Diethylstilbestrol

{{Short description|Chemical compound}} {{Infobox drug | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 464188812 | IUPAC_name = 4,4'-[(3''E'')-Hex-3-ene-3,4-diyl]diphenol | image = Diethylstilbestrol.svg | image_class = skin-invert-image | width = 250px | image2 = Diethylstilbestrol molecule ball.png | image_class2 = bg-transparent | width2 = 250px

<!--Clinical data--> | Drugs.com = {{drugs.com|CONS|diethylstilbestrol}} | pregnancy_category = X | routes_of_administration = By mouth, vaginal, topical, intravenous, intramuscular injection (as an ester) | class = Nonsteroidal estrogen

<!--Pharmacokinetic data--> | bioavailability = Well-absorbed<ref name="ChabnerLongo1996"/> | protein_bound = >95%<ref name="OelschlägerRothley1988"/> | metabolism = Hydroxylation, oxidation, glucuronidation<ref name="ChabnerLongo1996"/><ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/> | metabolites = • (''Z'',''Z'')-Dienestrol<ref name="ChabnerLongo1996"/><br />• Paroxypropione<ref name="ChabnerLongo1996"/><br />• Glucuronides<ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/> | elimination_half-life = 24 hours<ref name="ChabnerLongo1996"/><ref name="pmid7154205" /> | excretion = Urine, feces<ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/>

<!--Identifiers--> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 56-53-1 | ATC_prefix = G03 | ATC_suffix = CB02 | ATC_supplemental = {{ATC|G03|CC05}}, {{ATC|L02|AA01}} | PubChem = 448537 | IUPHAR_ligand = 2801 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00255 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 395306 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 731DCA35BT | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00577 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 41922 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 411 | synonyms = DES; Stilboestrol; Stilbestrol; (''E'')-11,12-Diethyl-4,13-stilbenediol

<!--Chemical data--> | C=18 | H=20 | O=2 | SMILES = Oc2ccc(/C(=C(/c1ccc(O)cc1)CC)CC)cc2 | 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+ | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = RGLYKWWBQGJZGM-ISLYRVAYSA-N }} <!-- Definition and medical uses --> '''Diethylstilbestrol''' ('''DES'''), also known as '''stilbestrol''' or '''stilboestrol''', is a nonsteroidal estrogen medication.<ref name="pmid4276416" /><ref name="Elks2014">{{cite book | vauthors = Elks J | date = 14 November 2014 | title = The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher = Springer | pages = 396– | isbn = 978-1-4757-2085-3 | url = https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA396 }}</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> Its use is now rare; in the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, 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 | date = 16 April 2007 | title = The Estrogen Elixir: A History of Hormone Replacement Therapy in America | publisher = JHU Press | pages = 26– | isbn = 978-0-8018-8602-7 | url = https://books.google.com/books?id=-tz4J4_hgdIC&pg=PA26 | 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 adverse reproductive health outcomes linked to DES, including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer.<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 by mouth, DES was available for use by other routes as well, such as vaginally, topically, and by injection.

<!-- Side effects and mechanism --> DES is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.<ref name="Kuhl2005" /> It is a synthetic and nonsteroidal estrogen of the stilbestrol group, and differs from the natural estrogen estradiol.<ref name="Kuhl2005" /> Compared to estradiol, DES has greatly improved bioavailability when taken by mouth, is more resistant to metabolism, and shows relatively increased effects in certain parts of the body like the liver and uterus.<ref name="Kuhl2005"/> These differences result in DES having an increased risk of blood clots, cardiovascular issues, 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 | date = June 2005 | title = The history of DES, lessons to be learned | journal = Pharmacy World & Science | volume = 27 | issue = 3 | pages = 139–143 | doi = 10.1007/s11096-005-3663-z | pmid = 16096877 | s2cid = 12630813 }}</ref><ref name="FeldbergLadd-Taylor2003">{{cite book | vauthors = Feldberg GD, Ladd-Taylor M, Li A | year = 2003 | title = Women, Health and Nation: Canada and the United States Since 1945 | publisher = McGill-Queen's Press - MQUP | pages = 103– | isbn = 978-0-7735-2501-6 | url = https://books.google.com/books?id=CRjtHlq1INcC&pg=PA103 | 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 clear-cell carcinoma, a rare vaginal tumor, in those who had been exposed to this medication ''in utero''.<ref name="pmid16096877"/><ref name="pmid4276416" /> The United States Food and Drug Administration 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 including 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 National Cancer Institute recommends 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.<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> 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/article/des-daughters-the-devastating-effects-of-a-1940s-wonder-pill-haunt-women-generations-later/ |work=Broadly |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 toxic effects of DES, it has largely been discontinued and is now mostly no longer marketed for human treatment.<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>

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==Medical uses== 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= The Medical Clinics of North America |volume= 58 |issue= 4 |pages= 793–810 |date= July 1974 |pmid= 4276416 |doi= 10.1016/S0025-7125(16)32122-8 }}</ref> * Recurrent miscarriage in pregnancy<ref>{{cite journal | vauthors = Herbst AL, Anderson D | date = September 2015 | title = Diethylstilbestrol (DES) Pregnancy Treatment: A Promising Widely Used Therapy with Unintended Adverse Consequences | journal = AMA Journal of Ethics | volume = 17 | issue = 9 | pages = 865–870 | doi = 10.1001/journalofethics.2015.17.9.mhst1-1509 | pmid = 26390210 }}</ref> * Menopausal hormone therapy<ref>{{cite web | date = 2021-12-23 | title = Diethylstilbestrol (DES) Exposure and Cancer - NCI | website = www.cancer.gov | url = https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/des-fact-sheet | access-date = 2026-04-20 }}</ref> for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy{{Citation needed|date=April 2026}} * Hormone therapy for hypoestrogenism (e.g., gonadal dysgenesis, premature ovarian failure, and after oophorectomy){{Citation needed|date=April 2026}} * Postpartum lactation suppression to prevent or reverse breast engorgement<ref name="Vorherr2012">{{cite book | vauthors = Vorherr H | date = 2 December 2012 | title = The Breast: Morphology, Physiology, and Lactation | publisher = Elsevier Science | pages = 201–203 | isbn = 978-0-323-15726-1 | url = https://books.google.com/books?id=wYxirvD2X2IC&pg=PA201 | 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><ref name=":5">{{cite journal | vauthors = Reed CE, Fenton SE | date = June 2013 | title = Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects | journal = Birth Defects Research. Part C, Embryo Today | volume = 99 | issue = 2 | pages = 134–146 | doi = 10.1002/bdrc.21035 | pmc = 3817964 | pmid = 23897597 }}</ref> * Gonorrheal vaginitis<ref>{{cite journal | vauthors = BROWN WE | date = 1942-08-01 | title = Treatment of Gonorrheal Vulvovaginitis WITH Estrogens | journal = Archives of Pediatrics & Adolescent Medicine | volume = 64 | issue = 2 | page = 221 | doi = 10.1001/archpedi.1942.02010080013002 | url = https://jamanetwork.com/journals/jamapediatrics/article-abstract/1179510 | archive-date = 2022-05-17 | archive-url = http://web.archive.org/web/20220517232339/https://jamanetwork.com/journals/jamapediatrics/article-abstract/1179510 | issn = 1072-4710 | url-access = subscription }}</ref> (discontinued following the introduction of the antibiotic penicillin){{Citation needed|date=April 2026}} * Prostate cancer and breast cancer<ref name=":5" /> * Prevention of tall stature in tall adolescent girls<ref name=":5" /><ref>{{Cite web |date=2009-04-05 |title=A 'too tall' tale: girls and the drug DES |url=https://www.latimes.com/opinion/la-oe-cosgrove5-2009apr05-story.html |access-date=2026-04-20 |website=Los Angeles Times |language=en-US}}</ref> * Treatment of acne in men and women<ref>{{cite journal | vauthors = Jarrett A | date = May 1955 | title = The effects of stilboestrol on the surface sebum and upon acne vulgaris | journal = The British Journal of Dermatology | volume = 67 | issue = 5 | pages = 165–179 | doi = 10.1111/j.1365-2133.1955.tb12715.x | pmid = 14363568 }}</ref><ref>{{cite journal | vauthors = White CB, Lehmann CF | date = May 1952 | title = Diethylstilbestrol therapy in young men with acne; correlation with the urinary 17-ketosteroids | journal = A.M.A. Archives of Dermatology and Syphilology | volume = 65 | issue = 5 | pages = 601–608 | doi = 10.1001/archderm.1952.01530240093012 | pmid = 14914180 }}</ref> * As an emergency postcoital contraceptive<ref name=":5" /> * As a means of chemical castration for treating hypersexuality, paraphilias, and sex offenders<ref name="Chatz1972">{{cite journal | vauthors = Chatz TL | date = June 1972 | title = Recognizing and Treating Dangerous Sex Offenders | journal = International Journal of Offender Therapy and Comparative Criminology | volume = 16 | issue = 2 | pages = 109–115 | doi = 10.1177/0306624X7201600202 | issn = 0306-624X | eissn = 1552-6933 | s2cid = 74365268 }}</ref><ref>{{cite journal | vauthors = Scott CL, Holmberg T | date = 2003 | title = Castration of sex offenders: prisoners' rights versus public safety | journal = The Journal of the American Academy of Psychiatry and the Law | volume = 31 | issue = 4 | pages = 502–509 | pmid = 14974806 }}</ref><ref>{{cite journal | vauthors = Huffman GB | date = 1999-05-15 | title = Treatment of Hypersexuality in Nursing Home Residents | language = en-US | journal = American Family Physician | volume = 59 | issue = 10 |page=2880 | url = https://www.aafp.org/pubs/afp/issues/1999/0515/p2880.html }}</ref> * Prevention of the testosterone flare at the start of gonadotropin-releasing hormone agonist (GnRH agonist) therapy<ref name="pmid16986003">{{cite journal | vauthors = Thompson IM | date = 2001 | title = Flare Associated with LHRH-Agonist Therapy | journal = Reviews in Urology | volume = 3 | issue = Suppl 3 |pages=S10–14 | pmc = 1476081 | pmid = 16986003 }}</ref><ref name="pmid8481213">{{cite journal | vauthors = Scaletscky R, Smith JA | date = April 1993 | title = Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it? | journal = Drug Safety | volume = 8 | issue = 4 | pages = 265–270 | doi = 10.2165/00002018-199308040-00001 | pmid = 8481213 | s2cid = 36964191 }}</ref> * Feminizing hormone therapy for transgender women<ref name="Hamburger1969">{{cite book | vauthors = Hamburger C | year = 1969 | veditors = Money J, Green R | chapter = Endocrine treatment of male and female transsexualism | title = Transsexualism and Sex Reassignment | publisher = Johns Hopkins Press | pages = 291–307 | isbn = 978-0-8018-1038-1 | 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 | oclc = 6866559 | url-status = live }}</ref><ref name="pmid794803">{{cite journal | vauthors = Ober WB | date = 1976 | title = Stilbestrol: a pathologist's view | journal = Pathology Annual | volume = 11 | pages = 227–254 | pmid = 794803 }}</ref>

DES was used at a dosage of 0.2 to 0.5&nbsp;mg/day in menopausal hormone therapy.<ref name="Buchsbaum2012">{{cite book | vauthors = Buchsbaum HJ | date = 6 December 2012 | title = The Menopause | publisher = Springer Science & Business Media | pages = 60– | isbn = 978-1-4612-5525-3 | url = https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA60 | 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= International Urology and Nephrology |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= Scandinavian Journal of Urology |volume= 48 |issue= 1 |pages= 4–14 |date= February 2014 |pmid= 24256023 |doi= 10.3109/21681805.2013.861508 |s2cid= 34563641 |doi-access= free }}</ref><ref name="pmid22578092">{{cite journal | vauthors = Bosset PO, Albiges L, Seisen T, de la Motte Rouge T, Phé V, Bitker MO, Rouprêt M | date = December 2012 | title = Current role of diethylstilbestrol in the management of advanced prostate cancer | journal = BJU International | volume = 110 | issue = 11 Pt C |pages=E826–E829 | doi = 10.1111/j.1464-410X.2012.11206.x | pmid = 22578092 | s2cid = 21407416 | doi-access = free }}</ref> However, use of bioidentical parenteral estrogens like polyestradiol phosphate 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= Clinical Genitourinary Cancer |volume= 5 |issue=3 |pages= 198–205 |date= December 2006 |pmid= 17239273 |doi= 10.3816/CGC.2006.n.037 }}</ref><ref name="pmid15046698">{{cite journal | vauthors = Oh WK | date = September 2002 | title = The evolving role of estrogen therapy in prostate cancer | journal = Clinical Prostate Cancer | volume = 1 | issue = 2 | pages = 81–89 | doi = 10.3816/cgc.2002.n.009 | pmid = 15046698 }}</ref><ref name="pmid7500443">{{cite journal | vauthors = Cox RL, Crawford ED | date = December 1995 | title = Estrogens in the treatment of prostate cancer | journal = The Journal of Urology | volume = 154 | issue = 6 | pages = 1991–1998 | doi = 10.1016/s0022-5347(01)66670-9 | pmid = 7500443 }}</ref> 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 | date = 1992 | title = Diethylstilboestrol: I, Pharmacology, Toxicology and carcinogenicity in humans | journal = European Journal of Cancer | volume = 28A | issue = 6–7 | pages = 1182–1189 | doi = 10.1016/0959-8049(92)90482-h | pmid = 1627392 }}</ref> However, similarly to the case of prostate cancer, arguments have been made<ref name="EllisDehdahti2014" /> for the use of bioidentical estrogens like estradiol 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 | year = 2014 | 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 | page = 16 | doi = 10.1158/0008-5472.SABCS-16 | issn = 0008-5472 }}</ref>

Oral DES at 0.25 to 0.5&nbsp;mg/day has been found effective in the treatment of hot flashes in men undergoing androgen deprivation therapy 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 Journal of Urology |volume = 35 |issue = 3 |pages = 189–196 |date = 2019 |pmid = 31367069 |pmc = 6639989 |doi = 10.4103/iju.IJU_56_19 |doi-access = free }}</ref>

==Side effects== At more than 1&nbsp;mg/day, DES is associated with high rates of side effects including nausea, vomiting, abdominal discomfort, headache, and bloating (incidence of 15–50%).<ref name="pmid13638626">{{cite journal | vauthors = Swyer GI | date = April 1959 | title = The oestrogens | journal = British Medical Journal | volume = 1 | issue = 5128 | pages = 1029–1031 | doi = 10.1136/bmj.1.5128.1029 | pmc = 1993181 | pmid = 13638626 | quote = [Diethylstilbestrol] 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 pigmentation of the breast areolae are often very dark and almost black with DES therapy.<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 | date = December 1939 | title = The Clinical Use of Stilbestrol, A Synthetic Estrogen: Preliminary Report | journal = The Yale Journal of Biology and Medicine | volume = 12 | issue = 2 | pages = 235–238 | pmc = 2602231 | pmid = 21433876 }}</ref><ref name="LisserCurtis1947">{{cite journal | vauthors = Lisser H, Curtis LE | date = October 1947 | 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 = 665–687 | doi = 10.1210/jcem-7-10-665 | pmid = 20270944 }}</ref> This is because the pigmentation that occurs with synthetic estrogens such as DES is much greater than with natural estrogens such as estradiol.<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> The mechanism of the difference is unknown.<ref name="pmid4276416" /> Progestogens like hydroxyprogesterone caproate have been reported to reduce the nipple hyperpigmentation induced by high-dose estrogen therapy.<ref name="pmid14278040">{{cite journal | vauthors = Crowley LG, Macdonald I | date = April 1965 | title = Delalutin and estrogens for the treatment of advanced mammary carcinoma in the postmenopausal woman | journal = Cancer | volume = 18 | issue = 4 | pages = 436–446 | doi = 10.1002/1097-0142(196504)18:4<436::aid-cncr2820180407>3.0.co;2-d | pmid = 14278040 | s2cid = 31370289 | doi-access = }}</ref>

In men treated with it for prostate cancer, DES has been found to produce high rates of gynecomastia (breast development) of 41 to 77%.<ref name="pmid16321765">{{cite journal | vauthors = Di Lorenzo G, Autorino R, Perdonà S, De Placido S | date = December 2005 | title = Management of gynaecomastia in patients with prostate cancer: a systematic review | journal = The Lancet. Oncology | volume = 6 | issue = 12 | pages = 972–979 | doi = 10.1016/S1470-2045(05)70464-2 | pmid = 16321765 }}</ref>

===Blood clots and cardiovascular issues=== In studies of DES as a form of high-dose estrogen therapy for those with prostate cancer, it has been associated with considerable cardiovascular morbidity and mortality.<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 venous thromboembolism.<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= Oncology & Hematology Review |volume= 10 |issue= 1 |pages= 42–47 |date= 2014 |pmid= 24932461 |pmc= 4052190 |doi= 10.17925/ohr.2014.10.1.42 |doi-broken-date= 5 May 2026 }}</ref> A 3&nbsp;mg/day dosage of DES has been associated with an incidence of thromboembolism 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 orchiectomy 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">{{cite journal |vauthors = Bamigboye AA, Morris J |title = Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes |journal = The Cochrane Database of Systematic Reviews |volume = 2003 |issue = 3 |article-number = CD004353 |date = 2003 |pmid = 12918007 |pmc = 9039959 |doi = 10.1002/14651858.CD004353 |url = }}</ref> * vaginal clear-cell adenocarcinoma * vaginal adenosis * T-shaped uterus * uterine fibroids * cervical weakness * breast cancer * infertility * hypogonadism * intersexual gestational defects * depression

A comprehensive animal study in 1993 found a plethora of adverse effects from DES such as (but not limited to) * genotoxicity (due to quinone metabolite) * teratogenicity * penile and testicular hypoplasia * cryptorchidism (in rats and rhesus monkeys), * liver and renal cancer (in hamsters), ovarian papillary carcinoma (in canines), and * malignant uterine mesothelioma (in squirrel monkeys).<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 F2 generation, 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 | date = August 2006 | 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 | doi = 10.1093/ije/dyl106 | pmid = 16723367 | doi-access = }}</ref> Additionally, evidence also points to transgenerational effects in F2 sons, such as hypospadias.<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 transgenerational effects in humans is not fully understood.<ref>{{cite web | date = 2021-12-23 | title = Diethylstilbestrol (DES) Exposure and Cancer - NCI | website = www.cancer.gov | url = https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/des-fact-sheet | access-date = 2026-04-20 }}</ref><ref name=":5" />

==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 | date = May 1977 | 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 = 2079–2078 | doi = 10.1001/jama.1977.03270460065023 | pmid = 576887 }}</ref><ref name="pmid13005120">{{cite journal | vauthors = Karnaky KJ | date = December 1952 | title = Micronized stilbestrol for dysfunctional uterine bleeding and endometriosis | journal = Southern Medical Journal | volume = 45 | issue = 12 | pages = 1166–1172 | doi = 10.1097/00007611-195212000-00009 | pmid = 13005120 }}</ref>

==Pharmacology==

===Pharmacodynamics===

====Estrogenic activity==== DES is an estrogen; specifically, it is a highly potent full agonist of both of the estrogen receptors (ERs).<ref name="Jordan2013">{{cite book | vauthors = Jordan VC | year = 2013 | title = Estrogen Action, Selective Estrogen Receptor Modulators, and Women's Health: Progress and Promise | publisher = World Scientific | pages = 143– | isbn = 978-1-84816-958-6 | url = https://books.google.com/books?id=ejS6CgAAQBAJ&pg=PA143 }}</ref><ref name="SeilerAutrup2012">{{cite book | vauthors = Seiler JP, Autrup JL, Autrup H | date = 6 December 2012 | title = Diversification in Toxicology — Man and Environment: Proceedings of the 1997 EUROTOX Congress Meeting Held in Århus, Denmark, June 25–28, 1997 | publisher = Springer Science & Business Media | pages = 23– | isbn = 978-3-642-46856-8 | url = https://books.google.com/books?id=ZlfrCAAAQBAJ&pg=PA23 }}</ref> It has approximately 468% and 295% of the affinity of estradiol at the ERα and ERβ, 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, EC₅₀ 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 agonist of the G protein-coupled estrogen receptor (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=[Diethylstilbestrol], 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 uterus, vagina, mammary glands, pituitary gland, and other tissues.<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 | year = 1996 | title = Cancer Chemotherapy and Biotherapy: Principles and Practice | publisher = Lippincott-Raven Publishers | page = 186 | isbn = 978-0-397-51418-2 | url = https://books.google.com/books?id=TZNrAAAAMAAJ | 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 | 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 | url-status = live }}</ref><ref name="pmid7154205">{{cite journal | vauthors = Abramson FP, Miller HC | date = December 1982 | title = Bioavailability, distribution and pharmacokinetics of diethystilbestrol produced from stilphostrol | journal = The Journal of Urology | volume = 128 | issue = 6 | pages = 1336–1339 | doi = 10.1016/s0022-5347(17)53502-8 | pmid = 7154205 }}</ref> Similarly to ethinylestradiol, DES shows a marked and disproportionately strong effect on liver protein synthesis.<ref name="Kuhl2005"/> Whereas its systemic estrogenic potency was about 3.8-fold of that of estropipate (piperazine estrone sulfate), which has similar potency to micronized estradiol, 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 mechanisms of action in the treatment of prostate cancer.<ref name="DenisGriffiths1999"/> It suppresses gonadal androgen production and hence circulating androgen levels due to its antigonadotropic effects; it stimulates hepatic sex hormone-binding globulin (SHBG) production, thereby increasing circulating levels of SHBG and decreasing the free fraction of testosterone and dihydrotestosterone (DHT) in the circulation; and it may have direct cytotoxic effects in the testes and prostate gland.<ref name="DenisGriffiths1999"/> DES has also been found to decrease DNA synthesis 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 | date = 17 April 2013 | title = Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie | publisher = Springer-Verlag | pages = 88– | isbn = 978-3-662-07635-4 | url = https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88 | 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==== [[File:Testosterone levels with different estrogen therapies in men with prostate cancer.png|thumb|right|300px|class=skin-invert-image|Testosterone levels with no treatment and with various estrogens in men with prostate cancer.<ref name="pmid4359746">{{cite journal | vauthors = Shearer RJ, Hendry WF, Sommerville IF, Fergusson JD | date = December 1973 | title = Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer | journal = British Journal of Urology | volume = 45 | issue = 6 | pages = 668–677 | doi = 10.1111/j.1464-410x.1973.tb12238.x | pmid = 4359746 }}</ref> Determinations were made with an early radioimmunoassay (RIA).<ref name="pmid4359746" /> Source was Shearer et al. (1973).<ref name="pmid4359746" />]] [[File:Testosterone levels with 0.2 to 5 mg per day diethylstilbestrol in men with prostate cancer.png|thumb|right|300px|class=skin-invert-image|Testosterone levels with placebo and 0.2 to 5&nbsp;mg/day diethylstilbestrol (DES) for 6&nbsp;months in men with prostate cancer.<ref name="pmid4699685">{{cite journal | vauthors = Kent JR, Bischoff AJ, Arduino LJ, Mellinger GT, Byar DP, Hill M, Kozbur X | date = May 1973 | title = Estrogen dosage and suppression of testosterone levels in patients with prostatic carcinoma | journal = The Journal of Urology | volume = 109 | issue = 5 | pages = 858–860 | doi = 10.1016/s0022-5347(17)60564-0 | pmid = 4699685 }}</ref> Determinations were made with a radioimmunoassay (RIA).<ref name="pmid4699685" /> Source was Kent et al. (1973).<ref name="pmid4699685" />]]

Due to its estrogenic activity, DES has antigonadotropic effects.<ref name="pmid29603164"/><ref name="DenisGriffiths1999"/><ref name="Salam2003"/><ref name="pmid16406864"/> That is, it exerts negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis), suppresses the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses sex hormone production as well as gamete production or maturation in the gonads.<ref name="pmid29603164"/><ref name="DenisGriffiths1999"/><ref name="Salam2003"/><ref name="pmid16406864"/> A study of ovulation 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 | year = 1966 | editor = Robert Benjamin Greenblatt | chapter = Antiovulatory Activity of Several Synthetic and Natural Estrogens | title = Ovulation: Stimulation, Suppression, and Detection | publisher = Lippincott | pages = 243–253 | isbn = 978-0-397-59010-0 | url = https://books.google.com/books?id=le1qAAAAMAAJ | 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= The Journal of Urology |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 |author=The Leuprolide Study Group | date = November 1984 | title = Leuprolide versus diethylstilbestrol for metastatic prostate cancer | journal = The New England Journal of Medicine | volume = 311 | issue = 20 | pages = 1281–1286 | doi = 10.1056/NEJM198411153112004 | pmid = 6436700 }}</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 | date = 1 March 1999 | title = Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment | publisher = CRC Press | pages = 294, 297– | isbn = 978-1-85317-422-3 | url = https://books.google.com/books?id=GreZlojD-tYC&pg=PA297 | 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 | year = 2003 | title = Principles & Practice of Urology: A Comprehensive Text | publisher = Universal-Publishers | pages = 684– | isbn = 978-1-58112-412-5 | url = https://books.google.com/books?id=y50kTcCCfEcC&pg=PA684 }}</ref> However, it has also been reported that 1&nbsp;mg/day DES results in approximately 50% suppression of testosterone levels, albeit with wide interindividual variability.<ref name="pmid29603164"/><ref name="pmid2669792">{{cite journal | vauthors = Seftel AD, Spirnak JP, Resnick MI | title = Hormonal therapy for advanced prostatic carcinoma | journal = Journal of Surgical Oncology. Supplement | 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 cyproterone acetate 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 | year = 2009 | chapter = Steroidal Antiandrogens | title = Hormone Therapy in Breast and Prostate Cancer | pages = 325–346 | isbn = 978-1-60761-471-5 | doi = 10.1007/978-1-59259-152-7_15 }}</ref><ref name="pmid2973529">{{cite journal | vauthors = Goldenberg SL, Bruchovsky N, Rennie PS, Coppin CM | date = December 1988 | title = The combination of cyproterone acetate and low dose diethylstilbestrol in the treatment of advanced prostatic carcinoma | journal = The Journal of Urology | volume = 140 | issue = 6 | pages = 1460–1465 | doi = 10.1016/S0022-5347(17)42073-8 | pmid = 2973529 }}</ref><ref name="pmid8677581">{{cite journal | vauthors = Goldenberg SL, Bruchovsky N, Gleave ME, Sullivan LD | date = June 1996 | title = Low-dose cyproterone acetate plus mini-dose diethylstilbestrol--a protocol for reversible medical castration | journal = Urology | volume = 47 | issue = 6 | pages = 882–884 | doi = 10.1016/S0090-4295(96)00048-9 | pmid = 8677581 }}</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 | date = November 1971 | title = Effect of hormonal therapy on plasma testosterone levels in prostatic carcinoma | journal = British Medical Journal | volume = 4 | issue = 5784 | pages = 391–394 | doi = 10.1136/bmj.4.5784.391 | pmc = 1799485 | pmid = 5124437 }}</ref>

====Other activities==== In addition to the ERs, an ''in vitro'' study found that DES also possesses activity, albeit relatively weak, at a variety of other steroid hormone receptors.<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 | date = March 2012 | title = Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer | journal = Endocrinology | volume = 153 | issue = 3 | pages = 1070–1081 | doi = 10.1210/en.2011-1608 | pmid = 22294742 | doi-access = free }}</ref> Whereas the study found EC₅₀ values of 0.18&nbsp;nM and 0.06&nbsp;nM of DES for the ERα and ERβ, respectively, the medication showed significant glucocorticoid activity at a concentration of 1&nbsp;μM that surpassed that of 0.1&nbsp;nM dexamethasone, as well as significant antagonism of the androgen, progesterone, and mineralocorticoid receptors (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 PPARγ and LXRα 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 animal models at pharmacologically relevant doses.<ref name="pmid22294742"/>

DES has been identified as an antagonist of all three isotypes of the estrogen-related receptors (ERRs), the ERRα, ERRβ, and ERRγ.<ref name="pmid15161930">{{cite journal | vauthors = Greschik H, Flaig R, Renaud JP, Moras D | date = August 2004 | 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 = 33639–33646 | doi = 10.1074/jbc.M402195200 | pmid = 15161930 | doi-access = free }}</ref><ref name="pmid16515477">{{cite journal | vauthors = Ariazi EA, Jordan VC | date = 2006 | title = Estrogen-related receptors as emerging targets in cancer and metabolic disorders | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 3 | pages = 203–215 | doi = 10.2174/1568026610606030203 | pmid = 16515477 }}</ref> Half-maximal inhibition occurs at a concentration of about 1&nbsp;μM.<ref name="pmid16515477" />

===Pharmacokinetics=== DES is well-absorbed with oral administration.<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"/> Sublingual administration 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 | year = 1967 | title = Topics in Medicinal Chemistry | publisher = Wiley-Interscience | page = 16 | isbn = 978-0-471-70468-3 | url = https://books.google.com/books?id=YXBtAAAAMAAJ | 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> Intrauterine DES has been studied for the treatment of uterine hypoplasia.<ref name="pmid14926876">{{cite journal | vauthors = Friedberg V | date = October 1951 | title = Die Behandlung der genitalen Hypoplasie mit intrauterinen Cyren-B-Kristallsuspensionen | language = de | journal = Geburtshilfe und Frauenheilkunde | volume = 11 | issue = 10 | pages = 923–930 | pmid = 14926876 | trans-title = Intrauterine Cyren-B Crystal Suspensions in Therapy of Genital Hypoplasia | issn = 0016-5751 }}</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 | year = 2008 | chapter = The Difficulty of Evaluating the Potency of Steroid Hormones by Different Routes of Administration in Humans | title = Ciba Foundation Symposium - Steroid Hormone Administration (Book II of Colloquia on Endocrinology, Vol. 3) | pages = 349–355 | isbn = 978-0-470-71515-4 | doi = 10.1002/9780470715154.ch10 | series = Novartis Foundation Symposia | issn = 1935-4657 }}</ref>

The distribution half-life of DES is 80&nbsp;minutes.<ref name="ChabnerLongo1996"/> It has no affinity for SHBG or corticosteroid-binding globulin, and hence is not bound to these proteins 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 plasma protein binding 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>

Hydroxylation of the aromatic rings of DES and subsequent conjugation of the ethyl side chains accounts for 80 to 90% of DES metabolism, while oxidation 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 | date = February 1993 | title = High-dose continuous-infusion fosfestrol in hormone-resistant prostate cancer | journal = Cancer | volume = 71 | issue = 3 Suppl | pages = 1123–1130 | doi = 10.1002/1097-0142(19930201)71:3+<1123::AID-CNCR2820711434>3.0.CO;2-T | pmid = 8428334 | s2cid = 23078614 | doi-access = free }}</ref> Conjugation of DES consists of glucuronidation, while oxidation includes dehydrogenation into (''Z'',''Z'')-dienestrol.<ref name="ChabnerLongo1996"/><ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/> The medication is also known to produce paroxypropione as a metabolite.<ref name=".v">{{cite book | vauthors = Chambers PL, Günzel P | date = 12 March 2013 | title = Mechanism of Toxic Action on Some Target Organs: Drugs and Other Substances | publisher = Springer Science & Business Media | pages = 276– | isbn = 978-3-642-67265-1 | url = https://books.google.com/books?id=zUH1CAAAQBAJ&pg=PA276 }}</ref> DES produces transient quinone-like reactive intermediates that cause cellular and genetic damage, which may help to explain the known carcinogenic 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 estradiol, the hydroxyl groups of DES do not undergo oxidation into an estrone-like equivalent.<ref name="pmid19737574">{{cite journal | vauthors = Jensen EV, Jacobson HI, Walf AA, Frye CA | date = February 2010 | title = Estrogen action: a historic perspective on the implications of considering alternative approaches | journal = Physiology & Behavior | volume = 99 | issue = 2 | pages = 151–162 | doi = 10.1016/j.physbeh.2009.08.013 | pmc = 2834267 | pmid = 19737574 }}</ref>

The elimination half-life of DES is 24&nbsp;hours.<ref name="ChabnerLongo1996"/> The metabolites of DES are excreted in urine and feces.<ref name="OelschlägerRothley1988"/><ref name="pmid8428334"/>

==Chemistry== [[File:Estradiol and diethylstilbestrol.png|thumb|right|265px|class=skin-invert-image|Chemical structures of estradiol and DES.<ref name="WermuthAldous2015">{{cite book | vauthors = Wermuth CG, Aldous D, Raboisson P, Rognan D | date = 1 July 2015 | title = The Practice of Medicinal Chemistry | publisher = Elsevier Science | pages = 244–245 | isbn = 978-0-12-417213-5 | url = https://books.google.com/books?id=dtScBAAAQBAJ&pg=PA244 }}</ref> Note the preservation of the two hydroxyl groups 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 stilbestrol (4,4'-dihydroxystilbene) group of compounds.<ref name="AcademicPress1945">{{cite book |editor1=Robert S. Harris |editor2=Kenneth V. Thimann | date = 1945 | title = Vitamins and Hormones | publisher = Academic Press |pages=[https://archive.org/details/in.ernet.dli.2015.5563/page/n253 233]– | url = https://archive.org/details/in.ernet.dli.2015.5563 }}</ref> It is a nonsteroidal open-ring analogue of the steroidal estrogen estradiol.<ref name="WermuthAldous2015"/> DES can be prepared from anethole, which also happens to be weakly estrogenic.<ref name="AcademicPress1945"/><ref name="MaximovMcDaniel2013">{{cite book | vauthors = Maximov PY, McDaniel RE, Jordan VC | date = 23 July 2013 | title = Tamoxifen: Pioneering Medicine in Breast Cancer | publisher = Springer Science & Business Media | pages = 3– | isbn = 978-3-0348-0664-0 | url = https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA3 }}</ref><ref name="Ravina2011">{{cite book | vauthors = Ravina | date = 11 January 2011 | title = T he Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs | publisher = John Wiley & Sons | pages = 177– | isbn = 978-3-527-32669-3 | url = https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA177 }}</ref><ref name="Sneader2005">{{cite book | vauthors = Sneader W | date = 31 October 2005 | title = Drug Discovery: A History | publisher = John Wiley & Sons | pages = 196–197 | isbn = 978-0-470-01552-0 | url = https://books.google.com/books?id=jglFsz5EJR8C&pg=PA196 }}</ref> Anethole was demethylated to form anol and anol then spontaneously dimerized into dianol and hexestrol, with DES subsequently being synthesized via structural modification of hexestrol.<ref name="AcademicPress1945"/><ref name="MaximovMcDaniel2013"/><ref name="Ravina2011"/><ref name="Sneader2005"/> As shown by X-ray crystallography, the molecular dimensions of DES are almost identical to those of estradiol, particularly in regards to the distance between the terminal hydroxyl groups.<ref name="Sneader2005"/>

==History==

===Synthesis=== DES was first synthesized in early 1938 by Leon Golberg, then a graduate student of Sir Robert Robinson at the Dyson Perrins Laboratory at the University of Oxford. Golberg's research was based on work by Wilfrid Lawson at the Courtauld Institute of Biochemistry, (led by Sir Edward Charles Dodds at Middlesex Hospital Medical School now part of University College London). A report of its synthesis was published in ''Nature'' 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 = Nature | volume = 141 | issue = 3562 | pages = 247–248 | 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 | publisher = Stanford University Press | location = Stanford | oclc = 1483899 }}</ref><ref name=meyers>{{cite book | vauthors = Meyers R | year = 1983 | title = D.E.S., the bitter pill | publisher = Seaview/Putnam | isbn = 0-399-31008-8 | url = https://archive.org/details/desbitterpill00meye | location = New York | url-access = registration }}</ref>

DES research was funded by the UK Medical Research Council (MRC), which had a policy against patenting drugs discovered using public funds.<ref>{{Cite web |title=The Open University |url=https://university.open.ac.uk/research-centres/herc/blog/diethylstilbestrol-des-2025-survivors-speak-parliament-listens-will-government-act |access-date=2026-04-20 |website=university.open.ac.uk |language=en-gb}}</ref> Because it was not patented, DES was produced by more than 200 pharmaceutical and chemical companies worldwide.<ref>{{Cite web |date=2025-11-04 |title=Worcester woman exposed to cancer-linked hormone drug seeks justice |url=https://www.bbc.co.uk/news/articles/c4g70md0m41o |access-date=2026-04-20 |website=BBC News |language=en-GB}}</ref>

===Clinical use=== DES was first marketed for medical use in 1939.<ref name="FeldbergLadd-Taylor2003" /> It was approved by the United States Food and Drug Administration (FDA) on September 19, 1941, in tablets up to 5&nbsp;mg for four indications: gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement.<ref name=meyers/> The gonorrheal vaginitis indication was dropped when the antibiotic penicillin 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 | publisher = Yale University Press | isbn = 978-0-300-13607-4 | location = New Haven, CT }}</ref> Thorough toxicological studies were not performed on the drug before it was dispensed to women in non-standardized doses worldwide.<ref name=":5" /><ref name=seaman>{{cite book | vauthors = Seaman B | year = 2003 | title = The greatest experiment ever performed on women: Exploding the estrogen myth | publisher = Hyperion | isbn = 978-0-7868-6853-7 | url = https://archive.org/details/greatestexperime00barb | url-access = registration | location = New York }}</ref>

In 1941, Charles Huggins and Clarence Hodges at the University of Chicago found estradiol benzoate and DES to be the first effective drugs for the treatment of metastatic prostate cancer.<ref name="pmid4625049">{{cite journal | vauthors = Huggins C, Hodges CV | year = 1972 | 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 = 232–240 | doi = 10.3322/canjclin.22.4.232 | pmid = 4625049 | 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> Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years, until the GnRH agonist leuprorelin 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 estrogen replacement therapy for estrogen deficiency states such as ovarian dysgenesis, premature ovarian failure, and after oophorectomy.{{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 Bristol-Myers Squibb, 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 | publisher = Cambridge University Press | isbn = 0-521-34023-3 | url = https://archive.org/details/worsethandisease0000dutt | location = Cambridge | url-access = registration }}</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 | publisher = Medical Economics | edition = 15th | page = 625 | location = Oradell NJ }}</ref> DES was originally considered effective and safe for both the pregnant woman and the developing baby.<ref>{{cite web | date = 2003 | title = DES update: for you, your family, and your health care provider | website = stacks.cdc.gov | url = https://stacks.cdc.gov/ | access-date = 2026-04-20 }}</ref> It was aggressively marketed and routinely prescribed. Sales peaked in 1953.{{cn|date=May 2024}}

In the early 1950s, a double-blind 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 | date = November 1953 | title = Does the administration of diethylstilbestrol during pregnancy have therapeutic value? | journal = American Journal of Obstetrics and Gynecology | volume = 66 | issue = 5 | pages = 1062–1081 | doi = 10.1016/S0002-9378(16)38617-3 | pmid = 13104505 }}</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 | publisher = Yale University Press | isbn = 0-300-03192-0 | url = https://archive.org/details/todonoharmdesdil0000apfe | location = New Haven | url-access = registration }}</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.<ref>{{cite web | date = 2007-01-30 | title = Mother's ruin: The facts about DES | website = The Independent | url = https://www.the-independent.com/life-style/health-and-families/health-news/mother-s-ruin-the-facts-about-des-434305.html | access-date = 2026-04-20 }}</ref> In 1971, a report published in the ''New England Journal of Medicine'' showed a probable link between DES and vaginal clear cell adenocarcinoma in girls and young women who had been exposed to this drug ''in utero''.<ref>{{cite journal | vauthors = Herbst AL, Ulfelder H, Poskanzer DC | date = April 1971 | title = Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women | journal = The New England Journal of Medicine | volume = 284 | issue = 15 | pages = 878–881 | doi = 10.1056/NEJM197104222841604 | pmid = 5549830 }}</ref> 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 periodical |author=United States Food and Drug Administration |year= 1971 |title= Certain estrogens for oral or parenteral use. Drugs for human use; drug efficacy study implementation |periodical=Federal Register |volume= 36 |issue= 217 |pages= 21537–21538 |id={{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.<ref>{{cite journal | vauthors = Titus-Ernstoff L, Troisi R, Hatch EE, Palmer JR, Wise LA, Ricker W, Hyer M, Kaufman R, Noller K, Strohsnitter W, Herbst AL, Hartge P, Hoover RN | date = July 2006 | title = Mortality in women given diethylstilbestrol during pregnancy | journal = British Journal of Cancer | volume = 95 | issue = 1 | pages = 107–111 | doi = 10.1038/sj.bjc.6603221 | pmc = 2360488 | pmid = 16786044 }}</ref> DES was also used in other countries, most notably France, the Netherlands, and Great Britain.<ref>{{cite journal | vauthors = Sheldon T | title = Dutch investigate if carcinogenic effects of diethylstilbestrol persist | journal = British Medical Journal | date = 2001 | volume = 322 | issue = 7282 | page = 318 | pmc = 1173203 }}</ref><ref name=":5" />

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 androgens in the treatment of advanced breast cancer 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 = 1271–1283 | 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 tamoxifen, a selective estrogen receptor modulator 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 hormone therapy for transgender women.<ref>{{cite journal | vauthors = Goodwin WE, Cummings RH | date = March 1984 | 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 = 553–554 | doi = 10.1016/s0022-5347(17)50493-0 | pmid = 6199525 }}</ref><ref>{{cite journal | vauthors = Lehrman KL | date = February 1976 | title = Pulmonary embolism in a transsexual man taking diethylstilbestrol | journal = JAMA | volume = 235 | issue = 5 | pages = 532–533 | doi = 10.1001/jama.1976.03260310046024 | pmid = 946104 }}</ref><ref>{{cite journal | vauthors = Seyler LE, Canalis E, Spare S, Reichlin S | date = July 1978 | 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 = 176–183 | doi = 10.1210/jcem-47-1-176 | pmid = 122396 }}</ref>

In 1973, in an attempt to restrict off-label use of DES as a postcoital contraceptive (which had become prevalent at many university health services following publication of an influential study in 1971 in ''JAMA'') 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 | date = October 1971 | title = Postcoital contraception with diethylstilbestrol | journal = JAMA | volume = 218 | issue = 4 | pages = 562–563 | doi = 10.1001/jama.218.4.562 | pmid = 5171004 }}</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 = 5451–5455 }}; {{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 Yuzpe regimen of certain regular combined oral contraceptive 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 | publisher = Irvington Publishers |pages=[https://archive.org/details/contraceptivetec0000hatc/page/152 152–157] | isbn = 0-8290-0705-9 | url = https://archive.org/details/contraceptivetec0000hatc | location = New York }}</ref>

In 1978, the FDA removed postpartum lactation suppression 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 = 49564–49567 }}; {{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, Eli Lilly, 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 as a 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 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> DES usage during pregnancy was common, 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 === thumb|right|upright=1.3|Container of "Vi-Gain" round pellets, a brand of synthetic estrogen diethylstilbestrol for veterinary use

In 1938, the FDA gained the authority to require that drugs demostrated their safety before being approved. DES became the first medication to go through the new approval process.<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> Initial studies provided to the FDA were mostly conducted on laboratory animals. These preliminary tests showed that DES could cause sexual differentiation in offspring that only emerged following sexual maturity. The FDA was concerned by these findings, with Walter Campbell, then-Commissioner of the FDA, arguing that the agency should be cautious approving drugs without evidence that they would not cause harm.<ref name=":3" />

In 1940 the FDA informed drug companies that New Drug Applications for DES approval should be withdrawn. The companies who were waiting for DES approval began working together with lobbyists, providing DES medications to doctors in the form of samples; this effectively created a marker for the drug before it had been officially approved. Following this, 51 doctors wrote to the FDA requesting its approval.<ref name=":3" /> Though the FDA was still uncertain about the safety of DES when used in humans, it approved the medication following political pressure to do so. However, a compromise was made that meant that DES would be a prescription-only medication, and would have warnings about its effects – including the potential for damaged fertility – on the bottle. Deapite this, 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 | article-number = 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 |article-number=9139 | date = November 2020 | pmid = 33266302 | pmc = 7731339 | doi = 10.3390/ijms21239139 | doi-access = free | bibcode = 2020IJMSc..21.9139E }}</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 ===

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 Food and Drug Administration (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, autonomy, non-maleficence, beneficence, and justice as there was little thought put into how DES would affect its users.<ref>{{cite book | vauthors = Beauchamp TL | date = 2018 | 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 | volume = 1 | pages = 91–119 | isbn = 978-1-78634-047-4 | doi = 10.1142/9781786340481_0004 | series = Intercultural Dialogue in Bioethics }}</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 [for DES were] 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 Supreme Court of California, ''Sindell v. Abbott Laboratories'', in which the court imposed a rebuttable presumption of market share liability 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 Daubert 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 |access-date=19 March 2014|newspaper=Huffington Post|date=9 January 2013}}</ref>

The advocacy group DES Action USA 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== Alan Turing, the ground-breaking cryptographer, founder of computing science and programmable computers, who also proposed the actual theoretical model of biological morphogenesis, was forcefully given this drug to induce chemical castration as a punitive 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/ }}</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 | date = 22 January 2023 | title = How 'gay conversion' drugs ruined this man's life | website = Stuff | url = https://www.stuff.co.nz/national/health/130948087/how-gay-conversion-drugs-ruined-this-mans-life/ | 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>

James Herriot describes a case regarding treating a small dog's testicular Sertoli cell tumor 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=Merck Veterinary Manual|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 feed conversion in beef and poultry. From 1947, DES was used as a growth hormone in the beef and poultry industries. In the following years high levels of DES were detected in poultry sold for human consumption. Mink farmers later noticed that their animals were having miscarriges after feeding them discarded chicken heads that contained DES implants. The use of DES in poultry was banned in chickens in 1959 after male agricultural workers reported sterility and breast growth.<ref name=":3" /> DES was later found to cause cancer by 1971, but was not phased out until 1979.<ref>{{cite journal | vauthors = Harris RM, Waring RH | date = June 2012 | title = Diethylstilboestrol--a long-term legacy | journal = Maturitas | volume = 72 | issue = 2 | pages = 108–112 | doi = 10.1016/j.maturitas.2012.03.002 | pmid = 22464649 }}</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 |page= 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= Frontiers: A Journal of Women Studies |volume= 38 |issue= 1 |pages= 31–63 |publisher= University of Nebraska Press |jstor= 10.5250/fronjwomestud.38.1.0031 |date= 2017 |doi= 10.5250/fronjwomestud.38.1.0031 |s2cid= 152010855 |doi-access= free }} {{refend}}

== External links == * [https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/des-fact-sheet Diethylstilbestrol (DES) and Cancer] National Cancer Institute * [https://www.cdc.gov/DES/ DES Update] from the U.S. Centers for Disease Control and Prevention * [https://desaction.org/ DES Action USA] national consumer organization providing comprehensive information for DES-exposed individuals * [https://web.archive.org/web/20070604145531/http://dccps.nci.nih.gov/ACSRB/pubs/DES_Pubs/directory.html DES Booklets] from the U.S. National Institutes of Health ({{circa|1980}}) * {{usurped|1=[https://web.archive.org/web/20110929172627/http://www.desfollowupstudy.org/ DES Follow-up Study]}} National Cancer Institute's longterm study of DES-exposed persons (including the DES-AD Project) * [https://voices.uchicago.edu/ccaregistry/ University of Chicago DES Registry] of patients with CCA (clear cell adenocarcinoma) of the vagina and/or cervix * [https://diethylstilbestrol.co.uk/ DES Diethylstilbestrol] Provides resources and social media links for general DES awareness

{{Estrogens and antiestrogens}} {{Estrogen receptor modulators}} {{Estrogen-related receptor modulators}}

Category:Abandoned drugs Category:Antigonadotropins Category:Drugs developed by Eli Lilly and Company Category:Endocrine disruptors Category:GPER modulators Category:Hormonal antineoplastic drugs Category:IARC Group 1 carcinogens Category:Intersex healthcare Category:4-Hydroxyphenyl compounds Category:Stilbenoids Category:Synthetic estrogens Category:Teratogens Category:Withdrawn drugs