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Revision as of 09:52, 5 December 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 464157689 of page Diethylstilbestrol for the Chem/Drugbox validation project (updated: '').		Latest revision as of 07:49, 24 December 2024 edit JJMC89 bot III (talk | contribs)Bots, Administrators3,685,221 editsm Moving Category:Intersex and medicine to Category:Intersex healthcare per Misplaced Pages:Categories for discussion/Log/2024 December 14#Category:Intersex and medicine
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			{{Short description|Chemical compound}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{Infobox drug
	{{drugbox
	| Verifiedfields = changed		| Verifiedfields = verified
			| Watchedfields = verified
	| verifiedrevid = 443637686
			| verifiedrevid = 464188812
	| IUPAC_name = 4,4'-(3''E'')-hex-3-ene-3,4-diyldiphenol
			| IUPAC_name = 4,4'-diphenol
	| image = Diethylstilbestrol.png
			| image = Diethylstilbestrol.svg
			| width = 250px
			| image2 = Diethylstilbestrol molecule ball.png
			| width2 = 250px
	<!--Clinical data-->		<!--Clinical data-->
	| Drugs.com = {{drugs.com|CONS|diethylstilbestrol}}		| Drugs.com = {{drugs.com|CONS|diethylstilbestrol}}
	| pregnancy_category = X		| pregnancy_category = X
			| routes_of_administration = ], ], ], ], ] (as an ])
	| routes_of_administration = ], oral
			| class = ]
			<!--Pharmacokinetic data-->
			| bioavailability = Well-absorbed<ref name="ChabnerLongo1996"/>
			| protein_bound = >95%<ref name="OelschlägerRothley1988"/>
			| metabolism = ], ], ]<ref name="ChabnerLongo1996"/><ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/>
			| metabolites = • ]<ref name="ChabnerLongo1996"/><br />• ]<ref name="ChabnerLongo1996"/><br />• ]s<ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/>
			| elimination_half-life = 24 hours<ref name="ChabnerLongo1996"/><ref name="pmid7154205" />
			| excretion = ], ]<ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/>
	<!--Identifiers-->		<!--Identifiers-->
	| CASNo_Ref = {{cascite|correct|CAS}}		| CAS_number_Ref = {{cascite|correct|CAS}}
	| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 56-53-1		| CAS_number = 56-53-1
	| ATC_prefix = G03		| ATC_prefix = G03
	| ATC_suffix = CB02		| ATC_suffix = CB02
	| ATC_supplemental = {{ATC|G03|CC05}}, {{ATC|L02|AA01}}		| ATC_supplemental = {{ATC|G03|CC05}}, {{ATC|L02|AA01}}
	| PubChem = 448537		| PubChem = 448537
			| IUPHAR_ligand = 2801
	| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
			| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB00255		| DrugBank = DB00255
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 411		| ChEMBL = 411
			| synonyms = DES; Stilboestrol; Stilbestrol; (''E'')-11,12-Diethyl-4,13-stilbenediol
	<!--Chemical data-->		<!--Chemical data-->
	| C=18 | H=20 | O=2		| C=18 | H=20 | O=2
			| SMILES = Oc2ccc(/C(=C(/c1ccc(O)cc1)CC)CC)cc2
	| molecular_weight = 268.35 g/mol
	| smiles = Oc2ccc(/C(=C(/c1ccc(O)cc1)CC)CC)cc2
	| InChI = 1/C18H20O2/c1-3-17(13-5-9-15(19)10-6-13)18(4-2)14-7-11-16(20)12-8-14/h5-12,19-20H,3-4H2,1-2H3/b18-17+
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C18H20O2/c1-3-17(13-5-9-15(19)10-6-13)18(4-2)14-7-11-16(20)12-8-14/h5-12,19-20H,3-4H2,1-2H3/b18-17+		| StdInChI = 1S/C18H20O2/c1-3-17(13-5-9-15(19)10-6-13)18(4-2)14-7-11-16(20)12-8-14/h5-12,19-20H,3-4H2,1-2H3/b18-17+
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	| StdInChIKey = RGLYKWWBQGJZGM-ISLYRVAYSA-N		| StdInChIKey = RGLYKWWBQGJZGM-ISLYRVAYSA-N
	}}		}}
			<!-- Definition and medical uses -->
			'''Diethylstilbestrol''' ('''DES'''), also known as '''stilbestrol''' or '''stilboestrol''', is a ] medication, which is presently rarely used.<ref name="pmid4276416" /><ref name="Elks2014">{{Cite book |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA396 |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |vauthors=Elks J |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |pages=396–}}</ref><ref name="Kuhl2005">{{cite journal |vauthors= Kuhl H |title= Pharmacology of estrogens and progestogens: influence of different routes of administration |journal= Climacteric |volume= 8 |issue= Suppl 1 |pages= 3–63 |date= August 2005 |pmid= 16112947 |doi= 10.1080/13697130500148875 |s2cid= 24616324 |url= http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf |access-date= 2018-02-24 |archive-date= 2016-08-22 |archive-url= https://web.archive.org/web/20160822055012/http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf |url-status= live }}</ref> In the past, it was widely used for a variety of indications, including ] support for those with a history of ], ] for ] and ], treatment of ] and ], and other uses.<ref name="pmid4276416" /> By 2007, it was only used in the treatment of prostate cancer and breast cancer.<ref name="Watkins2007">{{cite book |vauthors=Watkins ES |title=The Estrogen Elixir: A History of Hormone Replacement Therapy in America |url=https://books.google.com/books?id=-tz4J4_hgdIC&pg=PA26 |date=16 April 2007 |publisher=JHU Press |isbn=978-0-8018-8602-7 |pages=26– |access-date=3 September 2020 |archive-date=12 May 2024 |archive-url=https://web.archive.org/web/20240512211905/https://books.google.com/books?id=-tz4J4_hgdIC&pg=PA26#v=onepage&q&f=false |url-status=live }}</ref> In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including ], ], ], ], ], ], ], ] prior to age 45, breast cancer, ], and ].<ref>{{cite web | title = Effects of Diethylstilbestrol (DES), a Trans-placental Carcinogen | url = https://dceg.cancer.gov/research/public-health-impact/des | website = dceg.cancer.gov | date = 20 November 2012 | access-date = 3 September 2020 | archive-date = 8 February 2023 | archive-url = https://web.archive.org/web/20230208075515/https://dceg.cancer.gov/research/public-health-impact/des | url-status = live }}</ref> While most commonly taken ], DES was available for use by other ] as well, for instance, ], ], and by ].
			<!-- Side effects and mechanism -->
			DES is an ], or an ] of the ]s, the ] of estrogens like ].<ref name="Kuhl2005" /> It is a ] and ] of the ] group, and differs from the ] estrogen ] in various ways.<ref name="Kuhl2005"/> Compared to estradiol, DES has greatly improved ] when taken by mouth, is more resistant to ], and shows relatively increased effects in certain parts of the body like the ] and ].<ref name="Kuhl2005"/> These differences result in DES having an increased risk of ]s, ], and certain other adverse effects.<ref name="Kuhl2005"/>
			<!-- History, society, and culture -->
			DES was discovered in 1938 and introduced for medical use in 1939.<ref name="pmid16096877">{{cite journal |vauthors= Veurink M, Koster M, Berg LT |title= The history of DES, lessons to be learned |journal= Pharm World Sci |volume= 27 |issue= 3 |pages= 139–43 |date= June 2005 |pmid= 16096877 |doi= 10.1007/s11096-005-3663-z |s2cid= 12630813 }}</ref><ref name="FeldbergLadd-Taylor2003">{{cite book|vauthors=Feldberg GD, Ladd-Taylor M, Li A|title=Women, Health and Nation: Canada and the United States Since 1945|url=https://books.google.com/books?id=CRjtHlq1INcC&pg=PA103|year=2003|publisher=McGill-Queen's Press - MQUP|isbn=978-0-7735-2501-6|pages=103–|access-date=2020-09-03|archive-date=2023-01-14|archive-url=https://web.archive.org/web/20230114183724/https://books.google.com/books?id=CRjtHlq1INcC&pg=PA103|url-status=live}}</ref> From about 1940 to 1971, the medication was given to pregnant women in the incorrect belief that it would reduce the risk of pregnancy complications and losses.<ref name="pmid16096877"/> In 1971, DES was shown to cause ], a rare ], in those who had been exposed to this medication '']''.<ref name="pmid16096877"/><ref name="pmid4276416" /> The ] ] subsequently withdrew approval of DES as a treatment for pregnant women.<ref name="pmid16096877"/><ref name="pmid4276416" /> Follow-up studies have indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed (E.G infertility).<ref name="pmid16096877"/><ref name="urlDES Update: For Consumers. Centers for Disease Control and Prevention">{{cite web |url= https://www.cdc.gov/des/consumers/ |title= DES Update: For Consumers |publisher= United States Department of Health and Human Services: Centers for Disease Control and Prevention |access-date= 2011-06-30 |archive-date= 2020-12-11 |archive-url= https://web.archive.org/web/20201211201613/https://www.cdc.gov/des/consumers/ |url-status= live }}</ref>
			The United States ] recommends<ref>{{cite web |url= https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/des-fact-sheet |title= Diethylstilbestrol (DES) and Cancer |publisher= National Cancer Institute |access-date= 2011-06-30 |archive-date= 2015-02-23 |archive-url= https://web.archive.org/web/20150223031713/http://www.cancer.gov/cancertopics/factsheet/Risk/DES |url-status= live }}</ref> children born to mothers who took DES to undergo special medical exams on a regular basis to screen for complications as a result of the medication. Individuals who were exposed to DES during their mothers' pregnancies are commonly referred to as "DES daughters" and "DES sons".<ref name="pmid16096877"/><ref name=Broadly-DES-Daughters-2017>{{cite news |vauthors=Arnold A |title=The Devastating Effects of a 1940s 'Wonder Pill' Haunt Women Generations Later |url=https://www.vice.com/en_us/article/zmbvp9/des-daughters-the-devastating-effects-of-a-1940s-wonder-pill-haunt-women-generations-later |work=] |date=January 5, 2017 |access-date=July 27, 2019 |archive-date=August 14, 2020 |archive-url=https://web.archive.org/web/20200814152808/https://www.vice.com/en_us/article/zmbvp9/des-daughters-the-devastating-effects-of-a-1940s-wonder-pill-haunt-women-generations-later |url-status=live }}</ref> Since the discovery of the ] effects of DES, it has largely been discontinued and is now mostly no longer marketed.<ref name="pmid16096877"/><ref name="pmid15063479">{{cite journal |vauthors= Coelingh Bennink HJ |title= Are all estrogens the same? |journal= Maturitas |volume= 47 |issue= 4 |pages= 269–275 |date= April 2004 |pmid= 15063479 |doi= 10.1016/j.maturitas.2003.11.009 }}</ref>
			{{TOC limit|3}}
			==Medical uses==
			{{More citations needed section|date=September 2017}}
			DES has been used in the past for the following indications:<ref name="pmid4276416">{{cite journal |vauthors= Noller KL, Fish CR |title= Diethylstilbestrol usage: Its interesting past, important present, and questionable future |journal= Med. Clin. North Am. |volume= 58 |issue= 4 |pages= 793–810 |date= July 1974 |pmid= 4276416 |doi= 10.1016/S0025-7125(16)32122-8 }}</ref>{{Additional citation needed|date=May 2019}}
			* ] in ]
			* ] for the treatment of ] ]s such as ]es and ]
			* ] for ] (e.g., ], ], and after ])
			* ] ] to prevent or reverse ]<ref name="Vorherr2012">{{cite book |vauthors=Vorherr H |title=The Breast: Morphology, Physiology, and Lactation |url=https://books.google.com/books?id=wYxirvD2X2IC&pg=PA201 |date=2 December 2012 |publisher=Elsevier Science |isbn=978-0-323-15726-1 |pages=201–203 |access-date=3 September 2020 |archive-date=12 May 2024 |archive-url=https://web.archive.org/web/20240512211849/https://books.google.com/books?id=wYxirvD2X2IC&pg=PA201#v=onepage&q&f=false |url-status=live }}</ref>
			* ]l ] (discontinued following the introduction of the ] ])
			* ] and ]
			* Prevention of ] in tall adolescent girls
			* Treatment of ] in girls and women
			* As an ]
			* As a means of ] for treating ] and ]s and ]s<ref name="Chatz1972">{{cite journal |last1 = Chatz |first1 = T.L. |title = Recognizing and Treating Dangerous Sex Offenders |journal = International Journal of Offender Therapy and Comparative Criminology |date = June 1972 |volume = 16 |issue = 2 |pages = 109–115 |issn = 0306-624X |eissn = 1552-6933 |doi = 10.1177/0306624X7201600202 |pmid = |s2cid = 74365268 |url = }}</ref>{{Additional citation needed|date=August 2022}}
			* Prevention of the ] flare at the start of ] (GnRH agonist) therapy<ref name="pmid16986003">{{cite journal |vauthors= Thompson IM |title= Flare Associated with LHRH-Agonist Therapy |journal= Rev Urol |volume= 3 |issue = Suppl 3 |pages= S10–4 |date= 2001 |pmid= 16986003 |pmc= 1476081 }}</ref><ref name="pmid8481213">{{cite journal |vauthors= Scaletscky R, Smith JA |title= Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it? |journal= Drug Saf |volume= 8 |issue= 4 |pages= 265–70 |date= April 1993 |pmid= 8481213 |doi= 10.2165/00002018-199308040-00001 |s2cid= 36964191 }}</ref><ref name="pmid2973364">{{cite journal |vauthors= Kreis W, Ahmann FR, Jordan VC, de Haan H, Scott M |title= Oestrogen pre-treatment abolishes luteinising hormone-releasing hormone testosterone stimulation |journal= Br J Urol |volume= 62 |issue= 4 |pages= 352–4 |date= October 1988 |pmid= 2973364 |doi= 10.1111/j.1464-410X.1988.tb04364.x }}</ref><ref name="pmid3920802">{{cite journal |vauthors= Stein BS, Smith JA |title= DES lead-in to use of luteinizing hormone releasing hormone analogs in treatment of metastatic carcinoma of prostate |journal= Urology |volume= 25 |issue= 4 |pages= 350–3 |date= April 1985 |pmid= 3920802 |doi= 10.1016/0090-4295(85)90484-4 }}</ref><ref name="pmid2969641">{{cite journal |vauthors= Fernandez del Moral P, Litjens TT, Weil EH, Debruyne FM |title= Can combined DES and LHRH depot therapy (ICI 118630) prevent endocrinologic and clinical flare-up in metastatic prostate cancer? |journal= Urology |volume= 32 |issue= 2 |pages= 137–40 |date= August 1988 |pmid= 2969641 |doi= 10.1016/0090-4295(88)90316-0 }}</ref><ref name="pmid7688656">{{cite journal |vauthors= Bruchovsky N, Goldenberg SL, Akakura K, Rennie PS |title= Luteinizing hormone-releasing hormone agonists in prostate cancer. Elimination of flare reaction by pretreatment with cyproterone acetate and low-dose diethylstilbestrol |journal= Cancer |volume= 72 |issue= 5 |pages= 1685–91 |date= September 1993 |pmid= 7688656 |doi= 10.1002/1097-0142(19930901)72:5<1685::AID-CNCR2820720532>3.0.CO;2-3 |s2cid= 21824595 |doi-access= free }}</ref><ref name="pmid10678560">{{cite journal |vauthors= Kotake T, Usami M, Akaza H, Koiso K, Homma Y, Kawabe K, Aso Y, Orikasa S, Shimazaki J, Isaka S, Yoshida O, Hirao Y, Okajima E, Naito S, Kumazawa J, Kanetake H, Saito Y, Ohi Y, Ohashi Y |title= Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicenter, randomized, controlled trial in Japan. Zoladex Study Group |journal= Jpn. J. Clin. Oncol. |volume= 29 |issue= 11 |pages= 562–70 |date= November 1999 |pmid= 10678560 |doi= 10.1093/jjco/29.11.562 |doi-access= free }}</ref>
			* ] for ]<ref name="Hamburger1969">{{cite book |vauthors = Hamburger C |chapter = Endocrine treatment of male and female transsexualism |pages = 291–307 |veditors = Money J, Green R |title = Transsexualism and Sex Reassignment |year = 1969 |publisher = Johns Hopkins Press |isbn = 9780801810381 |oclc = 6866559 |url = https://books.google.com/books?id=eGm1tQEACAAJ |access-date = 2020-07-30 |archive-date = 2024-05-12 |archive-url = https://web.archive.org/web/20240512211819/https://books.google.com/books?id=eGm1tQEACAAJ |url-status = live }}</ref><ref name="pmid794803">{{cite journal |vauthors = Ober WB |title = Stilbestrol: a pathologist's view |journal = Pathol Annu |volume = 11 |pages = 227–54 |date = 1976 |pmid = 794803 }}</ref>
			DES was used at a dosage of 0.2 to 0.5&nbsp;mg/day in ].<ref name="Buchsbaum2012">{{cite book |vauthors=Buchsbaum HJ |title=The Menopause |url=https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA60 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-1-4612-5525-3 |pages=60– |access-date=3 September 2020 |archive-date=12 May 2024 |archive-url=https://web.archive.org/web/20240512211851/https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA60#v=onepage&q&f=false |url-status=live }}</ref><ref name="pmid4276416" />
			Interest in the use of DES to treat prostate cancer continues today.<ref name="pmid29600433">{{cite journal |vauthors= Reis LO, Zani EL, García-Perdomo HA |title= Estrogen therapy in patients with prostate cancer: a contemporary systematic review |journal= Int Urol Nephrol |volume= 50 |issue= 6 |pages= 993–1003 |date= June 2018 |pmid= 29600433 |doi= 10.1007/s11255-018-1854-5 |s2cid= 4403709 }}</ref><ref name="pmid24256023">{{cite journal |vauthors= Turo R, Smolski M, Esler R, Kujawa ML, Bromage SJ, Oakley N, Adeyoju A, Brown SC, Brough R, Sinclair A, Collins GN |title= Diethylstilboestrol for the treatment of prostate cancer: past, present and future |journal= Scand J Urol |volume= 48 |issue= 1 |pages= 4–14 |date= February 2014 |pmid= 24256023 |doi= 10.3109/21681805.2013.861508 |s2cid= 34563641 }}</ref><ref name="pmid22578092">{{cite journal |vauthors= Bosset PO, Albiges L, Seisen T, de la Motte Rouge T, Phé V, Bitker MO, Rouprêt M |title= Current role of diethylstilbestrol in the management of advanced prostate cancer |journal= BJU Int. |volume= 110 |issue= 11 Pt C |pages= E826–9 |date= December 2012 |pmid= 22578092 |doi= 10.1111/j.1464-410X.2012.11206.x |s2cid= 21407416 |doi-access= free }}</ref><ref name="pmid14532759">{{cite journal |vauthors= Scherr DS, Pitts WR |title= The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer |journal= J. Urol. |volume= 170 |issue= 5 |pages= 1703–8 |date= November 2003 |pmid= 14532759 |doi= 10.1097/01.ju.0000077558.48257.3d }}</ref><ref name="pmid15046698">{{cite journal |vauthors= Oh WK |title= The evolving role of estrogen therapy in prostate cancer |journal= Clin Prostate Cancer |volume= 1 |issue= 2 |pages= 81–9 |date= September 2002 |pmid= 15046698 |doi= 10.3816/cgc.2002.n.009 }}</ref><ref name="pmid11502463">{{cite journal |vauthors= Malkowicz SB |title= The role of diethylstilbestrol in the treatment of prostate cancer |journal= Urology |volume= 58 |issue= 2 Suppl 1 |pages= 108–13 |date= August 2001 |pmid= 11502463 |doi= 10.1016/s0090-4295(01)01252-3 }}</ref><ref name="pmid7500443">{{cite journal |vauthors= Cox RL, Crawford ED |title= Estrogens in the treatment of prostate cancer |journal= J. Urol. |volume= 154 |issue= 6 |pages= 1991–8 |date= December 1995 |pmid= 7500443 |doi= 10.1016/s0022-5347(01)66670-9 }}</ref>{{citation overkill|date=July 2024}} However, use of ] ] estrogens like ] has been advocated in favor of oral synthetic estrogens like DES due to their much lower risk of cardiovascular toxicity.<ref name="pmid17239273">{{cite journal |vauthors= Lycette JL, Bland LB, Garzotto M, Beer TM |title= Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities? |journal= Clin Genitourin Cancer |volume= 5 |issue=3 |pages= 198–205 |date= December 2006 |pmid= 17239273 |doi= 10.3816/CGC.2006.n.037 }}</ref><ref name="pmid15046698"/><ref name="pmid7500443"/> In addition to prostate cancer, some interest in the use of DES to treat breast cancer continues today as well.<ref name="pmid27889048a">{{cite journal |vauthors= Coelingh Bennink HJ, Verhoeven C, Dutman AE, Thijssen J |title=The use of high-dose estrogens for the treatment of breast cancer |journal= Maturitas |volume= 95 |pages=11–23 |date=January 2017 |pmid=27889048 |doi= 10.1016/j.maturitas.2016.10.010 |doi-access= free }}</ref><ref name="pmid1627392">{{cite journal |vauthors= Marselos M, Tomatis L |title= Diethylstilboestrol: I, Pharmacology, Toxicology and carcinogenicity in humans |journal= Eur. J. Cancer |volume= 28A |issue= 6–7 |pages=1182–9 |date=1992 |pmid= 1627392 |doi= 10.1016/0959-8049(92)90482-h }}</ref> However, similarly to the case of prostate cancer, arguments have been made<ref name="EllisDehdahti2014" /> for the use of bioidentical estrogens like ] instead of DES for breast cancer.<ref name="pmid27889048a"/><ref name="EllisDehdahti2014">{{primary source inline|date=September 2020}} {{cite journal |vauthors=Ellis MJ, Dehdahti F, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Jeffe DB, Gao F, Fleming G, Silverman P, Dickler M, Carey L |display-authors=6 |title=A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer. |journal=Cancer Research |volume=69 |issue=2 Supplement |year=2014 |pages=16 |issn=0008-5472 |doi=10.1158/0008-5472.SABCS-16}}</ref>
			Oral DES at 0.25 to 0.5&nbsp;mg/day is effective in the treatment of ]es in men undergoing ] for prostate cancer.<ref name="pmid31367069">{{cite journal |vauthors = Moorthy HK, Laxman Prabhu GG, Venugopal P |title = The resurgence of estrogens in the treatment of castration-resistant prostate cancer |journal = Indian J Urol |volume = 35 |issue = 3 |pages = 189–196 |date = 2019 |pmid = 31367069 |pmc = 6639989 |doi = 10.4103/iju.IJU_56_19 |doi-access = free }}</ref>
			Although DES was used to support pregnancy, it was later found not to be effective for this use and to actually be harmful.<ref name="pmid12918007">{{cite journal |vauthors = Bamigboye AA, Morris J |title = Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes |journal = Cochrane Database Syst Rev |volume = 2003 |issue = 3 |pages = CD004353 |date = 2003 |pmid = 12918007 |pmc = 9039959 |doi = 10.1002/14651858.CD004353 |url = }}</ref><ref name="pmid23392570">{{cite journal |vauthors = Hilakivi-Clarke L, de Assis S, Warri A |title = Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk |journal = J Mammary Gland Biol Neoplasia |volume = 18 |issue = 1 |pages = 25–42 |date = March 2013 |pmid = 23392570 |pmc = 3635108 |doi = 10.1007/s10911-013-9274-8 |url = |quote = From the early 1940's until 1970's, DES was given to pregnant women to prevent miscarriage, which is often proceeded by a decline in estrogen levels. It later became apparent that DES treatment was mostly ineffective in preventing miscarriage , but nevertheless physicians continued prescribing DES to pregnant women. A recent article summarizes the effects of maternal exposure to DES during pregnancy and its adverse effects on pregnancy and fetal development in women , and show that this exposure increased 2nd trimester miscarriage by 3.8 -fold.}}</ref><ref name="Langston2016">{{cite book |title = Clinical Research Involving Pregnant Women |last1 = Langston |first1 = Lucy |series = Research Ethics Forum |chapter = Better Safe Than Sorry: Risk, Stigma, and Research During Pregnancy |date = 2016 |volume = 3 |pages = 33–50 |publisher = Springer International Publishing |issn = 2212-9529 |eissn = 2212-9537 |doi = 10.1007/978-3-319-26512-4_3 |isbn = 978-3-319-26510-0 |url = }}</ref><ref name="pmid3538427">{{cite journal |vauthors = Barter JF, Orr JW, Hatch KD, Shingleton HM |title = Diethylstilbestrol in pregnancy: an update |journal = South Med J |volume = 79 |issue = 12 |pages = 1531–4 |date = December 1986 |pmid = 3538427 |doi = 10.1097/00007611-198612000-00016 |s2cid = 33869704 |url = |quote = Several decades ago, diethylstilbestrol (DES) was considered efficacious in improving pregnancy outcome. Later data did not support this, and the exposed mothers and offspring have suffered from a variety of problems attributed to the drug.}}</ref>
			==Side effects==
			At more than 1&nbsp;mg/day, DES is associated with high rates of ]s including ], ], ], ], and ] (incidence of 15–50%).<ref name="pmid13638626">{{cite journal |vauthors= Swyer GI |title= The oestrogens |journal= Br Med J |volume= 1 |issue= 5128 |pages= 1029–31 |date= April 1959 |pmid=13638626 |pmc= 1993181 |doi= 10.1136/bmj.1.5128.1029 |quote= suffers from the serious drawback that in doses above 1 mg. a day it is likely to produce nausea, vomiting, abdominal discomfort, headache, and bloating in a proportion of patients varyingly estimated from 15 to 50%.}}</ref>
			===Breast changes and feminization===
			The ] of the ] ] are often very dark and almost black with DES therapy.<ref name="pmid4276416" /><ref name="Del CastilloArgonz1954">{{cite journal | vauthors = Dell Castillo EB, Argonz J |title = Oestrogen treatment in cases of rudimentary ovary syndrome | journal = Acta Endocrinologica | volume = 15 | issue = 4 | pages = 299–312 |date = April 1954 |pmid = 13157878 | doi = 10.1530/acta.0.0150299 }}</ref><ref name="Labhart2012">{{cite book |vauthors=Labhart A |title=Clinical Endocrinology: Theory and Practice |url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA720 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-3-642-96158-8 |pages=720– |access-date=3 September 2020 |archive-date=12 May 2024 |archive-url=https://web.archive.org/web/20240512211837/https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA720#v=onepage&q&f=false |url-status=live }}</ref><ref name="DavisBoynton1941">{{cite journal |vauthors = Davis ME, Boynton MW |title=Indications, clinical use and toxicity of 4-4' dihydroxy diethyl stilbene |journal=The Journal of Clinical Endocrinology & Metabolism |volume=1 |issue=4 |year=1941 |pages=339–345 |issn=0021-972X |doi=10.1210/jcem-1-4-339}}</ref><ref name="DavisBoynton1945">{{cite journal |vauthors = Davis ME, Boynton MW, Ferguson JH, Rothman S |title=Studies on Pigmentation of Endocrine Origin |journal=The Journal of Clinical Endocrinology & Metabolism |volume=5 |issue=3 |year=1945 |pages=138–146 |issn=0021-972X |doi=10.1210/jcem-5-3-138}}</ref><ref name="pmid21433876">{{cite journal |vauthors = Lewis RM |title = The Clinical Use of Stilbestrol, A Synthetic Estrogen: Preliminary Report |journal = The Yale Journal of Biology and Medicine | volume = 12 |issue = 2 |pages = 235–8 |date = December 1939 | pmid=21433876 |pmc = 2602231 }}</ref><ref name="LisserCurtis1947">{{cite journal |vauthors = Lisser H, Curtis LE | title = The syndrome of congenitally aplastic ovaries with sexual infantilism, high urinary gonadotropins, short stature and other congenital abnormalities; tabular presentation of 25 previously unpublished cases |journal = The Journal of Clinical Endocrinology and Metabolism | volume = 7 |issue = 10 |pages = 665–87 |date = October 1947 |pmid = 20270944 |doi = 10.1210/jcem-7-10-665}}</ref><ref name="Hamblen1943">{{cite journal |vauthors = Hamblen EC |title=Endocrine therapy in gynecology and obstetrics |journal=American Journal of Obstetrics and Gynecology |volume=45 |issue=1 |year=1943 |pages=147–160 |issn=0002-9378 |doi=10.1016/S0002-9378(43)90672-6}}</ref> The pigmentation that occurs with synthetic estrogens such as DES is much greater than with natural estrogens such as ].<ref name="pmid4276416" /><ref name="Del CastilloArgonz1954" /> The mechanism of the difference is unknown.<ref name="pmid4276416" /> ]s like ] have been reported to reduce the nipple hyperpigmentation induced by high-dose estrogen therapy.<ref name="pmid14278040">{{cite journal | vauthors = Crowley LG, Macdonald I | title = Delalutin and estrogens for the treatment of advanced mammary carcinoma in the postmenopausal woman | journal = Cancer | volume = 18 | issue = 4| pages = 436–46 | date = April 1965 | pmid = 14278040 | doi = 10.1002/1097-0142(196504)18:4<436::aid-cncr2820180407>3.0.co;2-d | s2cid = 31370289 | doi-access = }}</ref>
			In men treated with it for prostate cancer, DES has been found to produce high rates of ] (breast development) of 41 to 77%.<ref name="pmid16321765">{{cite journal |vauthors= Di Lorenzo G, Autorino R, Perdonà S, De Placido S |title= Management of gynaecomastia in patients with prostate cancer: a systematic review |journal= Lancet Oncol. |volume= 6 |issue= 12 |pages= 972–9 |date= December 2005 |pmid= 16321765 |doi= 10.1016/S1470-2045(05)70464-2 }}</ref>
			===Blood clots and cardiovascular issues===
			In studies of DES as a form of ] therapy for those with ], it has been associated with considerable ] ] and ].<ref name="pmid24256023"/><ref name="pmid4276416" /> The risk is dose-dependent.<ref name="pmid24256023"/> A dosage of 5&nbsp;mg/day DES has been associated with a 36% increase in non-cancer-related (mostly cardiovascular) deaths.<ref name="pmid24256023"/> In addition, there is an up to 15% incidence of ].<ref name="pmid24932461">{{cite journal |vauthors= Phillips I, Shah SI, Duong T, Abel P, Langley RE |title= Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer |journal= Oncol Hematol Rev |volume= 10 |issue= 1 |pages= 42–47 |date= 2014 |pmid= 24932461 |pmc= 4052190 |doi= 10.17925/ohr.2014.10.1.42}}</ref> A 3&nbsp;mg/day dosage of DES has been associated with an incidence of ] of 9.6 to 17%, with an incidence of cardiovascular complications of 33.3%.<ref name="pmid24256023"/> A lower dosage of 1&nbsp;mg/day DES has been associated with a rate of death due to cardiovascular events of 14.8% (relative to 8.3% for ] alone).<ref name="pmid24256023"/>
			===Other long-term effects===
			{{See also|Birth defects of diethylstilbestrol}}
			DES has been linked to a variety of long-term adverse effects in women who were treated with it during pregnancy, and/or in their offspring, including increased risk of the following:<ref name="pmid12918007"/>
			* ]
			* ]
			* ]
			* ]
			* ]
			* ]
			* ]
			* ]
			* ] ]s
			* ]
			A comprehensive animal study in 1993 found a ] of ]s from DES such as (but not limited to)
			* ] (due to ] ])
			* ]
			* ] and ] ]
			* ] (in ]s and ]s),
			* ] and ] ] (in ]s), ] ] (in ]), and
			* ] ] ] (in ]s).<ref>{{cite journal | vauthors = Marselos M, Tomatis L | title = Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals | journal = European Journal of Cancer | volume = 29A | issue = 1 | pages = 149–155 | year = 1993 | pmid = 1445734 | doi = 10.1016/0959-8049(93)90597-9 }}</ref> Evidence was also found linking ADHD to F2 generations, demonstrating that there is at least some neurological and transgenerational effects in addition to the carcinogenic.<ref>{{cite journal | vauthors = Kioumourtzoglou MA, Coull BA, O'Reilly ÉJ, Ascherio A, Weisskopf MG | title = Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits | journal = JAMA Pediatrics | volume = 172 | issue = 7 | pages = 670–677 | date = July 2018 | pmid = 29799929 | pmc = 6137513 | doi = 10.1001/jamapediatrics.2018.0727 | doi-access = free }}</ref>
			Rodent studies reveal female reproductive tract cancers and abnormalities reaching to the ], and there is evidence of adverse effects such as irregular menstrual cycles intersexual in grandchildren of DES mothers.<ref>{{cite journal | vauthors = Titus-Ernstoff L, Troisi R, Hatch EE, Wise LA, Palmer J, Hyer M, Kaufman R, Adam E, Strohsnitter W, Noller K, Herbst AL, Gibson-Chambers J, Hartge P, Hoover RN | display-authors = 6 | title = Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES) | journal = International Journal of Epidemiology | volume = 35 | issue = 4 | pages = 862–868 | date = August 2006 | pmid = 16723367 | doi = 10.1093/ije/dyl106 | doi-access = }}</ref> Additionally, evidence also points to transgenerational effects in F2 sons, such as ]s.<ref>{{cite journal | vauthors = Kalfa N, Paris F, Soyer-Gobillard MO, Daures JP, Sultan C | title = Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study | journal = Fertility and Sterility | volume = 95 | issue = 8 | pages = 2574–2577 | date = June 2011 | pmid = 21458804 | doi = 10.1016/j.fertnstert.2011.02.047 | doi-access = free }}</ref>
			At this time however, the extent of DES ] effects in humans is not fully understood.{{cn|date=March 2023}}
			==Overdose==
			DES has been assessed in the past in clinical studies at extremely high doses of as much as 1,500 to 5,000&nbsp;mg/day.<ref name="pmid27889048a"/><ref name="pmid576887">{{cite journal |vauthors= Carter AC, Sedransk N, Kelley RM, Ansfield FJ, Ravdin RG, Talley RW, Potter NR |title= Diethylstilbestrol: recommended dosages for different categories of breast cancer patients. Report of the Cooperative Breast Cancer Group |journal= JAMA |volume= 237 |issue= 19 |pages= 2079–8 |date= May 1977 |pmid= 576887 |doi= 10.1001/jama.1977.03270460065023 }}</ref><ref name="pmid13005120">{{cite journal | vauthors = Karnaky KJ | title = Micronized stilbestrol for dysfunctional uterine bleeding and endometriosis | journal = South. Med. J. | volume = 45 | issue = 12 | pages = 1166–72 | date = December 1952 | pmid = 13005120 | doi = 10.1097/00007611-195212000-00009 }}</ref>
			==Pharmacology==
			===Pharmacodynamics===
			====Estrogenic activity====
			DES is an ]; specifically, it is a highly potent ] of both of the ]s (ERs).<ref name="Jordan2013">{{cite book | vauthors = Jordan VC |title= Estrogen Action, Selective Estrogen Receptor Modulators, and Women's Health: Progress and Promise |url= https://books.google.com/books?id=ejS6CgAAQBAJ&pg=PA143 |year= 2013 |publisher= World Scientific |isbn= 978-1-84816-958-6 |pages=143–}}</ref><ref name="SeilerAutrup2012">{{cite book | vauthors = Seiler JP, Autrup JL, Autrup H |title= Diversification in Toxicology — Man and Environment: Proceedings of the 1997 EUROTOX Congress Meeting Held in Århus, Denmark, June 25–28, 1997 |url= https://books.google.com/books?id=ZlfrCAAAQBAJ&pg=PA23 |date= 6 December 2012 |publisher= Springer Science & Business Media |isbn= 978-3-642-46856-8 |pages= 23–}}</ref> It has approximately 468% and 295% of the ] of ] at the ] and ], respectively.<ref name="pmid9048584">{{cite journal | vauthors = Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA | title = Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta | journal = Endocrinology | volume = 138 | issue = 3 | pages = 863–870 | date = March 1997 | pmid = 9048584 | doi = 10.1210/endo.138.3.4979 | doi-access = free }}</ref> However, ] values of 0.18&nbsp;nM and 0.06&nbsp;nM of DES for the ERα and ERβ, respectively, have been reported, suggesting, in spite of its binding affinity for the two receptors, several-fold preference for activation of the ERβ over the ERα.<ref name="pmid22294742"/> In addition to the nuclear ERs, DES is an ] of the ] (GPER), albeit with relatively low affinity (~1,000&nbsp;nM).<ref name="pmid26023144">{{cite journal | vauthors = Prossnitz ER, Arterburn JB | title = International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators | journal = Pharmacological Reviews | volume = 67 | issue = 3 | pages = 505–540 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }}</ref> DES produces all of the same biological effects attributed to natural estrogens like estradiol.<ref name="LacknerTulsky1941">{{cite journal |vauthors= Lackner JE, Tulsky AS |title=Effect of stilbestrol on the myometrial and endometrial activity of the human castrate uterus |journal=The Journal of Clinical Endocrinology & Metabolism |volume=1 |issue=5 |year=1941 |pages=415–418 |issn=0021-972X |doi=10.1210/jcem-1-5-415 |quote=, differing distinctly in chemical structure from the previously known estrogens, has been shown to produce all the biologic effects attributed to them, such as suppression of the antuitary (2), inhibition of body growth (2), proliferation of the ductile system of the breast (3), suppression of engorgement incident to lactation (4), hyperemia, edema, and distention of the uterus (5), proliferation of the endometrium (6), vaginal cornification (7), and swelling of the sexual skin (8). It likewise presumably has the supposed carcinogenic propensities of the true estrogens (9).}}</ref><ref name="JacobsenChristensen1939">{{cite journal |vauthors = Jacobsen E, Christensen SS |title=Comparison of the effects of stilboestrol and oestrone on the mammary tissue of castrated female rats |journal=Acta Pathologica et Microbiologica Scandinavica |volume=16 |issue=4 |year=1939 |pages=359–364 |issn=0365-5555 |doi=10.1111/j.1600-0463.1939.tb06045.x |quote=After it was shown by Dodds, Goldberg, Lawson, and Robinson that stilboestrol (4.4' dioxy-α-β-diethylstilbene had the same effects as the natural oestrones on the vaginal mucosa of castrated female rats, a great number of works have appeared, which show that this substance, despite its very great chemical difference from the natural female sexual hormones has practically the same effect as these in all respects. The most important of these investigations have been made by Dodds, Lawson and Noble, by Noble, by Bishop, Boycott and Zuckermann, by Erik Guldberg, by Engelhardt, by Winterton and MacGregor, by Erik Jacobsen and most recently by Kreitmair and Sickman, by Buschbeck and Hausknecht, by Cobet, Ratschow and Stechner. The previous experiments have been made on hens, mice, rats, guineapigs, rabbits, monkeys, and human subjects.}}</ref> This includes effects in the ], ], ]s, ], and other ]s.<ref name="LacknerTulsky1941" /><ref name="JacobsenChristensen1939" /><ref name="LewisTurner1941">{{cite journal| vauthors = Lewis AA, Turner CW |title=Effect of Stilbestrol on the Mammary Gland of the Mouse, Rat, Rabbit, and Goat|journal=Journal of Dairy Science|volume=24|issue=10|year=1941|pages=845–860|issn=0022-0302|doi=10.3168/jds.S0022-0302(41)95467-X|doi-access=free}}</ref><ref name="LewisTurner1942">{{cite journal| vauthors = Lewis AA, Turner CW |title=Effect of Diethylstilbestrol on Mammary Gland Development in Dairy Animals1|journal=Endocrinology|volume=31|issue=5|year=1942|pages=520–528|issn=0013-7227|doi=10.1210/endo-31-5-520}}</ref>
			A dosage of 1&nbsp;mg/day DES is approximately equivalent to a dosage of 50&nbsp;μg/day ethinylestradiol in terms of systemic estrogenic potency.<ref name="ChabnerLongo1996">{{cite book |vauthors=Chabner B, Longo DL |title=Cancer Chemotherapy and Biotherapy: Principles and Practice |url=https://books.google.com/books?id=TZNrAAAAMAAJ |year=1996 |publisher=Lippincott-Raven Publishers |isbn=978-0-397-51418-2 |page=186 |quote=Piperazine estrone sulfate and micronized estradiol were equipotent with respect to increases in SHBG, whereas DES was 28.4-fold more potent . With respect to decreased FSH, DES was 3.8-fold, and ethinyl estradiol was 80 to 200-fold more potent than was piperazine estrone sulfate. The dose equivalents for ethinyl estradiol (50 μg) and DES (1 mg) reflect these relative potencies.220 DES, a potent synthetic estrogen (Fig. 6-12), is absorbed well after an oral dosage. Patients given 1 mg of DES daily had plasma concentrations at 20 hours ranging from 0.9 to 1.9 ng per mL. The initial half-life of DES is 80 minutes, with a secondary half-life of 24 hours.223 The principal pathways of metabolism are conversion to the glucuronide and oxidation. The oxidative pathways include aromatic hydroxylation of the ethyl side chains and dehydrogenation to (Z,Z)-dienestrol, producing transient quinone-like intermediates that react with cellular macromolecules and cause genetic damage in eukaryotic cells.223 Metabolic activation of DES may explain its well-established carcinogenic properties.224 |access-date=2020-09-03 |archive-date=2024-05-12 |archive-url=https://web.archive.org/web/20240512211828/https://books.google.com/books?id=TZNrAAAAMAAJ |url-status=live }}</ref><ref name="pmid7154205">{{cite journal | vauthors = Abramson FP, Miller HC | title = Bioavailability, distribution and pharmacokinetics of diethystilbestrol produced from stilphostrol | journal = J Urol | volume = 128 | issue = 6 | pages = 1336–9 | date = December 1982 | pmid = 7154205 | doi = 10.1016/s0022-5347(17)53502-8 }}</ref> Similarly to ], DES shows a marked and disproportionately strong effect on ].<ref name="Kuhl2005"/> Whereas its systemic estrogenic potency was about 3.8-fold of that of ] (piperazine estrone sulfate), which has similar potency to ], the hepatic estrogenic potency of DES was 28-fold that of estropipate (or about 7.5-fold stronger potency for a dosage with equivalent systemic estrogenic effect).<ref name="ChabnerLongo1996"/>
			DES has at least three ] in the treatment of prostate cancer.<ref name="DenisGriffiths1999"/> It suppresses ]al androgen production and hence circulating androgen levels due to its ] effects; it stimulates hepatic ] (SHBG) production, thereby increasing circulating levels of SHBG and decreasing the free fraction of testosterone and ] (DHT) in the ]; and it may have direct ] effects in the ] and ].<ref name="DenisGriffiths1999"/> DES has also been found to decrease ] at high doses.<ref name="DenisGriffiths1999"/>
			DES is a long-acting estrogen, with a nuclear retention of around 24&nbsp;hours.<ref name="RunnebaumRabe2013">{{cite book|vauthors=Runnebaum B, Rabe T|title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie|url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=88–|access-date=3 September 2020|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114073135/https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|url-status=live}}</ref><ref name="WallachHammond1982">{{cite journal | vauthors = Hammond CB, Maxson WS | title = Current status of estrogen therapy for the menopause | journal = Fertility and Sterility | volume = 37 | issue = 1 | pages = 5–25 | date = January 1982 | pmid = 6277697 | doi = 10.1016/S0015-0282(16)45970-4 | doi-access = }}</ref>
			{{Relative oral potencies of estrogens}}
			{{Oral potencies of estrogens}}
			{{Parenteral potencies and durations of nonsteroidal estrogens}}
			====Antigonadotropic effects====
			] (RIA).<ref name="pmid4359746" /> Source was Shearer et al. (1973).<ref name="pmid4359746" />]]
			] (RIA).<ref name="pmid4699685" /> Source was Kent et al. (1973).<ref name="pmid4699685" />]]
			Due to its estrogenic activity, DES has ] effects.<ref name="pmid29603164"/><ref name="DenisGriffiths1999"/><ref name="Salam2003"/><ref name="pmid16406864"/> That is, it exerts ] on the ] (HPG axis), suppresses the ] of the ]s, ] (LH) and ] (FSH), and suppresses ] ] as well as ] production or maturation in the ]s.<ref name="pmid29603164"/><ref name="DenisGriffiths1999"/><ref name="Salam2003"/><ref name="pmid16406864"/> A study of ] inhibition found that 5&nbsp;mg/day oral DES was 92% effective, with ovulation occurring in only a single cycle.<ref name="Greenblatt1966B">{{cite book |vauthors=Martinez-Manautou J, Rudel HW |chapter=Antiovulatory Activity of Several Synthetic and Natural Estrogens |pages=243–253 |editor=Robert Benjamin Greenblatt |title=Ovulation: Stimulation, Suppression, and Detection |url=https://books.google.com/books?id=le1qAAAAMAAJ |year=1966 |publisher=Lippincott |isbn=9780397590100 |access-date=2020-09-03 |archive-date=2023-01-14 |archive-url=https://web.archive.org/web/20230114183724/https://books.google.com/books?id=le1qAAAAMAAJ |url-status=live }}</ref><ref name="HerrRevesz1970"/> DES consistently suppresses testosterone levels in men into the castrate range (<50&nbsp;ng/dL) within 1 to 2&nbsp;weeks at doses of 3&nbsp;mg/day and above.<ref name="pmid29603164"/><ref name="pmid16406864">{{cite journal |vauthors= Lam JS, Leppert JT, Vemulapalli SN, Shvarts O, Belldegrun AS |title= Secondary hormonal therapy for advanced prostate cancer |journal= J. Urol. |volume= 175 |issue= 1 |pages= 27–34 |date= January 2006 |pmid= 16406864 |doi= 10.1016/S0022-5347(05)00034-0 }}</ref><ref name="pmid6436700">{{cite journal |vauthors= ((The Leuprolide Study Group))|title=Leuprolide versus diethylstilbestrol for metastatic prostate cancer |journal=N Engl J Med |volume=311 |issue=20 |pages=1281–6 |date=November 1984 |pmid=6436700 |doi=10.1056/NEJM198411153112004 }}</ref> Conversely, a dosage of 1&nbsp;mg/day DES is unable to fully suppress testosterone levels into the castrate range in men, which instead often stabilize at just above castrate levels (>50&nbsp;ng/dL).<ref name="pmid24256023"/><ref name="DenisGriffiths1999">{{cite book|vauthors=Denis LJ, Griffiths E, Kaisary AV, Murphy GP|title=Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment|url=https://books.google.com/books?id=GreZlojD-tYC&pg=PA297|date=1 March 1999|publisher=CRC Press|isbn=978-1-85317-422-3|pages=294, 297–|access-date=3 September 2020|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114183722/https://books.google.com/books?id=GreZlojD-tYC&pg=PA297|url-status=live}}</ref><ref name="Salam2003">{{cite book| vauthors = Salam MA |title=Principles & Practice of Urology: A Comprehensive Text|url=https://books.google.com/books?id=y50kTcCCfEcC&pg=PA684|year=2003|publisher=Universal-Publishers|isbn=978-1-58112-412-5|pages=684–}}</ref> However, it has also been reported that 1&nbsp;mg/day DES results in approximately 50% suppression of testosterone levels, albeit with wide ].<ref name="pmid29603164"/><ref name="pmid2669792">{{cite journal | vauthors = Seftel AD, Spirnak JP, Resnick MI | title = Hormonal therapy for advanced prostatic carcinoma | journal = J Surg Oncol | volume = 42 |issue=Suppl 1 | pages = 14–20 | date = 1989 | pmid = 2669792 | doi = 10.1002/jso.2930420505 | s2cid = 44250508 }}</ref> It has been said that doses of DES of less than 1&nbsp;mg/day have no effect on testosterone levels.<ref name="pmid29603164"/> However, the addition of an "extremely low" dosage of 0.1&nbsp;mg/day DES to ] has been found to result in a synergistic antigonadotropic effect and to suppress testosterone levels into the castrate range in men.<ref name="SchröderRadlmaier2009">{{cite book| vauthors = Schröder FH, Radlmaier A |title=Hormone Therapy in Breast and Prostate Cancer|chapter=Steroidal Antiandrogens|year=2009|pages=325–346|doi=10.1007/978-1-59259-152-7_15|isbn=978-1-60761-471-5}}</ref><ref name="pmid2973529">{{cite journal |vauthors= Goldenberg SL, Bruchovsky N, Rennie PS, Coppin CM |title= The combination of cyproterone acetate and low dose diethylstilbestrol in the treatment of advanced prostatic carcinoma |journal= J. Urol. |volume= 140 |issue= 6 |pages= 1460–5 |date= December 1988 |pmid= 2973529 |doi= 10.1016/S0022-5347(17)42073-8 }}</ref><ref name="pmid8677581">{{cite journal |vauthors= Goldenberg SL, Bruchovsky N, Gleave ME, Sullivan LD |title= Low-dose cyproterone acetate plus mini-dose diethylstilbestrol--a protocol for reversible medical castration |journal= Urology |volume= 47 |issue= 6 |pages= 882–4 |date= June 1996 |pmid= 8677581 |doi= 10.1016/S0090-4295(96)00048-9 }}</ref> DES at 3&nbsp;mg/day has similar testosterone suppression to a dose of 300&nbsp;mg/day, suggesting that suppression of testosterone levels is maximal by 3&nbsp;mg/day.<ref name="pmid5124437">{{cite journal | vauthors = Robinson MR, Thomas BS | title = Effect of hormonal therapy on plasma testosterone levels in prostatic carcinoma | journal = Br Med J | volume = 4 | issue = 5784 | pages = 391–4 | date = November 1971 | pmid = 5124437 | pmc = 1799485 | doi = 10.1136/bmj.4.5784.391 }}</ref>
			====Other activities====
			In addition to the ERs, an '']'' study found that DES also possesses activity, albeit relatively weak, at a variety of other ]s.<ref name="pmid22294742">{{cite journal |vauthors= Coss CC, Jones A, Parke DN, Narayanan R, Barrett CM, Kearbey JD, Veverka KA, Miller DD, Morton RA, Steiner MS, Dalton JT |title= Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer |journal= Endocrinology |volume= 153 |issue= 3 |pages= 1070–81 |date= March 2012 |pmid= 22294742 |doi= 10.1210/en.2011-1608|doi-access= free }}</ref> Whereas the study found ] values of 0.18&nbsp;nM and 0.06&nbsp;nM of DES for the ERα and ERβ, respectively, the medication showed significant ] activity at a concentration of 1&nbsp;μM that surpassed that of 0.1&nbsp;nM ], as well as significant ] of the ], ], and ]s (75%, 85%, and 50% inhibition of positive control stimulation, respectively, all at a concentration of 1&nbsp;μM).<ref name="pmid22294742"/> It also showed approximately 25% inhibition of the activation of ] and ] at a concentration of 10&nbsp;μM.<ref name="pmid22294742"/> The researchers stated that, to the best of their knowledge, they were the first to report such actions of DES, and hypothesized that these actions could be involved in the clinical effects of DES, for instance, in prostate cancer (notably in which particularly high dosages of DES are employed).<ref name="pmid22294742"/> However, they also noted that the importance of the activities requires further study in ]s at ] relevant doses.<ref name="pmid22294742"/>
			DES has been identified as an ] of all three ] of the ]s (ERRs), the ], ], and ].<ref name="pmid15161930">{{cite journal |vauthors= Greschik H, Flaig R, Renaud JP, Moras D |title= Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity |journal= The Journal of Biological Chemistry |volume= 279 |issue= 32 |pages= 33639–46 |date= August 2004 |pmid= 15161930 |doi= 10.1074/jbc.M402195200|doi-access=free }}</ref><ref name="pmid16515477">{{cite journal | vauthors = Ariazi EA, Jordan VC | title = Estrogen-related receptors as emerging targets in cancer and metabolic disorders | journal = Curr Top Med Chem | volume = 6 | issue = 3 | pages = 203–15 | date = 2006 | pmid = 16515477 | doi = 10.2174/1568026610606030203 }}</ref> Half-maximal inhibition occurs at a concentration of about 1&nbsp;μM.<ref name="pmid16515477" />
			===Pharmacokinetics===
			DES is ] with ].<ref name="ChabnerLongo1996"/> With an oral dosage of 1&nbsp;mg/day DES, plasma levels of DES at 20&nbsp;hours following the last dose ranged between 0.9 and 1.9&nbsp;ng/mL (3.4 to 7.1&nbsp;nmol/L).<ref name="ChabnerLongo1996"/> ] of DES appears to have about the same estrogenic potency of oral DES in women.<ref name="RabinowitzMyerson1967">{{cite book|vauthors=Rabinowitz JL, Myerson RM|title=Topics in Medicinal Chemistry|url=https://books.google.com/books?id=YXBtAAAAMAAJ|year=1967|publisher=Wiley-Interscience|isbn=978-0-471-70468-3|page=16|access-date=2020-09-03|archive-date=2024-05-12|archive-url=https://web.archive.org/web/20240512211851/https://books.google.com/books?id=YXBtAAAAMAAJ|url-status=live}}</ref> ] DES has been studied for the treatment of ].<ref name="pmid14926876">{{cite journal | vauthors = Friedberg V | title = Die Behandlung der genitalen Hypoplasie mit intrauterinen Cyren-B-Kristallsuspensionen | trans-title = Intrauterine Cyren-B Crystal Suspensions in Therapy of Genital Hypoplasia | language = de | journal = Geburtshilfe Frauenheilkd | volume = 11 | issue = 10 | pages = 923–30 | date = October 1951 | issn = 0016-5751 | pmid = 14926876 }}</ref> Oral DES is thought to have about 17 to 50% of the clinical estrogenic potency of DES by injection.<ref name="Bishop2008">{{cite book| vauthors = Bishop PM |title=Ciba Foundation Symposium - Steroid Hormone Administration (Book II of Colloquia on Endocrinology, Vol. 3)|chapter=The Difficulty of Evaluating the Potency of Steroid Hormones by Different Routes of Administration in Humans|series=Novartis Foundation Symposia|year=2008|pages=349–355|issn=1935-4657|doi=10.1002/9780470715154.ch10|isbn=9780470715154}}</ref>
			The ] ] of DES is 80&nbsp;minutes.<ref name="ChabnerLongo1996"/> It has no affinity for SHBG or ], and hence is not ] to these ]s in the circulation.<ref name="pmid7195405">{{cite journal | vauthors = Pugeat MM, Dunn JF, Nisula BC | title = Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 53 | issue = 1 | pages = 69–75 | date = July 1981 | pmid = 7195405 | doi = 10.1210/jcem-53-1-69 }}</ref> The ] of DES is greater than 95%.<ref name="OelschlägerRothley1988">{{cite journal| vauthors = Oelschläger H, Rothley D, Dunzendorfer U |title=New Results on the Pharmacokinetics of Fosfestrol|journal=Urologia Internationalis|volume=43|issue=1|year=1988|pages=15–23|issn=1423-0399|doi=10.1159/000281427}}</ref>
			] of the ]s of DES and subsequent ] of the ] ]s accounts for 80 to 90% of DES ], while ] accounts for the remaining 10 to 20% and is dominated by conjugation reactions.<ref name="OelschlägerRothley1988"/><ref name="pmid8428334">{{cite journal |vauthors= Droz JP, Kattan J, Bonnay M, Chraibi Y, Bekradda M, Culine S |title= High-dose continuous-infusion fosfestrol in hormone-resistant prostate cancer |journal= Cancer |volume= 71 |issue= 3 Suppl |pages= 1123–30 |date= February 1993 |pmid= 8428334 |doi= 10.1002/1097-0142(19930201)71:3+<1123::AID-CNCR2820711434>3.0.CO;2-T |s2cid= 23078614 |doi-access= free }}</ref> Conjugation of DES consists of ], while ] includes ] into ].<ref name="ChabnerLongo1996"/><ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/> The medication is also known to produce ] as a ].<ref name=".v">{{cite book | vauthors = Chambers PL, Günzel P |title= Mechanism of Toxic Action on Some Target Organs: Drugs and Other Substances |url= https://books.google.com/books?id=zUH1CAAAQBAJ&pg=PA276 |date= 12 March 2013 |publisher= Springer Science & Business Media |isbn= 978-3-642-67265-1 |pages= 276–}}</ref> DES produces transient ]-like reactive ]s that cause ] and ], which may help to explain the known ] effects of DES in humans.<ref name="ChabnerLongo1996"/> However, other research indicates that the toxic effects of DES may simply be due to overactivation of the ERs.<ref name="pmid15458790">{{cite journal |vauthors= Couse JF, Korach KS |title= Estrogen receptor-alpha mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract |journal= Toxicology |volume= 205 |issue= 1–2 |pages= 55–63 |date= December 2004 |pmid= 15458790 |doi= 10.1016/j.tox.2004.06.046 |bibcode= 2004Toxgy.205...55C }}</ref> In contrast to ], the ]s of DES do not undergo oxidation into an ]-like equivalent.<ref name="pmid19737574">{{cite journal | vauthors = Jensen EV, Jacobson HI, Walf AA, Frye CA | title = Estrogen action: a historic perspective on the implications of considering alternative approaches | journal = Physiol. Behav. | volume = 99 | issue = 2 | pages = 151–62 | date = February 2010 | pmid = 19737574 | pmc = 2834267 | doi = 10.1016/j.physbeh.2009.08.013 }}</ref>
			The ] of DES is 24&nbsp;hours.<ref name="ChabnerLongo1996"/> The metabolites of DES are ] in ] and ].<ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/>
			==Chemistry==
			] and DES.<ref name="WermuthAldous2015">{{cite book| vauthors = Wermuth CG, Aldous D, Raboisson P, Rognan D |title=The Practice of Medicinal Chemistry|url=https://books.google.com/books?id=dtScBAAAQBAJ&pg=PA244|date=1 July 2015|publisher=Elsevier Science|isbn=978-0-12-417213-5|pages=244–245}}</ref> Note the preservation of the two ]s in DES and the similar distance between them relative to estradiol, which is notable when it is considered that DES was discovered serendipitously.<ref name="WermuthAldous2015"/><ref name="Sneader2005"/><ref name="Ravina2011"/>]]
			DES belongs to the ] (4,4'-dihydroxy]) group of compounds.<ref name="AcademicPress1945">{{cite book |title= Vitamins and Hormones |url= https://archive.org/details/in.ernet.dli.2015.5563 |date= 1945 |publisher= Academic Press |isbn= 978-0-08-086600-0 |pages= –}}</ref> It is a ] ] ] of the ]al estrogen ].<ref name="WermuthAldous2015"/> DES can be prepared from ], which also happens to be weakly estrogenic.<ref name="AcademicPress1945"/><ref name="MaximovMcDaniel2013">{{cite book | vauthors = Maximov PY, McDaniel RE, Jordan VC |title= Tamoxifen: Pioneering Medicine in Breast Cancer |url= https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA3 |date= 23 July 2013 |publisher= Springer Science & Business Media |isbn= 978-3-0348-0664-0 |pages= 3–}}</ref><ref name="Ravina2011">{{cite book | vauthors = Ravina |title= T he Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs |url= https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA177 |date= 11 January 2011 |publisher= John Wiley & Sons |isbn= 978-3-527-32669-3 |pages= 177–}}</ref><ref name="Sneader2005">{{cite book | vauthors = Sneader W |title= Drug Discovery: A History |url= https://books.google.com/books?id=jglFsz5EJR8C&pg=PA196 |date= 31 October 2005 |publisher= John Wiley & Sons |isbn= 978-0-470-01552-0 |pages= 196–197}}</ref> Anethole was ] to form ] and anol then spontaneously ]ized into ] and ], with DES subsequently being synthesized via ] of hexestrol.<ref name="AcademicPress1945"/><ref name="MaximovMcDaniel2013"/><ref name="Ravina2011"/><ref name="Sneader2005"/> As shown by ], the molecular dimensions of DES are almost identical to those of estradiol, particularly in regards to the distance between the terminal ]s.<ref name="Sneader2005"/>
			==History==
			===Synthesis===
			DES was first synthesized in early 1938 by Leon Golberg, then a graduate student of ] at the ] at the ]. Golberg's research was based on work by Wilfrid Lawson at the Courtauld Institute of Biochemistry, (led by ] at ] now part of ]). A report of its synthesis was published in '']'' on 5 February 1938.<ref name=Dodds_1938>{{cite journal |vauthors= Dodds EC, Goldberg L, Lawson W, Robinson R |year= 1938 |title= Estrogenic activity of certain synthetic compounds |journal= ] |volume= 141 |issue= 3562 |pages= 247–8 |doi= 10.1038/141247b0|s2cid= 4078256 }}</ref><ref name=dodds2>{{cite book |vauthors= Dodds EC |year= 1957 |title= Biochemical contributions to endocrinology; experiments in hormonal research |location= Stanford |publisher= Stanford University Press |oclc= 1483899}}</ref><ref name=meyers>{{cite book |vauthors= Meyers R |year= 1983 |title= D.E.S., the bitter pill |location= New York |publisher= Seaview/Putnam |isbn= 0-399-31008-8 |url-access= registration |url= https://archive.org/details/desbitterpill00meye }}</ref>
			DES research was funded by the UK Medical Research Council ], which had a policy against patenting drugs discovered using public funds. Because it was not patented, DES was produced by more than 200 pharmaceutical and chemical companies worldwide.{{cn|date=March 2023}}
			===Clinical use===
			DES was first marketed for medical use in 1939.<ref name="FeldbergLadd-Taylor2003" /> It was approved by the United States ] on September 19, 1941, in tablets up to 5&nbsp;mg for four indications: ]l ], ], ] symptoms, and postpartum ] suppression to prevent breast engorgement.<ref name=meyers/> The gonorrheal vaginitis indication was dropped when the ] ] became available. From its very inception, the drug was highly controversial.<ref name=langston>{{cite book |vauthors= Langston N |year= 2010 |title= Toxic bodies: Hormone disruptors and the legacy of DES |location=New Haven, CT |publisher= Yale University Press |isbn= 978-0-300-13607-4}}</ref><ref name=seaman>{{cite book |vauthors= Seaman B |year= 2003 |title= The greatest experiment ever performed on women: Exploding the estrogen myth |url= https://archive.org/details/greatestexperime00barb |url-access= registration |location= New York |publisher= Hyperion |isbn= 978-0-7868-6853-7}}</ref>
			In 1941, ] and Clarence Hodges at the ] found ] and DES to be the first effective drugs for the treatment of metastatic ].<ref name="pmid4625049">{{cite journal |vauthors= Huggins C, Hodges CV |title= Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate |journal= CA |volume= 22 |issue= 4 |pages= 232–40 |year= 1972 |pmid= 4625049 |doi= 10.3322/canjclin.22.4.232|s2cid= 19786742 |doi-access= free }}</ref><ref>{{cite journal |date= 15 December 1943 |title= Prostate cancer yields to a drug |journal= The New York Times |page= 29 |url= https://www.nytimes.com/1943/12/15/archives/prostate-cancer-yields-to-a-drug-control-of-disease-by-taking.html |access-date= 23 June 2018 |archive-date= 13 May 2024 |archive-url= https://web.archive.org/web/20240513000656/https://www.nytimes.com/1943/12/15/archives/prostate-cancer-yields-to-a-drug-control-of-disease-by-taking.html |url-status= live }}</ref> DES was the first cancer drug.<ref name="Lupulescu1990">{{cite book|vauthors=Lupulescu A|title=Hormones and Vitamins in Cancer Treatment|url=https://books.google.com/books?id=VddUa-2cp-YC&pg=PA36|date=24 October 1990|publisher=CRC Press|isbn=978-0-8493-5973-6|pages=36–|access-date=3 September 2020|archive-date=12 May 2024|archive-url=https://web.archive.org/web/20240512212413/https://books.google.com/books?id=VddUa-2cp-YC&pg=PA36#v=onepage&q&f=false|url-status=live}}</ref>
			] or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years, until the ] ] was found to have efficacy similar to DES without estrogenic effects and was approved in 1985.<ref name="pmid6436700"/>
			From the 1940s until the late 1980s, DES was FDA-approved as ] for estrogen deficiency states such as ], ], and after ].{{cn|date=March 2023}}
			In the 1940s, DES was used off-label to prevent adverse pregnancy outcomes in women with a history of miscarriage. On July 1, 1947, the FDA approved the use of DES for this indication. The first such approval was granted to ], allowing use of 25&nbsp;mg (and later 100&nbsp;mg) tablets of DES during pregnancy. Approvals were granted to other pharmaceutical companies later in the same year.<ref name=dutton>{{cite book |vauthors= Dutton DB |year= 1988 |title= Worse than the disease: pitfalls of medical progress |location= Cambridge |publisher= Cambridge University Press |isbn= 0-521-34023-3 |url-access= registration |url= https://archive.org/details/worsethandisease0000dutt }}</ref> The recommended regimen started at 5&nbsp;mg per day in the seventh and eighth weeks of pregnancy (from first day of last menstrual period), increased every other week by 5&nbsp;mg per day through the 14th week, and then increased every week by 5&nbsp;mg per day from 25&nbsp;mg per day in the 15th week to 125&nbsp;mg per day in the 35th week of pregnancy.<ref name=pdr1961>{{cite book |year= 1961 |title= Physicians' desk reference to pharmaceutical specialties and biologicals |edition= 15th |location= Oradell NJ |publisher= Medical Economics |page= 625 |isbn= 0-00-093447-X}}</ref>
			DES was originally considered effective and safe for both the ] woman and the developing baby. It was aggressively marketed and routinely prescribed. Sales peaked in 1953.{{cn|date=May 2024}}
			In the early 1950s, a ] clinical trial at the University of Chicago assessed pregnancy outcomes in women who were assigned to either receive or not receive DES.<ref name=dieckmann>{{cite journal |vauthors= Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE |title= Does the administration of diethylstilbestrol during pregnancy have therapeutic value? |journal= American Journal of Obstetrics and Gynecology |volume= 66 |issue= 5 |pages= 1062–81 |date= November 1953 |pmid= 13104505 |doi= 10.1016/S0002-9378(16)38617-3}}</ref> The study showed no benefit of taking DES during pregnancy; adverse pregnancy outcomes were not reduced in the women who were given DES. By the late 1960s, six of seven leading textbooks of obstetrics said DES was ineffective at preventing miscarriage.<ref name=dutton/><ref name=apfel>{{cite book |vauthors= Apfel RJ, Fisher SM |year= 1984 |title= To do no harm: DES and the dilemmas of modern medicine |location= New Haven |publisher= Yale University Press |isbn= 0-300-03192-0 |url-access= registration |url= https://archive.org/details/todonoharmdesdil0000apfe }}</ref>
			Despite an absence of evidence supporting the use of DES to prevent adverse pregnancy outcomes, DES continued to be given to pregnant women through the 1960s. In 1971, a report published in the ''New England Journal of Medicine'' showed a probable link between DES and ] in girls and young women who had been exposed to this drug ''in utero''. Later in the same year, the FDA sent an FDA Drug Bulletin to all U.S. physicians advising against the use of DES in pregnant women. The FDA also removed prevention of miscarriage as an indication for DES use and added pregnancy as a contraindication for DES use.<ref name=fr1971>{{cite journal |vauthors= ((United States Food and Drug Administration)) |year= 1971 |title= Certain estrogens for oral or parenteral use. Drugs for human use; drug efficacy study implementation |journal= Fed Regist |volume= 36 |issue= 217 |pages= 21537–8}}; {{Federal Register|36|21537}}</ref> On February 5, 1975, the FDA ordered 25&nbsp;mg and 100&nbsp;mg tablets of DES withdrawn, effective February 18, 1975.<ref name=des25mg/> The number of persons exposed to DES during pregnancy or ''in utero'' during the period of 1940 to 1971 is unknown, but may be as high as 2 million in the United States. DES was also used in other countries, most notably France, the Netherlands, and Great Britain.
			From the 1950s through the beginning of the 1970s, DES was prescribed to prepubescent girls to begin puberty and thus stop growth by closing growth plates in the bones. Despite its clear link to cancer, doctors continued to recommend the hormone for "excess height".<ref>{{cite web |vauthors= Zuger A |date= 2009-07-27 |title= At What Height, Happiness? A Medical Tale |url= https://www.nytimes.com/2009/07/28/health/28book.html |work= The New York Times |access-date= 2017-02-24 |archive-date= 2017-07-19 |archive-url= https://web.archive.org/web/20170719081939/http://www.nytimes.com/2009/07/28/health/28book.html |url-status= live }}</ref>
			In 1960, DES was found to be more effective than ]s in the treatment of advanced ] in postmenopausal women.<ref name="AMA1960a">{{cite journal |author= Council on Drugs |year= 1960 |title= Androgens and estrogens in the treatment of disseminated mammary carcinoma: retrospective study of nine hundred forty-four patients |journal= JAMA |volume= 172 |issue= 12 |pages= 1271–83 |doi= 10.1001/jama.1960.03020120049010}}</ref> DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977, when the FDA approved ], a ] with efficacy similar to DES but fewer side effects.<ref name="pmid7001242">{{cite journal |vauthors= Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S |title= Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer |journal= The New England Journal of Medicine |volume= 304 |issue= 1 |pages= 16–21 |date= January 1981 |pmid= 7001242 |doi=10.1056/NEJM198101013040104}}</ref>
			Several sources from medical literature in the 1970s and 1980s indicate that DES was used as a component of ] for ].<ref>{{cite journal |vauthors= Goodwin WE, Cummings RH |title= Squamous metaplasia of the verumontanum with obstruction due to hypertrophy: long-term effects of estrogen on the prostate in an aging male-to-female transsexual |journal= The Journal of Urology |volume= 131 |issue= 3 |pages= 553–4 |date= March 1984 |pmid= 6199525 |doi= 10.1016/s0022-5347(17)50493-0}}</ref><ref>{{cite journal |vauthors= Lehrman KL |title= Pulmonary embolism in a transsexual man taking diethylstilbestrol |journal= JAMA |volume= 235 |issue= 5 |pages= 532–3 |date= February 1976 |pmid= 946104 |doi=10.1001/jama.1976.03260310046024}}</ref><ref>{{cite journal |vauthors= Seyler LE, Canalis E, Spare S, Reichlin S |title= Abnormal gonadotropin secretory responses to LRH in transsexual women after diethylstilbestrol priming |journal= The Journal of Clinical Endocrinology and Metabolism |volume= 47 |issue= 1 |pages= 176–83 |date= July 1978 |pmid= 122396 |doi= 10.1210/jcem-47-1-176}}</ref>
			In 1973, in an attempt to restrict ] of DES as a ] (which had become prevalent at many university health services following publication of an influential study in 1971 in '']'') to emergency situations such as rape, an ''FDA Drug Bulletin'' was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES.<ref name="pmid5171004">{{cite journal |vauthors= Kuchera LK |title= Postcoital contraception with diethylstilbestrol |journal= JAMA |volume= 218 |issue= 4 |pages= 562–3 |date= October 1971 |pmid= 5171004 |doi= 10.1001/jama.218.4.562}}</ref>
			In 1975, the FDA said it had not actually given (and never did give) approval to any manufacturer to market DES as a postcoital contraceptive, but would approve that indication for emergency situations such as rape or incest if a manufacturer provided patient labeling and special packaging as set out in a FDA final rule published in 1975.<ref>{{cite journal |vauthors= FDA |year= 1975 |title= Diethylstilbestrol as posticoital oral contraceptive; patient labeling |journal= Fed Regist |volume= 40 |issue= 25 |pages= 5451–5}}; {{Federal Register|40|5451}}</ref> To discourage off-label use of DES as a postcoital contraceptive, the FDA in 1975 removed DES 25&nbsp;mg tablets from the market and ordered the labeling of lower doses (5&nbsp;mg and lower) of DES still approved for other indications changed to state: "This drug product should not be used as a postcoital contraceptive" in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label.<ref name=des25mg>{{cite journal |vauthors= FDA |year= 1975 |title= Certain estrogens for oral use. Notice of withdrawal of approval of new drug applications |journal= Fed Regist |volume= 40 |issue= 25 |page= 5384}}; {{Federal Register|25|5384}}</ref><ref>{{cite journal |vauthors= FDA |year= 1975 |title= Estrogens for oral or parenteral use. Drugs for human use; drug efficacy study; amended notice |journal= Fed Regist |volume= 40 |issue= 39 |page= 8242}}; {{Federal Register|39|8242}}</ref> In the 1980s, off-label use of the ] of certain regular ] pills superseded off-label use of DES as a postcoital contraceptive.<ref>{{cite book |vauthors= Hatcher RA, Stewart GK, Stewart F, Guest F, Josephs N, Dale J |year= 1982 |title= Contraceptive Technology 1982–1983 |location= New York |publisher= Irvington Publishers |isbn= 0-8290-0705-9 |pages= |url= https://archive.org/details/contraceptivetec0000hatc/page/152 }}</ref>
			In 1978, the FDA removed postpartum ] to prevent breast engorgement from their approved indications for DES and other estrogens.<ref>{{cite journal |vauthors= FDA |year= 1978 |title= Estrogens for postpartum breast engorgement |journal= Fed Regist |volume= 43 |issue= 206 |pages= 49564–7}}; {{Federal Register|43|49564}}</ref> In the 1990s, the only approved indications for DES were treatment of advanced prostate cancer and treatment of advanced breast cancer in postmenopausal women. The last remaining U.S. manufacturer of DES, ], stopped making and marketing it in 1997.{{Citation needed|date=May 2020}}
			=== Trials ===
			Diethylstilbestrol has been used countless times in studies on rats. Once it was discovered that DES was causing vaginal cancer, experiments began on both male and female rats.<ref name=":1">{{cite journal | vauthors = Toyama Y, Ohkawa M, Oku R, Maekawa M, Yuasa S | title = Neonatally administered diethylstilbestrol retards the development of the blood-testis barrier in the rat | journal = Journal of Andrology | volume = 22 | issue = 3 | pages = 413–423 | date = May 2001 | doi = 10.1002/j.1939-4640.2001.tb02197.x | pmid = 11330641 | s2cid = 14127534 | doi-access = free }}</ref> Many of these male rats were injected with DES while other male rats were injected with olive oil, and they were considered the control group.<ref name=":1" /> Each group received the same dosage on the same days, and the researchers performed light microscopy, electron microscopy, and confocal laser microscopy. With both the electron and confocal laser microscopy, it was prevalent that the Sertoli cells, which are somatic cells where spermatids develop in the testes, were formed 35 days later in the rats who were injected with Diethylstilbestrol compared to the rats in the control group.<ref name=":1" /> Proceeding the completion of the trial, it was understood that rats of older age who were injected with DES experienced delay in sertoli cell maturation, underdeveloped epididymides, and drastic decrease in weight compared to its counterparts.<ref name=":1" />
			The female rats used were inbred and most of them were given DES combined in their food. These rats were divided into three groups, one group who received no diethylstilbestrol, one group who had DES mixed into their diet, and the third group who had DES administered into their diet after day 13 of being pregnant.<ref name="Kawaguchi_2009">{{cite journal | vauthors = Kawaguchi H, Miyoshi N, Miyamoto Y, Souda M, Umekita Y, Yasuda N, Yoshida H | title = Effects of exposure period and dose of diethylstilbestrol on pregnancy in rats | journal = The Journal of Veterinary Medical Science | volume = 71 | issue = 10 | pages = 1309–1315 | date = October 2009 | pmid = 19887736 | doi = 10.1292/jvms.001309 | doi-access = free }}</ref> Some rats who were given DES unfortunately died before delivering their pup.<ref name="Kawaguchi_2009" /> The group that received DES in their food for 13 days while being pregnant resulted in early abortion and delivery failure.<ref name="Kawaguchi_2009" /> These outcomes showed that DES had a detrimental effect on pregnancy when administered as often as it was. Providing the dosing of diethylstilbestrol later in the pregnancy term also made visible the occurrence of abortions among the rats.<ref name="Kawaguchi_2009" /> Overall, any interaction with DES in female rats concluded in the rats' experiencing abortions, improper fetal growth, and the increase in sterility.<ref name="Kawaguchi_2009" />
			A review of people who had been treated or exposed to DES was done to find out what long-term effects would show.<ref name = "Giusti_1995">{{cite journal | vauthors = Giusti RM, Iwamoto K, Hatch EE | title = Diethylstilbestrol revisited: a review of the long-term health effects | journal = Annals of Internal Medicine | volume = 122 | issue = 10 | pages = 778–788 | date = May 1995 | pmid = 7717601 | doi = 10.7326/0003-4819-122-10-199505150-00008 | s2cid = 25131834 }}</ref> People for a long time had been treated during their pregnancy with DES, and there have been known to be toxic and adverse effects to the hormone therapy. "Exposure to DES has been associated with an increased risk for breast cancer in DES mothers (relative risk, <2.0) and with a lifetime risk of clear-cell cervicovaginal cancer in DES daughters of 1/1000 to 1/10 000."<ref name = "Giusti_1995" /> Side effects of DES are proving to be long-term as it can cause increased risks of cancer after use.<ref name = "Giusti_1995" /> There will be continued work to see how far the adverse effects of DES go after previous therapy and how it will affect offspring and the mothers longer-term.<ref name = "Giusti_1995" />
			=== Regulations ===
			In 1938, the ability to test the safety of DES on animals was first obtained by the FDA. The results from the preliminary tests showed that DES harmed the reproductive systems of animals. The application of these results to humans could not be determined, so the FDA could not act in a regulatory manner.<ref name=":3">{{Cite journal | vauthors = Langston N |date=2008 |title=The Retreat from Precaution: Regulating Diethylstilbestrol (Des), Endocrine Disruptors, and Environmental Health |journal=Environmental History |volume=13 |issue=1 |pages=41–65 |doi=10.1093/envhis/13.1.41 |jstor=25473193 |issn=1084-5453|doi-access=free }}</ref>
			New Drug Applications for DES approval were withdrawn in 1940 in a decision made by the FDA based on scientific uncertainty. However, this decision resulted in significant political pressure, so the FDA came to a compromise. The compromise meant that DES would be available only by prescription and would have to have warnings about its effects on the bottle, but the warning was dropped in 1945. In 1947, DES finally gained FDA approval for prescription to pregnant women who had diabetes as a method of preventing miscarriages. This led to the widespread prescription of DES to all pregnant women.<ref name=":3" />
			In 1971, the FDA recommended against the prescription of DES to pregnant women.<ref name=":4">{{cite journal | vauthors = Zamora-León P | title = Are the Effects of DES Over? A Tragic Lesson from the Past | journal = International Journal of Environmental Research and Public Health | volume = 18 | issue = 19 | pages = 10309 | date = September 2021 | pmid = 34639609 | pmc = 8507770 | doi = 10.3390/ijerph181910309 | doi-access = free }}</ref> As a result, DES then began to see a withdraw from the US market starting in 1972 and in the European market starting in 1978, but the FDA still did not withdraw its approval for the use of DES in humans.<ref>{{cite journal | vauthors = Eve L, Fervers B, Le Romancer M, Etienne-Selloum N | title = Exposure to Endocrine Disrupting Chemicals and Risk of Breast Cancer | journal = International Journal of Molecular Sciences | volume = 21 | issue = 23 | pages = 9139 | date = November 2020 | pmid = 33266302 | pmc = 7731339 | doi = 10.3390/ijms21239139 | doi-access = free }}</ref>
			DES was classified as a Group 1 carcinogen by the International Agency for Research on Cancer. After classification as a carcinogen, DES had its FDA approval withdrawn in 2000.<ref name=":4" /> DES is currently only in use for veterinary practices and in research trials as allowed by the FDA.<ref>{{cite journal | vauthors = Carey JL, Nader N, Chai PR, Carreiro S, Griswold MK, Boyle KL | title = Drugs and Medical Devices: Adverse Events and the Impact on Women's Health | language = English | journal = Clinical Therapeutics | volume = 39 | issue = 1 | pages = 10–22 | date = January 2017 | pmid = 28069260 | pmc = 5779632 | doi = 10.1016/j.clinthera.2016.12.009 }}</ref>
			=== Medical ethics ===
			] in regard to the approval and use of Diethylstilbestrol have been dismissed because of the actions of the FDA and pharmaceutical companies that were making DES at the time of its use. The Vice President of the American Drug Manufacturers Association, Carson Frailey, was employed by drug companies creating DES in order to help get it approved by the ] (FDA). Nancy Langston, the author of The Retreat from Precaution: Regulating Diethylstilbestrol (DES), Endocrine Disruptors, and Environmental Health, states that "Frailey persuaded fifty-four doctors from around the country to write to the FDA, describing their clinical experiences with a total of more than five thousand patients. Only four of these fifty-four doctors felt that DES should not be approved, and the result was that, against the concerns of many of the FDA medical staff, the FDA's drug chief Theodore Klumpp recommended that the FDA approve DES."<ref name=":2">{{cite journal | vauthors = Langston N | title = The retreat from precaution: Regulating diethylstilbestrol (DES), endocrine disruptors, and environmental health. | journal = Environmental History | date = January 2008 | volume = 13 | issue = 1 | pages = 41–65 | doi = 10.1093/envhis/13.1.41 | doi-access = free }}</ref> This excerpt describes how DES was unethically approved and shows that the motivation behind its approval was for the benefit of drug companies rather than the people who were going to use the drug. This approval of DES violates the values of medical ethics, ], ], ], and ] as there was little thought put into how DES would affect its users.<ref>{{cite book | vauthors = Beauchamp TL | chapter = The principles of biomedical ethics as universal principles. | title = Islamic Perspectives on the Principles of Biomedical Ethics: Muslim Religious Scholars and Biomedical Scientists in Face-to-Face Dialogue with Western Bioethicists | series = Intercultural Dialogue in Bioethics | date = 2018 | volume = 1 | pages = 91–119 | doi = 10.1142/9781786340481_0004 | isbn = 978-1-78634-047-4 }}</ref> The decisions made by the FDA leaders to approve DES without further study and convince doctors to dissimulate their opinions on the use of DES is unethical. Once DES was approved for public consumption the "warnings made available only on a separate circular that patients would not see. Doctors could get this warning circular only by writing to the drug companies and requesting it. Letters between companies and FDA regulators reveal that both groups feared that if a woman ever saw how many potential risks DES might present, she might refuse to take the drug—or else she might sue the company and the prescribing doctors if she did get cancer or liver damage after taking the drug."<ref name=":2" /> Women were not informed about the possible effects of DES because doctors and FDA regulators were afraid DES would fail and never be approved costing the drug companies millions of dollars. The act of distributing potentially dangerous medicine to patients regardless of the effect and harm it may do solely for monetary gain is unethical.{{cn|date=March 2023}}
			===Lawsuits===
			In the 1970s, the negative publicity surrounding the discovery of DES's long-term effects resulted in a huge wave of lawsuits in the United States against its manufacturers. These culminated in a landmark 1980 decision of the ], '']'', in which the court imposed a ] of ] upon all DES manufacturers, proportional to their share of the market at the time the drug was consumed by the mother of a particular plaintiff.{{cn|date=March 2023}}
			Eli Lilly, a pharmaceutical company manufacturing DES, and the University of Chicago, had an action filed against them in regard to clinical trials from the 1950s. Three women filed the claim that their daughters had developments of abnormal cervical cellular formations as well as reproductive abnormalities in themselves and their sons.<ref name=":0">{{cite journal | vauthors = Mastroianni AC, Faden R, Federman D | title = Women and health research: a report from the Institute of Medicine | journal = Kennedy Institute of Ethics Journal | volume = 4 | issue = 1 | pages = 55–62 | date = March 1994 | pmid = 10132589 | doi = 10.1353/ken.0.0121 | s2cid = 31494934 }}</ref> The plaintiffs had asked the courts to certify their case as a class action but were declined by the courts. However, the courts issued an opinion that their case had merit. The court held that Eli Lilly had a duty to notify about the risks of DES once they became aware of them or should have become aware of them.<ref name=":0" /> Under Illinois tort law, for the plaintiffs to recover under theories of breach of duty to warn and strict liability, the plaintiffs must have alleged injury to themselves. Ultimately, under their claims of breach of duty to warn and strict liability due to the plaintiffs citing risk of physical injury to others, not physical injury to themselves, the case was dismissed by the courts.<ref name=":0" /> Although the case was not certified as class action and their claims of breach of duty to warn and strict liability was dismissed, the courts did not dismiss the battery allegations.<ref name=":0" /> The issue was then to determine whether the University of Chicago had committed battery against these women but the case was settled before trial.<ref name=":0" /> Part of the settlement agreement for this case, Mink v. University of Chicago, attorneys for the plaintiffs negotiated for the university to provide free medical exams for all offspring exposed to DES in utero during the 1950 experiments as well as treat the daughters of any women involved who develop DES-associated vaginal or cervical cancer.<ref name=":0" />
			As of February 1991, there were over a thousand pending legal actions against DES manufacturers.<ref name=":0" /> There are over 300 companies that manufactured DES according to the same formula and the largest barrier to recovery is determining which manufacturer supplied the drug in each particular case.<ref name=":0" /> Many of the successful cases have relied on joint or several parties holding liability.
			A lawsuit was filed in Boston Federal Court by 53 DES daughters who say their breast cancers were the result of DES being prescribed to their mothers while pregnant with them. Their cases survived a ] hearing. In 2013, the Fecho sisters who initiated the breast cancer/DES link litigation agreed to an undisclosed settlement amount on the second day of trial. The remaining litigants have received various settlements.<ref>{{cite news | vauthors = Lavoie D |title=DES Pregnancy Drug Lawsuit: Settlement Reached Between Melnick Sisters And Eli Lilly And Co.|url=http://www.huffingtonpost.com/2013/01/09/des-pregnancy-drug-lawsuit-melnick-sisters_n_2442937.html |archive-url= https://web.archive.org/web/20130110093212/http://www.huffingtonpost.com/2013/01/09/des-pregnancy-drug-lawsuit-melnick-sisters_n_2442937.html |archive-date= 10 January 2013 |url-status= dead |access-date=19 March 2014|newspaper=Huffington Post|date=9 January 2013}}</ref>
			The advocacy group ] helped provide information and support for DES-exposed persons engaged in lawsuits.<ref>{{Cite web| title = Collection: DES Action USA records {{!}} Smith College Finding Aids| access-date = 2020-06-09| url = https://findingaids.smith.edu/repositories/2/resources/996| archive-date = 2020-06-09| archive-url = https://web.archive.org/web/20200609184734/https://findingaids.smith.edu/repositories/2/resources/996| url-status = live}}</ref>
			==Society and culture==
			], the ground-breaking ], founder of ] and programmable computers, who also proposed the actual ], was forcefully given this drug to induce chemical castration as a punitive and discredited "treatment" for homosexual behaviour, shortly before he died in ambiguous circumstances.<ref>{{cite web |vauthors= West-Taylor Z |title= The Alan Turing Law – a Formal Pardon for Unpardonable Homophobia |url= http://affinitymagazine.us/2016/09/24/the-alan-turing-law-a-formal-pardon-for-unpardonable-homophobia/ |website= Affinity magazine |date= 24 September 2016 |access-date= 3 December 2016 |archive-date= 3 December 2016 |archive-url= https://web.archive.org/web/20161203130225/http://affinitymagazine.us/2016/09/24/the-alan-turing-law-a-formal-pardon-for-unpardonable-homophobia/ |url-status= dead }}</ref>
			At least on one occasion in New Zealand in the early 1960s, diethylstilbestrol was prescribed for the "treatment" of homosexuality.<ref>{{cite web |author= Kilgallon, Steve |title= How 'gay conversion' drugs ruined this man's life |url= https://www.stuff.co.nz/national/health/130948087/how-gay-conversion-drugs-ruined-this-mans-life/ |website= Stuff |date= 22 January 2023 |access-date= 22 January 2023 |archive-date= 22 January 2023 |archive-url= https://web.archive.org/web/20230122031006/https://www.stuff.co.nz/national/health/130948087/how-gay-conversion-drugs-ruined-this-mans-life |url-status= live }}</ref>
			] describes a case regarding treating a small dog's testicular ] in his 1974 book ''All Things Bright and Beautiful''. Herriot decided to prescribe a high dose of stilboestrol for the recurring tumor, with the amusing side effect that the male dog became "attractive to other male dogs", who followed the terrier around the village for a few weeks. Herriot comments in the story that he knew "The new drug was said to have a feminising effect, but surely not to that extent."{{cn|date=May 2024}}
			==Veterinary use==
			===Canine incontinence===
			DES has been very successful in treating female canine incontinence stemming from poor sphincter control. It is still available from compounding pharmacies, and at the low (1&nbsp;mg) dose, does not have the carcinogenic properties that were so problematic in humans.<ref>{{cite web|title=Urinary Incontinence|url=https://www.merckvetmanual.com/?cfile=htm/bc/191024.htm|work=Merck Veterinary Manual|publisher=]|access-date=30 November 2012|archive-date=29 April 2023|archive-url=https://web.archive.org/web/20230429134419/https://www.merckvetmanual.com/?cfile=htm/bc/191024.htm|url-status=live}}</ref> It is generally administered once a day for seven to ten days and then once every week as needed.{{cn|date=March 2023}}
			===Livestock growth promotion===
			The greatest usage of DES was in the livestock industry, used to improve ] in beef and poultry. During the 1960s, DES was used as a ] in the beef and poultry industries. It was later found to cause cancer by 1971, but was not phased out until 1979.<ref>{{cite journal |vauthors= Harris RM, Waring RH |title= Diethylstilboestrol--a long-term legacy |journal= Maturitas |volume= 72 |issue= 2 |pages= 108–12 |date= June 2012 |pmid= 22464649 |doi= 10.1016/j.maturitas.2012.03.002}}</ref><ref name="urlenvirocancer.cornell.edu">{{cite web |url= https://ecommons.cornell.edu/bitstream/handle/1813/14514/fs37.hormones.pdf |title= Consumer Concerns About Hormones in Food |vauthors= Gandhi R, Snedeker S |date= 2000-06-01 |work= Fact Sheet #37, June 2000 |publisher= Program on Breast Cancer and Environmental Risk Factors, Cornell University |access-date= 2011-07-20 |url-status= live |archive-url= https://web.archive.org/web/20110719175735/http://envirocancer.cornell.edu/Factsheet/Diet/fs37.hormones.cfm |archive-date= 2011-07-19 }}</ref> Although DES was discovered to be harmful to humans, its veterinary use was not immediately halted. As of 2011, DES was still being used as a growth promoter in terrestrial livestock or fish in some parts of the world including China.<ref>{{cite journal |vauthors= Liu, WJ et al |title= Removal and Biodegradation of 17β-Estradiol and Diethylstilbestrol by the Freshwater Microalgae Raphidocelis subcapitata |journal= International Journal of Environmental Research and Public Health |volume= 15 |pages= 452 |date=2018 |issue= 3 |doi=10.3390/ijerph15030452|pmid= 29510598 |pmc= 5876997 |s2cid= 4711788 |doi-access= free }}</ref>
			==References==
			{{Reflist}}
			==Further reading==
			{{refbegin}}
			* {{cite journal |vauthors= Johnston E |title= Poisoned subjects: life writing of DES daughters |journal= ] |volume= 38 |issue= 1 |pages= 31–63 |publisher= ] |jstor= 10.5250/fronjwomestud.38.1.0031 |date= 2017 |doi= 10.5250/fronjwomestud.38.1.0031 |s2cid= 152010855 |url= http://muse.jhu.edu/article/653258 |access-date= 2017-05-25 |archive-date= 2017-07-30 |archive-url= https://web.archive.org/web/20170730113306/http://muse.jhu.edu/article/653258 |url-status= live }}
			{{refend}}
			==External links==
			* National Cancer Institute
			* from the U.S. Centers for Disease Control and Prevention
			* national consumer organization providing comprehensive information for DES-exposed individuals
			* from the U.S. National Institutes of Health ({{circa|1980}})
			* {{Webarchive|url=https://web.archive.org/web/20110929172627/http://www.desfollowupstudy.org/ |date=2011-09-29 }} National Cancer Institute's longterm study of DES-exposed persons (including the DES-AD Project)
			* of patients with CCA (clear cell adenocarcinoma) of the vagina and/or cervix
			* Provides resources and social media links for general DES awareness
			{{Estrogens and antiestrogens}}
			{{Estrogen receptor modulators}}
			{{Estrogen-related receptor modulators}}
			]
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