Estradiol (medication)

{{Short description|Steroidal hormone medication}} {{Redirect|Altrad|the French corporation "Groupe Altrad"|Mohed Altrad}} {{About|estradiol as a medication|its role as a hormone|Estradiol}} {{Use dmy dates|date=May 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 488623959 | drug_name = Estradiol | image = Estradiol.svg | image_class = skin-invert-image | width = 225 | alt = | image2 = Estradiol 3D ball.png | image_class2 = bg-transparent | width2 = 235 | alt2 =  | pronounce = {{IPAc-en|ˌ|ɛ|s|t|r|ə|ˈ|d|aɪ|oʊ|l}} {{respell|ES|trə|DY|ohl}}<ref name="FordRoach2013">{{cite book| vauthors = Ford SM, Roach SS |title=Roach's Introductory Clinical Pharmacology|url=https://books.google.com/books?id=LwOaAgAAQBAJ&pg=PA525|date=7 October 2013|publisher=Lippincott Williams & Wilkins|isbn=978-1-4698-3214-2|pages=525–}}</ref><ref name="HochadelMosby2015">{{cite book| vauthors = Hochadel M |title=Mosby's Drug Reference for Health Professions|url=https://books.google.com/books?id=IuF1BwAAQBAJ&pg=PA602|date=1 April 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-31103-8|pages=602–}}</ref> | tradename = Many | Drugs.com = {{drugs.com|monograph|estradiol}} | MedlinePlus = | DailyMedID = Estradiol | pregnancy_AU = B1 | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth (tablet) • Sublingual (tablet) • Intranasal (nasal spray) • Transdermal (patch, gel, cream, emulsion, spray) {{Font|size=98%|• Vaginal (tablet, cream, suppository, insert, ring)}} • {{abbr|IM|Intramuscular}} injection (oil solution) • {{abbr|SC|Subcutaneous}} injection ({{abbrlink|aq. soln.|aqueous solution}}) • Subcutaneous implant | class = Estrogen | ATC_prefix = G03 | ATC_suffix = CA03 | ATC_supplemental =  | legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Imvexxy Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99313 | access-date=5 June 2022 | archive-date=6 June 2022 | archive-url=https://web.archive.org/web/20220606052955/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99313 | url-status=live }}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = | legal_EU = Rx-only | legal_EU_comment = <ref>{{Cite web |url=https://www.ema.europa.eu/documents/psusa/estradiol-except-cream/balm/emulsion-application-female-genital-area-list-nationally-authorised-medicinal-products-psusa/00010440/202108_en.pdf |title=Active substance: estradiol (except cream/balm/emulsion for application in female genital area) | work = List of nationally authorised medicinal products | publisher = European Medicines Agency |access-date=10 June 2022 |archive-date=10 June 2022 |archive-url=https://web.archive.org/web/20220610034547/https://www.ema.europa.eu/en/documents/psusa/estradiol-except-cream/balm/emulsion-application-female-genital-area-list-nationally-authorised-medicinal-products-psusa/00010440/202108_en.pdf |url-status=live }}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| bioavailability = Oral: <5%<ref name="pmid23375353">{{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–727 | date = June 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 }}</ref> IM: 100%<ref name="pmid7169965">{{cite journal | vauthors = Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–324 | date = December 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0 }}</ref> | protein_bound = ~98%:<ref name="pmid23375353" /><ref name="FalconeHurd2007">{{cite book| vauthors = Falcone T, Hurd WW |title=Clinical Reproductive Medicine and Surgery|url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22|year=2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=22,362,388|access-date=27 November 2016|archive-date=15 April 2021|archive-url=https://web.archive.org/web/20210415210807/https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22|url-status=live}}</ref> • Albumin: 60% • {{abbr|SHBG|sex hormone-binding globulin}}: 38% • Free: 2% | metabolism = Liver (via hydroxylation, sulfation, glucuronidation) | metabolites = Major (90%):<ref name="pmid23375353" /> • Estrone • Estrone sulfate • Estrone glucuronide • Estradiol glucuronide | onset = | elimination_half-life = Oral: 13–20 hours<ref name="pmid23375353" /> Sublingual: 8–18 hours<ref name="PriceBlauer1997">{{cite journal | vauthors = Price TM, Blauer KL, Hansen M, Stanczyk F, Lobo R, Bates GW | title = Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17 beta-estradiol | journal = Obstetrics and Gynecology | volume = 89 | issue = 3 | pages = 340–345 | date = March 1997 | pmid = 9052581 | doi = 10.1016/S0029-7844(96)00513-3 | s2cid = 71641652 }}</ref> {{Font|size=95%|Transdermal (gel): 37 hours<ref name="NauntonAl Hadithy2006">{{cite journal | vauthors = Naunton M, Al Hadithy AF, Brouwers JR, Archer DF | title = Estradiol gel: review of the pharmacology, pharmacokinetics, efficacy, and safety in menopausal women | journal = Menopause | volume = 13 | issue = 3 | pages = 517–527 | year = 2006 | pmid = 16735950 | doi = 10.1097/01.gme.0000191881.52175.8c | s2cid = 42748448 }}</ref>}} IM (as {{abbrlink|EV|estradiol valerate}}): 4–5 days<ref name="pmid7169965" /> IM (as {{abbrlink|EC|estradiol cypionate}}): 8–10 days<ref name="pmid22078184">{{cite journal | vauthors = Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, Velázquez-Ramírez N, Godínez-Victoria M, Hernádez-Munguía IA, Padilla A, Garza-Flores J | title = Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg) | journal = Contraception | volume = 84 | issue = 6 | pages = 565–570 | date = December 2011 | pmid = 22078184 | doi = 10.1016/j.contraception.2011.03.014 }}</ref> {{abbrlink|IV|Intravenous injection}} (as {{abbr|E2|estradiol}}): 1–2 hours<ref name="pmid7169965" /> | duration_of_action = | excretion = Urine: 54%<ref name="pmid23375353" /> Feces: 6%<ref name="pmid23375353" />

| CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 50-28-2 | CAS_supplemental = | PubChem = 5757 | IUPHAR_ligand = 1013 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00783 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5554 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 4TI98Z838E | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00105 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 16469 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 135 | NIAID_ChemDB = | PDB_ligand = | synonyms = Oestradiol; E2; 17β-Estradiol; Estra-1,3,5(10)-triene-3,17β-diol

| IUPAC_name = (8''R'',9''S'',13''S'',14''S'',17''S'')-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthrene-3,17-diol | C = 18 | H = 24 | O = 2 | SMILES = Oc1ccc2[C@H]3CC[C@]4(C)[C@]5(CC[C@H]4[C@@H]3CCc2c1).O5 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C18H24O2/c1-18-9-8-14-13-5-3-12(19)10-11(13)2-4-15(14)16(18)6-7-17(18)20/h3,5,10,14-17,19-20H,2,4,6-9H2,1H3/t14-,15-,16+,17+,18+/m1/s1 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = VOXZDWNPVJITMN-ZBRFXRBCSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Estradiol''' ('''E2''') is a medication and naturally occurring steroid hormone.<ref name="pmid16112947">{{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 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | access-date = 5 December 2016 | url-status = live | s2cid = 24616324 | archive-url = https://web.archive.org/web/20160822055012/http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | archive-date = 22 August 2016 }}</ref><ref name="OettelSchillinger2012a">{{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens|url=https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA235|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-58616-3|pages=121, 226, 235–237|access-date=5 December 2016|archive-date=15 December 2020|archive-url=https://web.archive.org/web/20201215185305/https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA235|url-status=live}}</ref><ref name="OettelSchillinger2012b">{{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA268|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=163–178, 235–237, 252–253, 261–276, 538–543|access-date=27 November 2016|archive-date=14 September 2020|archive-url=https://web.archive.org/web/20200914140353/https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA268|url-status=live}}</ref> It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women.<ref name="pmid16112947" /><ref name="pmid28376481" /> It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women and some non-binary individuals, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses.<ref name="pmid23241152" /><ref name="pmid12290848" /><ref name="pmid28159148" /><ref name="pmid25992351" /><ref name="pmid27889048" /> Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.<ref name="pmid16112947" />

Side effects of estradiol in women include breast tenderness, breast enlargement, headache, fluid retention, and nausea among others.<ref name="pmid16112947" /><ref name="Estrace Label" /> Men and children who are exposed to estradiol may develop symptoms of feminization, such as breast development and a feminine pattern of fat distribution, and men may also experience low testosterone levels and infertility.<ref name="Pohanish2011" /><ref name="CecilBennett1996" /> Estradiol may increase the risk of endometrial hyperplasia and endometrial cancer in women with intact uteruses if it is not taken together with a progestogen such as progesterone.<ref name="pmid16112947" /> The combination of estradiol with a progestin, though not with oral progesterone, may increase the risk of breast cancer.<ref name="pmid27898258">{{cite journal | vauthors = Yang Z, Hu Y, Zhang J, Xu L, Zeng R, Kang D | title = Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis | journal = Gynecological Endocrinology | volume = 33 | issue = 2 | pages = 87–92 | date = February 2017 | pmid = 27898258 | doi = 10.1080/09513590.2016.1248932 | s2cid = 205631264 }}</ref><ref name="pmid24485796">{{cite journal | vauthors = Lambrinoudaki I | title = Progestogens in postmenopausal hormone therapy and the risk of breast cancer | journal = Maturitas | volume = 77 | issue = 4 | pages = 311–317 | date = April 2014 | pmid = 24485796 | doi = 10.1016/j.maturitas.2014.01.001 }}</ref> Estradiol should not be used in women who are pregnant or breastfeeding or who have breast cancer, among other contraindications.<ref name="Estrace Label" />

Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol.<ref name="pmid16112947" /> Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both women and men.<ref name="pmid3242384">{{cite journal | vauthors = Stege R, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A | title = Single drug polyestradiol phosphate therapy in prostatic cancer | journal = American Journal of Clinical Oncology | volume = 11 | issue = Suppl 2 | pages = S101–S103 | year = 1988 | pmid = 3242384 | doi = 10.1097/00000421-198801102-00024 | s2cid = 32650111 }}</ref><ref name="Ockrim_2003">{{cite journal | vauthors = Ockrim JL, Lalani EN, Laniado ME, Carter SS, Abel PD | title = Transdermal estradiol therapy for advanced prostate cancer--forward to the past? | journal = The Journal of Urology | volume = 169 | issue = 5 | pages = 1735–1737 | date = May 2003 | pmid = 12686820 | doi = 10.1097/01.ju.0000061024.75334.40 }}</ref> Estradiol differs from non-bioidentical estrogens like conjugated estrogens and ethinylestradiol in various ways, with implications for tolerability and safety.<ref name="pmid16112947" />

Estradiol was discovered in 1933.<ref name="Parl2000">{{cite book| vauthors = Parl FF |title=Estrogens, Estrogen Receptor and Breast Cancer|url=https://books.google.com/books?id=v7ai5Mz9TZQC&pg=PA4|year=2000|publisher=IOS Press|isbn=978-0-9673355-4-4|pages=4,111|access-date=27 November 2016|archive-date=6 May 2020|archive-url=https://web.archive.org/web/20200506202753/https://books.google.com/books?id=v7ai5Mz9TZQC&pg=PA4|url-status=live}}</ref><ref name="LauritzenStudd2005" /> It became available as a medication that same year, in an injectable form known as estradiol benzoate.<ref name="Kaufman1933" /><ref name="Buschbeck1934" /><ref name="Biskind1935" /> Forms that were more useful by mouth, estradiol valerate and micronized estradiol, were introduced in the 1960s and 1970s and increased its popularity by this route.<ref name="KlinWochenschr1966">{{cite journal | title = Neue Spezialitäten | journal = Klinische Wochenschrift | volume = 44 | issue = 23 | year = 1966 | page = 1381 | issn = 0023-2173 | doi = 10.1007/BF01747900 | s2cid = 20357182 | quote = NEUE SPEZIALITATEN [...] Progynova. 1 Dragee enthält 2 mg Oestradiolvalerinat (Klimakterium). Hersteller: Schering AG, Berlin 65.}}</ref><ref name="pmid5593020">{{cite journal | vauthors = Dapunt O | title = [The management of climacteric disorders using estradiol valerate (Progynova)] | language = de | journal = Medizinische Klinik | volume = 62 | issue = 35 | pages = 1356–61 passim | date = September 1967 | pmid = 5593020 | trans-title = The management of climacteric disorders using estradiol valerate (Progynova) }}</ref><ref name="Estrace-FDA" /> Estradiol is also used as other prodrugs, like estradiol cypionate.<ref name="pmid16112947" /> Related estrogens such as ethinylestradiol, which is the most common estrogen in birth control pills, and conjugated estrogens (brand name Premarin), which is used in menopausal hormone therapy, are used as medications as well.<ref name="pmid16112947" /> In 2023, it was the 56th most commonly prescribed medication in the United States, with more than 11{{nbsp}}million prescriptions.<ref name="Top300Drugs">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Estradiol Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Estradiol | access-date = 18 August 2025 }}</ref> It is available as a generic medication.<ref>{{cite web | title=First Generic Drug Approvals 2022 | website=U.S. Food and Drug Administration (FDA) | date=17 October 2022 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | access-date=28 November 2022}}</ref><ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. Food and Drug Administration (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals }}</ref><ref>{{cite web | title=First Generic Drug Approvals 2023 | website=U.S. Food and Drug Administration (FDA) | date=30 May 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003621/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref>

==Medical uses==

===Hormone therapy===

====Menopause==== {{See also|Menopausal hormone therapy}}

[[File:Hot flashes with placebo and different doses of oral estradiol in menopausal women.png|class=skin-invert-image|thumb|right|425px|Average number of moderate-to-severe hot flashes per week with placebo and different doses of oral estradiol in menopausal women<ref name="pmid10775738">{{cite journal | vauthors = Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J | title = Initial 17beta-estradiol dose for treating vasomotor symptoms | journal = Obstetrics and Gynecology | volume = 95 | issue = 5 | pages = 726–731 | date = May 2000 | pmid = 10775738 | doi = 10.1016/s0029-7844(99)00643-2 | s2cid = 42621608 }}</ref><ref name="WiegratzKuhl2007">{{cite journal| vauthors = Wiegratz I, Kuhl H |title=Praxis der Hormontherapie in der Peri- und Postmenopause|trans-title=Practice of peri- and postmenopausal hormone therapy|journal=Gynäkologische Endokrinologie|volume=5|issue=3|year=2007|pages=141–149|issn=1610-2894|doi=10.1007/s10304-007-0194-9|s2cid=27130717}}</ref>]]

Estradiol is used in menopausal hormone therapy to prevent and treat moderate to severe menopausal symptoms such as hot flashes, vaginal dryness and atrophy, and osteoporosis (bone loss).<ref name="pmid16112947" /> As unopposed estrogen therapy (using estrogen alone without progesterone) increases the risk of endometrial hyperplasia and endometrial cancer in women with intact uteruses, estradiol is usually combined with a progestogen like progesterone or medroxyprogesterone acetate to prevent the effects of estradiol on the endometrium.<ref name="pmid16112947" /><ref name="Mutschler">{{Cite book| vauthors = Mutschler E, Schäfer-Korting M |title=Arzneimittelwirkungen|language=de|location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|pages=434, 444|isbn=978-3-8047-1763-3}}</ref> This is not necessary if the woman has undergone a hysterectomy (surgical removal of the uterus).<ref name="pmid16112947" /> A 2017 meta-analysis found that estradiol had no effect on depressive symptoms in peri- and postmenopausal women.<ref name="pmid27603786">{{cite journal | vauthors = Whedon JM, KizhakkeVeettil A, Rugo NA, Kieffer KA | title = Bioidentical Estrogen for Menopausal Depressive Symptoms: A Systematic Review and Meta-Analysis | journal = Journal of Women's Health | volume = 26 | issue = 1 | pages = 18–28 | date = January 2017 | pmid = 27603786 | doi = 10.1089/jwh.2015.5628 }}</ref>

====Hypogonadism==== Estrogen is responsible for the mediation of puberty in females, and in girls with delayed puberty due to hypogonadism (low-functioning gonads, which can result in low sex hormone levels) such as in Turner syndrome, estradiol is used to induce the development of and maintain female secondary sexual characteristics such as breasts, wide hips, and a female fat distribution.<ref name="pmid28446424">{{cite journal | vauthors = Matthews D, Bath L, Högler W, Mason A, Smyth A, Skae M | title = Hormone supplementation for pubertal induction in girls | journal = Archives of Disease in Childhood | volume = 102 | issue = 10 | pages = 975–980 | date = October 2017 | pmid = 28446424 | doi = 10.1136/archdischild-2016-311372 | url = http://pure-oai.bham.ac.uk/ws/files/40333585/Revised_ADC_paper_accepted_.pdf | access-date = 16 August 2019 | url-status = live | s2cid = 39539979 | archive-url = https://web.archive.org/web/20200310044144/http://pure-oai.bham.ac.uk/ws/files/40333585/Revised_ADC_paper_accepted_.pdf | archive-date = 10 March 2020 }}</ref><ref name="pmid28376481">{{cite journal | vauthors = Christin-Maitre S | title = Use of Hormone Replacement in Females with Endocrine Disorders | journal = Hormone Research in Paediatrics | volume = 87 | issue = 4 | pages = 215–223 | date = 2017 | pmid = 28376481 | doi = 10.1159/000457125 | s2cid = 3785166 | doi-access = free }}</ref><ref name="RosenthalBurchum2017">{{cite book| vauthors = Rosenthal L, Burchum J |title=Lehne's Pharmacotherapeutics for Advanced Practice Providers - E-Book|url=https://books.google.com/books?id=gfYoDgAAQBAJ&pg=PA524|date=17 February 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-44779-9|pages=524–|access-date=3 July 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034548/https://books.google.com/books?id=gfYoDgAAQBAJ&pg=PA524|url-status=live}}</ref> It is also used to restore estradiol levels in adult premenopausal women with hypogonadism, for instance those with premature ovarian failure or who have undergone oophorectomy.<ref name="pmid28376481" /><ref name="RosenthalBurchum2017" /> It is used to treat women with hypogonadism due to hypopituitarism as well.<ref name="RosenthalBurchum2017" /><ref name="pmid28376481" />

====Transgender women==== {{Main|Feminizing hormone therapy}}

Estradiol is used as part of feminizing hormone therapy for transgender women and some non-binary individuals.<ref name="WPATH2011">{{citation | author = World Professional Association for Transgender Health | title = Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, Seventh Version | date = September 2011 | url = http://www.wpath.org/uploaded_files/140/files/IJT%20SOC,%20V7.pdf | archive-url = https://web.archive.org/web/20160106203349/http://www.wpath.org/uploaded_files/140/files/IJT%20SOC%2C%20V7.pdf | archive-date = 6 January 2016 | author-link = World Professional Association for Transgender Health }}</ref><ref name="pmid28159148">{{cite journal | vauthors = Wesp LM, Deutsch MB | title = Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons | journal = The Psychiatric Clinics of North America | volume = 40 | issue = 1 | pages = 99–111 | date = March 2017 | pmid = 28159148 | doi = 10.1016/j.psc.2016.10.006 }}</ref> The drug is used in higher dosages prior to gender-affirming surgery or orchiectomy to help suppress testosterone levels; after this procedure, estradiol continues to be used at lower dosages to maintain estradiol levels in the normal premenopausal female range.<ref name="WPATH2011" /><ref name="pmid28159148" />

===Birth control=== Although almost all combined oral contraceptives contain the synthetic estrogen ethinylestradiol,<ref name="pmid25841596">{{cite journal | vauthors = Evans G, Sutton EL | title = Oral contraception | journal = The Medical Clinics of North America | volume = 99 | issue = 3 | pages = 479–503 | date = May 2015 | pmid = 25841596 | doi = 10.1016/j.mcna.2015.01.004 }}</ref> natural estradiol itself is also used in some hormonal contraceptives, including in estradiol-containing oral contraceptives and combined injectable contraceptives.<ref name="pmid23241152">{{cite journal | vauthors = Christin-Maitre S, Laroche E, Bricaire L | title = A new contraceptive pill containing 17β-estradiol and nomegestrol acetate | journal = Women's Health | volume = 9 | issue = 1 | pages = 13–23 | date = January 2013 | pmid = 23241152 | doi = 10.2217/whe.12.70 | s2cid = 31617961 | doi-access = free }}</ref><ref name="pmid12290848">{{cite journal | vauthors = Newton JR, D'arcangues C, Hall PE | title = A review of "once-a-month" combined injectable contraceptives | journal = Journal of Obstetrics and Gynaecology | volume = 4 | issue = Suppl 1 | pages = S1-34 | year = 1994 | pmid = 12290848 | doi = 10.3109/01443619409027641 }}</ref> It is formulated in combination with a progestin such as dienogest, nomegestrol acetate, or medroxyprogesterone acetate, and is often used in the form of an ester prodrug like estradiol valerate or estradiol cypionate.<ref name="pmid23241152" /><ref name="pmid12290848" /> Hormonal contraceptives contain a progestin and/or estrogen and prevent ovulation and thus the possibility of pregnancy by suppressing the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the peak of which around the middle of the menstrual cycle causes ovulation to occur.<ref name="Glasier2010">{{cite book| vauthors = Glasier A | author-link = Anna Glasier |year=2010|chapter=Contraception| veditors = Jameson JL, De Groot LJ |title=Endocrinology |edition=6th |location=Philadelphia|publisher=Saunders Elsevier|pages=2417–2427|isbn=978-1-4160-5583-9}}</ref>

===Hormonal cancer===

====Prostate cancer==== Estradiol is used as a form of high-dose estrogen therapy to treat prostate cancer and is similarly effective to other therapies such as androgen deprivation therapy with castration and antiandrogens.<ref name="pmid25992351">{{cite journal | vauthors = Ali Shah SI | title = Emerging potential of parenteral estrogen as androgen deprivation therapy for prostate cancer | journal = South Asian Journal of Cancer | volume = 4 | issue = 2 | pages = 95–97 | date = 2015 | pmid = 25992351 | pmc = 4418092 | doi = 10.4103/2278-330X.155699 | doi-access = free }}</ref><ref name="OettelSchillinger2012b" /><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="pmid7500443">{{cite journal | vauthors = Cox RL, Crawford ED | title = Estrogens in the treatment of prostate cancer | journal = The Journal of Urology | volume = 154 | issue = 6 | pages = 1991–1998 | date = December 1995 | pmid = 7500443 | doi = 10.1016/S0022-5347(01)66670-9 }}</ref> It is used in the form of long-lasting injected estradiol prodrugs like polyestradiol phosphate, estradiol valerate, and estradiol undecylate,<ref name="OettelSchillinger2012b" /><ref name="pmid17239273" /><ref name="Altwein1983">{{cite book| vauthors = Altwein J |title=Cancer of the Prostate and Kidney|chapter=Controversial Aspects of Hormone Manipulation in Prostatic Carcinoma|series=NATO Advanced Science Institutes Series |year=1983|pages=305–316|publisher=Springer |doi=10.1007/978-1-4684-4349-3_38|isbn=978-1-4684-4351-6}}</ref> and has also more recently been assessed in the form of transdermal estradiol patches.<ref name="pmid17239273" /><ref name="pmid16006886">{{cite journal | vauthors = Ockrim JL, Lalani EN, Kakkar AK, Abel PD | title = Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism | journal = The Journal of Urology | volume = 174 | issue = 2 | pages = 527–33; discussion 532–3 | date = August 2005 | pmid = 16006886 | doi = 10.1097/01.ju.0000165567.99142.1f }}</ref> Estrogens are effective in the treatment of prostate cancer by suppressing testosterone levels into the castrate range, increasing levels of sex hormone-binding globulin (SHBG) and thereby decreasing the fraction of free testosterone, and possibly also via direct cytotoxic effects on prostate cancer cells.<ref name="HongHolland2010" /><ref name="pmid14532759" /><ref name="CossJones2012">{{cite journal | vauthors = Coss CC, Jones A, Parke DN, Narayanan R, Barrett CM, Kearbey JD, Veverka KA, Miller DD, Morton RA, Steiner MS, Dalton JT | title = Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer | journal = Endocrinology | volume = 153 | issue = 3 | pages = 1070–1081 | date = March 2012 | pmid = 22294742 | doi = 10.1210/en.2011-1608 | doi-access = free }}</ref> Parenteral estradiol is largely free of the cardiovascular side effects of the high oral dosages of synthetic estrogens like diethylstilbestrol ad ethinylestradiol that were used previously.<ref name="pmid17239273" /><ref name="pmid2664738">{{cite journal | vauthors = von Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R | title = Estrogen therapy and liver function--metabolic effects of oral and parenteral administration | journal = The Prostate | volume = 14 | issue = 4 | pages = 389–395 | year = 1989 | pmid = 2664738 | doi = 10.1002/pros.2990140410 | s2cid = 21510744 }}</ref><ref name="pmid17019433">{{cite journal | vauthors = Ockrim J, Lalani EN, Abel P | title = Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy | journal = Nature Clinical Practice. Oncology | volume = 3 | issue = 10 | pages = 552–563 | date = October 2006 | pmid = 17019433 | doi = 10.1038/ncponc0602 | s2cid = 6847203 }}</ref> In addition, estrogens may have advantages relative to castration in terms of hot flashes, sexual interest and function, osteoporosis, cognitive function, and quality of life.<ref name="pmid17239273" /><ref name="pmid17019433" /><ref name="pmid14532759">{{cite journal | vauthors = Scherr DS, Pitts WR | title = The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer | journal = The Journal of Urology | volume = 170 | issue = 5 | pages = 1703–1708 | date = November 2003 | pmid = 14532759 | doi = 10.1097/01.ju.0000077558.48257.3d }}</ref><ref name="pmid21074215">{{cite journal | vauthors = Wibowo E, Schellhammer P, Wassersug RJ | title = Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy | journal = The Journal of Urology | volume = 185 | issue = 1 | pages = 17–23 | date = January 2011 | pmid = 21074215 | doi = 10.1016/j.juro.2010.08.094 }}</ref> However, side effects such as gynecomastia and feminization in general may be difficult to tolerate and unacceptable for many men.<ref name="pmid17239273" />

====Breast cancer==== High-dose estrogen therapy is effective in the treatment of about 35% of cases of breast cancer in women who are at least 5 years menopausal and has comparable effectiveness to antiestrogen therapy with medications like the selective estrogen receptor modulator (SERM) tamoxifen.<ref name="pmid27889048">{{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="ThomasKeenan2012">{{cite book| vauthors = Thomas JA, Keenan EJ |title=Principles of Endocrine Pharmacology|url=https://books.google.com/books?id=mTagBQAAQBAJ&pg=PA148|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4684-5036-1|pages=148–}}</ref><ref name="MillerIngle2002">{{cite book| vauthors = Miller WR, Ingle JN |title=Endocrine Therapy in Breast Cancer|url=https://books.google.com/books?id=00_LBQAAQBAJ&pg=PA49|date=8 March 2002|publisher=CRC Press|isbn=978-0-203-90983-6|pages=49–52|access-date=9 December 2016|archive-date=14 January 2017|archive-url=https://web.archive.org/web/20170114075229/https://books.google.com/books?id=00_LBQAAQBAJ&pg=PA49|url-status=live}}</ref> Although estrogens are rarely used in the treatment of breast cancer today and synthetic estrogens like diethylstilbestrol and ethinylestradiol have most commonly been used, estradiol itself has been used in the treatment of breast cancer as well.<ref name="pmid27889048" /><ref name="Estrace Label" /><ref name="EllisDehdahti2014">{{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 |title=A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.|journal=Cancer Research|volume=69|issue=2 Supplement|year=2014|page=16|issn=0008-5472|doi=10.1158/0008-5472.SABCS-16}}</ref> It has been used orally at very high doses (30 mg/day) in the treatment of therapy-naive breast cancer and orally at low doses (2 to 6 mg/day) in the treatment of breast cancer in women who were previously treated with and benefited from but acquired resistance to aromatase inhibitors.<ref name="pmid27889048" /><ref name="pmid23933149a">{{cite journal | vauthors = Palmieri C, Patten DK, Januszewski A, Zucchini G, Howell SJ | title = Breast cancer: current and future endocrine therapies | journal = Molecular and Cellular Endocrinology | volume = 382 | issue = 1 | pages = 695–723 | date = January 2014 | pmid = 23933149 | doi = 10.1016/j.mce.2013.08.001 | s2cid = 3363705 }}</ref><ref name="Estrace Label" /> Polyestradiol phosphate is also used to treat breast cancer.<ref name="Pharmanovia-Estradurin">{{Cite web |url=http://pharmanovia.com/product/estradurin/ |title=Estradurin (Polyestradiol Phosphate) | work = Pharmanovia |access-date=29 June 2018 |archive-date=2 January 2018 |archive-url=https://web.archive.org/web/20180102072958/http://pharmanovia.com/product/estradurin/ }}</ref><ref name="pmid393380a">{{cite journal | vauthors = Ostrowski MJ, Jackson AW | title = Polyestradiol phosphate: a preliminary evaluation of its effect on breast carcinoma | journal = Cancer Treatment Reports | volume = 63 | issue = 11–12 | pages = 1803–1807 | date = 1979 | pmid = 393380 }}</ref>

===Other uses===

====Infertility==== Estrogens may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining.<ref name="Aiman2012">{{cite book| vauthors = Aiman J |title=Infertility: Diagnosis and Management|url=https://books.google.com/books?id=D4_TBwAAQBAJ&pg=PA133|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4613-8265-2|pages=133–134}}</ref><ref name="SchattmanEsteves2015">{{cite book| vauthors = Schattman GL, Esteves S, Agarwal A |title=Unexplained Infertility: Pathophysiology, Evaluation and Treatment|url=https://books.google.com/books?id=wCdACQAAQBAJ&pg=PA266|date=12 May 2015|publisher=Springer|isbn=978-1-4939-2140-9|pages=266–}}</ref>

It is also commonly used during in vitro fertilization (IVF). Estrogen helps maintain the endometrial lining of the uterus and help prepare for pregnancy. Research shows higher pregnancy rate if the mother takes estrogen in addition to progesterone.<ref name=":1">{{cite journal | vauthors = Pinheiro LM, Cândido PD, Moreto TC, Almeida WG, Castro EC | title = Estradiol use in the luteal phase and its effects on pregnancy rates in IVF cycles with GnRH antagonist: a systematic review | journal = JBRA Assisted Reproduction | volume = 21 | issue = 3 | pages = 247–250 | date = September 2017 | pmid = 28837035 | pmc = 5574648 | doi = 10.5935/1518-0557.20170046 }}</ref> Estradiol is the predominant form of estrogen during reproductive years and is most commonly prescribed.<ref name=":1" />

====Lactation suppression==== Estrogens can be used to suppress and cease lactation and breast engorgement in postpartum women who do not wish to breastfeed.<ref name="Labhart2012">{{cite book| vauthors = Labhart A |title=Clinical Endocrinology: Theory and Practice|url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA696|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=512, 696}}</ref><ref name="ThomasKeenan2012"/> They do this by directly decreasing the sensitivity of the alveoli of the mammary glands to the lactogenic hormone prolactin.<ref name="ThomasKeenan2012" />

====Tall stature==== Estrogens have been used to limit final height in adolescent girls with tall stature.<ref name="pmid11392377">{{cite journal | vauthors = Juul A | title = The effects of oestrogens on linear bone growth | journal = Human Reproduction Update | volume = 7 | issue = 3 | pages = 303–313 | year = 2001 | pmid = 11392377 | doi = 10.1093/humupd/7.3.303 | doi-access = free }}</ref> They do this by inducing epiphyseal closure and suppressing growth hormone-induced hepatic production and by extension circulating levels of insulin-like growth factor-1 (IGF-1), a hormone that causes the body to grow and increase in size.<ref name="pmid11392377" /> Although ethinylestradiol and conjugated estrogens have mainly been used for this purpose, estradiol can also be employed.<ref name="pmid28274950">{{cite journal | vauthors = Albuquerque EV, Scalco RC, Jorge AA | title = MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature | journal = European Journal of Endocrinology | volume = 176 | issue = 6 | pages = R339–R353 | date = June 2017 | pmid = 28274950 | doi = 10.1530/EJE-16-1054 | doi-access = free }}</ref><ref name="pmid27410906">{{cite journal | vauthors = Upners EN, Juul A | title = Evaluation and phenotypic characteristics of 293 Danish girls with tall stature: effects of oral administration of natural 17β-estradiol | journal = Pediatric Research | volume = 80 | issue = 5 | pages = 693–701 | date = November 2016 | pmid = 27410906 | doi = 10.1038/pr.2016.128 | s2cid = 24233612 | doi-access = free }}</ref>

====Breast enhancement==== Estrogens are involved in breast development and estradiol may be used as a form of hormonal breast enhancement to increase the size of the breasts.<ref name="GöretzlehnerLauritzen2012">{{cite book| vauthors = Göretzlehner G, Lauritzen C, Römer T, Rossmanith W |title=Praktische Hormontherapie in der Gynäkologie|url=https://books.google.com/books?id=TIs2WhfYzZ4C&pg=PA385|date=1 January 2012|publisher=Walter de Gruyter|isbn=978-3-11-024568-4|pages=385–|access-date=22 July 2018|archive-date=6 October 2021|archive-url=https://web.archive.org/web/20211006093318/https://books.google.com/books?id=TIs2WhfYzZ4C&pg=PA385|url-status=live}}</ref><ref name="ManselFodstad2007">{{cite book| vauthors = Mansel RE, Fodstad O, Jiang WG |title=Metastasis of Breast Cancer|url=https://books.google.com/books?id=14pb5b6gT-oC&pg=PA217|date=14 June 2007|publisher=Springer Science & Business Media|isbn=978-1-4020-5866-0|pages=217–|access-date=22 July 2018|archive-date=1 December 2016|archive-url=https://web.archive.org/web/20161201061335/https://books.google.com/books?id=14pb5b6gT-oC&pg=PA217|url-status=live}}</ref><ref name="pmid9610425">{{cite journal | vauthors = Hartmann BW, Laml T, Kirchengast S, Albrecht AE, Huber JC | title = Hormonal breast augmentation: prognostic relevance of insulin-like growth factor-I | journal = Gynecological Endocrinology | volume = 12 | issue = 2 | pages = 123–127 | date = April 1998 | pmid = 9610425 | doi = 10.3109/09513599809024960 }}</ref><ref name="Lauritzen1980">{{cite journal | vauthors = Lauritzen C | title = Hormonkur kann hypoplastischer Mamma aufhelfen | trans-title = Hormone therapy can help hypoplastic breasts | journal = Selecta | language = de | year = 1980 | volume = 22 | issue = 43 | pages = 3798–3801 | publisher = Selecta-Verlag | location = Planegg | issn = 0582-4877 | oclc = 643821347 }}</ref><ref name="KaiserLeidenberger1991">{{cite book | vauthors = Kaiser R, Leidenberger FA | title = Hormonbehandlung in der gynäkologischen Praxis | year = 1991 | edition = 6 | publisher = Georg Thieme Verlag | location = Stuttgart, New York | pages = 138–139 | isbn = 978-3-13-357407-5 }}</ref> Both polyestradiol phosphate monotherapy and pseudopregnancy with a combination of high-dosage intramuscular estradiol valerate and hydroxyprogesterone caproate have been assessed for this purpose in clinical studies.<ref name="GöretzlehnerLauritzen2012" /><ref name="ManselFodstad2007" /><ref name="pmid9610425" /><ref name="Lauritzen1980" /> However, acute or temporary breast enlargement is a well-known side effect of estrogens, and increases in breast size tend to regress following discontinuation of treatment.<ref name="GöretzlehnerLauritzen2012" /><ref name="pmid9610425" /><ref name="Lauritzen1980" /> Aside from those without prior established breast development, evidence is lacking for a sustained increases in breast size with estrogens.<ref name="GöretzlehnerLauritzen2012" /><ref name="pmid9610425" /><ref name="Lauritzen1980" />

====Schizophrenia==== Estradiol has been found to be effective in the adjunctive treatment of schizophrenia in women.<ref name="pmid22998932">{{cite journal | vauthors = Begemann MJ, Dekker CF, van Lunenburg M, Sommer IE | title = Estrogen augmentation in schizophrenia: a quantitative review of current evidence | journal = Schizophrenia Research | volume = 141 | issue = 2–3 | pages = 179–184 | date = November 2012 | pmid = 22998932 | doi = 10.1016/j.schres.2012.08.016 | s2cid = 40584474 }}</ref><ref name="pmid24732671">{{cite journal | vauthors = Kulkarni J, Gavrilidis E, Wang W, Worsley R, Fitzgerald PB, Gurvich C, Van Rheenen T, Berk M, Burger H | title = Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age | journal = Molecular Psychiatry | volume = 20 | issue = 6 | pages = 695–702 | date = June 2015 | pmid = 24732671 | doi = 10.1038/mp.2014.33 | s2cid = 30322760 | doi-access = free }}</ref><ref name="pmid27824682">{{cite journal | vauthors = Brzezinski A, Brzezinski-Sinai NA, Seeman MV | title = Treating schizophrenia during menopause | journal = Menopause | volume = 24 | issue = 5 | pages = 582–588 | date = May 2017 | pmid = 27824682 | doi = 10.1097/GME.0000000000000772 | s2cid = 3452898 }}</ref> It has been found to significantly reduce positive, negative, and cognitive symptoms, with particular benefits on positive symptoms.<ref name="pmid22998932" /><ref name="pmid24732671" /><ref name="pmid27824682" /><ref name="pmid28673758">{{cite journal | vauthors = McGregor C, Riordan A, Thornton J | title = Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms | journal = Frontiers in Neuroendocrinology | volume = 47 | pages = 19–33 | date = October 2017 | pmid = 28673758 | doi = 10.1016/j.yfrne.2017.06.003 | s2cid = 43291520 }}</ref> Other estrogens, as well as selective estrogen receptor modulators (SERMs) like raloxifene, have been found to be effective in the adjunctive treatment of schizophrenia in women similarly.<ref name="pmid22998932" /><ref name="pmid29321530">{{cite journal | vauthors = de Boer J, Prikken M, Lei WU, Begemann M, Sommer I | title = The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis | journal = npj Schizophrenia | volume = 4 | issue = 1 | article-number = 1 | date = January 2018 | pmid = 29321530 | pmc = 5762671 | doi = 10.1038/s41537-017-0043-3 }}</ref><ref name="pmid27193386">{{cite journal | vauthors = Khan MM | title = Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia | journal = CNS Drugs | volume = 30 | issue = 7 | pages = 589–601 | date = July 2016 | pmid = 27193386 | doi = 10.1007/s40263-016-0343-6 | s2cid = 22284610 }}</ref> Estrogens may be useful in the treatment of schizophrenia in men as well, but their use in this population is limited by feminizing side effects.<ref name="pmid28941299">{{cite journal | vauthors = Owens SJ, Murphy CE, Purves-Tyson TD, Weickert TW, Shannon Weickert C | title = Considering the role of adolescent sex steroids in schizophrenia | journal = Journal of Neuroendocrinology | volume = 30 | issue = 2 | article-number = e12538 | date = February 2018 | pmid = 28941299 | doi = 10.1111/jne.12538 | s2cid = 3391650 | hdl = 1959.4/unsworks_49994 | url = https://unsworks.unsw.edu.au/bitstreams/95caebf2-19c8-404b-a527-c55f4a60aa99/download | hdl-access = free }}</ref> SERMs, which have few or no feminizing side effects, have been found to be effective in the adjunctive treatment of schizophrenia in men similarly to in women and may be more useful than estrogens in this sex.<ref name="pmid29321530" /><ref name="pmid27193386" />

====Sexual deviance==== Estradiol has been used at high doses to suppress sex drive in men with sexual deviance such as paraphilias and in sex offenders.<ref name="Guay2009">{{cite journal | vauthors = Guay DR | title = Drug treatment of paraphilic and nonparaphilic sexual disorders | journal = Clinical Therapeutics | volume = 31 | issue = 1 | pages = 1–31 | date = January 2009 | pmid = 19243704 | doi = 10.1016/j.clinthera.2009.01.009 }}</ref><ref name="MorganMorgan1984">{{cite book| vauthors = Morgan HG, Morgan MH |title=Aids to Psychiatry|url=https://archive.org/details/aidstopsychiatry0000morg|url-access=registration|year=1984|publisher=Churchill Livingstone|isbn=978-0-443-02613-3|page=[https://archive.org/details/aidstopsychiatry0000morg/page/75 75]|quote=Treatment of sexual offenders. Hormone therapy. [...] Oestrogens may cause breast hypertrophy, testicular atrophy, osteoporosis (oral ethinyl oestradiol 0.01-0.05 mg/day causes least nausea). Depot preparation: oestradiol [undecyleate] 50-100mg once every 3–4 weeks. Benperidol or butyrophenone and the antiandrogen cyproterone acetate also used.}}</ref><ref name="Chatz1972">{{cite journal | vauthors = Chatz TL | title = Recognizing and Treating Dangerous Sex Offenders | journal = International Journal of Offender Therapy and Comparative Criminology | date = June 1972 | volume = 16 | issue = 2 | pages = 109–115 | issn = 0306-624X | eissn = 1552-6933 | doi = 10.1177/0306624X7201600202 | pmid = | s2cid = 74365268 | url = }}</ref> It has specifically been used for this indication in the forms of intramuscular injections of estradiol valerate and estradiol undecylate and of subcutaneous pellet implants of estradiol.<ref name="Guay2009" /><ref name="MorganMorgan1984" /><ref name="Chatz1972" />

===Available forms=== {{Available forms of estradiol}} Estradiol is available in a variety of different formulations, including oral, intranasal, transdermal/topical, vaginal, injectable, and implantable preparations.<ref name="pmid16112947" /><ref name="LemkeWilliams2012">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1419|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1419–|access-date=29 June 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034548/https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1419|url-status=live}}</ref> An ester may be attached to one or both of the hydroxyl groups of estradiol to improve its oral bioavailability and/or duration of action with injection.<ref name="pmid16112947" /> Such modifications give rise to forms such as estradiol acetate (oral and vaginal), estradiol valerate (oral and injectable), estradiol cypionate (injectable), estradiol benzoate (injectable), estradiol undecylate (injectable), and polyestradiol phosphate (injectable; a polymerized ester of estradiol), which are all prodrugs of estradiol.<ref name="pmid16112947" /><ref name="LemkeWilliams2012" /><ref name="pmid10230677">{{cite journal | vauthors = Mikkola A, Ruutu M, Aro J, Rannikko S, Salo J | title = The role of parenteral polyestradiol phosphate in the treatment of advanced prostatic cancer on the threshold of the new millennium | journal = Annales Chirurgiae et Gynaecologiae | volume = 88 | issue = 1 | pages = 18–21 | year = 1999 | pmid = 10230677 }}</ref>

{{Gallery | title= Gallery of available forms of estradiol | width=165 | height=155 | align=center  | style="font-size:small;"

| File:Progynova (estradiol valerate) tablets in the United Kingdom.jpg | Progynova ({{No selflink|estradiol valerate}}) 2 mg oral tablets.

| File:Generic estradiol (Mylan) 0.1 mg per day once-weekly transdermal systems.jpg | Generic {{No selflink|estradiol (medication)|estradiol}} (Mylan) 100 μg/day once-weekly transdermal patches.

| File:Estrogen patch.jpg | Vivelle-Dot ({{No selflink|estradiol (medication)|estradiol}}) 100 μg/day twice-weekly transdermal patches.

| File:EstroGel 0.06% (estradiol transdermal gel) pumps.jpg | EstroGel 0.06% ({{No selflink|estradiol (medication)|estradiol}}) once-daily hydroalcoholic transdermal gel. Delivers 0.75 mg estradiol per pump.

| File:Depo-Estradiol (estradiol cypionate) vials.jpg | Depo-Estradiol 5 mg/mL ({{No selflink|estradiol cypionate}} in oil solution) vials. Used by depot intramuscular injection.

}}

==Contraindications== Estrogens like estradiol have a number of contraindications.<ref name="pmid2215269" /><ref name="LauritzenStudd2005">{{cite book| vauthors = Lauritzen C, Studd JW |title=Current Management of the Menopause|url=https://books.google.com/books?id=WD7S7677xUUC&pg=PA95|date=22 June 2005|publisher=CRC Press|isbn=978-0-203-48612-2|pages=44,95–98,488|access-date=11 June 2019|archive-date=6 May 2020|archive-url=https://web.archive.org/web/20200506202729/https://books.google.com/books?id=WD7S7677xUUC&pg=PA95|url-status=live}}</ref><ref name="Lauritzen2001">{{cite book | vauthors = Laurtizen C | chapter = Hormone Substitution Before, During and After Menopause | pages = 67–88 | chapter-url = https://www.kup.at/kup/pdf/4978.pdf | veditors = Fisch FH | title = Menopause – Andropause: Hormone Replacement Therapy Through the Ages | year = 2001 | publisher = Krause & Pachernegg: Gablitz | isbn = 978-3-901299-34-6 | access-date = 11 June 2019 | archive-date = 10 May 2018 | archive-url = https://web.archive.org/web/20180510160638/http://www.kup.at/kup/pdf/4978.pdf | url-status = live }}</ref><ref name="Midwinter1976">{{cite book| vauthors = Midwinter A |chapter=Contraindications to estrogen therapy and management of the menopausal syndrome in these cases|pages=377–382|doi=10.1007/978-94-011-6165-7_33| veditors = Campbell S |title=The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London|year=1976|isbn=978-94-011-6167-1|publisher=MTP Press Limited}}</ref> Estradiol should be avoided when there is undiagnosed abnormal vaginal bleeding, known, suspected or a history of breast cancer, current treatment for metastatic disease, known or suspected estrogen-dependent neoplasia, deep vein thrombosis, pulmonary embolism or history of these conditions, active or recent arterial thromboembolic disease such as stroke, myocardial infarction, liver dysfunction or disease. Estradiol should not be taken by people with a hypersensitivity/allergy or those who are pregnant or are suspected pregnant.<ref name="Estrace Label" />

==Side effects== {{See also|Estrogen (medication)#Side effects|List of side effects of estradiol}}

Common side effects of estradiol in women include headache, breast pain or tenderness, breast enlargement, irregular vaginal bleeding or spotting, abdominal cramps, bloating, fluid retention, and nausea.<ref name="Estrace Label">{{cite web | title=Estrace- estradiol tablet | website=DailyMed | date=11 March 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a3803ba3-4eee-4e2e-ac8c-821a4e6720cc | access-date=17 May 2024}}</ref><ref name="Estring Label">{{cite web | title=Estring- estradiol ring | website=DailyMed | date=18 September 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa530dfd-3a48-46b9-9678-a7bc48316e41 | access-date=17 May 2024}}</ref><ref>{{cite web | title=Estring- estradiol system | website=DailyMed | date=27 February 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=110b9865-5a07-4d45-b560-e89947f12600 | access-date=17 May 2024}}</ref><ref name="pmid23375353" /> Other possible side effects of estrogens may include high blood pressure, high blood sugar, enlargement of uterine fibroids, melasma, vaginal yeast infections, and liver problems.<ref name="Estrace Label" /> In men, estrogens can cause breast pain or tenderness, gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (decreased libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility.<ref name="Pohanish2011">{{cite book|author=Richard P. Pohanish|title=Sittig's Handbook of Toxic and Hazardous Chemicals and Carcinogens|url=https://books.google.com/books?id=f6HclgoIkjcC&pg=PA1167|year=2011|publisher=William Andrew|isbn=978-1-4377-7869-4|pages=1167–|access-date=29 June 2018|archive-date=6 May 2020|archive-url=https://web.archive.org/web/20200506202804/https://books.google.com/books?id=f6HclgoIkjcC&pg=PA1167|url-status=live}}</ref><ref name="CecilBennett1996">{{cite book| vauthors = Cecil RL, Bennett JC, Plum F |title=Cecil Textbook of Medicine|url=https://archive.org/details/ceciltextbookofm02ceci|url-access=registration|year=1996|publisher=Saunders|isbn=978-0-7216-3575-0|quote=Estrogen excess in men causes inhibition of gonadotropin secretion and secondary hypogonadism. Estrogen excess may result from either exogenous administration of estrogens or estrogenic substances (e.g., diethylstilbestrol administration [...]}}</ref> {{Side effects of lower versus higher dose oral estradiol}}

===Blood clots=== {{See also|Estrogen (medication)#Cardiovascular events}}

Oral estradiol and estradiol valerate, for instance in menopausal hormone therapy or birth control pills, are associated with a significantly higher risk of venous thromboembolism (VTE) than non-use.<ref name="pmid29936403">{{cite journal | vauthors = Rovinski D, Ramos RB, Fighera TM, Casanova GK, Spritzer PM | title = Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis | journal = Thrombosis Research | volume = 168 | pages = 83–95 | date = August 2018 | pmid = 29936403 | doi = 10.1016/j.thromres.2018.06.014 | s2cid = 49421543 }}</ref><ref name="pmid29570359" /><ref name="pmid30626577" /><ref name="pmid30519125">{{cite journal | vauthors = Fruzzetti F, Cagnacci A | title = Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives? | journal = Open Access Journal of Contraception | volume = 9 | pages = 75–79 | date = 2018 | pmid = 30519125 | pmc = 6239102 | doi = 10.2147/OAJC.S179673 | doi-access = free }}</ref> Higher doses of oral estrogens are associated with higher risks of VTE.<ref name="pmid30626577" /><ref name="pmid23136837" /><ref name="pmid28049361">{{cite journal | vauthors = Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M | title = Oral Contraceptives and HRT Risk of Thrombosis | journal = Clinical and Applied Thrombosis/Hemostasis | volume = 24 | issue = 2 | pages = 217–225 | date = March 2018 | pmid = 28049361 | pmc = 6714678 | doi = 10.1177/1076029616683802 }}</ref> In contrast to oral estradiol, transdermal and vaginal estradiol at menopausal replacement dosages are not associated with a higher incidence of VTE.<ref name="pmid29936403" /><ref name="pmid29570359" /><ref name="pmid25223916" /><ref name="pmid30626577" /> Low doses (e.g., 50 μg/day) and high doses (e.g., 100 μg/day) of transdermal estradiol for menopausal replacement do not differ in terms of VTE risk.<ref name="pmid21262434">{{cite journal | vauthors = Olié V, Canonico M, Scarabin PY | title = Postmenopausal hormone therapy and venous thromboembolism | journal = Thrombosis Research | volume = 127 | issue = Suppl 3 | pages = S26–S29 | date = February 2011 | pmid = 21262434 | doi = 10.1016/S0049-3848(11)70008-1 }}</ref><ref name="pmid25223916">{{cite journal | vauthors = Scarabin PY | title = Hormones and venous thromboembolism among postmenopausal women | journal = Climacteric | volume = 17 | issue = Suppl 2 | pages = 34–37 | date = December 2014 | pmid = 25223916 | doi = 10.3109/13697137.2014.956717 | s2cid = 5084606 }}</ref><ref name="pmid26327865">{{cite journal | vauthors = Bińkowska M | title = Menopausal hormone therapy and venous thromboembolism | journal = Przeglad Menopauzalny = Menopause Review | volume = 13 | issue = 5 | pages = 267–272 | date = October 2014 | pmid = 26327865 | pmc = 4520375 | doi = 10.5114/pm.2014.46468 }}</ref><ref name="pmid30626577">{{cite journal | vauthors = Vinogradova Y, Coupland C, Hippisley-Cox J | title = Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases | journal = BMJ | volume = 364 | article-number = k4810 | date = January 2019 | pmid = 30626577 | pmc = 6326068 | doi = 10.1136/bmj.k4810 }}</ref> The higher risk of VTE with oral estradiol can be attributed to the first pass and a disproportionate effect on liver synthesis of coagulation factors.<ref name="pmid16112947" /><ref name="pmid30008249" /> Even high doses of parenteral estradiol, such as high-dose polyestradiol phosphate, have minimal influence on coagulation factors, in contrast to oral estrogen therapy.<ref name="pmid17019433" /><ref name="pmid17239273" /><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 January 2026 }}</ref> However, sufficient doses of parenteral estradiol, for instance very high doses of estradiol valerate by intramuscular injection, can nonetheless activate coagulation, presumably increasing VTE risk.<ref name="pmid16284988">{{cite journal | vauthors = Kohli M | title = Phase II study of transdermal estradiol in androgen-independent prostate carcinoma | journal = Cancer | volume = 106 | issue = 1 | pages = 234–5; author reply 235 | date = January 2006 | pmid = 16284988 | doi = 10.1002/cncr.21528 | s2cid = 11047031 | doi-access = free }}</ref><ref name="HorskyPresl1981">{{cite book | vauthors = Horský J, Presl J | chapter = Hormonal Treatment of Disorders of the Menstrual Cycle | pages = 309–332 | doi = 10.1007/978-94-009-8195-9_11 | editor1 = J. Horsky | editor2 = J. Presl | title = Ovarian Function and its Disorders: Diagnosis and Therapy | series = Developments in Obstetrics and Gynecology | chapter-url = https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA310 | date = 1981 | publisher = Springer Science & Business Media | isbn = 978-94-009-8195-9 | access-date = 26 December 2019 | archive-date = 18 June 2020 | archive-url = https://web.archive.org/web/20200618033124/https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA310 | url-status = live }}</ref>

In addition to the route of administration, the type of estrogen influences VTE risk.<ref name="pmid31465627" /><ref name="pmid30008249" /> Oral conjugated estrogens are associated with a higher risk of VTE than oral estradiol.<ref name="pmid26444994">{{cite journal | vauthors = Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, Santen RJ | title = Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 11 | pages = 3975–4011 | date = November 2015 | pmid = 26444994 | doi = 10.1210/jc.2015-2236 | doi-access = free }}</ref><ref name="pmid26327865" /><ref name="pmid24081194">{{cite journal | vauthors = Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS, Hwang M, Bis JC, McKnight B, Rice KM, Lumley T, Rosendaal FR, Heckbert SR, Psaty BM | title = Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens | journal = JAMA Internal Medicine | volume = 174 | issue = 1 | pages = 25–31 | date = January 2014 | pmid = 24081194 | pmc = 4636198 | doi = 10.1001/jamainternmed.2013.11074 }}</ref> Estradiol- and estradiol valerate-containing birth control pills are associated with a lower risk of VTE than birth control pills containing ethinylestradiol.<ref name="pmid30519125" /><ref name="pmid30008249" /> The relative risk of VTE is thought to be highest with oral ethinylestradiol, intermediate with oral conjugated estrogens, low with oral estradiol and parenteral estradiol valerate, and very low with transdermal estradiol.<ref name="pmid31465627">{{cite journal | vauthors = Connors JM, Middeldorp S | title = Transgender patients and the role of the coagulation clinician | journal = Journal of Thrombosis and Haemostasis | volume = 17 | issue = 11 | pages = 1790–1797 | date = November 2019 | pmid = 31465627 | doi = 10.1111/jth.14626 | s2cid = 201673648 }}</ref> Conjugated estrogens and ethinylestradiol are thought to have a higher risk of VTE than estradiol because they are resistant to hepatic metabolism and have a disproportionate influence on liver production of coagulation factors.<ref name="pmid16112947" /><ref name="pmid31465627" /><ref name="pmid30008249" />

The combination of oral or transdermal estradiol and a progestin is associated with a higher risk of VTE than estradiol alone.<ref name="pmid29570359">{{cite journal | vauthors = Scarabin PY | title = Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis | journal = Climacteric | volume = 21 | issue = 4 | pages = 341–345 | date = August 2018 | pmid = 29570359 | doi = 10.1080/13697137.2018.1446931 | s2cid = 4229701 }}</ref><ref name="pmid31372078" /> Dydrogesterone is associated with a lower risk than other progestins such as medroxyprogesterone acetate and norethisterone, while oral progesterone is associated with no increase in risk of VTE.<ref name="pmid29570359" /><ref name="pmid30626577" /> Older age, higher body weight, lower physical activity, and smoking are all associated with a higher risk of VTE with oral estrogen therapy.<ref name="pmid30008249">{{cite journal | vauthors = Beyer-Westendorf J, Bauersachs R, Hach-Wunderle V, Zotz RB, Rott H | title = Sex hormones and venous thromboembolism - from contraception to hormone replacement therapy | journal = VASA. Zeitschrift für Gefässkrankheiten | volume = 47 | issue = 6 | pages = 441–450 | date = October 2018 | pmid = 30008249 | doi = 10.1024/0301-1526/a000726 | s2cid = 51628832 }}</ref><ref name="pmid29526116">{{cite journal | vauthors = Davey DA | title = Menopausal hormone therapy: a better and safer future | journal = Climacteric | volume = 21 | issue = 5 | pages = 454–461 | date = October 2018 | pmid = 29526116 | doi = 10.1080/13697137.2018.1439915 | s2cid = 3850275 }}</ref><ref name="pmid31372078" /><ref name="pmid23136837">{{cite journal |author4-link=Suzanne Cannegieter | vauthors = Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A | title = The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy | journal = Journal of Thrombosis and Haemostasis | volume = 11 | issue = 1 | pages = 124–131 | date = January 2013 | pmid = 23136837 | doi = 10.1111/jth.12060 | s2cid = 22306721 | doi-access = free }}</ref> Risk of VTE with estrogen therapy is highest at the start of treatment, particularly during the first year, and decreases over time.<ref name="pmid30008249" /><ref name="pmid31372078" />

The absolute risk of VTE with estrogen and/or progestin therapy is small.<ref name="pmid27051991">{{cite journal | vauthors = Bateson D, Butcher BE, Donovan C, Farrell L, Kovacs G, Mezzini T, Raynes-Greenow C, Pecoraro G, Read C, Baber R | title = Risk of venous thromboembolism in women taking the combined oral contraceptive: A systematic review and meta-analysis | journal = Australian Family Physician | volume = 45 | issue = 1 | pages = 59–64 | date = 2016 | pmid = 27051991 | url = https://www.racgp.org.au/afp/2016/januaryfebruary/risk-of-venous-thromboembolism-in-women-taking-the-combined-oral-contraceptive-a-systematic-review-and-meta-analysis/ | access-date = 26 December 2019 | url-status = live | archive-url = https://web.archive.org/web/20210408052059/https://www.racgp.org.au/afp/2016/januaryfebruary/risk-of-venous-thromboembolism-in-women-taking-the-combined-oral-contraceptive-a-systematic-review-and-meta-analysis/ | archive-date = 8 April 2021 }}</ref><ref name="FDA2018">{{cite web |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-information-about-risk-blood-clots-women-taking-birth-control | work = FDA Drug Safety Communication | title = Updated information about the risk of blood clots in women taking birth control pills containing drospirenone |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20190427143241/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-information-about-risk-blood-clots-women-taking-birth-control |archive-date=27 April 2019 }}</ref><ref name="pmid31372078">{{cite journal | vauthors = Goldstein Z, Khan M, Reisman T, Safer JD | title = Managing the risk of venous thromboembolism in transgender adults undergoing hormone therapy | journal = Journal of Blood Medicine | volume = 10 | pages = 209–216 | date = 2019 | pmid = 31372078 | pmc = 6628137 | doi = 10.2147/JBM.S166780 | doi-access = free }}</ref> Women who are not on a birth control pill or hormone therapy have a risk of VTE of about 1 to 5 out of 10,000 women per year.<ref name="pmid27051991" /><ref name="FDA2018" /><ref name="pmid26327865" /><ref name="pmid31372078" /> In women taking a birth control pill containing ethinylestradiol and a progestin, the risk of VTE is in the range of 3 to 10 out of 10,000 women per year.<ref name="pmid27051991" /><ref name="FDA2018" /><ref name="pmid31372078" /> Birth control pills containing estradiol valerate and a progestin are associated with about half the risk of VTE of ethinylestradiol/progestin-containing birth control pills.<ref name="pmid30519125" /><ref name="pmid28902531">{{cite journal | vauthors = Grandi G, Facchinetti F, Bitzer J | title = Estradiol in hormonal contraception: real evolution or just same old wine in a new bottle? | journal = The European Journal of Contraception & Reproductive Health Care | volume = 22 | issue = 4 | pages = 245–246 | date = August 2017 | pmid = 28902531 | doi = 10.1080/13625187.2017.1372571 | s2cid = 13776462 | doi-access = free | hdl = 11380/1153791 | hdl-access = free }}</ref> Hormone therapy for transgender women likewise is associated with a lower risk of VTE than birth control pills containing ethinylestradiol and a progestin.<ref name="pmid30602475">{{cite journal | vauthors = Khan J, Schmidt RL, Spittal MJ, Goldstein Z, Smock KJ, Greene DN | title = Venous Thrombotic Risk in Transgender Women Undergoing Estrogen Therapy: A Systematic Review and Metaanalysis | journal = Clinical Chemistry | volume = 65 | issue = 1 | pages = 57–66 | date = January 2019 | pmid = 30602475 | doi = 10.1373/clinchem.2018.288316 | doi-access = free | hdl = 11343/240661 | hdl-access = free }}</ref><ref name="pmid31465627" /> The risk of VTE during pregnancy, when estrogens and progesterone increase to very high levels, is 5 to 20 in 10,000 women per year, while the risk is 40 to 65 per 10,000 women per year during the postpartum period.<ref name="FDA2018" /><ref name="pmid31372078" />

{{Risk of venous thromboembolism with hormone therapy and birth control pills (QResearch/CPRD)}}

===Long-term effects=== Uncommon but serious possible side effects of estrogens associated with long-term therapy may include breast cancer, uterine cancer, stroke, heart attack, blood clots, dementia, gallbladder disease, and ovarian cancer.<ref name="Estrace-FDA" /> Warning signs of these serious side effects include breast lumps, unusual vaginal bleeding, dizziness, faintness, changes in speech, severe headaches, chest pain, shortness of breath, pain in the legs, changes in vision, and vomiting.<ref name="Estrace-FDA" />

Due to health risks observed with the combination of conjugated estrogens and medroxyprogesterone acetate in the Women's Health Initiative (WHI) studies (see below), the US Food and Drug Administration (FDA) label for Estrace (estradiol) advises that estrogens should be used in menopausal hormone therapy only for the shortest time possible and at the lowest effective dose.<ref name="Estrace Label" /> While the FDA states that is unknown if these risks generalize to estradiol (alone or in combination with progesterone or a progestin), it advises that in the absence of comparable data, the risks should be assumed to be similar.<ref name="Estrace Label" /> When used to treat menopausal symptoms, the FDA recommends that discontinuation of estradiol should be attempted every three to six months via a gradual dose taper.<ref name="Estrace Label" />

The combination of bioidentical transdermal or vaginal estradiol and oral or vaginal progesterone appears to be a safer form of hormone therapy than the combination of oral conjugated estrogens and medroxyprogesterone acetate and may not share the same health risks.<ref name="pmid18775609">{{cite journal | vauthors = L'hermite M, Simoncini T, Fuller S, Genazzani AR | title = Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review | journal = Maturitas | volume = 60 | issue = 3–4 | pages = 185–201 | date = 2008 | pmid = 18775609 | doi = 10.1016/j.maturitas.2008.07.007 }}</ref><ref name="pmid19179815">{{cite journal | vauthors = Holtorf K | title = The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? | journal = Postgraduate Medicine | volume = 121 | issue = 1 | pages = 73–85 | date = January 2009 | pmid = 19179815 | doi = 10.3810/pgm.2009.01.1949 | s2cid = 2060730 }}</ref><ref name="pmid21464264">{{cite journal | vauthors = Conaway E | title = Bioidentical hormones: an evidence-based review for primary care providers | journal = The Journal of the American Osteopathic Association | volume = 111 | issue = 3 | pages = 153–164 | date = March 2011 | pmid = 21464264 | url = http://jaoa.org/article.aspx?articleid=2094168 | access-date = 29 June 2018 | url-status = live | archive-url = https://web.archive.org/web/20180629155035/http://jaoa.org/article.aspx?articleid=2094168 | archive-date = 29 June 2018 }}</ref><ref name="pmid22432810">{{cite journal | vauthors = Simon JA | title = What's new in hormone replacement therapy: focus on transdermal estradiol and micronized progesterone | journal = Climacteric | volume = 15 | issue = Suppl 1 | pages = 3–10 | date = April 2012 | pmid = 22432810 | doi = 10.3109/13697137.2012.669332 | s2cid = 27797540 }}</ref><ref name="pmid22432811">{{cite journal | vauthors = Mueck AO | title = Postmenopausal hormone replacement therapy and cardiovascular disease: the value of transdermal estradiol and micronized progesterone | journal = Climacteric | volume = 15 | issue = Suppl 1 | pages = 11–17 | date = April 2012 | pmid = 22432811 | doi = 10.3109/13697137.2012.669624 | s2cid = 8100346 }}</ref><ref name="pmid23848491">{{cite journal | vauthors = L'Hermite M | title = HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT | journal = Climacteric | volume = 16 | issue = Suppl 1 | pages = 44–53 | date = August 2013 | pmid = 23848491 | doi = 10.3109/13697137.2013.808563 | s2cid = 20401584 }}</ref><ref name="pmid24398406">{{cite journal | vauthors = Simon JA | title = What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead? | journal = Menopause | volume = 21 | issue = 7 | pages = 769–783 | date = July 2014 | pmid = 24398406 | doi = 10.1097/GME.0000000000000169 | s2cid = 30292136 }}</ref><ref name="pmid28301216">{{cite journal | vauthors = L'Hermite M | title = Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal | journal = Climacteric | volume = 20 | issue = 4 | pages = 331–338 | date = August 2017 | pmid = 28301216 | doi = 10.1080/13697137.2017.1291607 | s2cid = 4771048 }}</ref><ref name="pmid29526116"/> Advantages may include reduced or no risk of venous thromboembolism, cardiovascular disease, and breast cancer, among others.<ref name="pmid18775609" /><ref name="pmid19179815" /><ref name="pmid21464264" /><ref name="pmid22432810" /><ref name="pmid22432811" /><ref name="pmid23848491" /><ref name="pmid24398406" /><ref name="pmid28301216" /><ref name="pmid29526116" />

{{Results of the Women's Health Initiative menopausal hormone therapy randomized controlled trials}}

==Overdose== Estrogens are relatively safe in overdose.<ref name="pmid10230677" /> During pregnancy, levels of estradiol increase to very high concentrations that are as much as 100-fold normal levels.<ref name="Becker2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1059|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=889, 1059–1060, 2153|access-date=3 July 2018|archive-date=22 February 2022|archive-url=https://web.archive.org/web/20220222083158/https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1059|url-status=live}}</ref><ref name="Abbott2009">{{cite web |url=http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf |title= Estradiol | date = November 2009 | publisher = Abbott Laboratories |archive-url=https://web.archive.org/web/20211127070253/https://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf |archive-date=27 November 2021}}</ref><ref name="Smith2001">{{cite book| vauthors = Smith R |title=The Endocrinology of Parturition: Basic Science and Clinical Application|url=https://books.google.com/books?id=0N6Ua0O8gWwC&pg=PA89|date=1 January 2001|publisher=Karger Medical and Scientific Publishers|isbn=978-3-8055-7195-1|pages=89–}}</ref> In late pregnancy, the body produces and secretes approximately 100 mg of estrogens, including estradiol, estrone, and estriol, per day.<ref name="Becker2001" /> Doses of estradiol of as high as 200 mg per day by intramuscular injection for several weeks have been administered to humans in studies.<ref name="pmid4890101">{{cite book | vauthors = Song CS, Kappas A | title = The influence estrogens, progestins, and pregnancy on the liver | volume = 26 | pages = 147–195 | date = 1968 | pmid = 4890101 | doi = 10.1016/s0083-6729(08)60754-2 | isbn = 978-0-12-709826-5 | series = Vitamins & Hormones | publisher = Academic Press }}</ref><ref name="pmid14236214">{{cite journal | vauthors = Mueller MN, Kappas A | title = Estrogen Pharmacology. I. The Influence of Estradiol and Estriol on Hepatic Disposal of Sulfobromophthalein (BSP) in Man | journal = The Journal of Clinical Investigation | volume = 43 | issue = 10 | pages = 1905–1914 | date = October 1964 | pmid = 14236214 | pmc = 289635 | doi = 10.1172/JCI105064 }}</ref> Serious adverse effects have not been described following acute overdose of large doses of estrogen- and progestogen-containing birth control pills by small children.<ref name="pmid10230677" /> Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, vaginal bleeding, heavy legs, and leg cramps.<ref name="pmid2215269">{{cite journal | vauthors = Lauritzen C | title = Clinical use of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 199–214 | date = September 1990 | pmid = 2215269 | doi = 10.1016/0378-5122(90)90004-P }}</ref><ref name="pmid10230677" />

== Interactions ==

Inducers of cytochrome P450 enzymes like CYP3A4 such as St. John's wort, phenobarbital, carbamazepine and rifampicin decrease the circulating levels of estradiol by accelerating its metabolism, whereas inhibitors of cytochrome P450 enzymes like CYP3A4 such as erythromycin, cimetidine,<ref name="pmid11741520">{{cite journal | vauthors = Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH | title = Role of cytochrome P450 in estradiol metabolism in vitro | journal = Acta Pharmacologica Sinica | volume = 22 | issue = 2 | pages = 148–154 | date = February 2001 | pmid = 11741520 }}</ref> clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice<ref name="pmid7715468">{{cite journal | vauthors = Schubert W, Cullberg G, Edgar B, Hedner T | title = Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women | journal = Maturitas | volume = 20 | issue = 2–3 | pages = 155–163 | date = December 1994 | pmid = 7715468 | doi = 10.1016/0378-5122(94)90012-4 }}</ref> may slow its metabolism resulting in increased levels of estradiol in the circulation.<ref name="Estrace Label" /> There is an interaction between estradiol and alcohol such that alcohol considerably increases circulating levels of estradiol during oral estradiol therapy and also increases estradiol levels in normal premenopausal women and with parenteral estradiol therapy.<ref name="Elsevier2002">{{cite book|title=Hormones, Brain and Behavior|url=https://books.google.com/books?id=6GgHpQdk8vYC&pg=PA759|date=18 June 2002|publisher=Elsevier|isbn=978-0-08-053415-2|pages=759–761|access-date=23 July 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034548/https://books.google.com/books?id=6GgHpQdk8vYC&pg=PA759|url-status=live}}</ref><ref name="OettelSchillinger2012b" /><ref name="pmid8940324">{{cite journal | vauthors = Ginsburg ES, Mello NK, Mendelson JH, Barbieri RL, Teoh SK, Rothman M, Gao X, Sholar JW | title = Effects of alcohol ingestion on estrogens in postmenopausal women | journal = JAMA | volume = 276 | issue = 21 | pages = 1747–1751 | date = December 1996 | pmid = 8940324 | doi = 10.1001/jama.1996.03540210055034 }}</ref><ref name="pmid10397281">{{cite journal | vauthors = Sarkola T, Mäkisalo H, Fukunaga T, Eriksson CJ | title = Acute effect of alcohol on estradiol, estrone, progesterone, prolactin, cortisol, and luteinizing hormone in premenopausal women | journal = Alcoholism: Clinical and Experimental Research | volume = 23 | issue = 6 | pages = 976–982 | date = June 1999 | pmid = 10397281 | doi = 10.1111/j.1530-0277.1999.tb04215.x | url = https://www.academia.edu/download/40259827/Acute_Effect_of_Alcohol_on_Estradiol_Est20151122-30034-1yz90uv.pdf | access-date = 29 July 2018 | archive-url = https://web.archive.org/web/20220610034548/https://d1wqtxts1xzle7.cloudfront.net/40259827/Acute_Effect_of_Alcohol_on_Estradiol_Est20151122-30034-1yz90uv-with-cover-page-v2.pdf?Expires=1654836348&Signature=JoDUZ9Zi-C5ZG3FAUkP2-hLAttZPcM16VBHmPg6~rjOQ1LsplOFG~ISd9ENiymMjOifsgwT92oUIepr1uh-idiizo4sRMqf-0~~4gzZk7MYQ6silog7PmY6hd3QxotlDbNgDIPnzAiIVfuCY8vnjT8GdLpzucZtDyOCNst5eTZr8uFCErJnzj6ThFIdsvVfn99MPRjeAP~1mPOqVn92NO4Pqp4b77PYowSb0k5DBlmbkin9rDltZpg-e1LJ1ck9qe-6cWInnV~XWXJHPuLmxVSrKDG8FFP91bQ50QuSGh2ymhyl8ot1GOndz6~UMfsP8qoBYoR7~kuuCQUxzJyej7A__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-date = 10 June 2022 }}</ref> This appears to be due to a decrease in hepatic 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) activity and hence estradiol inactivation into estrone due to an alcohol-mediated increase in the ratio of NADH to NAD in the liver.<ref name="pmid8940324" /><ref name="pmid10397281" /> Spironolactone may reduce the bioavailability of high doses of oral estradiol.<ref name="pmid29756046">{{cite journal | vauthors = Leinung MC, Feustel PJ, Joseph J | title = Hormonal Treatment of Transgender Women with Oral Estradiol | journal = Transgender Health | volume = 3 | issue = 1 | pages = 74–81 | date = 2018 | pmid = 29756046 | pmc = 5944393 | doi = 10.1089/trgh.2017.0035 }}</ref>

==Pharmacology==

===Pharmacodynamics=== {{Main|Pharmacodynamics of estradiol}}

Estradiol is an estrogen, or an agonist of the estrogen receptors (ERs), the {{abbrlink|ERα|estrogen receptor alpha}} and {{abbrlink|ERβ|estrogen receptor beta}}.<ref name="pmid16112947" /> It is also an agonist of membrane estrogen receptors (mERs), including the {{abbrlink|GPER|G protein-coupled estrogen receptor}}, {{abbrlink|Gq-mER|Gq-coupled membrane estrogen receptor}}, ER-X, and ERx.<ref name="pmid23756388">{{cite journal | vauthors = Soltysik K, Czekaj P | title = Membrane estrogen receptors - is it an alternative way of estrogen action? | journal = Journal of Physiology and Pharmacology | volume = 64 | issue = 2 | pages = 129–142 | date = April 2013 | pmid = 23756388 }}</ref><ref name="pmid24530924">{{cite journal | vauthors = Prossnitz ER, Barton M | title = Estrogen biology: new insights into GPER function and clinical opportunities | journal = Molecular and Cellular Endocrinology | volume = 389 | issue = 1–2 | pages = 71–83 | date = May 2014 | pmid = 24530924 | pmc = 4040308 | doi = 10.1016/j.mce.2014.02.002 | bibcode = 2014MolCE.389...71P }}</ref> Estradiol is highly selective for these ERs and mERs, and does not interact importantly with other steroid hormone receptors.<ref name="pmid359134">{{cite journal | vauthors = Ojasoo T, Raynaud JP | title = Unique steroid congeners for receptor studies | journal = Cancer Research | volume = 38 | issue = 11 Pt 2 | pages = 4186–4198 | date = November 1978 | pmid = 359134 | url = http://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short | access-date = 28 March 2018 | url-status = live | archive-url = https://web.archive.org/web/20201127182040/https://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short | archive-date = 27 November 2020 }}</ref><ref name="pmid3695484">{{cite journal | vauthors = Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP | title = Towards the mapping of the progesterone and androgen receptors | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 1–3 | pages = 255–269 | date = 1987 | pmid = 3695484 | doi = 10.1016/0022-4731(87)90317-7 }}</ref><ref name="pmid7421203">{{cite journal | vauthors = Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP | title = Steroid hormone receptors and pharmacology | journal = Journal of Steroid Biochemistry | volume = 12 | pages = 143–157 | date = January 1980 | pmid = 7421203 | doi = 10.1016/0022-4731(80)90264-2 }}</ref> It is far more potent as an estrogen than are other bioidentical estrogens like estrone and estriol.<ref name="pmid16112947" /><ref name="Labhart2012p548" /> Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.<ref name="Labhart2012p548">{{cite book| vauthors = Labhart A |title=Clinical Endocrinology: Theory and Practice|url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA548|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=548–|access-date=11 November 2018|archive-date=3 January 2020|archive-url=https://web.archive.org/web/20200103073131/https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA548|url-status=live}}</ref>

The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, fat, skin, bone, liver, pituitary gland, hypothalamus, and other parts of the brain.<ref name="Parl2000" /> In accordance, estradiol has numerous effects throughout the body.<ref name="Parl2000" /><ref name="Dietrich2014">{{cite book| vauthors = Dietrich JE |title=Female Puberty: A Comprehensive Guide for Clinicians|url=https://books.google.com/books?id=ipEpBAAAQBAJ&pg=PA53|date=18 June 2014|publisher=Springer|isbn=978-1-4939-0912-4|pages=53–|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210732/https://books.google.com/books?id=ipEpBAAAQBAJ&pg=PA53|url-status=live}}</ref><ref name="ThornhillGangestad2008">{{cite book| vauthors = Thornhill R, Gangestad SW |title=The Evolutionary Biology of Human Female Sexuality|url=https://books.google.com/books?id=joX0BgAAQBAJ&pg=PT145|date=25 September 2008|publisher=Oxford University Press|isbn=978-0-19-988770-5|pages=145–|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210809/https://books.google.com/books?id=joX0BgAAQBAJ&pg=PT145|url-status=live}}</ref><ref name="pmid12762829">{{cite journal | vauthors = Raine-Fenning NJ, Brincat MP, Muscat-Baron Y | title = Skin aging and menopause: implications for treatment | journal = American Journal of Clinical Dermatology | volume = 4 | issue = 6 | pages = 371–378 | year = 2003 | pmid = 12762829 | doi = 10.2165/00128071-200304060-00001 | s2cid = 20392538 }}</ref><ref name="Hayward2003">{{cite book| vauthors = Hayward C |title=Gender Differences at Puberty|url=https://books.google.com/books?id=JnO_VCuH7scC&pg=PA22|date=31 July 2003|publisher=Cambridge University Press|isbn=978-0-521-00165-6|pages=22–|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210736/https://books.google.com/books?id=JnO_VCuH7scC&pg=PA22|url-status=live}}</ref><ref name="MelmedPolonsky2015">{{cite book| vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM |title=Williams Textbook of Endocrinology|url=https://books.google.com/books?id=iPIACwAAQBAJ&pg=PA1105|date=11 November 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-34157-8|pages=1105–|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210750/https://books.google.com/books?id=iPIACwAAQBAJ&pg=PA1105|url-status=live}}</ref><ref name="JonesLopez2013">{{cite book | vauthors = Jones RE, Lopez KH |title=Human Reproductive Biology|url=https://books.google.com/books?id=M4kEdSnS-pkC&pg=PA19|date=28 September 2013|publisher=Academic Press|isbn=978-0-12-382185-0|pages=19–}}</ref><ref name="OettelSchillinger2012b" /><ref name="HongHolland2010">{{cite book| vauthors = Hong WK, Holland JF |title=Holland-Frei Cancer Medicine 8|url=https://books.google.com/books?id=R0FbhLsWHBEC&pg=PA753|year=2010|publisher=PMPH-USA|isbn=978-1-60795-014-1|pages=753–|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210740/https://books.google.com/books?id=R0FbhLsWHBEC&pg=PA753|url-status=live}}</ref><ref name="Sloane2002">{{cite book| vauthors = Sloane E |title=Biology of Women|url=https://books.google.com/books?id=kqcYyk7zlHYC&pg=PA496|year=2002|publisher=Cengage Learning|isbn=978-0-7668-1142-3|pages=496–|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210805/https://books.google.com/books?id=kqcYyk7zlHYC&pg=PA496|url-status=live}}</ref><ref name="KingBrucker2010">{{cite book| vauthors = King TL, Brucker MC |title=Pharmacology for Women's Health|url=https://books.google.com/books?id=u1wq63x4VsYC&pg=PA1022|date=25 October 2010|publisher=Jones & Bartlett Learning|isbn=978-0-7637-5329-0|pages=1022–}}</ref><ref name="Lobo2007">{{cite book| vauthors = Lobo RA |title=Treatment of the Postmenopausal Woman: Basic and Clinical Aspects|url=https://books.google.com/books?id=gywV9hkcyOMC&pg=PA217|date=5 June 2007|publisher=Academic Press|isbn=978-0-08-055309-2|pages=177, 217–226, 770–771|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210745/https://books.google.com/books?id=gywV9hkcyOMC&pg=PA217|url-status=live}}</ref><ref name="WarshawskyJr.2005">{{cite book| vauthors = Warshawsky D, Landolph Jr JR |title=Molecular Carcinogenesis and the Molecular Biology of Human Cancer|url=https://books.google.com/books?id=zSvMBQAAQBAJ&pg=PA457|date=31 October 2005|publisher=CRC Press|isbn=978-0-203-50343-0|pages=457–|access-date=9 December 2016|archive-date=4 May 2020|archive-url=https://web.archive.org/web/20200504210813/https://books.google.com/books?id=zSvMBQAAQBAJ&pg=PA457|url-status=live}}</ref> Among other effects, estradiol produces breast development, feminization, changes in the female reproductive system, changes in liver protein synthesis, and changes in brain function.<ref name="MelmedPolonsky2015" /><ref name="JonesLopez2013" /><ref name="OettelSchillinger2012b" /><ref name="HongHolland2010" /><ref name="Sloane2002" /><ref name="KingBrucker2010" /><ref name="Lobo2007" /><ref name="WarshawskyJr.2005" /> The effects of estradiol can influence health in both positive and negative ways.<ref name="pmid16112947" /> In addition to the aforementioned effects, estradiol has antigonadotropic effects due to its estrogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production.<ref name="JonesLopez2013" /><ref name="OettelSchillinger2012b" /><ref name="HongHolland2010" /><ref name="pmid14532759" /><ref name="CossJones2012" /><ref name="pmid3242384" /><ref name="Ockrim_2003" /> At sufficiently high dosages, estradiol is a powerful antigonadotropin, capable of suppressing testosterone levels into the castrate/female range in men.<ref name="HongHolland2010" /><ref name="pmid14532759" /><ref name="CossJones2012" /><ref name="pmid3242384" /><ref name="Ockrim_2003" />

There are differences between estradiol and other estrogens, such as non-bioidentical estrogens like natural conjugated estrogens and synthetic estrogens like ethinylestradiol and diethylstilbestrol, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety.<ref name="pmid16112947" />

===Pharmacokinetics=== {{Main|Pharmacokinetics of estradiol}}

Estradiol can be taken by a variety of different routes of administration.<ref name="pmid16112947" /> These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches), vaginal (tablets, creams, rings, suppositories), rectal, by intramuscular or subcutaneous injection (in oil or aqueous), and as a subcutaneous implant.<ref name="pmid16112947" /> The pharmacokinetics of estradiol, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration.<ref name="pmid16112947" /> Likewise, the potency of estradiol, and its local effects in certain tissues, most importantly the liver, differ by route of administration as well.<ref name="pmid16112947" /> In particular, the oral route is subject to a high first-pass effect, which results in high levels of estradiol and consequent estrogenic effects in the liver and low potency due to first-pass hepatic and intestinal metabolism into metabolites like estrone and estrogen conjugates.<ref name="pmid16112947" /> Conversely, this is not the case for parenteral (non-oral) routes, which bypass the intestines and liver.<ref name="pmid16112947" />

Different estradiol routes and dosages can achieve widely varying circulating estradiol levels.<ref name="pmid16112947" /> For purposes of comparison with normal physiological circumstances, menstrual cycle circulating levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase, 250 pg/mL at the middle of the cycle, and 100 pg/mL during the mid-luteal phase.<ref name="Lobo2007" /> Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle have been reported to be in the range of 80 and 150 pg/mL, according to some sources.<ref name="NotelovitzKeep2012">{{cite book| vauthors = Notelovitz M, van Keep PA |title=The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28–November 2, 1984|url=https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA397|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-4145-8|pages=397, 399|quote=[...] following the menopause, circulating estradiol levels decrease from a premenopausal mean of 120 pg/ml to only 13 pg/ml.|access-date=27 November 2016|archive-date=15 December 2020|archive-url=https://web.archive.org/web/20201215185214/https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA397|url-status=live}}</ref><ref name="ChristianSchoultz1994">{{cite book| vauthors = Christian C, von Schoultz B |title=Hormone Replacement Therapy: Standardized or Individually Adapted Doses?|url=https://books.google.com/books?id=apU4AfUqSGwC&pg=PA9|date=15 March 1994|publisher=CRC Press|isbn=978-1-85070-545-1|pages=9–16, 60|quote=The mean integrated estradiol level during a full 28-day normal cycle is around 80 pg/ml.|access-date=23 July 2018|archive-date=15 December 2020|archive-url=https://web.archive.org/web/20201215184621/https://books.google.com/books?id=apU4AfUqSGwC&pg=PA9|url-status=live}}</ref><ref name="MüllerMacLeod2012">{{cite book| vauthors = Müller EE, MacLeod RM |title=Neuroendocrine Perspectives|url=https://books.google.com/books?id=TUXtBwAAQBAJ&pg=PA121|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-3554-5|pages=121–|quote=[...] [premenopausal] mean [estradiol] concentration of 150 pg/ml [...]|access-date=27 November 2016|archive-date=15 December 2020|archive-url=https://web.archive.org/web/20201215185053/https://books.google.com/books?id=TUXtBwAAQBAJ&pg=PA121|url-status=live}}</ref>

==Chemistry== {{Chemical structures of major endogenous estrogens medication version|align=right|caption=Note the hydroxyl (–OH) groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.}}

Estradiol is a naturally occurring estrane steroid.<ref name="pmid16112947" /><ref name="RizkSallam2012">{{cite book| vauthors = Rizk BR, Sallam HN |title=Clinical Infertility and In Vitro Fertilization|url=https://books.google.com/books?id=GdLBOMzvfBwC&pg=PA11|date=15 June 2012|publisher=JP Medical Ltd|isbn=978-93-5025-095-2|pages=11–|access-date=3 July 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034549/https://books.google.com/books?id=GdLBOMzvfBwC&pg=PA11|url-status=live}}</ref> It is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="pmid16112947" /> It has two hydroxyl groups, one at the C3 position and the other at the C17β position, as well as three double bonds in the A ring (the estra-1,3,5(10)-triene core).<ref name="RizkSallam2012" /><ref name="pmid18744783" /> Due to its two hydroxyl groups, estradiol is often abbreviated as E2.<ref name="RizkSallam2012" /> The structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4) have one, three, and four hydroxyl groups, respectively.<ref name="RizkSallam2012" /><ref name="GivensAnderson1981">{{cite book| vauthors = Givens JR, Anderson GD |title=Endocrinology of Pregnancy: Based on the Proceedings of the Fifth Annual Symposium on Gynecologic Endocrinology, Held March 3-5, 1980 at the University of Tennessee, Memphis, Tennessee|url=https://books.google.com/books?id=kE44AQAAIAAJ|year=1981|publisher=Year Book Medical Publishers|isbn=978-0-8151-3529-6|page=158|quote=Estetrol (E4) is an estrogen with four hydroxyl groups. More specifically, E4, is 15α-hydroxyestriol.|access-date=3 July 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034550/https://books.google.com/books?id=kE44AQAAIAAJ|url-status=live}}</ref>

===Hemihydrate=== A hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similarly to estradiol.<ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA406|access-date=13 September 2012|year=2000|publisher=Taylor & Francis US|isbn=978-3-88763-075-1|pages=404–406|archive-date=7 June 2021|archive-url=https://web.archive.org/web/20210607193711/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA406|url-status=live}}</ref> In terms of activity and bioequivalence, estradiol and its hemihydrate are identical, with the only disparities being an approximate 3% difference in potency by weight (due to the presence of water molecules in the hemihydrate form of the substance) and a slower rate of release with certain formulations of the hemihydrate.<ref name="HumansOrganization2007">{{cite book |author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans |author2=World Health Organization |author3=International Agency for Research On Cancer |title=Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy |url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA384 |access-date=13 September 2012 |year=2007 |publisher=World Health Organization |isbn=978-92-832-1291-1 |page=384 |archive-date=6 June 2013 |archive-url=https://web.archive.org/web/20130606230031/http://books.google.com/books?id=aGDU5xibtNgC&pg=PA384 |url-status=live }}</ref><ref name="DesaiLee2007">{{cite book | vauthors = Desai A, Lee M |title=Gibaldi's Drug Delivery Systems in Pharmaceutical Care |url=https://books.google.com/books?id=v0rLyVSc8EYC&pg=PA337 |access-date=13 September 2012 |date=7 May 2007 |publisher=ASHP |isbn=978-1-58528-136-7 |page=337 |archive-date=8 June 2013 |archive-url=https://web.archive.org/web/20130608042333/http://books.google.com/books?id=v0rLyVSc8EYC&pg=PA337 |url-status=live }}</ref> This is because estradiol hemihydrate is more hydrated than anhydrous estradiol, and for this reason, is more insoluble in water in comparison, which results in slower absorption rates with specific formulations of the drug such as vaginal tablets.<ref name="DesaiLee2007" /> Estradiol hemihydrate has also been shown to result in less systemic absorption as a vaginal tablet formulation relative to other topical estradiol formulations such as vaginal creams.<ref name="Wang-ChengNeuner2007">{{cite book| vauthors = Wang-Cheng R, Neuner JM, Barnabei VM |title= Menopause |url= https://books.google.com/books?id=mPs5Ly71OCQC&pg=PA91|year=2007|publisher=ACP Press|isbn=978-1-930513-83-9|pages=91–|access-date=27 November 2016|archive-date=10 June 2016|archive-url=https://web.archive.org/web/20160610230533/https://books.google.com/books?id=mPs5Ly71OCQC&pg=PA91|url-status=live}}</ref> Estradiol hemihydrate is used in place of estradiol in some estradiol products.<ref name="Drugs@FDA1" /><ref name="LeeDesai2007">{{cite book| vauthors = Lee M, Desai A |title=Gibaldi's Drug Delivery Systems in Pharmaceutical Care |url=https://books.google.com/books?id=v0rLyVSc8EYC&pg=PA336 |year=2007 |publisher=ASHP |isbn=978-1-58528-136-7 |pages=336–|access-date=22 July 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034551/https://books.google.com/books?id=v0rLyVSc8EYC&pg=PA336|url-status=live}}</ref><ref name="Nursing2013">{{cite book|title=Nursing2013 Drug Handbook|url=https://books.google.com/books?id=tliO2JeEZAwC&pg=PA528|year=2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-5023-0|pages=528–|access-date=22 July 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034551/https://books.google.com/books?id=tliO2JeEZAwC&pg=PA528|url-status=live}}</ref>

===Derivatives=== {{See also|List of estrogens#Estradiol derivatives|Estrogen ester|List of estrogen esters#Estradiol esters}}

A variety of C17β and/or C3 ester prodrugs of estradiol, such as estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol undecylate, estradiol valerate, and polyestradiol phosphate (an estradiol ester in polymeric form), among many others, have been developed and introduced for medical use as estrogens.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="pmid16112947" /><ref name="pmid1231448">{{cite journal | vauthors = Vermeulen A | title = Longacting steroid preparations | journal = Acta Clinica Belgica | volume = 30 | issue = 1 | pages = 48–55 | date = 1975 | pmid = 1231448 | doi = 10.1080/17843286.1975.11716973 }}</ref> Estramustine phosphate is also an estradiol ester, but with a nitrogen mustard moiety attached, and is used as a cytostatic antineoplastic agent in the treatment of prostate cancer.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="pmid21756277">{{cite journal | vauthors = Ravery V, Fizazi K, Oudard S, Drouet L, Eymard JC, Culine S, Gravis G, Hennequin C, Zerbib M | title = The use of estramustine phosphate in the modern management of advanced prostate cancer | journal = BJU International | volume = 108 | issue = 11 | pages = 1782–1786 | date = December 2011 | pmid = 21756277 | doi = 10.1111/j.1464-410X.2011.10201.x | s2cid = 33456591 | doi-access = free }}</ref> Cloxestradiol acetate and promestriene are ether prodrugs of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used.<ref name="Elks2014" /><ref name="IndexNominum2000" />

Synthetic derivatives of estradiol used as estrogens include ethinylestradiol, ethinylestradiol sulfonate, mestranol, methylestradiol, moxestrol, and quinestrol, all of which are 17α-substituted estradiol derivatives.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="pmid16112947" /> Synthetic derivatives of estradiol used in scientific research include 8β-VE2 and 16α-LE2.<ref name="VaudryKah2018">{{cite book| vauthors = Vaudry H, Kah O |title=Trends in Comparative Endocrinology and Neurobiology|url=https://books.google.com/books?id=a-NIDwAAQBAJ&pg=PA115|date=25 January 2018|publisher=Frontiers Media SA|isbn=978-2-88945-399-3|pages=115–|access-date=3 July 2018|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034551/https://books.google.com/books?id=a-NIDwAAQBAJ&pg=PA115|url-status=live}}</ref>

==History== {{See also|Estradiol#History}}

Estradiol was first discovered and synthesized in 1933 via reduction of estrone.<ref name="LauritzenStudd2005" /> Subsequently, estradiol was isolated for the first time in 1935.<ref name="Parl2000" /><ref name="ShoupeHaseltine2012">{{cite book | vauthors = Shoupe D, Haseltine FP |title=Contraception|url=https://books.google.com/books?id=cpDhBwAAQBAJ&pg=PA2|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-2730-4|pages=2–}}</ref> It was also originally known as ''dihydroxyestrin'', ''dihydrofolliculin'', or ''alpha-estradiol''.<ref name="pmid18744783" /><ref name="pmid18746057" />

Estradiol was first introduced for medical use, in the form of estradiol benzoate, a short-acting ester prodrug of estradiol administered by intramuscular injection in oil solution, under the brand name Progynon B in 1933.<ref name="Kaufman1933">{{cite journal| vauthors = Kaufman C |title=Die Behandlung der Amenorrhöe mit Hohen Dosen der Ovarialhormone|journal=Klinische Wochenschrift|volume=12|issue=40|year=1933|pages=1557–1562|issn=0023-2173|doi=10.1007/BF01765673|s2cid=25856898}}</ref><ref name="Buschbeck1934">{{cite journal| vauthors = Buschbeck H |title=Neue Wege der Hormontherapie in der Gynäkologie|trans-title=New ways of hormonal therapy in gynecology|journal=Deutsche Medizinische Wochenschrift|volume=60|issue=11|year=2009|pages=389–393|issn=0012-0472|doi=10.1055/s-0028-1129842|s2cid=72668930 }}</ref><ref name="Biskind1935">{{cite journal| vauthors = Biskind MS |title=Commercial Glandular Products|journal=Journal of the American Medical Association|volume=105|issue=9|year=1935|page=667|issn=0002-9955|doi=10.1001/jama.1935.92760350007009a|quote=Progynon-B, Schering Corporation: This is crystalline hydroxyestrin benzoate obtained by hydrogenation of theelin and subsequent conversion to the benzoate. [...] Progynon-B is marketed in ampules containing 1 cc. of a sesame oil solution of hydroxyestrin benzoate of either 2,500, 5,000, 10,000 or 50,000 international units.}}</ref><ref name="Novak1935">{{cite journal| vauthors = Novak E |title=The Therapeutic Use of Estrogenic Substances|journal=JAMA: The Journal of the American Medical Association|volume=104|issue=20|year=1935|page=1815|issn=0098-7484|doi=10.1001/jama.1935.92760200002012|quote=Progynon B (Schering), in 1 cc. ampules, of 10,000 or 50,000 international units of hydroxyestrin benzoate in sesame oil.}}</ref> Estradiol itself was also marketed in the 1930s and 1940s in the form of oral tablets and solutions, vaginal suppositories, and topical ointments under a variety of brand names including Dimenformon, Gynoestryl, Ovocyclin, Progynon, and Progynon DH.<ref name="Greene1941">{{cite journal| vauthors = Greene RR |title= Endocrine Therapy for Gynecologic Disorders|journal=Medical Clinics of North America |volume=25 |issue=1 |year=1941 |pages=155–168 |issn=0025-7125 |doi=10.1016/S0025-7125(16)36624-X}}</ref><ref name="pmid18744783">{{cite journal | vauthors = Fluhmann CF | title = Estrogenic Hormones: Their Clinical Usage | journal = California and Western Medicine | volume = 49 | issue = 5 | pages = 362–366 | date = November 1938 | pmid = 18744783 | pmc = 1659459 }}</ref><ref name="pmid29648134">{{cite journal | vauthors = Johnstone RW | title = Sex Hormone Therapy in Gynæcology | journal = Edinburgh Medical Journal | volume = 43 | issue = 11 | pages = 680–695 | date = November 1936 | pmid = 29648134 | pmc = 5303355 }}</ref><ref name="pmid18746057">{{cite journal | vauthors = Reilly WA | title = Estrogens: Their Use in Pediatrics | journal = California and Western Medicine | volume = 55 | issue = 5 | pages = 237–239 | date = November 1941 | pmid = 18746057 | pmc = 1634235 }}</ref><ref name="Fluhmann1944">{{cite journal| vauthors = Fluhmann CF |title=Clinical use of extracts from the ovaries|journal=Journal of the American Medical Association|volume=125|issue=1|year=1944|page=1|issn=0002-9955|doi=10.1001/jama.1944.02850190003001}}</ref><ref name="pmid29646930">{{cite journal | vauthors = Macpherson AI | title = The Use of Œstrogens in Obstetrics and Gynæcology | journal = Edinburgh Medical Journal | volume = 47 | issue = 6 | pages = 406–424 | date = June 1940 | pmid = 29646930 | pmc = 5306594 }}</ref><ref name="JAMA1943">{{cite journal|title=Nomenclature of Endocrine Preparations|journal=Journal of the American Medical Association|volume=123|issue=6|year=1943|page=351|issn=0002-9955|doi=10.1001/jama.1943.02840410033009}}</ref> Marketed vaginal estradiol suppositories were also used rectally.<ref name="Freed1941">{{cite journal| vauthors = Freed SC |title=Present Status of Commercial Endocrine Preparations|journal=JAMA: The Journal of the American Medical Association |volume=117 |issue=14 |year=1941 |page=1175|issn=0098-7484|doi=10.1001/jama.1941.72820400003010}}</ref> Estradiol dipropionate, another short-acting ester of estradiol in oil solution for use by intramuscular injection, was marketed under the brand name Di-Ovocylin by 1939.<ref name="DorrGreene1939">{{cite journal| vauthors = Dorr EM, Greene RR |title=Treatment of the menopause with estradiol dipropionate|journal=American Journal of Obstetrics and Gynecology|volume=38|issue=3|year=1939|pages=458–464|issn=0002-9378|doi=10.1016/S0002-9378(39)90763-5}}</ref><ref name="Greene1941" /> In contrast to estrone, estradiol was never marketed in oil solution for intramuscular injection.<ref name="pmid13359169">{{cite journal | vauthors = Cantor EB | title = A survey of estrogens | journal = Postgraduate Medicine | volume = 20 | issue = 3 | pages = 224–231 | date = September 1956 | pmid = 13359169 | doi = 10.1080/00325481.1956.11691266 }}</ref><ref name="JAMA1943" /><ref name="pmid15390574">{{cite journal | vauthors = Jones GF | title = Physiology and management of the climacteric | journal = California Medicine | volume = 71 | issue = 5 | pages = 345–348 | date = November 1949 | pmid = 15390574 | pmc = 1520053 }}</ref><ref name="NNR1949a">{{cite journal|title=NNR: Products Recently Accepted by the A. M. A. Council on Pharmacy and Chemistry|journal=Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.)|volume=10|issue=11|year=1949|pages=692–694|issn=0095-9561|doi=10.1016/S0095-9561(16)31995-8}}</ref><ref name="Greene1941" /><ref name="pmid18744783" /><ref name="pmid29648134" /><ref name="pmid18746057" /><ref name="Fluhmann1944" /><ref name="pmid29646930" /> This is attributable to its short duration of action and the availability of longer-acting estradiol esters like estradiol benzoate and estradiol dipropionate.<ref name="pmid13359169" /><ref name="Reifenstein1944">{{cite journal| vauthors = Reifenstein EC |title=Endocrinology: A Synopsis of Normal and Pathologic Physiology, Diagnostic Procedures, and Therapy|journal=Medical Clinics of North America|volume=28|issue=5|year=1944|pages=1232–1276|issn=0025-7125|doi=10.1016/S0025-7125(16)36180-6}}</ref>

Delivery of estrogens by nasal spray was studied in 1929,<ref name="Novak1935" /><ref name="Paul Pratt1932">{{cite journal| vauthors = Pratt JP |title=Ovarian Therapy |journal=Endocrinology |volume=16 |issue=1 |year=1932 |pages=45–51 |issn=0013-7227 |doi=10.1210/endo-16-1-45}}</ref> and an estradiol nasal spray for local use was marketed by Schering under the brand name Progynon DH Nasal Spray by 1941.<ref name="Schering1941">{{cite book | author = Medical Research Division | title = Female Sex Hormone Therapy, Part One: The Follicular Hormone: A Clinical Guide | url = https://books.google.com/books?id=tO1OAQAAMAAJ | year = 1941 | publisher = Schering Corporation | pages = 15, 50, 56 | quote = Progynon-DH is α-estradiol, the follicular hormone,1,2,3,4,9 supplied in a variety of preparations suitable for oral and local use, including tablets, solution, ointment, suppositories, and nasal spray. [...] PROGYNON-DH Nasal Spray has been prepared especially for use in [the treatment of atrophic rhinitis], the hormone being administered by atomizer twice a day following the usual irrigation. [...] Progynon-DH Nasal Spray, α-estradiol in oil, prepared for use in the treatment of atrophic rhinitis, otosclerosis, and kindred disorders; in bottle with atomizer, the solution containing 4800 R.U. (0.4 mg.) in 30 cc. | access-date = 31 December 2019 | archive-date = 10 June 2022 | archive-url = https://web.archive.org/web/20220610034552/https://books.google.com/books?id=tO1OAQAAMAAJ | url-status = live }}</ref><ref name="Howard1949">{{cite book| vauthors = Howard ME |title=Modern Drug Encyclopedia and Therapeutic Index|url=https://books.google.com/books?id=ltlLAQAAMAAJ|year=1949|publisher=Drug Publications|page=696|access-date=31 December 2019|archive-date=7 June 2020|archive-url=https://web.archive.org/web/20200607022312/https://books.google.com/books?id=ltlLAQAAMAAJ|url-status=live}}</ref> Sublingual administration of estradiol was first described in the early 1940s.<ref name="Walton1944">{{cite journal| vauthors = Walton RP |title=Sublingual Administration of Drugs|journal=Journal of the American Medical Association|volume=124|issue=3|year=1944|page=138|issn=0002-9955|doi=10.1001/jama.1944.02850030006002}}</ref><ref name="Corner1944">{{cite journal| vauthors = Corner GW |title=The Absorption of Steroid Hormones from the Oral Mucous Membranes, with Special Reference to the Sublingual Administration of Progesterone|journal=American Journal of Obstetrics and Gynecology|volume=47|issue=5|year=1944|pages=670–677|issn=0002-9378|doi=10.1016/S0002-9378(16)40321-2}}</ref><ref name="LisserGordan1950">{{cite journal | vauthors = Lisser H, Gordan GS, Aird RB, Arrick MS, Craig LS, Escamilla RF, Goldberg MB | title = Sublingual or buccal administration of steroidal hormones | journal = Postgraduate Medicine | volume = 8 | issue = 5 | pages = 393–400 | date = November 1950 | pmid = 14780947 | doi = 10.1080/00325481.1950.11694030 }}</ref> Buccal estradiol tablets were marketed by Schering under the brand name Progynon Buccal Tablets by 1949.<ref name="JAPA1949">{{cite journal|title=New Prescription Products|journal=Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.)|volume=10|issue=4|year=1949|pages=198–206|issn=0095-9561|doi=10.1016/S0095-9561(16)31795-9}}</ref> Estradiol tablets for use by the sublingual route were marketed under the brand name Estradiol Membrettes in 1950,<ref name="DrugReporter1950">{{cite book|title=Oil, Paint and Drug Reporter|url=https://books.google.com/books?id=Y9YhAQAAMAAJ|date=April 1950|quote=Trade Briefs Wyeth, Inc., Philadelphia, has commenced marketing "Estradiol Membrettes, 0.25 mg." as an addition to its hormone line.|access-date=12 December 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034552/https://books.google.com/books?id=Y9YhAQAAMAAJ|url-status=live}}</ref><ref name="APP1950">{{cite book|title=American Professional Pharmacist|url=https://books.google.com/books?id=gfcrAQAAMAAJ|year=1950|publisher=American Professional Pharmacist, Incorporated|page=647|access-date=12 December 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034553/https://books.google.com/books?id=gfcrAQAAMAAJ|url-status=live}}</ref><ref name="Romaine1950">{{cite book|title=Medical Times|url=https://books.google.com/books?id=4e2rAAAAIAAJ|year=1950|publisher=Romaine Pierson Pub.|page=248|access-date=12 December 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034553/https://books.google.com/books?id=4e2rAAAAIAAJ|url-status=live}}</ref><ref name="Welsh1951">{{cite book| vauthors = Welsh AL |title=Dermatological Formulary: A Guide for Medical Students and Resident Physicians in Dermatology|url=https://books.google.com/books?id=1m-C5uGARQEC|year=1951|publisher=Educational Publishers|page=155|access-date=12 December 2019|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829012048/https://books.google.com/books?id=1m-C5uGARQEC|url-status=live}}</ref> as well as under the brand name Diogynets by 1952.<ref name="Society1952">{{cite book|author=Omaha Midwest Clinical Society|title=Journal|url=https://books.google.com/books?id=-e0vAQAAMAAJ|year=1952|quote=DIOGYNETS*. Estradiol, U.S.P., Transmucosal Tablets 0.125 mg., 0.25 mg. and 1.0 mg.}}</ref><ref name="AAGP1954">{{cite book|title=General Practitioner|url=https://books.google.com/books?id=MxogAQAAMAAJ|date=April 1954|publisher=American Academy of General Practice|pages=168–170|quote=Diogynets* [...] * brand of estradiol transmucosal tablets, scored: 0.125 mg., 0.25 mg. and 1.0 mg., bottles of 50 and 100.|access-date=12 December 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034737/https://books.google.com/books?id=MxogAQAAMAAJ|url-status=live}}</ref><ref name="Spence1953">{{cite book|author=Allan William Spence|title=Clinical Endocrinology|url=https://books.google.com/books?id=-mdsAAAAMAAJ|year=1953|publisher=Cassell|page=547|access-date=15 December 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034738/https://books.google.com/books?id=-mdsAAAAMAAJ|url-status=live}}</ref> Longer-acting esters of estradiol in oil solution like estradiol valerate (Delestrogen, Progynon Depot), estradiol cypionate (Depo-Estradiol), and estradiol undecylate (Delestrec, Progynon Depot 100), as well as the polymeric estradiol ester polyestradiol phosphate in aqueous solution (Estradurin), were developed and introduced for use by intramuscular injection in the 1950s.<ref name="IndexNominum2000" /><ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA897|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=897–}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA2935-IA381|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3}}</ref><ref name="pmid7389356">{{cite journal | vauthors = Oriowo MA, Landgren BM, Stenström B, Diczfalusy E | title = A comparison of the pharmacokinetic properties of three estradiol esters | journal = Contraception | volume = 21 | issue = 4 | pages = 415–424 | date = April 1980 | pmid = 7389356 | doi = 10.1016/s0010-7824(80)80018-7 }}</ref>

Due to poor absorption and low potency relative to other estrogens, oral estradiol was not widely used as late as the early 1970s.<ref name="pmid5023261">{{cite journal | vauthors = Martin PL, Burnier AM, Greaney MO | title = Oral menopausal therapy using 17- micronized estradiol. A preliminary study of effectiveness, tolerance and patient preference | journal = Obstetrics and Gynecology | volume = 39 | issue = 5 | pages = 771–774 | date = May 1972 | pmid = 5023261 | url = https://journals.lww.com/greenjournal/Abstract/1972/05000/Oral_Menopausal_Therapy_Using_17___Micronized.22.aspx | access-date = 1 December 2019 }}</ref> Instead, synthetic and animal-derived estrogens like conjugated estrogens, ethinylestradiol, and diethylstilbestrol were typically used by the oral route.<ref name="pmid5023261" /> In 1966, oral estradiol valerate was introduced by Schering for medical use under the brand name Progynova.<ref name="KlinWochenschr1966"/><ref name="pmid5593020"/><ref name="pmid5728263">{{cite journal | vauthors = Velikay L | title = [The peroral treatment of the climacteric syndrome with estradiol valerate] | language = de | journal = Wiener Klinische Wochenschrift | volume = 80 | issue = 12 | pages = 229–233 | date = March 1968 | pmid = 5728263 | trans-title = The peroral treatment of the climacteric syndrome with estradiol valerate }}</ref><ref name="pmid5045321">{{cite journal | vauthors = Koed J | title = [Therapy of climacteric deficiency symptoms using progynova] | language = de | journal = Die Medizinische Welt | volume = 23 | issue = 22 | pages = 834–836 | date = May 1972 | pmid = 5045321 | trans-title = Therapy of climacteric deficiency symptoms using Progynova }}</ref> Esterification of estradiol, as in estradiol valerate, was believed to improve its metabolic stability with oral administration.<ref name="pmid16112947" /><ref name="pmid7169965"/> Studies in the 1960s showed that micronization of steroids such as spironolactone and norethisterone acetate improved their absorption and oral potency by several-fold.<ref name="Dorfman2016">{{cite book| vauthors = Dorfman RI |title=Steroidal Activity in Experimental Animals and Man|url=https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA392|date=5 December 2016|publisher=Elsevier Science|isbn=978-1-4832-7299-3|pages=392–|access-date=15 December 2019|archive-date=18 August 2020|archive-url=https://web.archive.org/web/20200818231558/https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA392|url-status=live}}</ref><ref name="HorskyPresl2012">{{cite book| vauthors = Horsky J, Presl J |title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA313|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=313–|access-date=8 December 2019|archive-date=21 October 2021|archive-url=https://web.archive.org/web/20211021002528/https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA313|url-status=live}}</ref><ref name="Brotherton1976">{{cite book| vauthors = Brotherton J |title=Sex Hormone Pharmacology|url=https://books.google.com/books?id=zt5sAAAAMAAJ|year=1976|publisher=Academic Press|isbn=978-0-12-137250-7|page=34}}</ref><ref name="pmid5753386">{{cite journal | vauthors = Gibian H, Kopp R, Kramer M, Neumann F, Richter H | title = Effect of particle size on biological activity of norethisterone acetate | journal = Acta Physiologica Latino Americana | volume = 18 | issue = 4 | pages = 323–326 | date = 1968 | pmid = 5753386 }}</ref><ref name="pmid2112080">{{cite journal | vauthors = He CH, Shi YE, Liao DL, Zhu YH, Xu JQ, Matlin SA, Vince PM, Fotherby K, Van Look PF | title = Comparative cross-over pharmacokinetic study on two types of postcoital contraceptive tablets containing levonorgestrel | journal = Contraception | volume = 41 | issue = 5 | pages = 557–567 | date = May 1990 | pmid = 2112080 | doi = 10.1016/0010-7824(90)90064-3 }}</ref> In 1972, micronization of estradiol was studied in women and was likewise found to improve the absorption and potency of estradiol by the oral route.<ref name="pmid5023261" /> Subsequently, oral micronized estradiol was introduced for medical use in the United States under the brand name Estrace in 1975.<ref name="Estrace-FDA">{{Cite web |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=084499 |title=Estrace: FDA-Approved Drugs |access-date=27 November 2016 |archive-date=6 May 2020 |archive-url=https://web.archive.org/web/20200506204048/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=084499&DrugName=ESTRACE&ActiveIngred=ESTRADIOL&SponsorApplicant=BRISTOL%20MYERS%20SQUIBB&ProductMktStatus=3&goto=Search.DrugDetails |url-status=live }}</ref><ref>{{cite web | title=Estrace: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=084500 | archive-url=https://web.archive.org/web/20170217104416/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=084500 | archive-date=17 February 2017 | access-date=6 September 2024}}</ref> However, oral micronized estradiol valerate had been introduced by Schering in 1968.<ref name="KuhlWiegratz2008">{{cite book| vauthors = Kuhl H, Wiegratz I |title=Klimakterium, Postmenopause und Hormonsubstitution|trans-title=Climacteric, Postmenopause and Hormone Replacement|edition=4|date=1 January 2008|language=de|publisher=UNI-MED-Verlag|isbn=978-3-83742-043-2|page=18|quote=With Progynon Depot-10, an oily solution of 10 mg estradiol valerate, an injection preparation had been available since 1953 and since 1966 coated tablets with estradiol valerate for oral therapy. The first Schering preparation containing micronized estradiol was marketed in 1968 as Progynova 21 (2 mg) and Progynova 21 mite (1 mg).}}</ref> Oral micronized estradiol and oral estradiol valerate have similar bioavailability and are both now widely used throughout the world.<ref name="pmid16112947" /><ref name="pmid7169965" />

After the introduction of oral micronized estradiol, vaginal and intranasal micronized estradiol were evaluated in 1977 and both subsequently introduced.<ref name="pmid591620">{{cite journal | vauthors = Rigg LA, Milanes B, Villanueva B, Yen SS | title = Efficacy of intravaginal and intranasal administration of micronized estradiol-17beta | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 45 | issue = 6 | pages = 1261–1264 | date = December 1977 | pmid = 591620 | doi = 10.1210/jcem-45-6-1261 | doi-access = free }}</ref><ref name="pmid16112947" />

The first transdermal estradiol gel, a hydroalcoholic gel known as EstroGel, was initially described in 1980 and was introduced in Europe around 1981.<ref name="pmid16530874">{{cite journal | vauthors = Yoo JW, Lee CH | title = Drug delivery systems for hormone therapy | journal = Journal of Controlled Release | volume = 112 | issue = 1 | pages = 1–14 | date = May 2006 | pmid = 16530874 | doi = 10.1016/j.jconrel.2006.01.021 | quote = Transdermal gels. The first system used for estrogen delivery through skin was the application of estrogen dissolved into a water–alcohol solvent in a form of gel for the treatment of postmenopausal symptoms [80] [...] EstroGel (Solvay) has been in the Europe market for more than 25 years, but approved in the US only in 2004. EstroGel contains 17β-estradiol in a hydro-alcoholic gel base which renders a controlled release profile. [...] Estrasorb (Novavax, Malvern, PA) is launched in 2003 as the first topical, lotion-like nanoemulsion for the treatment of vasomotor symptoms. [...] Conventional reservoir patches. The first transdermal patch for HT was Estraderm (Novartis, Switzerland) which was launched in Europe in 1985 and has been widely used ever since. [...] Transdermal matrix patches. [...] Climara (Berlex, Montville, NJ) was first introduced as the matrix patch in 1995. A year later, Vivelle (Novogyne, Miami, FL) was introduced in the market [...] }}</ref> Transdermal estradiol gel did not become available in the United States until 2004, when EstroGel was introduced in this country as well.<ref name="pmid16530874" /> A transdermal estradiol emulsion, Estrasorb, was marketed in the United States in 2003 as well.<ref name="pmid16530874" /> One of the earliest reports of transdermal estradiol patches was published in 1983.<ref name="pmid16530874" /><ref name="pmid15845914">{{cite journal | vauthors = Davis SR, Dinatale I, Rivera-Woll L, Davison S | title = Postmenopausal hormone therapy: from monkey glands to transdermal patches | journal = The Journal of Endocrinology | volume = 185 | issue = 2 | pages = 207–222 | date = May 2005 | pmid = 15845914 | doi = 10.1677/joe.1.05847 | quote = One of the earliest reports of the novel transdermal patch delivery system for oestradiol was published in 1983 (Laufer et al. 1983). | doi-access = free }}</ref> Estraderm, a reservoir patch and the first transdermal estradiol patch to be marketed, was introduced in Europe in 1985 and in the United States in 1986.<ref name="BensonWatkinson2011">{{cite book| vauthors = Benson HA, Watkinson AC | veditors = Benson HA, Watkinson AC |title=Transdermal and Topical Drug Delivery Today|year=2011| publisher = Wiley |doi=10.1002/9781118140505|quote=Table 18.1 Passive Transdermal Drugs for Systemic Drug Delivery Launched in the United States and Europe [...] Drug: Estradiol. Indication: Female HRT. U.S. approval: 1986. Marketed in the EU: Yes.|isbn=978-1-118-14050-5}}</ref><ref name="pmid15040576">{{cite journal | vauthors = Prausnitz MR, Mitragotri S, Langer R | title = Current status and future potential of transdermal drug delivery | journal = Nature Reviews. Drug Discovery | volume = 3 | issue = 2 | pages = 115–124 | date = February 2004 | pmid = 15040576 | doi = 10.1038/nrd1304 | quote = Timeline: Important events in transdermal drug delivery: [...] 1986: Estraderm (17β-oestradiol) patch, FDA approval for hormone replacement. | s2cid = 28888964 | author1-link = Mark Prausnitz }}</ref> The first transdermal matrix estradiol patches to be introduced were Climara and Vivelle between 1994 and 1996, and were followed by many others.<ref name="pmid16530874" /><ref name="pmid25560046">{{cite journal | vauthors = Pastore MN, Kalia YN, Horstmann M, Roberts MS | title = Transdermal patches: history, development and pharmacology | journal = British Journal of Pharmacology | volume = 172 | issue = 9 | pages = 2179–2209 | date = May 2015 | pmid = 25560046 | pmc = 4403087 | doi = 10.1111/bph.13059 }}</ref>

Ethinylestradiol, a synthetic derivative of estradiol, was synthesized from estradiol by Inhoffen and Hohlweg in 1938 and was introduced for oral use by Schering in the United States under the brand name Estinyl in 1943.<ref name="OettelSchillinger2012">{{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens|url=https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA8|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-58616-3|pages=7–8}}</ref><ref name="MosbyGenRx2001">{{cite book|title=Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs|url=https://books.google.com/books?id=QxsobYYgm8oC|year=2001|publisher=Mosby|isbn=978-0-323-00629-3|page=944}}</ref> Starting in the 1950s, ethinylestradiol became widely used in birth control pills.<ref name="OettelSchillinger2012" /> Estradiol-containing birth control pills were initially studied in the 1970s, with the first report published in 1977.<ref name="pmid319864">{{cite journal | vauthors = Astedt B, Svanberg L, Jeppsson S, Liedholm P, Rannevik G | title = The natural oestrogenic hormone oestradiol as a new component of combined oral contraceptives | journal = British Medical Journal | volume = 1 | issue = 6056 | page = 269 | date = January 1977 | pmid = 319864 | pmc = 1604185 | doi = 10.1136/bmj.1.6056.269 }}</ref><ref name="pmid23384741">{{cite journal | vauthors = Christin-Maitre S | title = History of oral contraceptive drugs and their use worldwide | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 27 | issue = 1 | pages = 3–12 | date = February 2013 | pmid = 23384741 | doi = 10.1016/j.beem.2012.11.004 }}</ref> Development of birth control pills containing estradiol was motivated by the thrombotic risks of ethinylestradiol that were uncovered in the 1960s and 1970s.<ref name="pmid28712325">{{cite journal | vauthors = Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G | title = Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis | journal = Expert Review of Clinical Pharmacology | volume = 10 | issue = 10 | pages = 1129–1144 | date = October 2017 | pmid = 28712325 | doi = 10.1080/17512433.2017.1356718 | s2cid = 205931204 }}</ref><ref name="pmid20136565">{{cite journal | vauthors = Alsina JC | title = After 50 years of ethinylestradiol, another oestrogen in combined oral contraceptives | journal = The European Journal of Contraception & Reproductive Health Care | volume = 15 | issue = 1 | pages = 1–3 | date = February 2010 | pmid = 20136565 | doi = 10.3109/13625180903585431 | s2cid = 9642823 }}</ref><ref name="pmid23931030">{{cite journal | vauthors = Chabbert-Buffet N, Gerris J, Jamin C, Lello S, Lete I, Lobo P, Nappi RE, Pintiaux A | title = Toward a new concept of "natural balance" in oral estroprogestin contraception | journal = Gynecological Endocrinology | volume = 29 | issue = 10 | pages = 891–896 | date = October 2013 | pmid = 23931030 | doi = 10.3109/09513590.2013.824963 | s2cid = 207489327 }}</ref><ref name="pmid23384741"/> More than 15 attempts were made at development of an estradiol-containing birth control pill starting in the 1970s, but were unsuccessful due to unacceptable menstrual bleeding patterns.<ref name="pmid23384741" /> Estradiol valerate/cyproterone acetate (Femilar) was introduced for use as a birth control pill in Finland in 1993, but was never marketed elsewhere.<ref name="pmid20004267">{{cite journal | vauthors = Fruzzetti F, Bitzer J | title = Review of clinical experience with estradiol in combined oral contraceptives | journal = Contraception | volume = 81 | issue = 1 | pages = 8–15 | date = January 2010 | pmid = 20004267 | doi = 10.1016/j.contraception.2009.08.010 }}</ref> Subsequently, estradiol valerate/dienogest (Natazia, Qlaira) was marketed as a birth control pill in 2008<ref name="pmid22468839">{{cite journal | vauthors = Fruzzetti F, Trémollieres F, Bitzer J | title = An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest | journal = Gynecological Endocrinology | volume = 28 | issue = 5 | pages = 400–408 | date = May 2012 | pmid = 22468839 | pmc = 3399636 | doi = 10.3109/09513590.2012.662547 }}</ref> and estradiol/nomegestrol acetate (Naemis, Zoely) was introduced in 2012.<ref name="pmid28902531"/>

==Society and culture==

===Generic names=== Estradiol is the generic name of estradiol in American English and its {{abbrlink|INN|International Nonproprietary Name|INN}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Drugs.com1">{{Cite web | url=https://www.drugs.com/international/estradiol.html | title=Estradiol | access-date=27 November 2016 | archive-date=18 June 2018 | archive-url=https://web.archive.org/web/20180618175221/https://www.drugs.com/international/estradiol.html | url-status=live }}</ref><ref name="IndexNominum2000" /><ref name="Elks2014"/><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA206|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=206–}}</ref><ref name="KEGG">{{Cite web | url=http://www.kegg.jp/entry/D00105 | title=KEGG DRUG: Estradiol | access-date=30 November 2016 | archive-date=28 November 2016 | archive-url=https://web.archive.org/web/20161128133208/http://www.kegg.jp/entry/D00105 | url-status=live }}</ref> Estradiolo is the name of estradiol in Italian and the {{abbrlink|DCIT|Denominazione Comune Italiana}}<ref name="Drugs.com1" /> and estradiolum is its name in Latin, whereas its name remains unchanged as estradiol in Spanish, Portuguese, French, and German.<ref name="Drugs.com1" /><ref name="IndexNominum2000" /> Oestradiol was the former {{abbrlink|BAN|British Approved Name}} of estradiol and its name in British English,<ref name="MortonHall2012" /> but the spelling was eventually changed to estradiol.<ref name="Drugs.com1" /> When estradiol is provided in its hemihydrate form, its {{abbrlink|INN|International Nonproprietary Name|INN}} is estradiol hemihydrate.<ref name="IndexNominum2000" />

===Brand names=== {{See also|List of estrogen esters#Estradiol esters|Combined injectable contraceptive#Available forms|Estradiol-containing oral contraceptive}}

Estradiol is marketed under a large number of brand names throughout the world.<ref name="IndexNominum2000" /><ref name="Drugs.com1"/> Examples of major brand names in which estradiol has been marketed in include Climara, Climen, Dermestril, Divigel, Estrace, Natifa, Estraderm, Estraderm TTS, Estradot, Estreva, Estrimax, Estring, Estrofem, EstroGel, Evorel, Fem7 (or FemSeven), Imvexxy, Menorest, Oesclim, OestroGel, Sandrena, Systen, and Vagifem.<ref name="IndexNominum2000" /><ref name="Drugs.com1" /> Estradiol valerate is marketed mainly as Progynova and Progynon-Depot, while it is marketed as Delestrogen in the US.<ref name="IndexNominum2000" /><ref name="Drugs@FDA1" />{{failed verification|reason=broken FDA link|date=June 2020}} Estradiol cypionate is used mainly in the US and is marketed under the brand name Depo-Estradiol.<ref name="IndexNominum2000" /><ref name="Drugs@FDA1" />{{failed verification|reason=broken FDA link|date=June 2020}} Estradiol acetate is available as Femtrace, Femring, and Menoring.<ref name="Drugs@FDA1" />{{failed verification|reason=broken FDA link|date=June 2020}}

Estradiol is also widely available in combination with progestogens.<ref name="Drugs.com1" /> It is available in combination with norethisterone acetate under the major brand names Activelle, Cliane, Estalis, Eviana, Evorel Conti, Evorel Sequi, Kliogest, Novofem, Sequidot, and Trisequens; with drospirenone as Angeliq; with dydrogesterone as Femoston, Femoston Conti; and with nomegestrol acetate as Zoely.<ref name="Drugs.com1" /> Estradiol valerate is available with cyproterone acetate as Climen; with dienogest as Climodien and Qlaira; with norgestrel as Cyclo-Progynova and Progyluton; with levonorgestrel as Klimonorm; with medroxyprogesterone acetate as Divina and Indivina; and with norethisterone enantate as Mesigyna and Mesygest.<ref name="Drugs.com1" /> Estradiol cypionate is available with medroxyprogesterone acetate as Cyclo-Provera, Cyclofem, Feminena, Lunelle, and Novafem;<ref name="pmid12290848"/> estradiol enantate with algestone acetophenide as Deladroxate and Topasel;<ref name="Drugs.com1" /><ref name="Rowlands2009">{{cite journal | vauthors = Rowlands S | title = New technologies in contraception | journal = BJOG | volume = 116 | issue = 2 | pages = 230–239 | date = January 2009 | pmid = 19076955 | doi = 10.1111/j.1471-0528.2008.01985.x | url = http://wrap.warwick.ac.uk/28852/1/WRAP_Rowlands_NewtechnologiesincontraceptionBJOG2008_Uni_repos_version.pdf | access-date = 9 December 2019 | url-status = live | s2cid = 3415547 | archive-url = https://web.archive.org/web/20210828042808/http://wrap.warwick.ac.uk/28852/1/WRAP_Rowlands_NewtechnologiesincontraceptionBJOG2008_Uni_repos_version.pdf | archive-date = 28 August 2021 }}</ref> and estradiol benzoate is marketed with progesterone as Mestrolar and Nomestrol.<ref name="Drugs.com1" />

Estradiol valerate is also widely available in combination with prasterone enantate (DHEA enantate) under the brand name Gynodian Depot.<ref name="Drugs.com1" />

===Slang names===

Estradiol has a number of humorous nicknames among the transgender community. Among them are titty skittles, tit-tacs, breast mints, femme&m's, antiboyotics, anticistamines, trans-mission fluid, and the Notorious H.R.T.<ref>{{Cite journal |title=Surgical Informed Consent and Recognizing a Perioperative Duty to Disclose in Transgender Health Care |last=Ashley |first=Florence |journal=McGill Journal of Law and Health |date=23 July 2020 |access-date=19 May 2023 |url=https://papers.ssrn.com/sol3/Delivery.cfm/SSRN_ID3633573_code2805951.pdf?abstractid=3633573&mirid=1 |page=75 |ssrn=3633573}}</ref>

===Availability=== Estradiol and/or its esters are widely available in countries throughout the world in a variety of formulations.<ref name="Drugs.com1" /><ref name="Martindale">{{cite book |editor=Sweetman, Sean C. |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |page=2097 |publisher=Pharmaceutical Press |location=London |isbn=978-0-85369-840-1 |chapter-url=https://www.medicinescomplete.com/mc/martindale/2009/ms-9083-y.htm |access-date=1 March 2018 |archive-date=10 June 2022 |archive-url=https://web.archive.org/web/20220610034758/https://about.medicinescomplete.com/ |url-status=live }}</ref><ref name="Micromedex">{{Cite web | url=http://www.micromedexsolutions.com | title=IBM Watson Health Products: Please Login | access-date=10 June 2022 | archive-date=18 August 2020 | archive-url=https://web.archive.org/web/20200818092536/https://www.micromedexsolutions.com/ | url-status=live }}</ref><ref name="IndexNominum2000" /><ref name="Drugs@FDA1" />{{failed verification|reason=broken FDA link|date=June 2020}}

Shortages of estradiol began around 2022, caused partly by the COVID-19 pandemic disrupting supply and due to increasing demand. In Britain, for example, prescriptions for all hormone replacement therapy drugs more than doubled between 2018 and 2022. The shortage remains as of March 2024.<ref>{{Cite news |last=Kollewe |first=Julia |date=24 September 2022 |title=HRT: inside the complex global supply chain behind a $20bn market |url=https://www.theguardian.com/business/2022/sep/24/hrt-inside-the-complex-global-supply-chain-behind-a-20bn-market |access-date=16 May 2024 |work=The Guardian }}</ref><ref>{{Cite news |last=Miles |first=Daniel |date=1 March 2024 |title=Women 'tearing their hair out' amid continuing global shortage of vital menopause medication |url=https://www.abc.net.au/news/2024-03-01/global-shortage-menopause-medication-hormone-treatment/103512288 |access-date=16 May 2024 |work=ABC News }}</ref><ref>{{Cite news |last=Swift |first=Molly |date=22 March 2024 |title=Women resorting to desperate measures amid menopause medication shortage |url=https://www.newshub.co.nz/home/new-zealand/2024/03/women-resorting-to-desperate-measures-as-new-zealand-s-menopause-medication-shortage-continues.html |archive-url=https://web.archive.org/web/20240322000401/https://www.newshub.co.nz/home/new-zealand/2024/03/women-resorting-to-desperate-measures-as-new-zealand-s-menopause-medication-shortage-continues.html |archive-date=22 March 2024 |access-date=16 May 2024 |work=Newshub }}</ref>

====United States==== {{See also|List of estrogens available in the United States}} thumb|right|225px|Vivelle-Dot, an estradiol patch

{{As of|2016|11}}, estradiol is available in the United States in the following forms:<ref name="Drugs@FDA1">{{cite web |title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 26 July 2018 | url = https://www.accessdata.fda.gov/scripts/cder/daf/| archive-url = https://web.archive.org/web/20161104020628/http://www.accessdata.fda.gov/scripts/cder/daf/| url-status = live| archive-date = 4 November 2016}}</ref>{{failed verification|reason=broken FDA link|date=June 2020}} * Oral tablets (Femtrace (as estradiol acetate), Gynodiol, Innofem, generics) * Transdermal patches (Alora, Climara, Esclim, Estraderm, FemPatch, Menostar, Minivelle, Vivelle, Vivelle-Dot, generics) * Topical gels (Divigel, Elestrin, EstroGel, Sandrena), emulsions (Estrasorb), and sprays (Evamist) * Vaginal tablets (Vagifem, generics), creams (Estrace), inserts (Imvexxy), and rings (Estring, Femring (as estradiol acetate)) * Oil solution for intramuscular injection (Delestrogen (as estradiol valerate), Depo-Estradiol (as estradiol cypionate))

Oral estradiol valerate (Progynova) and other esters of estradiol that are used by injection like estradiol benzoate, estradiol enantate, and estradiol undecylate all are not marketed in the US.<ref name="Drugs@FDA1" />{{failed verification|reason=broken FDA link|date=June 2020}} Polyestradiol phosphate (Estradurin) was marketed in the US previously but is no longer available.<ref>{{cite web |title=FDA-Approved Drugs, New Drug Application 010753 |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=010753 |website=Drugs@FDA |access-date=16 January 2021 |archive-date=21 March 2021 |archive-url=https://web.archive.org/web/20210321203437/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=010753 }}</ref>

Estradiol is also available in the US in combination with progestogens for the treatment of menopausal symptoms and as a combined hormonal contraceptive:<ref name="Drugs@FDA1" />{{failed verification|reason=broken FDA link|date=June 2020}} * Oral oil-filled capsules with progesterone (Bijuva)<ref name="AdisInsight-TX-001-HR">{{Cite web | url=http://adisinsight.springer.com/drugs/800038089 | title=Estradiol/Progesterone - TherapeuticsMD - AdisInsight | access-date=27 November 2016 | archive-date=22 October 2016 | archive-url=https://web.archive.org/web/20161022091555/http://adisinsight.springer.com/drugs/800038089 | url-status=live }}</ref><ref name="pmid25944519">{{cite journal | vauthors = Pickar JH, Bon C, Amadio JM, Mirkin S, Bernick B | title = Pharmacokinetics of the first combination 17β-estradiol/progesterone capsule in clinical development for menopausal hormone therapy | journal = Menopause | volume = 22 | issue = 12 | pages = 1308–1316 | date = December 2015 | pmid = 25944519 | pmc = 4666011 | doi = 10.1097/GME.0000000000000467 }}</ref> * Oral tablets with drospirenone (Angeliq) and norethisterone acetate (Activella, Amabelz) and as estradiol valerate with dienogest (Natazia) * Transdermal patches with levonorgestrel (Climara Pro) and norethisterone acetate (Combipatch)

Estradiol and estradiol esters are also available in custom preparations from compounding pharmacies in the US.<ref name="pmid26035149">{{cite journal | vauthors = Kaunitz AM, Kaunitz JD | title = Compounded bioidentical hormone therapy: time for a reality check? | journal = Menopause | volume = 22 | issue = 9 | pages = 919–920 | date = September 2015 | pmid = 26035149 | doi = 10.1097/GME.0000000000000484 }}</ref> This includes subcutaneous pellet implants, which are not available in the United States as FDA-approved pharmaceutical drugs.<ref name="pmid26418479">{{cite journal | vauthors = Pinkerton JV, Pickar JH | title = Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy | journal = Menopause | volume = 23 | issue = 2 | pages = 215–223 | date = February 2016 | pmid = 26418479 | pmc = 4927324 | doi = 10.1097/GME.0000000000000523 }}</ref> In addition, topical creams that contain estradiol are generally regulated as cosmetics rather than as drugs in the US and hence are also sold over-the-counter and may be purchased without a prescription on the Internet.<ref name="pmid17549577">{{cite journal | vauthors = Fugh-Berman A, Bythrow J | title = Bioidentical hormones for menopausal hormone therapy: variation on a theme | journal = Journal of General Internal Medicine | volume = 22 | issue = 7 | pages = 1030–1034 | date = July 2007 | pmid = 17549577 | pmc = 2219716 | doi = 10.1007/s11606-007-0141-4 }}</ref>

====Other countries==== Pharmaceutical estradiol subcutaneous pellet implants were formerly available in the United Kingdom and Australia under the brand name Estradiol Implants or Oestradiol Implants (Organon; 25, 50, or 100 mg), but have been discontinued.<ref name="IndexNominum2000" /><ref name="Melville2015">{{cite book| vauthors = Melville C |title=Sexual and Reproductive Health at a Glance|url=https://books.google.com/books?id=UiadCgAAQBAJ&pg=PA108|date=22 September 2015|publisher=Wiley|isbn=978-1-119-23516-3|pages=108–|access-date=17 February 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034739/https://books.google.com/books?id=UiadCgAAQBAJ&pg=PA108|url-status=live}}</ref><ref name="Dollery1991">{{cite book| vauthors = Dollery CT |title=Therapeutic Drugs|url=https://books.google.com/books?id=fjBtAAAAMAAJ|year=1991|publisher=Churchill Livingstone|isbn=978-0-443-02846-5|quote=Parenteral preparations 1. Oestradiol implants (Organon, UK) are sterilized pellets containing 25, 50 or 100 mg. They are supplied individually in glass tubes.|access-date=17 February 2019|archive-date=11 April 2022|archive-url=https://web.archive.org/web/20220411035527/https://books.google.com/books?id=fJbtAAAAMAAJ|url-status=live}}</ref><ref name="Kar2005">{{cite book| vauthors = Kar A |title=Medicinal Chemistry|url=https://books.google.com/books?id=07g30rxCA0EC&pg=PA614|year=2005|publisher=New Age International|isbn=978-81-224-1565-0|pages=614–|quote=Oestradiol Implants(R) (Organon, U.K.). Dose. [...] implantation, 20 to 100 mg.|access-date=17 February 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034745/https://books.google.com/books?id=07g30rxCA0EC&pg=PA614|url-status=live}}</ref><ref name="Walters1986">{{cite book| vauthors = Walters WA |title= Transsexualism and sex reassignment|url=https://books.google.com/books?id=ev5rAAAAMAAJ|date=10 July 1986|publisher=Oxford University Press|isbn=978-0-19-554462-6|page=159|quote=2. Injections or implants [...] Oestradiol Implants (Organon) 20 mg pellets. 50 mg pellets. 100 mg pellets.|access-date=17 February 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034740/https://books.google.com/books?id=ev5rAAAAMAAJ|url-status=live}}</ref> However, an estradiol subcutaneous implant with the brand name Meno-Implant (Organon; 20 mg) continues to be available in the Netherlands.<ref name="Drugs.com1" /><ref name="IndexNominum2000" /><ref name="Braam2006">{{cite book| vauthors = Braam WJ |title=Broze botten|url=https://books.google.com/books?id=NjNUbonqKMYC&pg=PA79|year=2006|publisher=Inmerc|isbn=978-90-6611-844-7|pages=79–|access-date=17 February 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034741/https://books.google.com/books?id=NjNUbonqKMYC&pg=PA79|url-status=live}}</ref><ref name="Gezondheids">https://www.gezondheidsnet.nl/medicijnen/meno-implantr{{Dead link|date=January 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> Previously, for instance in the 1970s and 1980s, other subcutaneous estradiol implant products such as Progynon Pellets (Schering; 25 mg) and Estropel Pellets (25 mg; Bartor Pharmacol) were marketed.<ref name="Eskin1988">{{cite book| vauthors = Eskin BA |title=The Menopause: Comprehensive Management|url=https://books.google.com/books?id=Q8ZsAAAAMAAJ|year=1988|publisher=Macmillan|isbn=978-0-02-334230-1|page=278|quote=Estradiol Pellets — (Progynon Pellets — Progynon Associates), 25 mg (Estropel Pellets — Bartor Pharmacal).|access-date=17 February 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034741/https://books.google.com/books?id=Q8ZsAAAAMAAJ|url-status=live}}</ref><ref name="AMA1977">{{cite book | chapter = Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents | pages = 540–572 | author1 = American Medical Association. Dept. of Drugs | author2 = Council on Drugs (American Medical Association) | author3 = American Society for Clinical Pharmacology and Therapeutics | title = AMA drug evaluations | url = https://books.google.com/books?id=0h7s_rfEZgkC | date = 1 February 1977 | publisher = Publishing Sciences Group | isbn = 978-0-88416-175-2 | quote = Subcutaneous implantation: (Estradiol) One 25 mg pellet every three to four months or two 25 mg pellets every four to six months. Preparations. Progynon (Schering). Implantation: Pellets 25 mg. | access-date = 17 February 2019 | archive-date = 1 August 2020 | archive-url = https://web.archive.org/web/20200801102046/https://books.google.com/books?id=0h7s_rfEZgkC | url-status = live }}</ref><ref name="Jones1979">{{cite book| vauthors = Jones JM |title=Physicians' Desk Reference|url=https://books.google.com/books?id=hKZKAQAAIAAJ|year=1979|publisher=Medical Economics Company|page=1508|isbn=978-0-8478-9982-1 |quote=PROGYNON Pellets for subcutaneous implantation are cylindrical in shape with an approximate diameter of 3.2 mm. and length of 3.5 mm. Each PROGYNON Pellet contains 25 mg. estradiol.|access-date=17 February 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034742/https://books.google.com/books?id=hKZKAQAAIAAJ|url-status=live}}</ref> It has been said that pharmaceutical estradiol implants have been almost exclusively used in the United Kingdom.<ref name="BirkhauserBarlow2005">{{cite book| vauthors = Birkhauser M, Barlow D, Notelovitz M, Rees M |title=Health Plan for the Adult Woman: Management Handbook|url=https://books.google.com/books?id=5ZuuGI556GEC&pg=PA27|date=12 August 2005|publisher=CRC Press|isbn=978-0-203-49009-9|pages=27–|access-date=17 February 2019|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610034742/https://books.google.com/books?id=5ZuuGI556GEC&pg=PA27|url-status=live}}</ref> Subcutaneous estradiol implants are also available as custom compounded products in some countries.<ref name="pmid25387347">{{cite journal | vauthors = Pinkerton JV | title = What are the concerns about custom-compounded "bioidentical" hormone therapy? | journal = Menopause | volume = 21 | issue = 12 | pages = 1298–1300 | date = December 2014 | pmid = 25387347 | doi = 10.1097/GME.0000000000000376 }}</ref><ref name="pmid26418479"/><ref name="pmid27032319">{{cite journal | vauthors = Santoro N, Braunstein GD, Butts CL, Martin KA, McDermott M, Pinkerton JV | title = Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 101 | issue = 4 | pages = 1318–1343 | date = April 2016 | pmid = 27032319 | doi = 10.1210/jc.2016-1271 | s2cid = 33802990 | doi-access = free }}</ref>

===Economics=== Generic oral estradiol tablets are much less expensive than other forms of estradiol such as transdermal gel and patches and vaginal rings.<ref name="JAMA2019">{{cite journal | vauthors = | title = Estradiol/Progesterone (Bijuva) for Menopausal Vasomotor Symptoms | journal = JAMA | volume = 322 | issue = 12 | pages = 1206–1207 | date = September 2019 | pmid = 31550026 | doi = 10.1001/jama.2019.10692 | s2cid = 202748463 }}</ref>

==Research== A variety of estradiol-containing combined birth control pills were studied but never marketed.<ref name="pmid20004267"/> In addition, a variety of estradiol-containing combined injectable contraceptives were studied but never marketed.<ref name="pmid12290848"/><ref name="pmid8013219">{{cite journal | vauthors = Garza-Flores J | title = Pharmacokinetics of once-a-month injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 347–359 | date = April 1994 | pmid = 8013219 | doi = 10.1016/0010-7824(94)90032-9 }}</ref><ref name="pmid8013221">{{cite journal | vauthors = Koetsawang S | title = Once-a-month injectable contraceptives: efficacy and reasons for discontinuation | journal = Contraception | volume = 49 | issue = 4 | pages = 387–398 | date = April 1994 | pmid = 8013221 | doi = 10.1016/0010-7824(94)90034-5 }}</ref><ref name="pmid8013216">{{cite journal | vauthors = Toppozada MK | title = Existing once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 293–301 | date = April 1994 | pmid = 8013216 | doi = 10.1016/0010-7824(94)90029-9 }}</ref><ref name="Toppozada1983">{{cite book | vauthors = Toppozada MK | chapter = Monthly Injectable Contraceptives | pages = 93–103 | editor1 = Alfredo Goldsmith | editor2 = Mokhtar Toppozada | title = Long-Acting Contraception | year = 1983 | oclc = 35018604 | url = https://scholar.google.com/scholar?cluster=14664537528797672080 | access-date = 27 December 2019 | archive-date = 10 June 2022 | archive-url = https://web.archive.org/web/20220610034743/https://scholar.google.com/scholar?cluster=14664537528797672080 | url-status = live }}</ref>

Estradiol has been studied in the treatment of postpartum depression and postpartum psychosis.<ref name="pmid16344831">{{cite journal | vauthors = Gentile S | title = The role of estrogen therapy in postpartum psychiatric disorders: an update | journal = CNS Spectrums | volume = 10 | issue = 12 | pages = 944–952 | date = December 2005 | pmid = 16344831 | doi = 10.1017/S1092852900010518 | s2cid = 24450591 }}</ref><ref name="pmid20795848">{{cite journal | vauthors = Ng RC, Hirata CK, Yeung W, Haller E, Finley PR | title = Pharmacologic treatment for postpartum depression: a systematic review | journal = Pharmacotherapy | volume = 30 | issue = 9 | pages = 928–941 | date = September 2010 | pmid = 20795848 | doi = 10.1592/phco.30.9.928 | s2cid = 23053672 }}</ref><ref name="pmid19874247">{{cite journal | vauthors = di Scalea TL, Wisner KL | title = Pharmacotherapy of postpartum depression | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 16 | pages = 2593–2607 | date = November 2009 | pmid = 19874247 | pmc = 2929691 | doi = 10.1517/14656560903277202 }}</ref><ref name="pmid19661765">{{cite journal | vauthors = Moses-Kolko EL, Berga SL, Kalro B, Sit DK, Wisner KL | title = Transdermal estradiol for postpartum depression: a promising treatment option | journal = Clinical Obstetrics and Gynecology | volume = 52 | issue = 3 | pages = 516–529 | date = September 2009 | pmid = 19661765 | pmc = 2782667 | doi = 10.1097/GRF.0b013e3181b5a395 }}</ref><ref name="pmid14521476">{{cite journal | vauthors = Sharma V | title = Pharmacotherapy of postpartum psychosis | journal = Expert Opinion on Pharmacotherapy | volume = 4 | issue = 10 | pages = 1651–1658 | date = October 2003 | pmid = 14521476 | doi = 10.1517/14656566.4.10.1651 | s2cid = 23193276 }}</ref>

Estrogens such as estradiol appear to improve sexual desire and function in women.<ref name="pmid26589379">{{cite journal | vauthors = Cappelletti M, Wallen K | title = Increasing women's sexual desire: The comparative effectiveness of estrogens and androgens | journal = Hormones and Behavior | volume = 78 | pages = 178–193 | date = February 2016 | pmid = 26589379 | pmc = 4720522 | doi = 10.1016/j.yhbeh.2015.11.003 }}</ref><ref name="pmid26944462">{{cite journal | vauthors = Santoro N, Worsley R, Miller KK, Parish SJ, Davis SR | title = Role of Estrogens and Estrogen-Like Compounds in Female Sexual Function and Dysfunction | journal = The Journal of Sexual Medicine | volume = 13 | issue = 3 | pages = 305–316 | date = March 2016 | pmid = 26944462 | doi = 10.1016/j.jsxm.2015.11.015 }}</ref> However, the available evidence overall does not support the use of estradiol and other estrogens for improving sexual desire and function in women as of 2016.<ref name="pmid26944462" /> An exception is the use of estrogens to treat vaginal atrophy.<ref name="pmid26944462" />

Estrogen therapy has been proposed as a potential treatment for autism but clinical studies are needed.<ref name="pmid27789681">{{cite journal | vauthors = Crider A, Pillai A | title = Estrogen Signaling as a Therapeutic Target in Neurodevelopmental Disorders | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 360 | issue = 1 | pages = 48–58 | date = January 2017 | pmid = 27789681 | pmc = 5193073 | doi = 10.1124/jpet.116.237412 }}</ref>

== References == {{Reflist}}

== Further reading == {{refbegin}} * {{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 }} * {{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens|url=https://books.google.com/books?id=0BfrCAAAQBAJ|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-58616-3}} * {{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1}} * {{cite journal | vauthors = Fruzzetti F, Trémollieres F, Bitzer J | title = An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest | journal = Gynecological Endocrinology | volume = 28 | issue = 5 | pages = 400–408 | date = May 2012 | pmid = 22468839 | pmc = 3399636 | doi = 10.3109/09513590.2012.662547 }} * {{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–727 | date = June 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 }} {{refend}}

== External links == * {{cite web | title=Estradiol Topical: MedlinePlus Drug Information | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a605041.html }} * {{cite web | title=Estradiol Transdermal Patch: MedlinePlus Drug Information | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a605042.html }}

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