Просмотр кода страницы Английская Википедия:Ethinylestradiol

{{Английская Википедия/Панель перехода}}
{{Short description|Estrogen medication}}
{{Use dmy dates|date=December 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| Verifiedfields = verified
| Watchedfields = verified
| verifiedrevid = 458286647
| image = Ethinylestradiol.svg
| width = 235
| alt = 
| image2 = Ethinylestradiol molecule ball.png
| width2 = 235
| alt2 = 

<!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|ɛ|θ|ᵻ|n|ᵻ|l|ˌ|ɛ|s|t|r|ə|ˈ|d|aɪ|.|əl}}
| tradename = Many
| Drugs.com = {{drugs.com|international|ethinylestradiol}}
| MedlinePlus = a604032
| pregnancy_category = 
| routes_of_administration = • [[Oral administration|By mouth]], [[Transdermal]], [[Vaginal administration|Vaginal]]
| class = [[Estrogen (medication)|Estrogen]]
| ATC_prefix = G03
| ATC_suffix = CA01
| ATC_supplemental = {{ATC|L02|AA03}}

| legal_status = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability = 38–48%<ref name="pmid2256522"/><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><ref name="pmid8842581">{{cite journal | vauthors = Fotherby K | title = Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy | journal = Contraception | volume = 54 | issue = 2 | pages = 59–69 | date = August 1996 | pmid = 8842581 | doi = 10.1016/0010-7824(96)00136-9 }}</ref>
| protein_bound = 97–98% (to [[human serum albumin|albumin]];<ref name="(Firm)Inc2005">{{cite book|author1=Facts and Comparisons (Firm)|author2=Ovid Technologies, Inc|title=Drug Facts and Comparisons 2005: Pocket Version|url=https://books.google.com/books?id=zumzLgzj1CsC&q=ethinyl+estradiol+albumin|year=2005|publisher=Facts and Comparisons|isbn=978-1-57439-179-4|page=121}}</ref> is not bound to {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="Micromedex2003">{{cite book|author=Micromedex|title=USP DI 2003: Drug Information for Healthcare Professionals|url=https://books.google.com/books?id=zEzWtsVl-KgC|date=1 January 2003|publisher=Thomson Micromedex|isbn=978-1-56363-429-1|pages=1253, 1258, 1266}}</ref>
| metabolism = [[Liver]] (primarily [[CYP3A4]])<ref name="HughesWaters2016">{{cite book| vauthors = Hughes CL, Waters MD |title=Translational Toxicology: Defining a New Therapeutic Discipline|url=https://books.google.com/books?id=5qPWCwAAQBAJ&pg=PA73|date=23 March 2016|publisher=Humana Press|isbn=978-3-319-27449-2|pages=73–}}</ref>
| metabolites = • [[Ethinylestradiol sulfate]]<ref name="pmid16112947" /><ref name="OettelSchillinger2012" /><br />• Others<ref name="pmid16112947" /><ref name="OettelSchillinger2012" />
| elimination_half-life = 7–36 hours<ref name="HughesWaters2016" /><ref name="pmid2256522">{{cite journal | vauthors = Goldzieher JW, Brody SA | title = Pharmacokinetics of ethinyl estradiol and mestranol | journal = American Journal of Obstetrics and Gynecology | volume = 163 | issue = 6 Pt 2 | pages = 2114–2119 | date = December 1990 | pmid = 2256522 | doi = 10.1016/0002-9378(90)90550-Q }}</ref><ref name="pmid23375353" /><ref name="Shellenberger1986" />
| excretion = [[Feces]]: 62%<ref name="pmid23375353" /><br />[[Urine]]: 38%<ref name="pmid23375353" />

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 57-63-6
| PubChem = 5991
| IUPHAR_ligand = 7071
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00977
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5770
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 423D2T571U
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00554
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 4903
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 691
| synonyms = Ethynylestradiol; Ethinyl estradiol; Ethinyl oestradiol; EE; EE2; 17α-Ethynylestradiol; 17α-Ethynylestra-1,3,5(10)-triene-3,17β-diol; NSC-10973<ref name="Elks2014" />

<!-- Chemical data -->
| IUPAC_name = (8''R'',9''S'',13''S'',14''S'',17''R'')-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6''H''-cyclopenta[''a'']phenanthrene-3,17-diol
| C=20 | H=24 | O=2
| SMILES = Oc1cc4c(cc1)[C@H]3CC[C@]2([C@@H](CC[C@]2(C#C)O)[C@@H]3CC4)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H24O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,5,7,12,16-18,21-22H,4,6,8-11H2,2H3/t16-,17-,18+,19+,20+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BFPYWIDHMRZLRN-SLHNCBLASA-N
| melting_point = 182
| melting_high = 184
}}
<!-- Definition and medical uses -->
'''Ethinylestradiol''' ('''EE''') is an [[estrogen (medication)|estrogen]] medication which is used widely in [[birth control pills]] in combination with [[progestin]]s.<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 | s2cid = 24616324 }}</ref><ref name="OettelSchillinger2012">{{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=PA369|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=4,10,15,165,247–248,276–291,363–408,424,514,540,543,581|quote=The binding affinity of EE2 for the estrogen receptor is similar to that of estradiol. [...] During daily intake, the EE2 levels increase up to a steady state which is reached after about 1 week.}}</ref> In the past, EE was widely used for various indications such as the treatment of [[menopause|menopausal]] [[symptom]]s, [[gynecological disorder]]s, and certain [[hormone-sensitive cancer]]s. It is usually taken [[oral administration|by mouth]] but is also used as a [[transdermal patch|patch]] and [[vaginal ring]].<ref name="pmid16112947" /><ref name="Drugs@FDA" />

<!-- Side effects -->
The general [[side effect]]s of EE include [[breast tenderness]] and [[breast enlargement|enlargement]], [[headache]], [[water retention (medicine)|fluid retention]], and [[nausea]] among others.<ref name="pmid16112947" /> In men, EE can additionally cause [[gynecomastia|breast development]], [[feminization (biology)|feminization]] in general, [[hypogonadism]], and [[sexual dysfunction]]. Rare but serious side effects include [[blood clot]]s, [[liver damage]], and [[endometrial cancer|cancer of the uterus]].<ref name="pmid16112947" />

<!-- Mechanism of action -->
EE is an [[estrogen (medication)|estrogen]], or an [[agonist]] of the [[estrogen receptor]]s, the [[biological target]] of estrogens like [[estradiol]].<ref name="pmid16112947" /> It is a [[synthetic compound|synthetic]] [[chemical derivative|derivative]] of [[estradiol (medication)|estradiol]], a [[natural product|natural]] estrogen, and differs from it in various ways.<ref name="pmid16112947" /> Compared to estradiol, EE is more resistant to [[metabolism]], has greatly improved [[bioavailability]] when taken by mouth, and shows relatively increased effects in certain parts of the body like the [[liver]] and [[uterus]].<ref name="pmid16112947" /> These differences make EE more favorable for use in birth control pills than estradiol, though also result in an increased risk of blood clots and certain other rare adverse effects.<ref name="pmid16112947" />

<!-- History, society, and culture -->
EE was developed in the 1930s and was introduced for medical use in 1943.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=978-3-527-60749-5|page=482|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA482|language=en}}</ref><ref name="Estinyl 1943" /> The medication started being used in birth control pills in the 1960s.<ref name="GruhnKazer2013" /> Ethinylestradiol is found in almost all [[combined oral contraceptive pill|combined]] forms of birth control pills and is nearly the exclusive estrogen used for this purpose, making it one of the most widely used estrogens.<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><ref name="ShoupeHaseltine2012">{{cite book| vauthors = Shoupe D, Haseltine FP |title=Contraception|url=https://books.google.com/books?id=cpDhBwAAQBAJ&pg=PA112|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-2730-4|pages=112–}}</ref>

In 2021, the combination with [[norethisterone]] was the 52nd most commonly prescribed medication in the United States, with more than 12{{nbsp}}million prescriptions;<ref name="Top 300 of 2021">{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Ethinyl Estradiol; Norethindrone - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EthinylEstradiolNorethindrone | access-date = 14 January 2024}}</ref> the version with [[norgestimate]] was the 76th most commonly prescribed medication in the US, with more than 8{{nbsp}}million prescriptions;<ref name="Top 300 of 2021" /><ref>{{cite web | title=Ethinyl Estradiol; Norgestimate - Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/EthinylEstradiolNorgestimate | access-date=14 January 2024}}</ref> the combination with [[levonorgestrel]] was the 144th most commonly prescribed medication in the US, with more than 4{{nbsp}}million prescriptions;<ref name="Top 300 of 2021" /><ref>{{cite web | title = Ethinyl Estradiol; Levonorgestrel - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EthinylEstradiolLevonorgestrel | access-date = 14 January 2024}}</ref> the combination with [[etonogestrel]] was the 198th most commonly prescribed medication in the US, with more than 2{{nbsp}}million prescriptions;<ref name="Top 300 of 2021" /><ref>{{cite web | title = Ethinyl Estradiol ; Etonogestrel - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EthinylEstradiolEtonogestrel | access-date = January 14, 2024}}</ref> the combination with [[norgestrel]] was the 227th most commonly prescribed medication in the US, with more than 2{{nbsp}}million prescriptions;<ref name="Top 300 of 2021" /><ref>{{cite web | title = Ethinyl Estradiol ; Norgestrel - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EthinylEstradiolNorgestrel | access-date = January 14, 2024}}</ref> the combination with [[Etynodiol diacetate|etynodiol]] was the 276th most commonly prescribed medication in the US, with more than 800,000 prescriptions;<ref name="Top 300 of 2021" /><ref>{{cite web | title = Ethinyl Estradiol; Ethynodiol - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EthinylEstradiolEthynodiol | access-date = 14 January 2024 | archive-date = 18 January 2024 | archive-url = https://web.archive.org/web/20240118044937/https://clincalc.com/DrugStats/Drugs/EthinylEstradiolEthynodiol | url-status = live }}</ref> the combination with [[drospirenone]] and [[levomefolic acid]] was the 277th most commonly prescribed medication in the US, with more than 800,000 prescriptions;<ref name="Top 300 of 2021" /><ref>{{cite web | title = Drospirenone; EthinylEstradiol; Levomefolate - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/DrospirenoneEthinylEstradiolLevomefolate | access-date = 14 January 2024}}</ref>
{{TOC limit|3}}

==Medical uses==
There are many uses for EE. It is most commonly used as [[contraception]] in [[combined oral contraceptives]] (COC), also known as [[birth control]], to prevent pregnancy after sex. EE in its birth control formulation is not only used to prevent pregnancy, but can also be used to treat absence of menstruation, symptoms during menstruation, and [[acne]].

EE is also used as [[menopausal hormone therapy]].<ref name="pmid16860174">{{cite journal | vauthors = Rowan JP, Simon JA, Speroff L, Ellman H | title = Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5 mg/2.5 microg) in women with postmenopausal symptoms: updated analysis of three randomized, controlled trials | journal = Clinical Therapeutics | volume = 28 | issue = 6 | pages = 921–932 | date = June 2006 | pmid = 16860174 | doi = 10.1016/j.clinthera.2006.06.013 }}</ref> The main reason for using HRT in menopausal women is to relieve common [[vasomotor symptoms]] such as [[hot flashes]], [[night sweats]], and [[flushing (physiology)|flushing]]. Studies have found that estrogen replacement helps improve these symptoms when compared to a placebo.<ref>{{Cite journal| vauthors = Hamoda H, Panay N, Arya R, Savvas M |date= December 2016|title=The British Menopause Society & Women's Health Concern 2016 recommendations on hormone replacement therapy in menopausal women|journal=Post Reproductive Health|volume=22|issue=4|pages=165–183|doi=10.1177/2053369116680501|doi-access=free|hdl=1983/d96e4479-2ccc-44c3-963c-d3918b1e325b|hdl-access=free}}</ref> Other common menopause symptoms, such as vaginal dryness (which can cause pain during sexual intercourse), vaginal itching, and depressed mood, can benefit from HRT. In addition to treatment of menopausal symptoms, EE has been used as a component of [[feminizing hormone therapy]] for [[transgender women]].<ref name="pmid28078219">{{cite journal | vauthors = Unger CA | title = Hormone therapy for transgender patients | journal = Translational Andrology and Urology | volume = 5 | issue = 6 | pages = 877–884 | date = December 2016 | pmid = 28078219 | pmc = 5182227 | doi = 10.21037/tau.2016.09.04 | doi-access = free }}</ref> However, it is no longer commonly used nor recommended for this purpose, with [[estradiol (medication)|estradiol]] having largely superseded it.<ref name="pmid28078219" />

EE can also be used to treat [[hypogonadism]] in women, prevent osteoporosis in women, and has been used as [[palliative care]] for [[prostate cancer]] in men and [[breast cancer]] in women.<ref name="OettelSchillinger2012" /><ref name="pmid27889048a">{{cite journal | vauthors = Coelingh Bennink HJ, Verhoeven C, Dutman AE, Thijssen J | title = The use of high-dose estrogens for the treatment of breast cancer | journal = Maturitas | volume = 95 | pages = 11–23 | date = January 2017 | pmid = 27889048 | doi = 10.1016/j.maturitas.2016.10.010 | doi-access = free }}</ref> It has also been used to reduce [[sex drive]] in [[sex offender]]s.<ref name="pmid20459370">{{cite journal | vauthors = Thibaut F, De La Barra F, Gordon H, Cosyns P, Bradford JM | title = The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias | journal = The World Journal of Biological Psychiatry | volume = 11 | issue = 4 | pages = 604–655 | date = June 2010 | pmid = 20459370 | doi = 10.3109/15622971003671628 | s2cid = 14949511 }}</ref><ref name="pmid4607733">{{cite journal | vauthors = Bancroft J, Tennent G, Loucas K, Cass J | title = The control of deviant sexual behaviour by drugs. I. Behavioural changes following oestrogens and anti-androgens | journal = The British Journal of Psychiatry | volume = 125 | pages = 310–315 | date = September 1974 | issue = 586 | pmid = 4607733 | doi = 10.1192/bjp.125.3.310 | s2cid = 10971754 }}</ref>

EE or any estrogen alone is contraindicated for women who have a uterus due to the increased risk of [[endometrial cancer]]; giving a [[progestogen (medication)|progestogen]] with an estrogen mitigates the risk.<ref name="ACS2015">{{cite web |title=Menopausal Hormone Therapy and Cancer Risk |url=https://www.cancer.org/cancer/cancer-causes/medical-treatments/menopausal-hormone-replacement-therapy-and-cancer-risk.html |publisher=American Cancer Society |date=13 February 2015}}</ref>

===Available forms===
EE is available in combination with a progestin in a vast number of COCs.<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=PA433|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=157, 433–}}</ref> It is also available in combination with progestins as a [[transdermal administration|transdermal]] [[contraceptive patch]] and as a [[contraceptive vaginal ring]].<ref name="Drugs@FDA" /> In addition, there is a single preparation (brand name FemHRT) containing very low doses of EE (2.5 and 5&nbsp;µg) plus a progestin in an oral [[tablet (pharmacy)|tablet]] that remains in use for menopausal hormone therapy.<ref name="Drugs@FDA" /><ref name="pmid16860174" /> EE was previously available by itself under brand names like Estinyl and Lynoral in the form of 0.002, 0.01, 0.02, 0.025, 0.05, 0.1, 0.5, and 1.0&nbsp;mg (2, 10, 20, 25, 50, 100, 500, and 1000&nbsp;µg) tablets.<ref name="Becker2001" /><ref name="DIANE1995">{{cite book | author = DIANE Publishing Company | date = 1995 | title = Approved Drug Products with Therapeutic Evaluations | publisher = DIANE Publishing | isbn = 978-0-7881-0405-3 | url = https://books.google.com/books?id=uo0QFvym_90C&pg=RA4-PA4 | page = 3-122 | quote = ETHINYL ESTRADIOL: TABLET; ORAL: ESTINYL: SCHERING: 0.02MG; 0.05MG; 0.5MG}}</ref><ref name="U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Bureau of Drugs1980">{{cite book | date = 1980 | title = Approved Prescription Drug Products with Therapeutic Equivalence Evaluations | publisher = U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Bureau of Drugs | pages = | oclc = 7074861 | url = https://books.google.com/books?id=XOP58uLdW_MC | quote = }}</ref><ref name="Muller1998">{{cite book | author = Muller | date = 19 June 1998 | title = European Drug Index: European Drug Registrations, Fourth Edition | edition = 4 | publisher = CRC Press | pages = 457– | isbn = 978-3-7692-2114-5 | url = https://books.google.com/books?id=2HBPHmclMWIC&pg=PA457 | quote = Ethinyl oestradiol 0,05mg cpr 0,05 mg ethinylestradiol (G03CA01) (FR) Ethinylestradiol tablets 50 mcg Ethinylestradiol (G03CA01) (RUS) Ethinylestradiol 25μg (Jenapharm) Dragees: Ethinylestradiol 25μg (G03CA01) (DE) Ethinylestradiol pch 0,002mg cpr 0,002 mg ethinylestradiol (FR) Ethinylestradiolum tablet 0,05mg ethinylestradiol 0,05 mg (G03CA01) (NL) [...] Etifollin tab 0,5mg (Nycomed pharma a/s) ethinylestradiol (L02AA03) (NO) Etifollin tab 50mcg (Nycomed pharma a/s) ethinylestradiol (G03CA01) (NO)}}</ref><ref name="MonfardiniBrunnerCrowther2012">{{cite book | editor1 = S. Monfardini | editor2 = K. Brunner | editor3 = D. Crowther | editor4 = S. Eckhardt | editor5 = D. Olive | editor6 = S. Tanneberger | editor7 = A. Veronesi | editor8 = J.M.A. Whitehouse | editor9 = R. Wittes | date = 6 December 2012 | title = Manual of Adult and Paediatric Medical Oncology | publisher = Springer Science & Business Media | pages = 78– | isbn = 978-3-642-82489-0 | oclc = 1058058829 | url = https://books.google.com/books?id=CeXnCAAAQBAJ&pg=PA78 | quote = Ethinyloestradiol (Lynoral, 0.05-mg, 0.1-mg, 1-mg tablets)}}</ref>

The amount of EE in COCs has reduced over the years.<ref name="OettelSchillinger2012" /> Previously, COCs contained high doses of EE of as much as 100&nbsp;µg/day.<ref name="LipHall2007">{{cite book| vauthors = Lip GY, Hall JE |title=Comprehensive Hypertension E-Book|url=https://books.google.com/books?id=XQajBQAAQBAJ&pg=PA865|date=28 June 2007|publisher=Elsevier Health Sciences|isbn=978-0-323-07067-6|pages=865–}}</ref> Doses of more than 50&nbsp;µg EE are considered high-dose, doses of 30 and 35&nbsp;µg EE are considered low-dose, and doses of 10 to 25&nbsp;µg EE are considered very low dose.<ref name="AlldredgeCorelli2012">{{cite book| vauthors = Alldredge BK, Corelli RL, Ernst ME |title=Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs|url=https://books.google.com/books?id=qcVpuHngXK0C&pg=PA1072|date=1 February 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-713-7|pages=1072–}}</ref> Today, COCs generally contain 10 to 50&nbsp;µg EE.<ref name="AlldredgeCorelli2012" /> The higher doses of EE were discontinued due to a high risk of VTE and cardiovascular problems.<ref name="LipHall2007" />

==Contraindications==
EE should be avoided in individuals with a history of or known susceptibility to [[arterial thrombosis|arterial]] or [[venous thrombosis]] ([[blood clots]]), due to an increased risk of [[cardiovascular]] problems such as [[venous thromboembolism]] (VTE), [[myocardial infarction]], and [[ischemic stroke]].<ref>{{cite magazine | url=https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6504.pdf | title=U.S. Selected Practice Recommendations for Contraceptive Use, 2016 | publisher=Centers for Disease Control and Prevention |magazine=Recommendations and Reports | date=29 July 2016 |volume=65 | issue= 4}}</ref> This includes women with:
* History of [[deep vein thrombosis]] (DVT) or [[pulmonary embolism]] (PE) not receiving [[anticoagulants]]
* Acute DVT/PE
* Prolonged immobilization due to major surgery
* Advanced [[diabetes mellitus]] with vascular disease
* [[Migraine with aura]]
* [[Hypertension]] ≥160/100
* [[Vascular disease]]
* Current and history of [[ischemic heart disease]]
* Multiple risk factors for [[atherosclerotic cardiovascular disease]] (e.g. older age, smoking, diabetes, hypertension, low HDL, high LDL, or high triglyceride levels)
* Age ≥35 and smoking ≥15 cigarettes/day
* History of [[cerebrovascular accident]]
* Systemic [[lupus erythematosus]] with positive (or unknown) antiphospholipid antibodies
* Complicated [[valvular heart disease]]

Except when being used to treat it, EE should be avoided in women with current [[breast cancer]] due to a possible worsening of prognosis.<ref name="CDC2016">{{cite magazine | url=https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6504.pdf | title=U.S. Selected Practice Recommendations for Contraceptive Use, 2016 | publisher=Centers for Disease Control and Prevention |magazine=Recommendations and Reports | date=29 July 2016 |volume=65 | issue= 4}}</ref>

EE should also be avoided in [[breastfeeding]] women who are less than 21 days [[postpartum]] due to an increased risk of VTE.<ref name="cdc.gov">{{cite magazine | url=https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf | title=U.S. Medical Eligibility Criteria for Contraceptive Use, 2016 | date=29 July 2016| publisher=Centers for Disease Control and Prevention |magazine=Recommendations and Reports |volume=65 | issue=3}}</ref> EE use in breastfeeding women who are at least 21 days postpartum should be discussed with a provider and include information on the advantages, disadvantages, and alternatives for using EE.<ref name="cdc.gov">{{cite magazine | url=https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf | title=U.S. Medical Eligibility Criteria for Contraceptive Use, 2016 | date=29 July 2016| publisher=Centers for Disease Control and Prevention |magazine=Recommendations and Reports |volume=65 | issue=3}}</ref>

Due to risk of [[cholestatic hepatotoxicity]], it is widely considered that COCs containing EE should be avoided in women with a history of [[cholestasis of pregnancy]], [[hepatic tumor]]s, active [[hepatitis]], and familial defects in biliary excretion.<ref name="Aronson2009" />

==Side effects==
{| class="wikitable floatright" style="margin: 1em auto;"
|+ class="nowrap" | Dose of ethinylestradiol in [[birth control pill]]s and risk of [[venous thromboembolism]] (VTE)
|-
! Ethinylestradiol dose !! No. of VTE cases !! Woman-years !! VTE rate !! Adjusted {{Abbr|RR|relative risk}}<sup>a</sup>
|-
| Low (<50&nbsp;μg) || 53 || 127,000 || 4.2 in 10,000 woman-years || 1.0
|-
| Intermediate (50&nbsp;μg) || 69 || 98,000 || 7.0 in 10,000 woman-years || 1.5
|-
| High (>50&nbsp;μg) || 20 || 20,000 || 10.0 in 10,000 woman-years || 1.7
|-
| All || 142 || 245,000 || 5.8 in 10,000 woman-years || –
|- class="sortbottom"
| colspan="5" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Footnotes:''' <sup>a</sup> = Relative to low-dose (not to non-use). '''Notes:''' In birth control pills containing a [[first-generation progestin]], such as [[norethisterone]] or [[levonorgestrel]]. '''Sources:''' ''Main'':<ref name="pmid1983896">{{cite journal | vauthors = Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE | title = Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease | journal = American Journal of Epidemiology | volume = 133 | issue = 1 | pages = 32–37 | date = January 1991 | pmid = 1983896 | doi = 10.1093/oxfordjournals.aje.a115799 }}</ref><ref name="RunnebaumRabe2013">{{cite book| veditors = Runnebaum B, Rabe T |chapter=Kontrazeption|title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie|chapter-url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA411|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=411–512}}</ref> ''Additional'':<ref name="pmid1983923">{{cite journal | vauthors = Gerstman BB, Gross TP, Kennedy DL, Bennett RC, Tomita DK, Stadel BV | title = Trends in the content and use of oral contraceptives in the United States, 1964-88 | journal = American Journal of Public Health | volume = 81 | issue = 1 | pages = 90–96 | date = January 1991 | pmid = 1983923 | pmc = 1404924 | doi = 10.2105/ajph.81.1.90 }}</ref>
|}
The severity of side effects can vary based on the dose and administration route of EE.<ref>{{cite journal | vauthors = Gallo MF, Nanda K, Grimes DA, Lopez LM, Schulz KF | title = 20 µg versus >20 µg estrogen combined oral contraceptives for contraception | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 8 | pages = CD003989 | date = August 2013 | pmid = 23904209 | pmc = 7173696 | doi = 10.1002/14651858.CD003989.pub5 }}</ref> General side effects of EE are the same as for other estrogens and include [[breast tenderness]], [[headache]], [[water retention (medicine)|fluid retention]] ([[bloating]]), [[nausea]], [[dizziness]], and [[weight gain]].<ref name="pmid23375353" /><ref name="Aronson2009" /> The estrogen component of oral contraceptives, which is almost always EE, can cause [[breast tenderness]] and [[breast enlargement|fullness]].<ref name="Becker2001" /> In males, EE has additional side effects, including [[gynecomastia]] (breast development), [[feminization (biology)|feminization]] in general, [[hypogonadism]], [[infertility]], and [[sexual dysfunction]] (e.g., reduced [[libido]] and [[erectile dysfunction]]). In men who received [[high-dose estrogen]] therapy with 200&nbsp;μg/day oral EE for more than three months, gynecomastia occurred in 98% and decreased libido occurred in 42 to 73%.<ref name="Pincus2013">{{cite book| vauthors = Pincus G |title=Hormones and Atherosclerosis: Proceedings of the Conference Held in Brighton, Utah, March 11-14, 1958|url=https://books.google.com/books?id=NiXgBAAAQBAJ&pg=PA411|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4832-7064-7|pages=411–}}</ref>

===Long-term effects===
{| class="wikitable sortable floatright" style="text-align:left; border:none;"
|+ class="nowrap" | Beneficial and adverse effects of {{No selflink|ethinylestradiol}}-containing birth control pills
|-
! colspan="2" | [[Therapeutic effect|Beneficial effect]]s !! colspan="2" | [[Adverse effect]]s
|-
! [[Disease]] || {{abbrlink|RR|Relative risk}} || [[Disease]] || {{abbrlink|RR|Relative risk}}
|-
| [[Iron-deficiency anemia]] || 0.58 || [[Cardiovascular disease]]s (total) || 1.5
|-
| [[Menorrhagia]] || 0.52 || [[Myocardial infarction]] (heart attack) (total) || 3.3
|-
| [[Irregular menstruation]] || 0.65 || [[Myocardial infarction]] (non-[[smoking|smoker]]s) || 1.0
|-
| [[Breakthrough bleeding|Intermenstrual bleeding]] || 0.72 || [[Myocardial infarction]] (light [[smoking|smoker]]s) || 3.5
|-
| [[Dysmenorrhea]] || 0.37 || [[Myocardial infarction]] (heavy [[smoking|smoker]]s) || 20
|-
| [[Pelvic inflammatory disease]] (incidence) || 0.50 || [[Cerebrovascular disease]]s (total) || 1.4
|-
| [[Pelvic inflammatory disease]] ([[hospitalization]]) || 0.22 || [[Cerebral thrombosis|Cerebral thromboses]] (strokes) || 2.5
|-
| [[Trichomonas vaginitis]] || 0.56 || [[Subarachnoidal bleeding]] (heavy [[smoking|smoker]]s) || 10
|-
| [[Benign breast disease]] || 0.69 || [[Pulmonary embolism]] || 3.0
|-
| [[Fibrocystic breast disease]] || 0.66 || [[Deep vein thrombosis|Deep vein thromboses]] || 2.5
|-
| [[Benign breast fibroadenomas]] || 0.35 || [[Gall bladder disease|Gall-bladder diseases]] || 3.0
|-
| [[Rheumatoid arthritis]] || 0.49 || [[Benign liver tumor]]s || 50
|-
| [[Endometrial cancer]] || 0.40–0.50 || [[Hepatocellular carcinoma]] || 3.0
|-
| [[Ovarian cancer]] (incidence) || 0.37–0.64 || [[Erythema nodosum et multiforme]] || 3.0
|-
| [[Ovarian cancer]] (death) || 0.20 || [[Pruritus]] (itching) || 2.0
|-
| [[Follicular cyst of ovary|Benign follicular cyst]]s (high-dose COCs) || 0.24 || [[Photosensitive eczema]] || 4.0
|-
| [[Acne vulgaris]] || 0.44 || [[Irritant agent eczema]] || 2.0
|-
| [[Low bone mineral density]] (later in life) || 0.35<sup>a</sup> || [[Dermatitis]] (eczema) || 2.0
|-
| [[Ectopic pregnancy]] || 0.19 || [[Chloasma]] (melasma) || 1.5
|-
| || || [[Cervicitis]] (6 years of use) || 3.0
|-
| || || [[Chlamydia infection]]s || 2.5
|- class="sortbottom"
| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Footnotes:''' <sup>a</sup> = [[Odds ratio]]. '''Sources:''' <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=PA390|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1 |page=390}}</ref><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=PA1027 |year=2001 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-1750-2 |page=1027}}</ref>
|}

====Blood clots====

VTE is a [[blood clot]] in a [[vein]], and includes [[deep vein thrombosis]] (DVT) and [[pulmonary embolism]] (PE).<ref name="pmid16112947" /><ref name="Legato2009">{{cite book | vauthors = Legato MJ |title=Principles of Gender-Specific Medicine |url=https://books.google.com/books?id=whb9hsUgZtwC&pg=PA225 |date=29 October 2009 |publisher=Academic Press |isbn=978-0-08-092150-1 |pages=225–234}}</ref><ref name="Stein2016">{{cite book | vauthors = Stein PD |title=Pulmonary Embolism |url=https://books.google.com/books?id=V2zkCwAAQBAJ&pg=PA187 |date=5 April 2016 |publisher=Wiley |isbn=978-1-119-03909-9 |pages=187–}}</ref> Estrogens are known to increase the risk of VTE due to their effects on [[liver protein synthesis|liver synthesis]] of [[coagulation factor]]s.<ref name="pmid16112947" /><ref name="Legato2009" /><ref name="Stein2016" /> EE carries a greater risk of blood clot formation and VTE than does natural [[estradiol (medication)|estradiol]], which is thought to be due to [[chemical structure|structural]] differences between the two compounds and different susceptibilities to [[liver]] [[metabolism|inactivation]].<ref name="pmid16112947" />

A 2012 [[meta-analysis]] estimated that the [[absolute risk]] of VTE is 2 per 10,000 women for non-use, 8 per 10,000 women for EE and [[levonorgestrel]]-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing EE and a [[third-generation progestin|third-]] or [[fourth-generation progestin]] such as [[desogestrel]] or [[drospirenone]].<ref name="pmid27793376">{{cite journal | title = Combined hormonal contraception and the risk of venous thromboembolism: a guideline | journal = Fertility and Sterility | volume = 107 | issue = 1 | pages = 43–51 | date = January 2017 | pmid = 27793376 | doi = 10.1016/j.fertnstert.2016.09.027 | doi-access = free | vauthors = Pfeifer S, Butts S, Dumesic D, Fossum G, Gracia C, La Barbera A, Mersereau J, Odem R, Penzias A, Pisarska M, Rebar R, Reindollar R, Rosen M, Sandlow J, Sokol R, Vernon M, Widra E | collaboration = Practice Committee of the American Society for Reproductive Medicine }}</ref> For comparison, the absolute risk of VTE is generally estimated as 1 to 5 per 10,000 woman–years for non-use, 5 to 20 per 10,000 woman–years for pregnancy, and 40 to 65 per 10,000 woman–years for the [[postpartum]] period.<ref name="pmid27793376" /> Modern COCs are associated with about a 2- to 4-fold higher risk of VTE than non-use.<ref name="pmid27793376" /> The [[route of administration]] of EE does not appear to influence VTE risk, as EE/progestin-containing [[contraceptive vaginal ring]]s and [[contraceptive patch]]es have the same or even higher risk of VTE than COCs.<ref name="pmid27793376" /><ref name="pmid23384743">{{cite journal | vauthors = Plu-Bureau G, Maitrot-Mantelet L, Hugon-Rodin J, Canonico M | title = Hormonal contraceptives and venous thromboembolism: an epidemiological update | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 27 | issue = 1 | pages = 25–34 | date = February 2013 | pmid = 23384743 | doi = 10.1016/j.beem.2012.11.002 }}</ref> Pregnancy is associated with about a 4.3-fold increase in risk of VTE.<ref name="pmid27793376" /> It has been estimated that at least 300 to 400 healthy young women die each year in the United States due to VTE caused by EE-containing birth control pills.<ref name="KeenanKerr2019">{{cite journal | vauthors = Keenan L, Kerr T, Duane M, Van Gundy K | title = Systematic Review of Hormonal Contraception and Risk of Venous Thrombosis | journal = The Linacre Quarterly | volume = 85 | issue = 4 | pages = 470–477 | date = November 2018 | pmid = 32431379 | pmc = 6322116 | doi = 10.1177/0024363918816683 }}</ref>

Modern COCs contain 10 to 35&nbsp;μg EE, but typically 20, 30, or 35&nbsp;μg.<ref name="pmid27793376" /><ref name="FalconeHurd2007" /> The initial formulations of COCs that were introduced in the 1960s contained 100 to 150&nbsp;μg EE.<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 | doi-access = free }}</ref><ref name="pmid1983923" /><ref name="FalconeHurd2007" /> However, it was soon found that EE is associated with increased risk of VTE and that the risk is dose-dependent.<ref name="FalconeHurd2007" /> Following these events, the dose of EE was greatly reduced, and is now always less than 50&nbsp;μg.<ref name="Becker2001b">{{cite book | vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism |url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1024 |year=2001 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-1750-2 |pages=1024, 1027, 1035, 2153 |quote=Low-dose COCs contain <50 μg of estrogen and are the primary choice for oral contraception. COCs containing ≥50 μg of estrogen should no longer be routinely used for contraception. [...] The estrogen component of COCs can cause breast fullness and tenderness.}}</ref><ref name="BreastCancer1991">{{cite book|author=Committee on the Relationship Between Oral Contraceptives and BreastCancer |title=Oral Contraceptives and Breast Cancer |url=https://books.google.com/books?id=upYrAAAAYAAJ&pg=PA143 |date=1 January 1991 |publisher=National Academies |pages=143– |isbn=978-0-309-04493-6 |id=NAP:13774 |quote=Following a recommendation by its Fertility and Maternal Health Drugs Advisory Committee, the Food and Drug Administration (FDA) recently ordered the removal from the market of all oral contraceptives with [ethinylestradiol] contents greater than 50 μg.}}</ref><ref name="DIANE">{{cite book |title=Multigenerational Reproductive Toxicology Study of Ethinyl Estradiol (CAS No. 57636) in SpragueDawley Rats (Feed Studies) |url=https://books.google.com/books?id=wAnRHsPQcBQC&pg=PA27 |publisher=DIANE Publishing |isbn=978-1-4379-4231-6 |pages=27– |quote=Oral contraceptive formulations containing greater than 50 ug ethinyl estradiol were removed from the United States market in 1989, and currently marketed formulations generally contain between 20 and 35 μg ethinyl estradiol.}}</ref> These lower doses have a significantly reduced risk of VTE with no loss of contraceptive effectiveness.<ref name="FalconeHurd2007" /> Gerstman et al. (1991) found that COCs containing more than 50&nbsp;μg EE had 1.7-fold and COCs containing 50&nbsp;μg EE 1.5-fold the risk of VTE of COCs containing less than 50&nbsp;μg.<ref name="pmid1983896" /> A 2014 [[Cochrane (organization)|Cochrane]] review found that COCs containing 50&nbsp;μg EE with levonorgestrel had 2.1- to 2.3-fold the risk of COCs containing 30&nbsp;μg or 20&nbsp;μg EE with levonorgestrel, respectively.<ref name="pmid27793376" /> COCs containing 20&nbsp;μg EE are likewise associated with a significantly lower risk of cardiovascular events than COCs containing 30 or 40&nbsp;μg EE.<ref name="pmid27678035">{{cite journal | vauthors = Sitruk-Ware R | title = Hormonal contraception and thrombosis | journal = Fertility and Sterility | volume = 106 | issue = 6 | pages = 1289–1294 | date = November 2016 | pmid = 27678035 | doi = 10.1016/j.fertnstert.2016.08.039 | doi-access = free }}</ref> However, discontinuation of COCs is more common with doses of EE from 10 to 20&nbsp;μg due to problematic changes in bleeding patterns.<ref name="pmid23904209">{{cite journal | vauthors = Gallo MF, Nanda K, Grimes DA, Lopez LM, Schulz KF | title = 20 µg versus >20 µg estrogen combined oral contraceptives for contraception | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 8 | pages = CD003989 | date = August 2013 | pmid = 23904209 | pmc = 7173696 | doi = 10.1002/14651858.CD003989.pub5 }}</ref>

Women with [[thrombophilia]] have a dramatically higher risk of VTE with EE-containing contraception than women without thrombophilia.<ref name="pmid27793376" /><ref name="pmid23384743" /> Depending on the condition, risk of VTE can be increased 5- to 50-fold relative to non-use in such women.<ref name="pmid27793376" /><ref name="pmid23384743" />

[[Sex hormone-binding globulin]] (SHBG) levels indicate hepatic estrogenic exposure and may be a [[surrogate marker]] for [[coagulation]] and VTE risk with estrogen therapy, although this topic has been debated.<ref name="pmid12047300">{{cite journal | vauthors = Odlind V, Milsom I, Persson I, Victor A | title = Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 81 | issue = 6 | pages = 482–490 | date = June 2002 | pmid = 12047300 }}</ref><ref name="pmid22469296">{{cite journal | vauthors = Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, Ballieux B, VAN Vliet H | title = Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives | journal = Journal of Thrombosis and Haemostasis | volume = 10 | issue = 6 | pages = 992–997 | date = June 2012 | pmid = 22469296 | doi = 10.1111/j.1538-7836.2012.04720.x | s2cid = 20803995 | doi-access = free }}</ref><ref name="pmid18692609">{{cite journal | vauthors = Stanczyk FZ, Grimes DA | title = Sex hormone-binding globulin: not a surrogate marker for venous thromboembolism in women using oral contraceptives | journal = Contraception | volume = 78 | issue = 3 | pages = 201–203 | date = September 2008 | pmid = 18692609 | doi = 10.1016/j.contraception.2008.04.004 }}</ref> SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with [[levonorgestrel]], 2.5- to 4-fold with [[desogestrel]] and [[gestodene]], 3.5- to 4-fold with [[drospirenone]] and [[dienogest]], and 4- to 5-fold with [[cyproterone acetate]].<ref name="pmid12047300" /> [[Contraceptive vaginal ring]]s and [[contraceptive patch]]es likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.<ref name="pmid12047300" /> Birth control pills containing high doses of ethinylestradiol (>50&nbsp;μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.<ref name="WintersHuhtaniemi2017">{{cite book| vauthors = Winters SJ, Huhtaniemi IT |title=Male Hypogonadism: Basic, Clinical and Therapeutic Principles|url=https://books.google.com/books?id=UFi-DgAAQBAJ&pg=PA307|date=25 April 2017|publisher=Humana Press|isbn=978-3-319-53298-1|pages=307–}}</ref> Conversely, increases in SHBG levels are much lower with [[estradiol (medication)|estradiol]], especially when used parenterally.<ref name="pmid16915215">{{cite journal | vauthors = Notelovitz M | title = Clinical opinion: the biologic and pharmacologic principles of estrogen therapy for symptomatic menopause | journal = MedGenMed | volume = 8 | issue = 1 | page = 85 | date = March 2006 | pmid = 16915215 | pmc = 1682006 }}</ref><ref name="pmid22011208">{{cite journal | vauthors = Goodman MP | title = Are all estrogens created equal? A review of oral vs. transdermal therapy | journal = Journal of Women's Health | volume = 21 | issue = 2 | pages = 161–169 | date = February 2012 | pmid = 22011208 | doi = 10.1089/jwh.2011.2839 }}</ref><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="pmid2664738" /><ref name="pmid3817605">{{cite journal | vauthors = Ottosson UB, Carlström K, Johansson BG, von Schoultz B | title = Estrogen induction of liver proteins and high-density lipoprotein cholesterol: comparison between estradiol valerate and ethinyl estradiol | journal = Gynecologic and Obstetric Investigation | volume = 22 | issue = 4 | pages = 198–205 | date = 1986 | pmid = 3817605 | doi = 10.1159/000298914 }}</ref> High-dose parenteral [[polyestradiol phosphate]] therapy has been found to increase SHBG levels by about 1.5-fold.<ref name="pmid2664738" />

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

====Cardiovascular issues====
When used orally at high dosages, for instance as a form of high-dose estrogen therapy in men with prostate cancer and in women with breast cancer, [[synthetic compound|synthetic]] and non-[[bioidentical]] estrogens like EE and [[diethylstilbestrol]] are associated with fairly high rates of severe [[cardiovascular]] complications such as VTE, [[myocardial infarction]], and [[stroke]].<ref name="pmid27889048a" /><ref name="pmid24256023">{{cite journal | vauthors = Turo R, Smolski M, Esler R, Kujawa ML, Bromage SJ, Oakley N, Adeyoju A, Brown SC, Brough R, Sinclair A, Collins GN | title = Diethylstilboestrol for the treatment of prostate cancer: past, present and future | journal = Scandinavian Journal of Urology | volume = 48 | issue = 1 | pages = 4–14 | date = February 2014 | pmid = 24256023 | doi = 10.3109/21681805.2013.861508 | s2cid = 34563641 }}{{dead link|date=July 2022|bot=medic}}{{cbignore|bot=medic}}</ref><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 }}</ref> Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of VTE in men treated with it for prostate cancer.<ref name="pmid24256023" /><ref name="pmid24932461" /> EE has a to some degree lower risk of [[cardiovascular]] complications than does diethylstilbestrol when used in the treatment of prostate cancer in men.<ref name="OettelSchillinger2012" /> However, both EE and diethylstilbestrol nonetheless have highly disproportionate effects on [[liver protein synthesis]], which is thought to be responsible for their cardiovascular toxicity.<ref name="pmid16112947" /><ref name="pmid24932461" />

In contrast to oral synthetic estrogens like EE and diethylstilbestrol, high-dosage [[polyestradiol phosphate]] and [[transdermal administration|transdermal]] estradiol have not been found to increase the risk of cardiovascular [[mortality rate|mortality]] or [[thromboembolism]] in men with prostate cancer.<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 }}</ref><ref name="HongHolland2010">{{cite book| vauthors = Hong WK, Holland JK |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–}}</ref><ref name="pmid28667081">{{cite journal | vauthors = Russell N, Cheung A, Grossmann M | title = Estradiol for the mitigation of adverse effects of androgen deprivation therapy | journal = Endocrine-Related Cancer | volume = 24 | issue = 8 | pages = R297–R313 | date = August 2017 | pmid = 28667081 | doi = 10.1530/ERC-17-0153 | doi-access = free }}</ref> However, significantly increased cardiovascular [[morbidity]] has been observed with high-dosage polyestradiol phosphate.<ref name="pmid24932461" /><ref name="HongHolland2010" /><ref name="pmid28667081" /> In any case, these estrogens are considered to be much safer than oral synthetic estrogens like EE and diethylstilbestrol.<ref name="pmid24932461" /><ref name="HongHolland2010" /><ref name="pmid28667081" /> In addition, [[ethinylestradiol sulfonate]] (EES), an oral but [[parenteral]]-like long-lasting prodrug of EE, is used in the treatment of prostate cancer, and is said to have a considerably better profile of cardiovascular safety than EE.<ref name="OettelSchillinger2012" />

Because of its disproportionate effects on liver protein synthesis and associated cardiovascular risks, synthetic estrogens like EE and diethylstilbestrol are no longer used in menopausal hormone therapy.<ref name="OettelSchillinger2012" /> They are also being replaced by parenteral forms of estradiol like polyestradiol phosphate and transdermal estradiol in the treatment of prostate cancer.<ref name="pmid24932461" />

====Liver damage====
At the lower dosages that are now used in birth control pills, EE has been associated rarely with [[cholestasis|cholestatic]] [[hepatotoxicity]] similarly to [[17α-alkylated anabolic steroid|17α-alkylated]] [[androgen]]s/[[anabolic steroid]]s and 17α-ethynylated [[19-nortestosterone]] progestins.<ref name="TraunerJansen2004">{{cite book| vauthors = Trauner M, Jansen PJ |title=Molecular Pathogenesis of Cholestasis|url=https://books.google.com/books?id=ley1iZ-OongC&pg=PA260|year=2004|publisher=Springer Science & Business Media|isbn=978-0-306-48240-3|pages=260–}}</ref><ref name="ClavienBaillie2008">{{cite book| vauthors = Clavien PA, Baillie J |title=Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment|url=https://books.google.com/books?id=zF3iRcsxc3YC&pg=PA363|date=15 April 2008|publisher=John Wiley & Sons|isbn=978-0-470-98697-4|pages=363–}}</ref> Cholestasis can manifest as [[pruritus]] and [[jaundice]].<ref name="Kuhl1999" /> [[Glucuronide]] [[metabolite]]s of EE, via effects on the [[ABCB11|ABCB11 (BSEP)]] and [[Multidrug resistance-associated protein 2|MRP2 (ABCC2)]] [[protein]]s and consequent changes in [[bile]] flow and [[bile salt]] [[excretion]], appear to be responsible for the cholestasis.<ref name="O'BrienBruce2010">{{cite book| vauthors = O'Brien PJ, Bruce WR |title=Endogenous Toxins: Diet, Genetics, Disease and Treatment|url=https://books.google.com/books?id=UaLR0RSuXvsC&pg=PA302|year=2010|publisher=John Wiley & Sons|isbn=978-3-527-32363-0|pages=302–}}</ref> Very high concentrations of estradiol, via its metabolite [[estradiol glucuronide]], are also implicated in cholestasis, for instance in [[cholestasis of pregnancy]].<ref name="ClavienBaillie2008" /> However, the incidence and severity of cholestatic hepatotoxicity appear to be much greater with EE than with estradiol, which is thought to be due to the reactive C17α ethynyl substitution in EE as well as its greatly reduced susceptibility to hepatic metabolism.<ref name="Aronson2009">{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Endocrine and Metabolic Drugs|url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA177|date=21 February 2009|publisher=Elsevier|isbn=978-0-08-093292-7|pages=177, 219, 223, 224, 230, 232, 239, 242}}</ref><ref name="pmid2086334" /> Whereas abnormal [[liver function test]]s (LFTs) are normally found in about 1% of women not on birth control pills or taking lower-dose EE-containing birth control pills, this increases to more than 10% of women taking birth control pills containing 50&nbsp;μg/day EE or more.<ref name="pmid2086334">{{cite journal | vauthors = Kuhl H | title = [Ovulation inhibitors: the significance of estrogen dose] | language = German | journal = Geburtshilfe und Frauenheilkunde | volume = 50 | issue = 12 | pages = 910–922 | date = December 1990 | pmid = 2086334 | doi = 10.1055/s-2008-1026392 | s2cid = 73398961 | trans-title = Ovulation inhibitors: the significance of estrogen dose }}</ref><ref name="Kuhl1999" /> With birth control pills containing 50&nbsp;μg/day EE, [[alanine aminotransferase]] (ALT) levels increase by 50%, [[hematocrit]] by 19%, and [[leukocytes]] by 50%, while [[gamma-glutamyltransferase]] (GGT) decreases by 30%.<ref name="pmid2086334" /> However, the values usually remain in the normal range.<ref name="pmid2086334" /> In addition to abnormal LFTs, pathological changes in partial liver functions and liver [[morphology (biology)|morphology]] can be observed in half of women on birth control pills with 50&nbsp;μg/day EE.<ref name="pmid2086334" /> EE-containing birth control pills have also been associated with a 25- to 50-fold increase in the risk of rare [[benign liver tumor]]s and a 3- to 6-fold increase in the risk of [[hepatocellular carcinoma]],<ref name="Kuhl1999">{{cite book | series = Handbook of Experimental Pharmacology | vauthors = Kuhl H | title = Estrogens and Antiestrogens II | chapter = Hormonal Contraception | date = 1999 | volume = 135 / 2 | pages = 363–407 | publisher = Springer Berlin Heidelberg | issn = 0171-2004 | eissn = 1865-0325 | doi = 10.1007/978-3-642-60107-1_18 | isbn = 978-3-642-64261-6 | url = }}</ref><ref name="pmid30020636">{{cite web | vauthors = Shreenath AP, Kahloon A | title = Hepatic Adenoma | publisher = StatPearls | date = January 2022 | pmid = 30020636 | doi = | url = https://www.ncbi.nlm.nih.gov/books/NBK513264/}}</ref><ref name="pmid17261770">{{cite journal | vauthors = Giannitrapani L, Soresi M, La Spada E, Cervello M, D'Alessandro N, Montalto G | title = Sex hormones and risk of liver tumor | journal = Annals of the New York Academy of Sciences | volume = 1089 | issue = 1 | pages = 228–236 | date = November 2006 | pmid = 17261770 | doi = 10.1196/annals.1386.044 | s2cid = 7932937 | bibcode = 2006NYASA1089..228G }}</ref> as well as greater risk of other liver complications.<ref name="pmid31009688">{{cite journal | vauthors = Ponnatapura J, Kielar A, Burke LM, Lockhart ME, Abualruz AR, Tappouni R, Lalwani N | title = Hepatic complications of oral contraceptive pills and estrogen on MRI: Controversies and update - Adenoma and beyond | journal = Magnetic Resonance Imaging | volume = 60 | issue = | pages = 110–121 | date = July 2019 | pmid = 31009688 | doi = 10.1016/j.mri.2019.04.010 | s2cid = 128359413 }}</ref><ref name="pmid18814084">{{cite journal | vauthors = Perarnau JM, Bacq Y | title = Hepatic vascular involvement related to pregnancy, oral contraceptives, and estrogen replacement therapy | journal = Seminars in Liver Disease | volume = 28 | issue = 3 | pages = 315–327 | date = August 2008 | pmid = 18814084 | doi = 10.1055/s-0028-1085099 | s2cid = 260318275 }}</ref> At one time, EE-containing birth control pills were estimated to be responsible for 84% of all drug-related and histologically verified liver damage.<ref name="pmid2086334" /> However, these risks now are reduced with modern lower-dose EE-containing birth control pills, with contain 35&nbsp;μg/day EE or less.<ref name="Kuhl1999" /><ref name="pmid17261770" />

====Uterine cancer====
The high doses of EE that were used in early COCs were associated with a significantly increased risk of [[endometrial cancer]] in certain preparations, for instance those containing the progestogen [[dimethisterone]].<ref name="Blaustein2013">{{cite book| vauthors = Blaustein A |title=Pathology of the Female Genital Tract|url=https://books.google.com/books?id=4MXSBwAAQBAJ&pg=PA291|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4757-1767-9|pages=291–}}</ref> Unopposed estrogens like EE have carcinogenic effects in the endometrium and progestogens protect against these effects, but dimethisterone is a relatively weak progestogen and was unable to adequately antagonize the endometrial carcinogenic effects of EE, in turn resulting in the increased risk of endometrial cancer.<ref name="Blaustein2013" /> COCs containing dimethisterone have since been discontinued (with more potent progestogens used instead) and doses of EE in COCs in general have been dramatically reduced, abrogating the risk.<ref name="Blaustein2013" /> In turn, most studies of modern COCs have found a decreased risk of endometrial cancer.<ref name="SurwitAlberts2012">{{cite book| vauthors = Surwit EA, Alberts D |title=Endometrial Cancer|url=https://books.google.com/books?id=jbshBQAAQBAJ&pg=PA11|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4613-0867-6|pages=11–}}</ref>

=== Ecological Effects ===
[[Wastewater]] contains various estrogens, including EE, that are not completely broken down by [[Wastewater treatment|wastewater treatment procedures]].<ref name=":0">{{cite journal | vauthors = Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM, Flick RW | title = Collapse of a fish population after exposure to a synthetic estrogen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 21 | pages = 8897–8901 | date = May 2007 | pmid = 17517636 | pmc = 1874224 | doi = 10.1073/pnas.0609568104 | doi-access = free | bibcode = 2007PNAS..104.8897K }}</ref> The input of artificial estrogens into [[Fresh water|freshwater]] ecosystems affects [[fish]] and [[amphibian]] populations. Chronic exposure to low levels of EE over seven years led to the collapse of [[fathead minnow]] populations in an [[Experimental Lakes Area|experimental lake]] in [[Ontario|Ontario, Canada]].<ref name=":0" /> EE changed [[oogenesis]] in female fish and feminized male fish such that they produced a protein associated with egg maturation, [[vitellogenin]], as well as early-stage eggs.<ref name=":0" /> In amphibians, exposure to EE can reduce hatching success and alter [[Development of the gonads|gonadal development]].<ref name=":1">{{cite journal | vauthors = Park BJ, Kidd K | title = Effects of the synthetic estrogen ethinylestradiol on early life stages of mink frogs and green frogs in the wild and in situ | journal = Environmental Toxicology and Chemistry | volume = 24 | issue = 8 | pages = 2027–2036 | date = August 2005 | pmid = 16152976 | doi = 10.1897/04-227R.1 | s2cid = 32669410 }}</ref> Exposure to hormones can change frogs' gonadal development even though it is [[Sex chromosome|encoded]] in their [[gene]]s.<ref name=":1" /> A study of [[mink frog]]s found more [[intersex]] [[tadpole]]s in those experimentally exposed to EE than those not exposed to EE, and [[Lithobates clamitans|green frogs]] showed much lower rates of hatching success.<ref name=":1" />

==Overdose==
{{See also|Estrogen (medication)#Overdose}}

Estrogens like EE are relatively safe in acute [[overdose]].{{Citation needed|date=July 2018}}

== Interactions ==

EE is metabolized by certain [[cytochrome P450]] isoforms, including [[CYP3A4]] and [[CYP2C9]].<ref>{{cite journal | vauthors = Wang B, Sanchez RI, Franklin RB, Evans DC, Huskey SE | title = The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol | journal = Drug Metabolism and Disposition | volume = 32 | issue = 11 | pages = 1209–1212 | date = November 2004 | pmid = 15304426 | doi = 10.1124/dmd.104.000182 | s2cid = 86245855 }}</ref> Thus, [[enzyme inducer|inducer]]s of enzymes such as CYP3A4 can decrease circulating concentrations of EE.<ref name="Aronson2009" /> Examples of inducers include [[anticonvulsant]]s like [[phenytoin]], [[primidone]], [[ethosuximide]], [[phenobarbital]], and [[carbamazepine]]; [[azole]] [[antifungal]]s like [[fluconazole]]; and [[rifamycin]] [[antibiotic]]s like [[rifampin]] ([[rifampicin]]).<ref name="Aronson2009" /> Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes may increase circulating levels of EE.<ref name="Aronson2009" /> An example is [[troleandomycin]], which is a potent and highly selective inhibitor of CYP3A4.<ref name="Aronson2009" />

[[Paracetamol]] (acetaminophen) has been found to [[competitive inhibition|competitively inhibit]] the sulfation of EE, with pretreatment of 1,000&nbsp;mg of paracetamol significantly increasing the [[area-under-curve (pharmacokinetics)|AUC]] levels of EE (by 22%) and decreasing the AUC levels of [[ethinylestradiol sulfate]] (EE sulfate) in women.<ref name="Aronson2009" /> The same has been found for [[ascorbic acid]] (vitamin C) and EE, although the significance of the interaction has been regarded as dubious.<ref name="Aronson2009" />

In contrast to estradiol, it is unlikely that there is a pharmacokinetic interaction between [[smoking]] (which potently induces certain [[cytochrome P450]] [[enzyme]]s and markedly increases the 2-hydroxylation of estradiol) and EE.<ref name="Aronson2009" /> This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes.<ref name="Aronson2009" /> There is, however, an increased risk of cardiovascular complications with smoking and EE, similarly to the case of smoking and other estrogens.<ref name="Aronson2009" />

EE is known to [[enzyme inhibitor|inhibit]] several [[cytochrome P450]] enzymes, including [[CYP1A2]], [[CYP2B6]], [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]], and is possibly an [[enzyme inducer|inducer]] of [[CYP2A6]].<ref name="pmid17253885">{{cite journal | vauthors = Zhang H, Cui D, Wang B, Han YH, Balimane P, Yang Z, Sinz M, Rodrigues AD | title = Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug | journal = Clinical Pharmacokinetics | volume = 46 | issue = 2 | pages = 133–157 | date = 2007 | pmid = 17253885 | doi = 10.2165/00003088-200746020-00003 | s2cid = 71784426 }}</ref> As a result, it can affect the metabolism and concentrations of many other drugs.<ref name="pmid17253885" /> Examples of known interactions include [[bupropion]], [[caffeine]], [[mephenytoin]], [[midazolam]], [[nicotine]], [[nifedipine]], [[omeprazole]], [[propranolol]], [[proguanil]], [[selegiline]], [[theophylline]], and [[tizanidine]].<ref name="pmid17253885" /><ref name="Aronson2009" /> One of the most notable interactions is that EE strongly increases levels of [[selegiline]], a substrate of CYP2B6 and CYP2C19.<ref name="pmid17253885" /> EE may also induce [[glucuronidation]] and possibly alter [[sulfation]].<ref name="pmid17253885" /> It has been found to increase the clearance of and reduce the concentrations of a variety of drugs known to be glucuronidated.<ref name="pmid17253885" /> Examples include [[clofibrate]], [[lamotrigine]], [[lorazepam]], [[oxazepam]], and [[propranolol]].<ref name="pmid17253885" />

Progestins, which are often used in combination with EE, are also known to inhibit cytochrome P450 enzymes, and this may contribute to drug interactions with EE-containing contraceptives as well.<ref name="pmid17253885" /> Examples include [[gestodene]], [[desogestrel]], and [[etonogestrel]], which are CYP3A4 and CYP2C19 inhibitors.<ref name="pmid17253885" /> In addition, these progestins are known to progressively inhibit the metabolism of and increase concentrations of EE itself.<ref name="Aronson2009" />

==Pharmacology==

===Pharmacodynamics===
EE is an [[estrogen (medication)|estrogen]] similarly to natural estrogens like estradiol and [[conjugated estrogens]] (Premarin) and synthetic estrogens like [[diethylstilbestrol]]. It binds to and activates both [[isoform]]s of the [[estrogen receptor]], [[Estrogen receptor alpha|ERα]] and [[Estrogen receptor beta|ERβ]].<ref name="OettelSchillinger2012" /> In one study, EE was found to have 233% and 38% of the [[affinity (pharmacology)|affinity]] of [[estradiol]] for the ERα and ERβ, respectively.<ref name="pmid16554039">{{cite journal | vauthors = Escande A, Pillon A, Servant N, Cravedi JP, Larrea F, Muhn P, Nicolas JC, Cavaillès V, Balaguer P | title = Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta | journal = Biochemical Pharmacology | volume = 71 | issue = 10 | pages = 1459–1469 | date = May 2006 | pmid = 16554039 | doi = 10.1016/j.bcp.2006.02.002 }}</ref> In another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively.<ref name="pmid21321128">{{cite journal | vauthors = Jeyakumar M, Carlson KE, Gunther JR, Katzenellenbogen JA | title = Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities | journal = The Journal of Biological Chemistry | volume = 286 | issue = 15 | pages = 12971–12982 | date = April 2011 | pmid = 21321128 | pmc = 3075970 | doi = 10.1074/jbc.M110.205112 | doi-access = free }}</ref> EE also appears to act as a [[potency (pharmacology)|potent]] agonist of the [[G protein-coupled estrogen receptor]] (GPER) (affinity unknown), a [[membrane estrogen receptor]], similarly to estradiol.<ref name="pmid26023144">{{cite journal | vauthors = Prossnitz ER, Arterburn JB | title = International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators | journal = Pharmacological Reviews | volume = 67 | issue = 3 | pages = 505–540 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }}</ref><ref name="pmid20403194">{{cite journal | vauthors = Yates MA, Li Y, Chlebeck PJ, Offner H | title = GPR30, but not estrogen receptor-alpha, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol | journal = BMC Immunology | volume = 11 | page = 20 | date = April 2010 | pmid = 20403194 | pmc = 2864220 | doi = 10.1186/1471-2172-11-20 | doi-access = free }}</ref><ref name="pmid21844907">{{cite journal | vauthors = Prossnitz ER, Barton M | title = The G-protein-coupled estrogen receptor GPER in health and disease | journal = Nature Reviews. Endocrinology | volume = 7 | issue = 12 | pages = 715–726 | date = August 2011 | pmid = 21844907 | pmc = 3474542 | doi = 10.1038/nrendo.2011.122 | quote = Further research showed that the therapeutic effect of ethynylestradiol in established EAE was mediated via GPER, but not via ERα, and possibly involved production of the anti-inflammatory cytokine Il‑10.115 }}</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 | quote = In addition, the therapeutic effect of ethinyl estradiol in established disease was demonstrated to require expression of GPER but not ERα, and was associated with the production of the anti-inflammatory cytokine IL-10 (Yates et al., 2010). }}</ref> Estrogens have [[antigonadotropic]] effects through activation of the ERα.<ref name="QuaynorStradtman2013">{{cite journal | vauthors = Quaynor SD, Stradtman EW, Kim HG, Shen Y, Chorich LP, Schreihofer DA, Layman LC | title = Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant | journal = The New England Journal of Medicine | volume = 369 | issue = 2 | pages = 164–171 | date = July 2013 | pmid = 23841731 | pmc = 3823379 | doi = 10.1056/NEJMoa1303611 }}</ref> As a contraceptive, EE acts in concert with a progestin to inhibit the mid-cycle surge in [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH) via its antigonadotropic effects, thereby inhibiting [[folliculogenesis]] and preventing [[ovulation]] and hence the possibility of [[pregnancy]].<ref name="CraigStitzel2004">{{cite book| vauthors = Craig CR, Stitzel RE |title=Modern Pharmacology with Clinical Applications|url=https://books.google.com/books?id=KqA29hQ-m3AC&pg=PA708|year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-3762-3|pages=708–}}</ref><ref name="AllahbadiaAgrawal2007">{{cite book| vauthors = Allahbadia G, Agrawal R |title=Polycystic Ovary Syndrome|url=https://books.google.com/books?id=HX0JxcrWJvAC&pg=PA257|year=2007|publisher=Anshan|isbn=978-1-904798-74-3|pages=257–}}</ref>

EE is a long-acting estrogen, with a nuclear retention of about 24&nbsp;hours.<ref name="RunnebaumRabe2013" /><!--{{cite book| vauthors = Runnebaum B, Rabe T |title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie|url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=88–}}</ref-->

Orally, EE is on the order of 100&nbsp;times as potent by weight as natural estrogens like [[micronized estradiol]] and conjugated estrogens, which is largely due to substantially greater resistance to [[first-pass metabolism]].<ref name="GomelMunro1990">{{cite book| vauthors = Gomel V, Munro MG, Rowe TC |title=Gynecology: a practical approach|url=https://books.google.com/books?id=8-JsAAAAMAAJ|year=1990|publisher=Williams & Wilkins|isbn=978-0-683-03631-2|page=132,134|quote=The synthetic estrogen, ethinyl estradiol, more commonly used in oral contraceptives, has a biological activity 100 times that of the native and conjugated substances.}}</ref><ref name="Shoupe2007">{{cite book| vauthors = Shoupe D |title=The Handbook of Contraception: A Guide for Practical Management|url=https://books.google.com/books?id=sczb0Tk_2IwC&pg=PA23|date=7 November 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-150-5|pages=23–|quote=EE2 has about 100 times the potency of an equivalent weight of conjugated equine estrogen or estrone sulfate for stimulating synthesis of hepatic proteins. [...] EE2 is about 1.7 times as potent as the same weight of mestranol.}}</ref><ref name="McConaghy2013">{{cite book| vauthors = McConaghy N |title=Sexual Behavior: Problems and Management|url=https://books.google.com/books?id=eVD0BwAAQBAJ&pg=PA177|date=21 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4899-1133-9|pages=177–|quote=Meyer et al. found that ethinyl estradiol was 75 to 100 times more potent than conjugated estrogen on the basis of the doses required to lower testosterone to the adult female range, 0.1 mg of the former and 7.5 to 10 mg of the latter being necessary.}}</ref> It is specifically in the range of 80 to 200&nbsp;times as potent as [[estropipate]] (piperazine estrone sulfate), which has similar potency to micronized estradiol, in terms of systemic estrogenic potency.<ref name="ChabnerLongo1996">{{cite book| vauthors = Chabner B, Longo DL |title=Cancer Chemotherapy and Biotherapy: Principles and Practice|url=https://books.google.com/books?id=TZNrAAAAMAAJ|year=1996|publisher=Lippincott-Raven Publishers|isbn=978-0-397-51418-2|page=186|quote=The relative potency of several estrogens has been assayed by determination of effects on plasma FSH, a measure of the systemic effect, and by increases in SHBG, CBG, and angiotensinogen, all of which indicate the hepatic effect. Piperazine estrone sulfate and micronized estradiol were equipotent with respect to increases in SHBG, whereas conjugated estrogens were 3.2-fold more potent, DES was 28.4-fold more potent, and ethinyl estradiol was 600-fold more potent. With respect to decreased FSH, conjugated estrogens were 1.4-fold, DES was 3.8-fold, and ethinyl estradiol was 80 to 200-fold more potent than was piperazine estrone sulfate.}}</ref><ref name="pmid6291391">{{cite journal | vauthors = Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF, Mishell DR | title = Comparison of pharmacodynamic properties of various estrogen formulations | journal = American Journal of Obstetrics and Gynecology | volume = 144 | issue = 5 | pages = 511–518 | date = November 1982 | pmid = 6291391 | doi = 10.1016/0002-9378(82)90218-6 }}</ref> In contrast, the potencies of EE and natural estrogens are similar when they are administered [[intravenous injection|intravenous]]ly, due to the bypassing of first-pass metabolism.<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=PA388|year=2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=388–}}</ref> Relative to its [[prodrug]] [[mestranol]], EE is about 1.7&nbsp;times as potent by weight orally.<ref name="Shoupe2007" />

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

{{Relative affinities of estrogens for steroid hormone receptors and blood proteins}}

{{Relative oral potencies of estrogens}}

{{Oral potencies of estrogens}}

====Antiandrogenic and antigonadotropic effects====
[[File:Testosterone levels with different estrogen therapies in men with prostate cancer.png|thumb|right|300px|Testosterone levels with no treatment and with various estrogens in men with prostate cancer.<ref name="pmid4359746">{{cite journal | vauthors = Shearer RJ, Hendry WF, Sommerville IF, Fergusson JD | title = Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer | journal = British Journal of Urology | volume = 45 | issue = 6 | pages = 668–677 | date = December 1973 | pmid = 4359746 | doi = 10.1111/j.1464-410x.1973.tb12238.x }}</ref> Determinations were made with an early [[radioimmunoassay]] (RIA).<ref name="pmid4359746" /> Source was Shearer et al. (1973).<ref name="pmid4359746" />]]

EE is a potent functional [[antiandrogen]] in both women and men.<ref name="Ekback2017">{{cite journal | vauthors = Ekback MP | title = Hirsutism, What to do? | journal = International Journal of Endocrinology and Metabolic Disorders | volume = 3 | issue = 3 | year = 2017 | doi = 10.16966/2380-548X.140 | issn=2380-548X | format = PDF | url = https://www.researchgate.net/publication/321245014| doi-access = free }}</ref> It mediates its antiandrogenic effects by 1) stimulating the [[biosynthesis|production]] of [[sex hormone-binding globulin]] (SHBG) in the [[liver]], which decreases free and thus bioactive concentrations of testosterone in the blood; and by 2) suppressing [[luteinizing hormone]] (LH) [[secretion]] from the [[pituitary gland]], which decreases production of testosterone by the [[gonad]]s.<ref name="Ekback2017" /><ref name="NieschlagBehre2012">{{cite book| vauthors = Nieschlag E, Behre HM, Nieschlag S |title=Testosterone: Action, Deficiency, Substitution|url=https://books.google.com/books?id=MkrAPaQ4wJkC&pg=PA62|date=26 July 2012|publisher=Cambridge University Press|isbn=978-1-107-01290-5|pages=62–}}</ref><ref name="HumansOrganization2007" /><ref name="pmid22294742">{{cite journal | vauthors = Coss CC, Jones A, Parke DN, Narayanan R, Barrett CM, Kearbey JD, Veverka KA, Miller DD, Morton RA, Steiner MS, Dalton JT | title = Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer | journal = Endocrinology | volume = 153 | issue = 3 | pages = 1070–1081 | date = March 2012 | pmid = 22294742 | doi = 10.1210/en.2011-1608 | doi-access = free }}</ref> Birth control pills that contain EE are useful in the treatment of [[androgen-dependent condition]]s like [[acne]] and [[hirsutism]] by virtue of their antiandrogenic effects.<ref name="Ekback2017" /><ref name="pmid18338653">{{cite journal | vauthors = Rich P | title = Hormonal contraceptives for acne management | journal = Cutis | volume = 81 | issue = 1 Suppl | pages = 13–18 | date = January 2008 | pmid = 18338653 }}</ref>

Birth control pills containing EE have been found in women to reduce total testosterone levels by 30% on average, to increase circulating SHBG levels by about 3-fold on average (but variable depending on progestin, range 1.5- to 5-fold increase), and to reduce free testosterone concentrations by 60% on average (range 40 to 80%).<ref name="pmid24082040">{{cite journal | vauthors = Zimmerman Y, Eijkemans MJ, Coelingh Bennink HJ, Blankenstein MA, Fauser BC | title = The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis | journal = Hum Reprod Update | volume = 20 | issue = 1 | pages = 76–105 | date = 2014 | pmid = 24082040 | pmc = 3845679 | doi = 10.1093/humupd/dmt038 | url = }}</ref><ref name="pmid12047300" /><ref name="pmid37419659">{{cite journal | vauthors = Özcan Ö, den Elzen WP, Hillebrand JJ, den Heijer M, van Loendersloot LL, Fischer J, Hamer H, de Jonge R, Heijboer AC | title = The effect of hormonal contraceptive therapy on clinical laboratory parameters: a literature review | journal = Clin Chem Lab Med | volume = 62 | issue = 1 | pages = 18–40 | date = January 2024 | pmid = 37419659 | doi = 10.1515/cclm-2023-0384 | s2cid = 259361637 | url = | doi-access = free }}</ref><ref name="HumansOrganization2007" /> Birth control pills containing high doses of EE can increase SHBG levels in women by as much as 5- to 10-fold.<ref name="WintersHuhtaniemi2017">{{cite book| vauthors = Winters SJ, Huhtaniemi IT |title=Male Hypogonadism: Basic, Clinical and Therapeutic Principles|url=https://books.google.com/books?id=UFi-DgAAQBAJ&pg=PA307|date=25 April 2017|publisher=Humana Press|isbn=978-3-319-53298-1|pages=307–}}</ref> This is similar to the 5- to 10-fold increase in SHBG levels that occurs during [[pregnancy]].<ref name="WintersHuhtaniemi2017" /> Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with EE-containing birth control pills.<ref name="pmid23375353" /> In men, a study found that treatment with a relatively low dosage of 20&nbsp;μg/day EE for five weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease in free testosterone levels, increased total circulating levels of testosterone by 50% (via upregulation of gonadal testosterone production due to reduced [[negative feedback]] by androgens on the [[hypothalamic–pituitary–gonadal axis]]).<ref name="NieschlagBehre2012" /> The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol, owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body.<ref name="pmid16112947" /><ref name="pmid23375353" /><ref name="pmid22950535">{{cite journal | vauthors = Yang LP, Plosker GL | title = Nomegestrol acetate/estradiol: in oral contraception | journal = Drugs | volume = 72 | issue = 14 | pages = 1917–1928 | date = October 2012 | pmid = 22950535 | doi = 10.2165/11208180-000000000-00000 | s2cid = 44335732 }}</ref>

Estrogens are [[antigonadotropin]]s and are able to suppress the secretion of LH and FSH from the pituitary gland and by extension gonadal testosterone production.<ref name="pmid7000222">{{cite journal | vauthors = Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R | title = Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial | journal = British Journal of Urology | volume = 52 | issue = 3 | pages = 208–215 | date = June 1980 | pmid = 7000222 | doi = 10.1111/j.1464-410x.1980.tb02961.x }}</ref><ref name="pmid3217277">{{cite journal | vauthors = Gunnarsson PO, Norlén BJ | title = Clinical pharmacology of polyestradiol phosphate | journal = The Prostate | volume = 13 | issue = 4 | pages = 299–304 | year = 1988 | pmid = 3217277 | doi = 10.1002/pros.2990130405 | s2cid = 33063805 }}</ref> [[High-dose estrogen]] therapy, including with EE, is able to suppress testosterone levels in men by around 95%, or into the castrate/female range.<ref name="pmid2630306">{{cite journal | vauthors = Stahl F, Schnorr D, Bär CM, Fröhlich G, Dörner G | title = Suppression of plasma androgen levels with a combination therapy of depot-estrogen (Turisteron) and Dexamethasone in patients with prostatic cancer | journal = Experimental and Clinical Endocrinology | volume = 94 | issue = 3 | pages = 239–243 | year = 1989 | pmid = 2630306 | doi = 10.1055/s-0029-1210905 | s2cid = 40497389 }}</ref><ref name="pmid7000222" /><ref name="pmid3217277" /> The dosage of EE required for use as a component of [[transgender hormone therapy (male-to-female)|hormone therapy]] for preoperative [[transgender women]] is 50 to 100&nbsp;µg/day.<ref name="JamesonGroot2010">{{cite book| vauthors = Jameson JL, De Groot LJ |title=Endocrinology - E-Book: Adult and Pediatric|url=https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA2282|date=18 May 2010|publisher=Elsevier Health Sciences|isbn=978-1-4557-1126-0|pages=2282–}}</ref> This high dosage is associated with a high incidence of VTE, particularly in those over the age of 40&nbsp;years, and it has been said that it should not be used.<ref name="JamesonGroot2010" /> The dosage of EE used in the treatment of prostate cancer in men is 150 to 1,000&nbsp;µg/day (0.15–1.0&nbsp;mg/day).<ref name="OettelSchillinger2012" /><ref name="DenisGriffiths1999">{{cite book| vauthors = Denis LJ, Griffiths K, Kaisary AV, Murphy GP |title=Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment|url=https://books.google.com/books?id=GreZlojD-tYC&pg=PA297|date=1 March 1999|publisher=CRC Press|isbn=978-1-85317-422-3|pages=297–}}</ref> A dosage of EE of 50&nbsp;μg twice daily (100&nbsp;μg/day total) has been found to suppress testosterone levels in men to an equivalent extent as 3&nbsp;mg/day oral [[diethylstilbestrol]], which is the minimum dosage of diethylstilbestrol required to consistently suppress testosterone levels into the castrate range.<ref name="pmid29603164b">{{cite journal | vauthors = Scott WW, Menon M, Walsh PC | title = Hormonal Therapy of Prostatic Cancer | journal = Cancer | volume = 45 | issue = Suppl 7 | pages = 1929–1936 | date = April 1980 | pmid = 29603164 | doi = 10.1002/cncr.1980.45.s7.1929 | s2cid = 4492779 | doi-access = free }}</ref> The ovulation-inhibiting dose of EE by itself and not in combination with a progestin in women is 100&nbsp;μg/day.<ref name="pmid4568621">{{cite journal | vauthors = Bingel AS, Benoit PS | title = Oral contraceptives: therapeutics versus adverse reactions, with an outlook for the future I | journal = Journal of Pharmaceutical Sciences | volume = 62 | issue = 2 | pages = 179–200 | date = February 1973 | pmid = 4568621 | doi = 10.1002/jps.2600620202 }}</ref><ref name="RietbrockStaib2013b">{{cite book | vauthors = Rietbrock N, Staib AH, Loew D |title=Klinische Pharmakologie: Arzneitherapie |url=https://books.google.com/books?id=FkwEBgAAQBAJ&pg=PA426|date=11 March 2013|publisher=Springer-Verlag|isbn=978-3-642-57636-2 |pages=426–}}</ref> However, it has been found to be about 75 to 90% effective at inhibiting ovulation at a dosage of 20&nbsp;μg/day and about 97 or 98% effective at a dosage of 50&nbsp;μg/day.<ref name="Elger1972">{{cite book | vauthors = Elger W |title=Reviews of Physiology Biochemistry and Experimental Pharmacology, Volume 67|chapter=Physiology and pharmacology of female reproduction under the aspect of fertility control|series=Ergebnisse der Physiologie Reviews of Physiology |volume=67|year=1972|pages=69–168|doi=10.1007/BFb0036328|pmid=4574573|isbn=3-540-05959-8}}</ref><ref name="BastianelliFarris2018">{{cite journal | vauthors = Bastianelli C, Farris M, Rosato E, Brosens I, Benagiano G | title = Pharmacodynamics of combined estrogen-progestin oral contraceptives 3. Inhibition of ovulation | journal = Expert Review of Clinical Pharmacology | volume = 11 | issue = 11 | pages = 1085–1098 | date = November 2018 | pmid = 30325245 | doi = 10.1080/17512433.2018.1536544 | s2cid = 53246678 }}</ref><ref name="Greenblatt1966b">{{cite book | vauthors = Martinez-Manautou J, Rudel HW |chapter=Antiovulatory Activity of Several Synthetic and Natural Estrogens |pages=243–253 | veditors = Greenblatt RB |title=Ovulation: Stimulation, Suppression, and Detection |url=https://books.google.com/books?id=le1qAAAAMAAJ |year=1966 |publisher=Lippincott|isbn=978-0-397-59010-0}}</ref><ref name="HerrRevesz1970k">{{cite book | vauthors = Herr F, Revesz C, Manson AJ, Jewell JB |title=Chemical and Biological Aspects of Steroid Conjugation|chapter=Biological Properties of Estrogen Sulfates |year=1970|pages=368–408 |doi=10.1007/978-3-642-49793-3_8 |isbn=978-3-642-49506-9}}</ref> In another study, ovulation occurred in 25.2% with an EE dose of 50&nbsp;μg/day.<ref name="pmid1146927">{{cite journal | vauthors = Goldzieher JW, Pena A, Chenault CB, Woutersz TB | title = Comparative studies of the ethynyl estrogens used in oral contraceptives. II. Antiovulatory potency | journal = American Journal of Obstetrics and Gynecology | volume = 122 | issue = 5 | pages = 619–624 | date = July 1975 | pmid = 1146927 | doi = 10.1016/0002-9378(75)90061-7 }}</ref>

Lower dosages of EE also have significant antigonadotropic effects.<ref name="JamesonGroot2010" /> A "very low" dosage of 15&nbsp;µg/day EE has been described as the "borderline" amount required for suppression of LH and testosterone levels in men, and a study found that LH and testosterone levels were "reliably" suppressed in men by a dosage of 30&nbsp;µg/day EE.<ref name="OettelSchillinger2012" /> However, other clinical studies have found that 20&nbsp;µg/day EE increased testosterone levels by 50% in men (as described above)<ref name="NieschlagBehre2012" /> and that dosages of 32&nbsp;µg/day and 42&nbsp;µg/day EE suppressed FSH levels in men but did not significantly affect LH levels.<ref name="OettelSchillinger2012" /> A stronger suppression of testosterone levels was observed in men following daily treatment with a combined oral contraceptive containing 50&nbsp;µg ethinylestradiol and 0.5&nbsp;mg [[norgestrel]] for 9&nbsp;days.<ref name="OettelSchillinger2012" /> However, investigation revealed that the progestin was the more important component responsible for the suppression in testosterone levels.<ref name="OettelSchillinger2012" /> In accordance, the progestin component of COCs is primarily responsible for inhibition of [[ovulation]] in women.<ref name="OettelSchillinger2012" /> A combination of 20&nbsp;µg/day EE and 10&nbsp;mg/day [[methyltestosterone]] was found to suppress FSH secretion in men to an extent sufficient to stop [[spermatogenesis]].<ref name="OettelSchillinger2012" /> Studies in women have found that 50&nbsp;µg/day EE suppresses LH and FSH levels both by about 70% in postmenopausal women.<ref name="pmid6291391">{{cite journal | vauthors = Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF, Mishell DR | title = Comparison of pharmacodynamic properties of various estrogen formulations | journal = American Journal of Obstetrics and Gynecology | volume = 144 | issue = 5 | pages = 511–518 | date = November 1982 | pmid = 6291391 | doi = 10.1016/0002-9378(82)90218-6 }}</ref>

In addition to its antigonadotropic effects, EE can significantly suppress androgen production by the [[adrenal gland]]s at high concentrations.<ref name="OettelSchillinger2012" /><ref name="MargiorisChrousos2001">{{cite book| vauthors = Margioris AN, Chrousos GP |title=Adrenal Disorders|url=https://books.google.com/books?id=XB73BwAAQBAJ&pg=PA84|date=20 April 2001|publisher=Springer Science & Business Media|isbn=978-1-59259-101-5|pages=84–}}</ref><ref name="pmid7586614">{{cite journal | vauthors = Polderman KH, Gooren LJ, van der Veen EA | title = Effects of gonadal androgens and oestrogens on adrenal androgen levels | journal = Clinical Endocrinology | volume = 43 | issue = 4 | pages = 415–421 | date = October 1995 | pmid = 7586614 | doi = 10.1111/j.1365-2265.1995.tb02611.x | s2cid = 6815423 }}</ref> One study found that treatment with a high dosage of 100&nbsp;µg/day EE suppressed circulating [[adrenal androgen]] levels by 27 to 48% in transgender women.<ref name="OettelSchillinger2012" /><ref name="MargiorisChrousos2001" /><ref name="pmid7586614" /> This may additionally contribute to suppression of androgen levels by estrogens.<ref name="OettelSchillinger2012" /><ref name="MargiorisChrousos2001" /><ref name="pmid7586614" />

====Effects on liver protein synthesis====
EE has marked effects on [[liver protein synthesis]], even at low dosages and regardless of [[route of administration]].<ref name="OettelSchillinger2012" /><ref name="pmid16112947" /> These effects are mediated by its estrogenic activity.<ref name="OettelSchillinger2012" /><ref name="pmid16112947" /> The medication dose-dependently increases circulating levels of SHBG, [[corticosteroid-binding globulin]] (CBG), and [[thyroxine-binding globulin]] (TBG), and also affects a broad range of other liver proteins.<ref name="OettelSchillinger2012" /><ref name="pmid16112947" /> EE affects [[triglyceride]] levels at a dose as low as 1&nbsp;μg/day and [[LDL cholesterol|LDL]] and [[HDL cholesterol]] levels at a dose as low as 2.5&nbsp;μg/day.<ref name="pmid22244780">{{cite journal | vauthors = Trémollieres F | title = [Oral combined contraception: is there any difference between ethinyl-estradiol and estradiol?] | language = fr | journal = Gynécologie, Obstétrique & Fertilité | volume = 40 | issue = 2 | pages = 109–115 | date = February 2012 | pmid = 22244780 | doi = 10.1016/j.gyobfe.2011.10.009 | trans-title = Oral combined contraception: is there any difference between ethinyl-estradiol and estradiol? }}</ref> EE affects several hepatic proteins at a dosage as low as 5&nbsp;µg/day.<ref name="OettelSchillinger2012" /> At doses above 20&nbsp;µg/day, the incremental effects of EE on liver protein synthesis become continuously smaller.<ref name="OettelSchillinger2012" />

EE at 5&nbsp;μg/day has been found to increase SHBG levels by 100% in postmenopausal women, while a dosage of 20&nbsp;µg/day EE increased them by 200%.<ref name="OettelSchillinger2012" /> Androgens decrease hepatic SHBG production, and have been found to oppose the effects of EE on SHBG levels.<ref name="OettelSchillinger2012" /> This is of particular relevance when it is considered that many progestins used in COCs have varying degrees of weak androgenic activity.<ref name="OettelSchillinger2012" /> A combination of 20&nbsp;µg/day EE and 0.25&nbsp;mg/day [[levonorgestrel]], a progestin with relatively high androgenicity, decreases SHBG levels by 50%; 30&nbsp;µg/day EE and 0.25&nbsp;mg/day levonorgestrel has no effect on SHBG levels; 30&nbsp;µg/day EE and 0.15&nbsp;mg/day levonorgestrel increases SHBG levels by 30%; and [[triphasic]] COCs containing EE and levonorgestrel increase SHBG levels by 100 to 150%.<ref name="OettelSchillinger2012" /> The combination of 30&nbsp;µg/day EE and 150&nbsp;µg/day [[desogestrel]], a progestin with relatively weak androgenicity than levonorgestrel, increases SHBG levels by 200%, while the combination of 35&nbsp;µg/day EE and 2&nbsp;mg/day [[cyproterone acetate]], a progestin with potent [[antiandrogen]]ic activity, increases SHBG levels by 400%.<ref name="OettelSchillinger2012" /> As such, the type and dosage of progestin contained in COCs potently moderates the effects of EE on SHBG levels.<ref name="OettelSchillinger2012" />

A dosage of 10&nbsp;µg/day EE has been found to increase CBG levels by 50%, while a dosage of 20&nbsp;µg/day EE increased them by 100%.<ref name="OettelSchillinger2012" /> Progestins that are progesterone derivatives have no effect on CBG levels, while androgenic progestins like the [[19-nortestosterone]] derivatives have only a weak effect on CBG levels.<ref name="OettelSchillinger2012" /> COCs may increase CBG levels by 100 to 150%.<ref name="OettelSchillinger2012" /> A dosage of 5&nbsp;µg/day EE has been found to increase TBG levels by 40%, while a dosage of 20&nbsp;µg/day EE increased them by 60%.<ref name="OettelSchillinger2012" /> Progestins that are progesterone derivatives do not affect TBG levels, while progestins with androgenic activity may decrease TBG levels.<ref name="OettelSchillinger2012" /> A combination of 30&nbsp;µg/day EE and 1&nbsp;mg/day [[norethisterone]], a moderately androgenic progestin, have been found to increase TBG levels by 50 to 70%, while the combination of 30&nbsp;µg/day EE and 150&nbsp;µg/day desogestrel increased them by 100%.<ref name="OettelSchillinger2012" />

====Differences from estradiol====
[[File:Levels of estrogen-sensitive proteins with oral estradiol valerate and ethinylestradiol in postmenopausal women.png|thumb|right|375px|Changes in levels of estrogen-sensitive proteins after treatment with oral estradiol or oral ethinylestradiol in postmenopausal women.<ref name="pmid2664738" /><ref name="pmid3817605" /> FSH is a pituitary protein and represents general/systemic estrogenic effect, while SHBG and {{abbrlink|PZP|pregnancy zone protein}} are hepatic proteins and represent liver estrogenic effect.<ref name="pmid2664738" /><ref name="pmid3817605" />]]
[[File:SHBG levels with polyestradiol phosphate, ethinylestradiol, and orchiectomy.png|thumb|right|400px|SHBG levels in men with 1) intramuscular injection of 320 mg [[polyestradiol phosphate]] once every 4 weeks alone; 2) the combination of intramuscular injection of 80 mg polyestradiol phosphate once every 4 weeks plus 150 µg/day oral ethinylestradiol; 3) orchiectomy only.<ref name="pmid3242384" />]]

EE shows strong and disproportionate effects on [[liver protein synthesis]] relative to estradiol.<ref name="pmid16112947" /> The [[liver]] as well as the [[uterus]] express [[17β-hydroxysteroid dehydrogenase]] (17β-HSD), and this [[enzyme]] serves to inactivate estradiol and effectively suppress its potency in these tissues by reversibly converting it into the far less potent estrogen [[estrone (medication)|estrone]] (which has approximately 4% of the estrogenic activity of estradiol).<ref name="pmid16112947" /> In contrast to estradiol, the 17α-ethynyl group of EE prevents [[oxidation]] of the C17β position of EE by 17β-HSD, and for this reason, EE is not inactivated in these tissues and has much stronger relative estrogenic activity in them.<ref name="pmid16112947" /><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=PA770|date=5 June 2007|publisher=Academic Press|isbn=978-0-08-055309-2|pages=177, 770–771}}</ref><ref name="Shellenberger1986">{{cite book| vauthors = Shellenberger TE |chapter=Pharmacology of estrogens|year=1986|pages=393–410|doi=10.1007/978-94-009-4145-8_36|title=The Climacteric in Perspective|isbn=978-94-010-8339-3|quote=Ethinyl estradiol is a synthetic and comparatively potent estrogen. As a result of the alkylation in 17-C position it is not a substrate for 17β dehydrogenase, an enzyme which transforms natural estradiol-17β to the less potent estrone in target organs.}}</ref> This is the mechanism of the disproportionately strong effects of EE on hepatic protein production,<ref name="pmid16112947" /><ref name="Lobo2007" /> which results in a greatly increased magnitude of effect on VTE and cardiovascular risks relative to estradiol.<ref name="Shoupe2011">{{cite book| vauthors = Shoupe D |title=Contraception|url=https://books.google.com/books?id=ksjJcx1CeKcC&pg=PA79|date=10 February 2011|publisher=John Wiley & Sons|isbn=978-1-4443-4263-5|pages=79–}}</ref>

On the other hand, due to the loss of inactivation of EE by 17β-HSD in the [[endometrium]] (uterus), EE is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence of [[vaginal bleeding|vaginal bleeding and spotting]] in comparison.<ref name="pmid16112947" /> This is particularly so in the case of combined estrogen and progestogen therapy (as in COCs or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium.<ref name="pmid16112947" /> The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol,<ref name="pmid22468839" /> in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).<ref name="pmid21538049">{{cite journal | vauthors = Sitruk-Ware R, Nath A | title = Metabolic effects of contraceptive steroids | journal = Reviews in Endocrine & Metabolic Disorders | volume = 12 | issue = 2 | pages = 63–75 | date = June 2011 | pmid = 21538049 | doi = 10.1007/s11154-011-9182-4 | s2cid = 23760705 }}</ref>

EE has been found to have disproportionate effects on liver protein synthesis and VTE risk regardless of whether the [[route of administration]] is oral, transdermal, or vaginal, indicating that the use of [[parenteral]] routes over the oral route does not result in EE having proportional hepatic actions relative to non-hepatic actions.<ref name="Lobo2007" /><ref name="OettelSchillinger2012" /> However, the potency of EE on liver protein synthesis is in any case reduced with parenteral administration.<ref name="OettelSchillinger2012" /> A dosage of 10&nbsp;µg/day vaginal EE has been found to be equivalent to 50&nbsp;µg oral EE in terms of effects on liver protein synthesis, such as stimulation of hepatic SHBG production.<ref name="OettelSchillinger2012" /> As such, parenteral EE, which bypasses the first pass through the liver that occurs with oral EE, has been found to have a 5-fold lower impact on liver protein synthesis by weight than oral EE.<ref name="OettelSchillinger2012" /> In contrast to EE as well as to oral estradiol, transdermal estradiol shows few or no effects on liver protein synthesis at typical menopausal dosages.<ref name="pmid16112947" />

{| class="wikitable"
|+ Comparison of estradiol and ethinylestradiol
! Parameters !! [[Estradiol (medication)|Estradiol]] !! Ethinylestradiol
|-
| {{abbrlink|ER|Estrogen receptor}} [[Affinity (pharmacology)|affinity]] || 1 × 10{{Sup|10}} M{{Sup|-1}} || 2–5 × 10{{Sup|11}} M{{Sup|-1}}
|-
| Nuclear retention || 6–8 hours || 24 hours
|-
| [[Elimination half-life]] || 90 minutes || 7 hours
|-
| [[Substrate (biochemistry)|Substrate]] for {{abbrlink|17β-HSD|17β-hydroxysteroid dehydrogenase}}? || Yes || No
|-
| [[Plasma protein binding|Bound]] to {{abbrlink|SHBG|Sex hormone-binding globulin}}? || Yes || No
|-
| Relative [[oral administration|oral]] [[liver]] [[potency (pharmacology)|potency]] || 1 || ~500–1,500
|-
| Relative [[oral administration|oral]] [[pituitary gland|pituitary]] potency || 1 || 200
|- class="sortbottom"
| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Sources:'''<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>
|}

===Pharmacokinetics===

====Absorption====
[[File:Ethinylestradiol levels following a single 20 µg oral dose of ethinylestradiol in women.png|thumb|right|350px|EE levels while [[fasting]] or with a high-[[fat]] meal following ingestion of [[tablet (pharmacy)|tablet]]s containing a single oral dose of 20&nbsp;µg EE and 2&nbsp;mg [[norethisterone acetate]] in women.<ref name="pmid12520628">{{cite journal | vauthors = Boyd RA, Zegarac EA, Eldon MA | title = The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy | journal = Journal of Clinical Pharmacology | volume = 43 | issue = 1 | pages = 52–58 | date = January 2003 | pmid = 12520628 | doi = 10.1177/0091270002239706 | s2cid = 27729272 }}</ref><ref name="pmid16112947" />]]

The [[oral administration|oral]] [[bioavailability]] of EE is 45% on average, with a wide range of 20% to 74% (though most commonly between 38 and 48%) that is due to high [[interindividual variability]].<ref name="pmid23375353" /><ref name="pmid8842581" /> Although relatively low, the oral bioavailability of EE is considerably higher than that of micronized estradiol (5%).<ref name="pmid2256522"/><ref name="pmid23375353" /> Following a single 20&nbsp;μg dose of EE in combination with 2&nbsp;mg [[norethisterone acetate]] in postmenopausal women, EE concentrations have been found to reach a maximum of 50&nbsp;pg/mL within an average of 1.5&nbsp;hours.<ref name="pmid16112947" /> Following the first dose, mean levels of EE in general further increase by about 50% until [[steady-state concentration]]s are reached;<ref name="pmid16112947" /><ref name="pmid12520628" /> steady-state is reached after one week of daily administration.<ref name="OettelSchillinger2012" /> For comparison, the mean peak levels of estradiol achieved with 2&nbsp;mg micronized estradiol or [[estradiol valerate]] are 40&nbsp;pg/mL following the first dose and 80&nbsp;pg/mL after three weeks of administration.<ref name="pmid16112947" /> These maximal concentrations of estradiol are in the same range as the concentrations of EE that are produced by an oral dose of EE that is 100&nbsp;times lower by weight, which is in accordance with the approximately 100-fold increased oral potency of EE relative to estradiol.<ref name="GomelMunro1990" /><ref name="pmid16112947" /> In accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels.<ref name="pmid16112947" /><ref name="DodickSilberstein2016" /> A dosage of EE of 50&nbsp;μg/day has been found to achieve a wide range of circulating EE levels of about 100 to 2,000&nbsp;pg/mL.<ref name="pmid6342899" /><ref name="DodickSilberstein2016">{{cite book| vauthors = Dodick D, Silberstein SD |title=Migraine|url=https://books.google.com/books?id=Y-wmDAAAQBAJ&pg=PA272|year=2016|publisher=Oxford University Press|isbn=978-0-19-979361-7|pages=272–}}</ref> Taking EE in combination with a high-[[fat]] meal has been found to significantly decrease its peak concentrations.<ref name="pmid12520628" /><ref name="pmid16112947" />

EE levels after a single 50&nbsp;μg dose by intravenous injection are several times higher than levels of EE after a single 50&nbsp;mg dose given orally.<ref name="pmid6342899">{{cite journal | vauthors = Orme ML, Back DJ, Breckenridge AM | title = Clinical pharmacokinetics of oral contraceptive steroids | journal = Clinical Pharmacokinetics | volume = 8 | issue = 2 | pages = 95–136 | date = 1983 | pmid = 6342899 | doi = 10.2165/00003088-198308020-00001 | s2cid = 43298472 }}</ref> Besides the difference in levels, the course of elimination is similar for the two routes.<ref name="pmid6342899" />

There may be gender-specific differences in the [[pharmacokinetics]] of EE, such that EE may have greater oral potency in women than in men.<ref name="OettelSchillinger2012" /> A study found that a combination of 60&nbsp;μg/day EE and 0.25&nbsp;mg/day [[levonorgestrel]] in women and men resulted in peak levels of EE of 495&nbsp;pg/mL and 251&nbsp;pg/mL, [[area-under-the-curve level]]s of EE of 6.216&nbsp;pg/mL/hour and 2.850&nbsp;pg/mL/hour, and [[elimination half-lives]] of 16.5&nbsp;hours and 10.2&nbsp;hours, respectively.<ref name="OettelSchillinger2012" /> It has been suggested that this phenomenon could represent a "protection mechanism" of males against [[xenoestrogen|environmental estrogen]] exposure.<ref name="OettelSchillinger2012" />

====Distribution====
The [[plasma protein binding]] of EE is 97 to 98%, and it is bound almost exclusively to [[human serum albumin|albumin]].<ref name="(Firm)Inc2005" /><ref name="pmid16112947" /><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><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=PA395|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-4145-8|pages=395–}}</ref> Unlike estradiol, which binds with high affinity to SHBG, EE has very low affinity for this protein, about 2% of that of estradiol, and hence does not bind to it importantly.<ref name="pmid7195405">{{cite journal | vauthors = Pugeat MM, Dunn JF, Nisula BC | title = Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 53 | issue = 1 | pages = 69–75 | date = July 1981 | pmid = 7195405 | doi = 10.1210/jcem-53-1-69 }}</ref>

====Metabolism====
Due to high first-pass metabolism in the [[intestine]]s and [[liver]], only 1% of an oral dose of an EE appears in the circulation as EE itself.<ref name="pmid16112947" /> During first-pass metabolism, EE is extensively [[conjugation (pharmacokinetics)|conjugated]] via [[glucuronidation]] and [[sulfation]] into the hormonally inert ethinylestradiol [[glucuronide]]s and [[ethinylestradiol sulfate]] (EE sulfate), and levels of EE sulfate in circulation are between 6- and 22-fold higher than those of EE.<ref name="pmid16112947" /><ref name="pmid8842581" /> For comparison, with oral administration of 2&nbsp;mg micronized estradiol, levels of [[estrone (medication)|estrone]] and [[estrone sulfate (medication)|estrone sulfate]] are 4- to 6-fold and 200-fold higher than those of estradiol, respectively.<ref name="pmid16112947" /> In contrast to estradiol, EE, due to [[steric hindrance]] by its C17α ethynyl group, is not metabolized or inactivated by 17β-HSD,<ref name="Shellenberger1986" /> and this is the primary factor responsible for the dramatically increased potency of oral EE relative to oral estradiol.<ref name="pmid16112947" /> EE is also not metabolized into estradiol.<ref name="pmid30809949">{{cite journal | vauthors = Backeljauw P, Klein K | title = Sex hormone replacement therapy for individuals with Turner syndrome | journal = American Journal of Medical Genetics. Part C, Seminars in Medical Genetics | volume = 181 | issue = 1 | pages = 13–17 | date = March 2019 | pmid = 30809949 | doi = 10.1002/ajmg.c.31685 | s2cid = 73487051 }}</ref>

Aside from sulfate conjugation, EE is mainly [[metabolism|metabolized]] by [[hydroxylation]] into [[catechol estrogen]]s.<ref name="pmid16112947" /> This is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily by [[CYP3A4]].<ref name="pmid23375353" /> Hydroxylation of EE at the C4, C6α, and C16β positions into 4-, 6α-, and 16β-hydroxy-EE has also been reported, but appears to contribute to its metabolism to only a small extent.<ref name="pmid23375353" /> 2- and 4-methoxy-EE are also formed via transformation by [[catechol O-methyltransferase]] of 2- and 4-hydroxy-EE.<ref name="pmid16112947" /> Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to [[steric hindrance]] by its ethynyl group at C17α.<ref name="pmid23375353" /><ref name="pmid16112947" /> The ethynylation of EE is largely irreversible, and so EE is not metabolized into estradiol, unlike [[estradiol ester]]s.<ref name="pmid16112947" /> A review found that the range of the reported [[elimination half-life]] of EE in the literature was 13.1 to 27.0 hours.<ref name="pmid2256522"/> Another review reported an elimination half-life of EE of 10 to 20 hours.<ref name="pmid23375353" /> However, the elimination half-life of EE has also been reported by other sources to be as short as 7 hours<ref name="Shellenberger1986" /> and as long as 36 hours.<ref name="HughesWaters2016" />

Unlike the case of estradiol, in which there is a rapid rise in its levels and which remain elevated in a plateau-like curve for many hours, levels of EE fall rapidly after peaking.<ref name="pmid16112947" /> This is thought to be because estrone and estrone sulfate can be reversibly converted back into estradiol and serve as a hormonally inert reservoir for estradiol, whereas the EE sulfate reservoir for EE is much smaller in comparison.<ref name="pmid16112947" /><ref name="pmid8842581" /> In any case, due to the formation of EE sulfate, [[enterohepatic recirculation]] is involved in the [[pharmacokinetics]] of EE similarly to estradiol, although to a lesser extent.<ref name="pmid16112947" /><ref name="pmid25099693">{{cite journal | vauthors = Mattison DR, Karyakina N, Goodman M, LaKind JS | title = Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps | journal = Critical Reviews in Toxicology | volume = 44 | issue = 8 | pages = 696–724 | date = September 2014 | pmid = 25099693 | doi = 10.3109/10408444.2014.930813 | s2cid = 11212469 }}</ref> The contribution of enterohepatic recirculation to total circulating EE levels appears to be 12 to 20% or less, and is not observed consistently.<ref name="OettelSchillinger2012" /><ref name="pmid25099693" /> A secondary peak in EE levels 10 to 14&nbsp;hours after administration can often be observed with oral EE.<ref name="pmid25099693" />

EE, following [[oxidation|oxidative]] formation of a very reactive [[metabolite]], [[irreversible inhibition|irreversibly inhibit]]s [[cytochrome P450]] [[enzyme]]s involved in its metabolism, and this may also play a role in the increased potency of EE relative to estradiol.<ref name="pmid16112947" /> Indeed, EE is said to have a marked effect on hepatic metabolism, and this is one of the reasons, among others, that natural estrogens like estradiol may be preferable.<ref name="NotelovitzKeep2012" /> A 2-fold accumulation in EE levels with an EE-containing COC has been observed following 1&nbsp;year of therapy.<ref name="pmid25099693" />

====Elimination====
EE is [[elimination (pharmacokinetics)|eliminated]] 62% in the [[feces]] and 38% in the [[urine]].<ref name="pmid23375353" />

==Chemistry==
EE, also known as 17α-ethynylestradiol or as 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol, is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[estradiol (medication)|estradiol]] with an [[ethynyl group|ethynyl substitution]] at the C17α position.<ref name="Elks2014" /><ref name="IndexNominum2000" /> The 17α-ethynylation of estradiol to create EE is analogous to the 17α-substitution of [[testosterone (medication)|testosterone]] to make testosterone derivatives such as 17α-ethynylated progestins like [[ethisterone]] (17α-ethynyltestosterone) and [[norethisterone]] (17α-ethynyl-19-nortestosterone) as well as [[17α-alkylated anabolic steroid|17α-alkylated]] [[androgen]]s/[[anabolic steroid]]s like [[methyltestosterone]] (17α-methyltestosterone).

===Analogues===
{{See also|List of estrogens#17α-Substituted estradiol derivatives}}

A number of [[chemical derivative|derivative]]s of EE exist.<ref name="Elks2014" /><ref name="IndexNominum2000" /> These include [[mestranol]] (EE 3-methyl ether), [[quinestrol]] (EE 3-cyclopentyl ether), [[ethinylestradiol sulfonate]] (EE 3-isopropylsulfonate), and [[moxestrol]] (11β-methoxy-EE).<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="OettelSchillinger2012" /> The former three are [[prodrug]]s of EE, while the latter one is not.<ref name="OettelSchillinger2012" /> A few [[structural analog|analogue]]s of EE with other [[substituent|substitution]]s at the C17α position exist.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Examples include the estradiol derivatives [[methylestradiol]] (17α-methylestradiol) and [[ethylestradiol]] (17α-ethylestradiol), and the [[estriol (medication)|estriol]] derivatives [[ethinylestriol]] (17α-ethynylestriol) and [[nilestriol]] (17α-ethynylestriol 3-cyclopentyl ether).<ref name="Elks2014" /><ref name="IndexNominum2000" /> [[Androstane]] analogues of EE with significant although weak estrogenic activity include [[ethinylandrostenediol]] (17α-ethynyl-5-androstenediol), [[17α-ethynyl-3β-androstanediol]], [[17α-ethynyl-3α-androstanediol]], and [[methandriol]] (17α-methyl-5-androstenediol).

==History==
EE was the first orally active synthetic estrogen and was described in 1938 by Hans Herloff Inhoffen and Walter Hohlweg of [[Schering AG]] in [[Berlin]].<ref name="Inhoffen 1938">{{Cite journal | vauthors = Inhoffen HH, Hohlweg W | doi = 10.1007/BF01681040 | title = Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Aethinyl-oestradiol und Pregnen-in-on-3-ol-17 (New female glandular derivatives active per os: 17α-ethynyl-estradiol and pregnen-in-on-3-ol-17) | journal = [[Die Naturwissenschaften|Naturwissenschaften]] | volume = 26 | issue = 6 | page = 96| year = 1938 | bibcode = 1938NW.....26...96I| s2cid = 46648877 }}</ref><ref name="Maisel 1965">{{cite book | vauthors = Maisel AQ |year=1965 |title=The Hormone Quest |location=New York |publisher=Random House |oclc=543168}}</ref><ref name="Petrow 1970">{{cite journal | vauthors = Petrow V | title = The contraceptive progestagens | journal = Chemical Reviews | volume = 70 | issue = 6 | pages = 713–726 | date = December 1970 | pmid = 4098492 | doi = 10.1021/cr60268a004 }}</ref><ref name="Sneader 2005">{{cite book | vauthors = Sneader W |year=2005 |title=Drug discovery: a history |url=https://archive.org/details/drugdiscoveryhis00snea |url-access=limited |location=Hoboken, NJ |publisher=John Wiley & Sons |isbn=978-0-471-89980-8 |chapter=Hormone analogues |pages=[https://archive.org/details/drugdiscoveryhis00snea/page/n201 188]–225}}</ref><ref name="Djerassi 2006">{{cite journal | vauthors = Djerassi C | title = Chemical birth of the pill. 1992 | journal = American Journal of Obstetrics and Gynecology | volume = 194 | issue = 1 | pages = 290–298 | date = January 2006 | pmid = 16389046 | doi = 10.1016/j.ajog.2005.06.010 }}</ref> It was approved by the US [[Food and Drug Administration]] (FDA) in June 1943, and marketed by [[Schering-Plough|Schering]] under the brand name Estinyl.<ref name="Estinyl 1943">{{cite web |author=U.S. [[Food and Drug Administration]] (FDA) |year=2007 |title=Approval history: Estinyl (ethinyl estradiol) NDA 005292 |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=005292&DrugName=ESTINYL&ActiveIngred=ETHINYL%20ESTRADIOL&SponsorApplicant=SCHERING&ProductMktStatus=3&goto=Search.Label_ApprovalHistory }} search: Estinyl</ref> The FDA withdrew approval of Estinyl effective 4 June 2004 at the request of [[Schering AG|Schering]], which had discontinued marketing it.<ref name="Estinyl 2004">{{cite journal |author=U.S. [[Food and Drug Administration]] (FDA) |date=5 May 2004 |title=Schering Corp. et al.; Withdrawal of Approval of 92 New Drug Applications and 49 Abbreviated New Drug Applications. Notice |journal=[[Federal Register]] |volume=69 |issue=87 |pages=25124–30 |url=http://edocket.access.gpo.gov/2004/pdf/04-10194.pdf }}</ref>

EE was never introduced for use by [[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>

EE was first used in COCs, as an alternative to [[mestranol]], in 1964, and shortly thereafter superseded mestranol in COCs.<ref name="GruhnKazer2013">{{cite book| vauthors = Gruhn JG, Kazer RR |title=Hormonal Regulation of the Menstrual Cycle: The Evolution of Concepts|url=https://books.google.com/books?id=lFn0BwAAQBAJ&pg=PA185|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4899-3496-3|pages=185–|quote=In 1964, ethinyl estradiol was introduced as an alternative to mestranol as the estrogenic component, [...]}}</ref>

Early COCs contained 40 to 100&nbsp;μg/day EE and 50 to 150&nbsp;μg/day mestranol.<ref name="BellerKnörr1974">{{cite book| vauthors = Beller FK, Knörr K, Lauritzen C, Wynn RM |title=Gynecology|chapter=Family Planning|year=1974|pages=189–213|doi=10.1007/978-1-4615-7128-5_17|isbn=978-0-387-90087-2}}</ref><ref name="Haller1968">{{cite book| vauthors = Haller J |title=Die Gestagene|chapter=Die antikonzeptionelle Therapie|year=1968|pages=1125–1178|doi=10.1007/978-3-642-99941-3_8|isbn=978-3-642-99942-0}}</ref>

==Society and culture==

===Generic names===
''Ethinylestradiol'' is the [[English language|English]] [[generic drug|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Drugs.com">{{cite web|url=https://www.drugs.com/international/ethinylestradiol.html|title=Ethinylestradiol - Drugs.com}}</ref><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=PA522|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=522–}}</ref><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=PA115|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=115–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1321|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|page=412}}</ref> It has also been spelled as ''ethynylestradiol'', ''ethynyloestradiol'', and ''ethinyloestradiol'' (all having the same pronunciation), and the latter was formerly its {{abbrlink|BAN|British Approved Name}} but was eventually changed.<ref name="Drugs.com" /><ref name="Elks2014" /><ref name="IndexNominum2000" /> In addition, a space is often included in the name of EE such that it is written as ''ethinyl estradiol'' (as well as variations thereof), and this is its {{abbrlink|USP|United States Pharmacopeia}} name.<ref name="Drugs.com" /><ref name="IndexNominum2000" /> The generic name of EE in [[French language|French]] and its {{abbrlink|DCF|Dénomination Commune Française}} are ''éthinylestradiol'', in [[Spanish language|Spanish]] is ''etinilestradiol'', in [[Italian language|Italian]] and its {{abbrlink|DCIT|Denominazione Comune Italiana}} are ''etinilestradiolo'', and in [[Latin language|Latin]] is ''ethinylestradiolum''.<ref name="Drugs.com" /><ref name="IndexNominum2000" />

The name of the drug is often abbreviated as ''EE'' or as ''EE2'' in the [[medical literature]].

===Brand names===
EE has been marketed as a standalone oral drug under the brand names ''Esteed'', ''Estinyl'', ''Feminone'', ''Lynoral'', ''Menolyn'', ''Novestrol'', ''Palonyl'', ''Spanestrin'', and ''Ylestrol'' among others, although most or all of these formulations are now discontinued.<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 = Ethinyl Estradiol [Estinyl, Feminone, Lynoral, Novestrol, Palonyl]}}</ref><ref name="Pharmaceuticals1983">{{cite book|author=American Society of Hospital Pharmacists. Committee on Pharmacy and Pharmaceuticals|title=American Hospital Formulary Service: A Two-volume Collection of Drug Monographs and Other Information|url=https://books.google.com/books?id=bO0jAQAAMAAJ|year=1983|publisher=American Society of Hospital Pharmacists|isbn=978-0-930530-02-0|quote=ETHINYL ESTRADIOL U.S.P. (Esteed®, Estinyl®, Lynoral®, Menolyn®, Novestrol®, Palonyl®, Spanestrin®, Ylestrol®)}}</ref><ref name="IndexNominum2000" /> It is marketed under a very large number of brand names throughout the world in combination with progestins for use as an oral contraceptive.<ref name="Drugs.com" /> In addition, EE is marketed in the {{abbr|U.S.|United States}} in combination with [[norelgestromin]] under the brand names ''[[Ortho Evra]]'' and ''[[Xulane]]'' as a [[contraceptive patch]], in combination with [[etonogestrel]] under the brand name ''[[NuvaRing]]'' as a [[contraceptive vaginal ring]], and in combination with [[norethisterone acetate]] under the brand name ''[[FemHRT]]'' in oral hormone replacement therapy for the treatment of menopausal symptoms.<ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = U.S. [[Food and Drug Administration]] (FDA) | access-date = 22 December 2016 | url = http://www.accessdata.fda.gov/scripts/cder/daf/}}</ref>

===Availability===
Ethinylestradiol is marketed throughout the world.<ref name="Drugs.com" /><ref name="IndexNominum2000" /> It is marketed exclusively or almost exclusively in combination with progestins.<ref name="Drugs.com" />

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{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|pages=4,10,15,165,247–248,276–291,363–408,424,514,540,543,581}}
* {{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 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 }}
* {{cite journal | vauthors = Mattison DR, Karyakina N, Goodman M, LaKind JS | title = Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps | journal = Critical Reviews in Toxicology | volume = 44 | issue = 8 | pages = 696–724 | date = September 2014 | pmid = 25099693 | doi = 10.3109/10408444.2014.930813 | s2cid = 11212469 }}
{{refend}}

{{Estrogens and antiestrogens}}
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