike bicalutamide, nilutamide is able to weakly activate the AR at high concentrations.[62] It does not inhibit 5α-reductase.[64]

    Like other NSAAs such as flutamide and bicalutamide, nilutamide, without concomitant GnRH analogue therapy, increases serum androgen (by two-fold in the case of testosterone), estrogen, and prolactin levels due to inhibition of AR-mediated suppression of steroidogenesis via negative feedback on the hypothalamic–pituitary–gonadal axis.[22] As such, though nilutamide is still effective as an antiandrogen as a monotherapy, it is given in combination with a GnRH analogue such as leuprorelin in prostate cancer to suppress androgen concentrations to castrate levels in order to attain maximal androgen blockade (MAB).[22]

    Like flutamide and bicalutamide, nilutamide is able to cross the blood–brain barrier and has central antiandrogen actions.[65]

    Relative affinities (%) of antiandrogens at steroid-hormone receptors
    AntiandrogenARPRERGRMR
    Cyproterone acetate8–1060<0.151
    Chlormadinone acetate5175<0.1381
    Megestrol acetate5152<0.1503
    Spironolactone70.4a<0.12a182
    Trimethyltrienolone3.6<1<1<1<1
    Inocoterone0.8<0.1<0.1<0.1<0.1
    Inocoterone acetate<0.1<0.1<0.1<0.1<0.1
    Flutamide<0.1<0.1<0.1<0.1<0.1
    Hydroxyflutamide0.5–0.8<0.1<0.1<0.1<0.1
    Nilutamide0.5–0.8<0.1<0.1<0.1<0.1
    Bicalutamide1.8<0.1<0.1<0.1<0.1
    Notes: (1): Reference ligands (100%) were testosterone for the AR, progesterone for the PR, estradiol for the ER, dexamethasone for the GR, and aldosterone for the MR. (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0°C) were 24 hours (AR, a), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. Sources: See template.
    Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor
    SpeciesIC50 (nM)RBA (ratio)
    Bicalutamide2-HydroxyflutamideNilutamideBica / 2-OH-fluBica / niluRef
    Rat190700ND4.0ND[66]
    Rat~400~900~9002.32.3[67]
    RatNDNDND3.3ND[68]
    Rata35954565186201.35.2[69]
    Human~300~700~5002.51.6[59]
    Human~100~300ND~3.0ND[70]
    Humana2490234553001.02.1[69]
    Footnotes: a = Controversial data. Sources: See template.

    Cytochrome P450 inhibition

    Nilutamide is known to inhibit several cytochrome P450 enzymes, including CYP1A2, CYP2C9, and CYP3A4, and can result in increased levels of medications that are metabolized by these enzymes.[71] It has also been found to inhibit the enzyme CYP17A1 (17α-hydroxylase/17,20-lyase) in vitro and thus the biosynthesis of androgens.[72][73] However, nilutamide monotherapy significantly increases testosterone levels in vivo, so the clinical significance of this finding is uncertain.[72][73]

    Pharmacokinetics

    Nilutamide has an elimination half-life of 23 to 87 hours, with a mean of 56 hours,[9] or about two days; this allows for once-daily administration.[44] Steady state (plateau) levels of the drug are attained after two weeks of administration with a dosage of 150 mg twice daily (300 mg/day total).[74] It is metabolized by CYP2C19, with at least five metabolites.[8] Virtually all of the antiandrogenic activity of nilutamide comes from the parent drug (as opposed to metabolites).[75]

    Chemistry

    Nilutamide is structurally related to the first-generation NSAAs flutamide and bicalutamide as well as to the second-generation NSAAs enzalutamide and apalutamide.

    History

    Nilutamide was developed by Roussel and was first described in 1977.[12][76][77] It was first introduced for medical use in 1987 in France[9][13] and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995.[44][78] It was not introduced until 1996 in the United States.[79][80][81]

    Society and culture

    Generic names

    Nilutamide is the generic name of the drug and its INN, USAN, BAN, and DCF.[12][82][83][84]

    Brand names

    Nilutamide is marketed under the brand name Nilandron in the United States and under the brand name Anandron elsewhere in the world such as in Australia, Canada, Europe, and Latin America.[82][84]

    Availability

    Nilutamide is or has been available in the United States, Canada, Australia, Europe, Latin America, Egypt, and Lebanon.[82][84] In Europe, it is or has been available in Belgium, Croatia, the Czech Republic, Finland, France, the Netherlands, Norway, Poland, Portugal, Serbia, Sweden, Switzerland, and Yugoslavia.[82][84] in Latin America, it is or has been available in Argentina, Brazil, and Mexico.[82][84]

    Research

    The combination of an estrogen and nilutamide as a form of combined androgen blockade for the treatment of prostate cancer has been studied in animals.[85]

    Nilutamide has been studied in the treatment of advanced breast cancer.[86][87]

    References

    1. 1 2 3 "Nilutamide - LiverTox". National Institutes of Health. Archived from the original on 24 September 2018. Retrieved 24 September 2018. In large registration clinical trials, ALT elevations occurred in 2% to 33% of patients during nilutamide therapy. The elevations were usually mild, asymptomatic and transient, rarely requiring drug discontinuation. In rare instances, clinically apparent acute liver injury has occurred during nilutamide therapy, but the number of published cases are few, and the agent appears to be far less hepatotoxic than flutamide.
    2. 1 2 "DailyMed - NILUTAMIDE tablet". dailymed.nlm.nih.gov. Archived from the original on 24 March 2021. Retrieved 13 November 2021.
    3. 1 2 3 4 5 6 7 "Nilutamide Monograph for Professionals". Drugs.com. Archived from the original on 4 March 2016. Retrieved 13 November 2021.
    4. 1 2 3 4 5 6 Richard A. Lehne (2013). Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 1297–. ISBN 978-1-4377-3582-6. Archived from the original on 27 July 2020. Retrieved 4 October 2021.
    5. ↑ "Nilutamide (Nilandron) Use During Pregnancy". Archived from the original on 28 October 2020. Retrieved 4 October 2021.
    6. 1 2 3 4 5 Michael C. Perry; Donald C. Doll; Carl E. Freter (30 July 2012). Perry's The Chemotherapy Source Book. Lippincott Williams & Wilkins. pp. 711–. ISBN 978-1-4698-0343-2.
    7. 1 2 3 4 5 Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1373–. ISBN 978-1-60913-345-0. Archived from the original on 14 September 2021. Retrieved 4 October 2021.
    8. 1 2 Bruce A. Chabner; Dan L. Longo (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 680–. ISBN 978-1-60547-431-1. Archived from the original on 27 July 2020. Retrieved 4 October 2021.
    9. 1 2 3 4 5 6 7 Kolvenbag, Geert J. C. M.; Furr, Barrington J. A. (2009). "Nonsteroidal Antiandrogens". In V. Craig Jordan; Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. doi:10.1007/978-1-59259-152-7_16. ISBN 978-1-60761-471-5. Although the t1/2 of nilutamide is h (mean 56 h) (39), suggesting that once-daily dosing would be appropriate, a three times per day regimen has been employed in most clinical trials.
    10. 1 2 3 <Baudewijntje P.C. Kreukels; Thomas D. Steensma; Annelou L.C. de Vries (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. Archived from the original on 14 September 2021. Retrieved 4 October 2021.
    11. ↑ 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.
    12. 1 2 3 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 873–. ISBN 978-1-4757-2085-3.
    13. 1 2 János Fischer; Christian Klein; Wayne E. Childers (16 April 2018). Successful Drug Discovery. Wiley. pp. 98–. ISBN 978-3-527-80868-7. Archived from the original on 28 October 2021. Retrieved 4 October 2021.
    14. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
    15. 1 2 "Nilutamide Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 8 November 2016. Retrieved 13 November 2021.
    16. 1 2 3 Chawnshang Chang (1 January 2005). Prostate Cancer: Basic Mechanisms and Therapeutic Approaches. World Scientific. pp. 11–. ISBN 978-981-256-920-2. Archived from the original on 25 April 2016. Retrieved 4 October 2021.
    17. ↑ Jonathan Upfal (2006). The Australian Drug Guide: Every Person's Guide to Prescription and Over-the-counter Medicines, Street Drugs, Vaccines, Vitamins and Minerals... Black Inc. pp. 283–. ISBN 978-1-86395-174-6.
    18. ↑ Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU Int. 91 (5): 455–61. doi:10.1046/j.1464-410X.2003.04026.x. PMID 12603397. S2CID 8639102. Trial experience with nilutamide monotherapy is limited to one small non-comparative study involving 26 patients with metastatic disease given nilutamide 100 mg three times daily (the dose used when nilutamide is administered as a component of MAB) [14]. The median progression-free survival in these patients was 9 months, with a median overall survival of 23 months. There have been no comparative trials of nilutamide with other antiandrogens or with castration [15]. The limited available data on nilutamide monotherapy means that no meaningful conclusions about the role of nilutamide in this setting can be determined. Nilutamide is not licensed as monotherapy.
    19. ↑ Thompson IM (2001). "Flare Associated with LHRH-Agonist Therapy". Rev Urol. 3 Suppl 3: S10–4. PMC 1476081. PMID 16986003.
    20. ↑ Scaletscky R, Smith JA (April 1993). "Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it?". Drug Saf. 8 (4): 265–70. doi:10.2165/00002018-199308040-00001. PMID 8481213. S2CID 36964191.
    21. ↑ Kuhn JM, Billebaud T, Navratil H, Moulonguet A, Fiet J, Grise P, Louis JF, Costa P, Husson JM, Dahan R (August 1989). "Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide)". N. Engl. J. Med. 321 (7): 413–8. doi:10.1056/NEJM198908173210701. PMID 2503723.
    22. 1 2 3 4 Louis Denis (6 December 2012). Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment. Springer Science & Business Media. pp. 194–210. ISBN 978-3-642-45745-6.
    23. 1 2 3 4 5 Asscheman, H.; Gooren, I. J. G.; Peereboom-Wynia, J. D. R. (1989). "Reduction in undesired sexual hair growth with Anandron in male-to-female transsexuals-experiences with a novel androgen receptor blocker". Clinical and Experimental Dermatology. 14 (5): 361–363. doi:10.1111/j.1365-2230.1989.tb02585.x. ISSN 0307-6938. PMID 2612040. S2CID 45303518.
    24. 1 2 3 4 5 6 7 8 9 Rao, B.Ramanath; de Voogt, H.J.; Geldof, A.A.; Gooren, L.J.G.; Bouman, F.G. (1988). "Merits and considerations in the use of anti-androgen". Journal of Steroid Biochemistry. 31 (4): 731–737. doi:10.1016/0022-4731(88)90024-6. ISSN 0022-4731. PMID 3143862.
    25. 1 2 3 4 van Kemenade, Johannes F. L. M.; Cohen-Kettenis, Peggy T.; Cohen, Leo; Gooren, Louis J. G. (1989). "Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals". Archives of Sexual Behavior. 18 (3): 217–228. doi:10.1007/BF01543196. ISSN 0004-0002. PMID 2751416. S2CID 44664956.
    26. 1 2 3 4 5 6 Gooren, L.; Spinder, T.; Spijkstra, J. J.; Van Kessel, H.; Smals, A.; Rao, B. R.; 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". The Journal of Clinical Endocrinology & Metabolism. 64 (4): 763–770. doi:10.1210/jcem-64-4-763. ISSN 0021-972X. PMID 3102546.
    27. 1 2 3 De Voogt, H. J.; Rao, B. R.; Geldof, A. A.; Gooren, L. J. G.; Bouman, F. G. (1987). "Androgen action blockade does not result in reduction in size but changes histology of the normal human prostate". The Prostate. 11 (4): 305–311. doi:10.1002/pros.2990110403. ISSN 0270-4137. PMID 2960959. S2CID 84632739.
    28. ↑ 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.
    29. ↑ Drugs & Aging. Adis International. 1993. Archived from the original on 28 October 2021. Retrieved 4 October 2021. In 16 male subjects undergoing androgen blockade with nilutamide 100 to 300 mg/day for 8 weeks for male to female gender reassignment, prostate volume was not changed (de Voogt et al. 1987).
    30. 1 2 Couzinet B, Thomas G, Thalabard JC, Brailly S, Schaison G (1989). "Effects of a pure antiandrogen on gonadotropin secretion in normal women and in polycystic ovarian disease". Fertil. Steril. 52 (1): 42–50. doi:10.1016/s0015-0282(16)60786-0. PMID 2744186.
    31. 1 2 Namer M (1988). "Clinical applications of antiandrogens". J. Steroid Biochem. 31 (4B): 719–29. doi:10.1016/0022-4731(88)90023-4. PMID 2462132.
    32. ↑ Robert A. Meyers (2 March 2018). Translational Medicine: Molecular Pharmacology and Drug Discovery. Wiley. pp. 46–. ISBN 978-3-527-68719-0. Archived from the original on 28 October 2021. Retrieved 4 October 2021.
    33. 1 2 Richard C. Dart (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 521–. ISBN 978-0-7817-2845-4. Archived from the original on 23 April 2016. Retrieved 4 October 2021.
    34. ↑ Lisa M DeAngelis MD; Jerome B Posner MD (12 September 2008). Neurologic Complications of Cancer. Oxford University Press, USA. pp. 479–. ISBN 978-0-19-971055-3. Archived from the original on 27 July 2020. Retrieved 4 October 2021.
    35. ↑ 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 Urológicas Españolas (English Edition). 38 (1): 34–40. doi:10.1016/j.acuroe.2013.10.002. ISSN 2173-5786. PMID 23850393. [...] the frequency of gynecomastia with antiandrogens in monotherapy is [...] around [...] 79% with nilutamide [...]
    36. ↑ Deepinder, Fnu; Braunstein, Glenn D (2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–795. doi:10.1517/14740338.2012.712109. ISSN 1474-0338. PMID 22862307. S2CID 22938364. 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 [...]
    37. ↑ Michalopoulos, Nikolaos V.; Keshtgar, Mohammed R. (2012). "Gynecomastia Induced by Prostate-Cancer Treatment". New England Journal of Medicine. 367 (15): 1449. doi:10.1056/NEJMicm1209166. ISSN 0028-4793. PMID 23050528. Gynecomastia occurs in up to 80% of patients who receive nonsteroidal antiandrogens (eg, bicalutamide, flutamide, or nilutamide), usually within the first 6 to 9 months after the initiation of treatment.
    38. ↑ Di Lorenzo G, Autorino R, Perdonà S, De Placido S (December 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.
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    54. 1 2 Merwat, Shehzad N.; Kabbani, Wareef; Adler, Douglas G. (2008). "Fulminant Hepatic Failure due to Nilutamide Hepatotoxicity". Digestive Diseases and Sciences. 54 (4): 910–913. doi:10.1007/s10620-008-0406-8. ISSN 0163-2116. PMID 18688719. S2CID 27421870. In addition, nilutamide is noted to exhibit mitochondrial toxicity by inhibiting complex I activity of the mitochondrial respiratory chain leading to the impairment of ATP formation and the biosynthesis of glutathione, thereby possibly predisposing the liver to toxicity [13].
    55. ↑ Chitturi, Shivakumar; Farrell, Geoffrey C (2013). "Adverse Effects of Hormones and Hormone Antagonists on the Liver". Drug-Induced Liver Disease. Current Treatment Options in Gastroenterology. Vol. 3. pp. 605–619. doi:10.1016/B978-0-12-387817-5.00033-9. ISBN 9780123878175. PMID 11096606. Liver injury is well recognized with all antiandrogens (Table 33-3). Thus, among all published cases identified between 1986 and 2003, flutamide (46), cyproterone (21), nilutamide (4), and bicalutamide (1) were implicated [107,108].
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