Editing Antiandrogen (section)

==History==
{{See also|Discovery and development of antiandrogens}}

Antigonadotropins like estrogens and progestogens were both first introduced in the 1930s.<ref name="FritzSperoff2012">{{cite book| vauthors = Fritz MA, Speroff L |title=Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=KZLubBxJEwEC&pg=PA750|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4847-3|pages=750–751, 963}}</ref> The beneficial effects of androgen deprivation via surgical castration or high-dose estrogen therapy on prostate cancer were discovered in 1941.<ref name="FiggChau2010"/>{{rp|56}}<ref name="KavoussiCostabile2012">{{cite book | vauthors = Kavoussi P, Costabile RA, Salonia A |title=Clinical Urologic Endocrinology: Principles for Men's Health |url=https://books.google.com/books?id=osURyQf4-2EC&pg=PR7 |date=17 October 2012 |publisher=Springer Science & Business Media |isbn=978-1-4471-4404-5 |pages=7–}}</ref> AR antagonists were first discovered in the early 1960s.<ref name="Weber2015" /> The steroidal antiandrogen cyproterone acetate was discovered in 1961 and introduced in 1973, and is often described as the first antiandrogen to have been marketed.<ref name="AcademicPress1997">{{cite book|title=Advances in Drug Research|url=https://books.google.com/books?id=f1aKl17UpxkC&pg=PA34|date=12 August 1997|publisher=Academic Press|isbn=978-0-08-052628-7|pages=34–}}</ref><ref name="StunkardBaum1989" /> However, spironolactone was introduced in 1959,<ref name="Jugdutt2014">{{cite book|vauthors=Jugdutt BI|title=Aging and Heart Failure: Mechanisms and Management|url=https://books.google.com/books?id=0e23BAAAQBAJ&pg=PA175|date=19 February 2014|publisher=Springer Science & Business Media|isbn=978-1-4939-0268-2|pages=175–|access-date=27 December 2016|archive-date=11 January 2023|archive-url=https://web.archive.org/web/20230111122900/https://books.google.com/books?id=0e23BAAAQBAJ&pg=PA175|url-status=live}}</ref><ref name="Wermuth2011">{{cite book| vauthors = Wermuth CG |title=The Practice of Murl=https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34|date=2 May 2011|publisher=Academic Press|isbn=978-0-08-056877-5|pages=34–|author-link = Camille Georges Wermuth}}</ref> although its antiandrogen effects were not recognized or taken advantage of until later and were originally an unintended off-target action of the drug.<ref name="Azziz2007">{{cite book| vauthors = Azziz R |title=Androgen Excess Disorders in Women|url=https://books.google.com/books?id=Ch-BsGAOtucC&pg=PA382|date=8 November 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-179-6|pages=382–}}</ref> In addition to spironolactone, chlormadinone acetate and megestrol acetate are steroidal antiandrogens that are weaker than cyproterone acetate but were also introduced earlier, in the 1960s.<ref name="RunnebaumRabe2012">{{cite book| vauthors = Runnebaum BC, Rabe T, Kiesel L |title=Female Contraception: Update and Trends|url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA136|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=136–}}</ref><ref name="OrfanosMontagna2012">{{cite book| vauthors = Orfanos CE, Montagna W, Stüttgen G |title=Hair Research: Status and Future Aspects; Proceedings of the First International Congress on Hair Research, Hamburg, March 13th–16, 1979|url=https://books.google.com/books?id=4gBJCAAAQBAJ&pg=PT587|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-81650-5|pages=587–}}</ref><ref name="Marks2010">{{cite book| vauthors = Marks L |title=Sexual Chemistry: A History of the Contraceptive Pill|url=https://books.google.com/books?id=_i-s4biQs7MC&pg=PA76|year=2010|publisher=Yale University Press|isbn=978-0-300-16791-7|pages=76–78}}</ref> Other early steroidal antiandrogens that were developed around this time but were never marketed include [[benorterone]] (SKF-7690; 17α-methyl-''B''-nortestosterone), [[BOMT]] (Ro 7–2340), [[cyproterone]] (SH-80881), and [[trimethyltrienolone]] (R-2956).<ref name="HorskyPresl2012">{{cite book| vauthors = Horsky J, Presl J |title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA112|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=112–}}</ref><ref name="AcademicPress1976">{{cite book|title=Vitamins and Hormones|url=https://books.google.com/books?id=5ZbLRONHoDoC&pg=PA682|date=18 May 1976|publisher=Academic Press|isbn=978-0-08-086630-7|pages=682–}}</ref>

The nonsteroidal antiandrogen flutamide was first reported in 1967.<ref name="SmithWilliams2005" /> It was introduced in 1983 and was the first nonsteroidal antiandrogen marketed.<ref name="Neal2012">{{cite book| vauthors = Neal DE |title=Tumours in Urology|url=https://books.google.com/books?id=k28yBwAAQBAJ&pg=PT233|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4471-2086-5|pages=233–}}</ref><ref name="OttowWeinmann2008">{{cite book| vauthors = Ottow E, Weinmann H |title= Nuclear Receptors as Drug Targets|url=https://books.google.com/books?id=iATfLbPgRugC&pg=PA255|date=8 September 2008|publisher=John Wiley & Sons|isbn=978-3-527-62330-3|pages=255–}}</ref> Another early nonsteroidal antiandrogen,<ref name="SinghalThomas1976">{{cite book| vauthors = Singhal RL, Thomas JA |title=Cellular Mechanisms Modulating Gonadal Action|url=https://books.google.com/books?id=2eNqAAAAMAAJ|date=1 January 1976|publisher=University Park Press|isbn=978-0-8391-0776-7|page=239}}</ref> [[DIMP (antiandrogen)|DIMP]] (Ro 7–8117), which is structurally related to [[thalidomide]]<ref name="LiuSu2010">{{cite journal | vauthors = Liu B, Su L, Geng J, Liu J, Zhao G | title = Developments in nonsteroidal antiandrogens targeting the androgen receptor | journal = ChemMedChem | volume = 5 | issue = 10 | pages = 1651–1661 | date = October 2010 | pmid = 20853390 | doi = 10.1002/cmdc.201000259 | s2cid = 23228778 }}</ref> and is a relatively weak antiandrogen,<ref name="HeynsG.1976">{{cite journal | vauthors = Heyns W, Verhoeven G, De Moor P | title = Androgen binding in rat uterus cytosol. Study of the specificity | journal = Journal of Steroid Biochemistry | volume = 7 | issue = 5 | pages = 335–343 | date = May 1976 | pmid = 180344 | doi = 10.1016/0022-4731(76)90092-3 }}</ref><ref>{{cite book|title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=qsFCGskRHZQC&pg=PA182|date=16 September 1986|publisher=Academic Press|isbn=978-0-08-058365-5|pages=182–}}</ref> was first described in 1973 and was never marketed.<ref name="BorisScott1973">{{cite journal | vauthors = Boris A, Scott JW, DeMartino L, Cox DC | title = Endocrine profile of a nonsteroidal antiandrogen N-(3,5-dimethyl-4-isoxazolylmethyl)phthalimide (DIMP) | journal = Acta Endocrinologica | volume = 72 | issue = 3 | pages = 604–614 | date = March 1973 | pmid = 4739363 | doi = 10.1530/acta.0.0720604 }}</ref> Flutamide was followed by nilutamide in 1989, and bicalutamide in 1995.<ref name="BéguéBonnet-Delpon2008">{{cite book|vauthors=Bégué JP, Bonnet-Delpon D|title=Bioorganic and Medicinal Chemistry of Fluorine|url=https://books.google.com/books?id=QMVSvZ-R7I0C&pg=PA327|date=2 June 2008|publisher=John Wiley & Sons|isbn=978-0-470-28187-1|pages=327–|access-date=27 December 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112173104/https://books.google.com/books?id=QMVSvZ-R7I0C&pg=PA327|url-status=live}}</ref> In addition to these three drugs, which have been regarded as first-generation nonsteroidal antiandrogens, the second-generation nonsteroidal antiandrogens [[enzalutamide]] and [[apalutamide]] were introduced in 2012 and 2018, respectively.<ref name="pmid23341368">{{cite journal | vauthors = Menon MP, Higano CS | title = Enzalutamide, a second generation androgen receptor antagonist: development and clinical applications in prostate cancer | journal = Current Oncology Reports | volume = 15 | issue = 2 | pages = 69–75 | date = April 2013 | pmid = 23341368 | doi = 10.1007/s11912-013-0293-9 | s2cid = 8725297 }}</ref><ref name="pmid19359544">{{cite journal | vauthors = 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 | display-authors = 6 | title = Development of a second-generation antiandrogen for treatment of advanced prostate cancer | journal = Science | volume = 324 | issue = 5928 | pages = 787–790 | date = May 2009 | pmid = 19359544 | pmc = 2981508 | doi = 10.1126/science.1168175 | bibcode = 2009Sci...324..787T }}</ref><ref name="FDA2018">{{Cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596768.htm|title=FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint|website=[[Food and Drug Administration]]|date=24 March 2020|access-date=1 April 2018|archive-date=23 April 2019|archive-url=https://web.archive.org/web/20190423072230/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596768.htm|url-status=live}}</ref> They differ from the earlier nonsteroidal antiandrogens namely in that they are much more efficacious in comparison.<ref name="pmid19359544" />

The androgen synthesis inhibitors aminoglutethimide and ketoconazole were first marketed in 1960 and 1977, respectively,<ref name="Sneader2005">{{cite book| vauthors = Sneader W |title=Drug Discovery: A History|url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA367|date=23 June 2005|publisher=John Wiley & Sons|isbn=978-0-471-89979-2|pages=367–}}</ref><ref name="Golan2008">{{cite book|vauthors=Golan DE|title=Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy|url=https://books.google.com/books?id=az8uSDkB0mgC&pg=PA624|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-8355-2|pages=624–|access-date=2016-12-27|archive-date=2023-01-10|archive-url=https://web.archive.org/web/20230110131048/https://books.google.com/books?id=az8uSDkB0mgC&pg=PA624|url-status=live}}</ref> and the newer drug abiraterone acetate was introduced in 2011.<ref name="Demos2011">{{cite book|title=Prostate Cancer|url=https://books.google.com/books?id=WJkjgbRJe3EC&pg=PA518|date=20 December 2011|publisher=Demos Medical Publishing|isbn=978-1-935281-91-7|pages=518–}}</ref> GnRH modulators were first introduced in the 1980s.<ref name="BowsherCarter2008">{{cite book| vauthors = Bowsher W, Carter A |title= Challenges in Prostate Cancer|url=https://books.google.com/books?id=E3VNhLkqPmUC&pg=PA138|date=15 April 2008|publisher=John Wiley & Sons|isbn=978-1-4051-7177-9|pages=138–}}</ref> The 5α-reductase inhibitors finasteride and dutasteride were introduced in 1992. and 2002. respectively.<ref name="AllahbadiaAgrawal2007">{{cite book| vauthors = Allahbadia G, Agrawal R, Merchant R |title=Polycystic Ovary Syndrome|url=https://books.google.com/books?id=HX0JxcrWJvAC&pg=PA184|year=2007|publisher=Anshan|isbn=978-1-904798-74-3|pages=184–}}</ref><ref name="Bentham2010">{{cite book|title=Frontiers in Medicinal Chemistry|url=https://books.google.com/books?id=b7hCWvdP5OYC&pg=PA329|year=2010|publisher=Bentham Science Publishers|isbn=978-1-60805-208-0|pages=329–}}</ref> [[Elagolix]], the first orally active GnRH modulator to be marketed, was introduced in 2018.<ref name="AdisInsight-Elagolix">{{Cite web | url = https://adisinsight.springer.com/drugs/800020238 | title = Elagolix - Abbvie/Neurocrine Biosciences | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 2018-07-30 | archive-date = 2018-09-20 | archive-url = https://web.archive.org/web/20180920082806/https://adisinsight.springer.com/drugs/800020238 | url-status = live }}</ref>

===Timeline===
The following is a timeline of events in the history of antiandrogens:<ref name="pmid29730201">{{cite journal | vauthors = Crawford ED, Schellhammer PF, McLeod DG, Moul JW, Higano CS, Shore N, Denis L, Iversen P, Eisenberger MA, Labrie F | title = Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens | journal = J. Urol. | volume = 200 | issue = 5 | pages = 956–966 | date = November 2018 | pmid = 29730201 | doi = 10.1016/j.juro.2018.04.083 | s2cid = 19162538 }}</ref>

* 1941: Hudgins and Hodges show that androgen deprivation via high-dose estrogen therapy or surgical castration treats prostate cancer
* 1957: The steroidal antiandrogen spironolactone is first synthesized<ref name="pmid28634268">{{cite journal | vauthors = Kolkhof P, Bärfacker L | title = 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development | journal = J. Endocrinol. | volume = 234 | issue = 1 | pages = T125–T140 | date = July 2017 | pmid = 28634268 | pmc = 5488394 | doi = 10.1530/JOE-16-0600 }}</ref>
* 1960: Spironolactone is first introduced for medical use, as an antimineralocorticoid<ref name="pmid28634268" />
* 1961: The steroidal antiandrogen cyproterone acetate is first synthesized<ref name="pmid9476091">{{cite journal | vauthors = Pucci E, Petraglia F | title = Treatment of androgen excess in females: yesterday, today and tomorrow | journal = Gynecol. Endocrinol. | volume = 11 | issue = 6 | pages = 411–33 | date = December 1997 | pmid = 9476091 | doi = 10.3109/09513599709152569 }}</ref>
* 1962: Spironolactone is first reported to produce gynecomastia in men<ref name="pmid28634268" /><ref name="Smith1962">{{cite journal| vauthors = Smith WG |title=Spironolactone and gynaecomastia|journal=The Lancet|volume=280|issue=7261|year=1962|pages=886|issn=0140-6736|doi=10.1016/S0140-6736(62)90668-2}}</ref>
* 1966: Benorterone is the first known antiandrogen to be studied clinically, to treat acne and hirsutism in women<ref name="pmid148431">{{cite journal | vauthors = Stewart ME, Pochi PE | title = Antiandrogens and the skin | journal = Int. J. Dermatol. | volume = 17 | issue = 3 | pages = 167–79 | date = April 1978 | pmid = 148431 | doi = 10.1111/j.1365-4362.1978.tb06057.x | s2cid = 43649686 }}</ref><ref name="pmid4225258">{{cite journal | vauthors = Zarate A, Mahesh VB, Greenblatt RB | title = Effect of an antiandrogen, 17-alpha-methyl-B-nortestosterone, on acne and hirsutism | journal = J. Clin. Endocrinol. Metab. | volume = 26 | issue = 12 | pages = 1394–8 | date = December 1966 | pmid = 4225258 | doi = 10.1210/jcem-26-12-1394 }}</ref>
* 1963: The antiandrogenic activity of cyproterone acetate is discovered<ref name="Neumann1996">{{cite book| vauthors = Neumann F |title=Antiandrogens in Prostate Cancer|chapter=Pharmacology of Cyproterone Acetate — A Short Review|year=1996|pages=31–44|doi=10.1007/978-3-642-45745-6_3|isbn=978-3-642-45747-0}}</ref><ref name="pmid14071315">{{cite journal | vauthors = Hamada H, Neumann F, Junkmann K | title = Intrauterine Antimaskuline Beeinflussung von Rattenfeten Durch ein Stark Gestagen Wirksames Steroid | language = de | journal = Acta Endocrinologica | volume = 44 | issue = 3 | pages = 380–388 | date = November 1963 | pmid = 14071315 | doi = 10.1530/acta.0.0440380 | trans-title = Intrauterine antimasculine influence of Rat Fetuses by Birtue of a Powerful Steroid Acting as a Progestogen }}</ref>
* 1967: A known antiandrogen, benorterone, is first reported to induce gynecomastia in males<ref name="pmid148431" />
* 1967: The first-generation nonsteroidal antiandrogen flutamide is first synthesized
* 1967: Cyproterone acetate was first studied clinically, to treat sexual deviance in men<ref name="pmid20459370">{{cite journal | vauthors = Thibaut F, De La Barra F, Gordon H, Cosyns P, Bradford JM | title = The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias | journal = World J. Biol. Psychiatry | volume = 11 | issue = 4 | pages = 604–55 | date = June 2010 | pmid = 20459370 | doi = 10.3109/15622971003671628 | s2cid = 14949511 }}</ref>
* 1969: Cyproterone acetate was first studied in the treatment of acne, hirsutism, seborrhea, and scalp hair loss in women<ref name="pmid4304873">{{cite journal | vauthors = Hammerstein J, Cupceancu B | title = Behandlung des Hirsutismus mit Cyproteronacetat | trans-title = Management of hirsutism using cyproterone acetate | language = de | journal = Deutsche Medizinische Wochenschrift | volume = 94 | issue = 16 | pages = 829–34 | date = April 1969 | issn = 0012-0472 | pmid = 4304873 | doi = 10.1055/s-0028-1111126 | s2cid = 71214286 }}</ref>
* 1969: The antiandrogenic activity of spironolactone is discovered<ref name="pmid5344274">{{cite journal | vauthors = Steelman SL, Brooks JR, Morgan ER, Patanelli DJ | title = Anti-androgenic activity of spironolactone | journal = Steroids | volume = 14 | issue = 4 | pages = 449–50 | year = 1969 | pmid = 5344274 | doi = 10.1016/s0039-128x(69)80007-3}}</ref>
* 1972: The antiandrogenic activity of flutamide is first reported<ref name="pmid4264731">{{cite journal | vauthors = Neri R, Florance K, Koziol P, Van Cleave S | title = A biological profile of a nonsteroidal antiandrogen, SCH 13521 (4'-nitro-3'trifluoromethylisobutyranilide) | journal = Endocrinology | volume = 91 | issue = 2 | pages = 427–37 | date = August 1972 | pmid = 4264731 | doi = 10.1210/endo-91-2-427 }}</ref><ref name="pmid4116667">{{cite journal | vauthors = Neri RO, Monahan M | title = Effects of a novel nonsteroidal antiandrogen on canine prostatic hyperplasia | journal = Invest Urol | volume = 10 | issue = 2 | pages = 123–30 | date = September 1972 | pmid = 4116667 }}</ref>
* 1973: Cyproterone acetate was first introduced for medical use, to treat sexual deviance<ref name="pmid8005205">{{cite journal | vauthors = Neumann F | title = The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research | journal = Exp. Clin. Endocrinol. | volume = 102 | issue = 1 | pages = 1–32 | date = 1994 | pmid = 8005205 | doi = 10.1055/s-0029-1211261 | doi-access = free }}</ref>
* 1977: The first-generation antiandrogen nilutamide is first described<ref name="pmid385986">{{cite journal | vauthors = Raynaud JP, Bonne C, Bouton MM, Lagace L, Labrie F | title = Action of a non-steroid anti-androgen, RU 23908, in peripheral and central tissues | journal = J. Steroid Biochem. | volume = 11 | issue = 1A | pages = 93–9 | year = 1979 | pmid = 385986 | doi = 10.1016/0022-4731(79)90281-4}}</ref>
* 1978: Spironolactone is first studied in the treatment of hirsutism in women<ref name="pmid6205409"/><ref name="pmid717935">{{cite journal | vauthors = Ober KP, Hennessy JF | title = Spironolactone therapy for hirsutism in a hyperandrogenic woman | journal = Ann. Intern. Med. | volume = 89 | issue = 5 Pt 1 | pages = 643–4 | year = 1978 | pmid = 717935 | doi = 10.7326/0003-4819-89-5-643}}</ref>
* 1979: Combined androgen blockade is first studied<ref name="pmid16631454">{{cite journal | vauthors = Klotz L | title = Combined androgen blockade: an update | journal = Urol. Clin. North Am. | volume = 33 | issue = 2 | pages = 161–6, v–vi | date = May 2006 | pmid = 16631454 | doi = 10.1016/j.ucl.2005.12.001 }}</ref><ref name="pmid6819101">{{cite journal | vauthors = Labrie F, Dupont A, Belanger A, Cusan L, Lacourciere Y, Monfette G, Laberge JG, Emond JP, Fazekas AT, Raynaud JP, Husson JM | title = New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen | journal = Clin Invest Med | volume = 5 | issue = 4 | pages = 267–75 | date = 1982 | pmid = 6819101 }}</ref>
* 1980: Medical castration via a GnRH analogue is first achieved{{Citation needed|date=March 2020}}
* 1982: The first-generation antiandrogen bicalutamide is first described<ref name="EngelKleemann2014">{{cite book | vauthors = Engel J, Kleemann A, Kutscher B, Reichert D |title=Pharmaceutical Substances: Syntheses, Patents and Applications of the most relevant APIs |edition=5th |year=2009 |url=https://books.google.com/books?id=4lCGAwAAQBAJ&pg=PA153 |publisher=Thieme |isbn=978-3-13-179275-4 |pages=153–154}}</ref>
* 1982: Combined androgen blockade for prostate cancer is developed
* 1983: Flutamide is first introduced, in Chile, for medical use, to treat prostate cancer<ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1695|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1695–|access-date=2 January 2019|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112173105/https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1695|url-status=live}}</ref><ref name="Ireland2013">{{cite book|title=The Irish Reports: Containing Reports of Cases Argued and Determined in the Court of Appeal, the High Court of Justice, the Court of Bankruptcy, in Ireland, and the Irish Land Commission|url=https://books.google.com/books?id=FQhMAQAAIAAJ|year=1990|publisher=Incorporated Council of Law Reporting for Ireland|pages=501–502|access-date=2019-01-02|archive-date=2023-01-12|archive-url=https://web.archive.org/web/20230112173103/https://books.google.com/books?id=FQhMAQAAIAAJ|url-status=live}}</ref>
* 1987: Nilutamide is first introduced, in France, for medical use, to treat prostate cancer<ref name="BéguéBonnet-Delpon2008"/>
* 1989: Combined androgen blockade via flutamide and a GnRH analogue is found to be superior to a GnRH analogue alone for prostate cancer
* 1989: Flutamide is first introduced for medical use in the United States, to treat prostate cancer<ref name="Regitz-Zagrosek2012">{{cite book| vauthors = Regitz-Zagrosek V |title=Sex and Gender Differences in Pharmacology |url= https://books.google.com/books?id=J3VxihGDh9wC&pg=PA575| date=2 October 2012 |publisher=Springer Science & Business Media|isbn=978-3-642-30725-6|pages=575–}}</ref>
* 1989: Flutamide is first studied in the treatment of hirsutism in women<ref name="pmid2147859"/>
* 1992: The androgen synthesis inhibitor abiraterone acetate is first described<ref name="ICR2014">{{Cite web|url=https://www.icr.ac.uk/news-features/latest-features/abiraterone-a-story-of-scientific-innovation-and-commercial-partnership|title=Abiraterone: A story of scientific innovation and commercial partnership - the Institute of Cancer Research, London|access-date=2019-01-02|archive-date=2019-01-01|archive-url=https://web.archive.org/web/20190101101202/https://www.icr.ac.uk/news-features/latest-features/abiraterone-a-story-of-scientific-innovation-and-commercial-partnership|url-status=live}}</ref>
* 1995: Bicalutamide is first introduced for medical use, to treat prostate cancer<ref name="BéguéBonnet-Delpon2008" />
* 1996: Nilutamide is first introduced for medical use in the United States, to treat prostate cancer<ref name="AdisInsight-Nilutamide">{{Cite web | url = http://adisinsight.springer.com/drugs/800004379 | title = Nilutamide | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 2019-01-02 | archive-date = 2021-05-05 | archive-url = https://web.archive.org/web/20210505173834/https://adisinsight.springer.com/drugs/800004379 | url-status = live }}</ref>
* 2006: The second-generation nonsteroidal antiandrogen enzalutamide is first described<ref name="US20070004753">Sawyers, C., Jung, M., Chen, C., Ouk, S., Welsbie, D., Tran, C., ... & Yoo, D. (2006). U.S. Patent Application No. 11/433,829. https://patents.google.com/patent/US20070004753 [https://patents.google.com/patent/US20070004753]</ref>
* 2007: The second-generation nonsteroidal antiandrogen apalutamide is first described<ref name="WO2007126765">{{Cite web|url=https://worldwide.espacenet.com/publicationDetails/originalDocument?FT=D&date=20071108&DB=EPODOC&locale=en_EP&CC=WO&NR=2007126765A2&KC=A2&ND=6|title=Espacenet - Original document|access-date=2019-01-02|archive-date=2021-11-04|archive-url=https://web.archive.org/web/20211104133256/https://worldwide.espacenet.com/publicationDetails/originalDocument?FT=D&date=20071108&DB=EPODOC&locale=en_EP&CC=WO&NR=2007126765A2&KC=A2&ND=6|url-status=live}}</ref>
* 2011: Abiraterone acetate is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Abiraterone-Acetate">{{Cite web|url=https://adisinsight.springer.com/drugs/800005133|title=Abiraterone acetate - Johnson & Johnson|work=AdisInsight|publisher=Springer Nature Switzerland AG|access-date=2019-01-02|archive-date=2019-01-03|archive-url=https://web.archive.org/web/20190103055744/https://adisinsight.springer.com/drugs/800005133|url-status=live}}</ref>
* 2012: Enzalutamide is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Enzalutamide">{{Cite web | url = https://adisinsight.springer.com/drugs/800026688 | title = Enzalutamide - Astellas Pharma/Medivation | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 2019-01-02 | archive-date = 2018-07-17 | archive-url = https://web.archive.org/web/20180717212735/https://adisinsight.springer.com/drugs/800026688 | url-status = live }}</ref>
* 2018: Apalutamide is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Apalutamide">{{Cite web | url = http://adisinsight.springer.com/drugs/800032695 | title = Apalutamide - Janssen Research and Development | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 2019-01-02 | archive-date = 2019-01-03 | archive-url = https://web.archive.org/web/20190103110524/https://adisinsight.springer.com/drugs/800032695 | url-status = live }}</ref>
* 2018: Elagolix is the first orally active GnRH antagonist to be introduced for medical use<ref name="AdisInsight-Elagolix" />
* 2019: Relugolix is the second orally active GnRH antagonist to be introduced for medical use<ref name="AdisInsight-Relugolix">{{Cite web | url = https://adisinsight.springer.com/drugs/800028257 | title = Relugolix - Myovant/Takeda | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 2021-08-19 | archive-date = 2021-08-19 | archive-url = https://web.archive.org/web/20210819053135/https://adisinsight.springer.com/drugs/800028257 | url-status = live }}</ref>
* 2019: Darolutamide is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Darolutamide">{{cite web | title=Darolutamide - Bayer HealthCare/Orion | website=AdisInsight | date=21 January 2025 | url=https://adisinsight.springer.com/drugs/800033671 | access-date=8 May 2025}}</ref>