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			{{Short description|Estrogen medication}}
	{{Drugbox
			{{Distinguish|Estrogen conjugate|Esterified estrogens}}
	| verifiedrevid = 447130674
			{{Use dmy dates|date=March 2024}}
			{{cs1 config|name-list-style=vanc|display-authors=6}}
			{{Infobox drug
			| Verifiedfields = verified
			| Watchedfields = verified
			| verifiedrevid = 455284681
			| type = combo
			| image = Estrone sulfate.svg
			| width = 225
			| alt =
			| caption = ], the primary active component in conjugated estrogens (constitutes about 50 to 70% of total content)
			| image2 = Equilin sulfate.svg
			| width2 = 225
			| alt2 =
			| caption2 = ], the second most major active component in conjugated estrogens (constitutes about 20 to 30% of total content)
	<!--Combo data-->		<!-- Combo data -->
			| component1 = Estrone sulfate
	| type = combo
			| class1 = ]
	| component1 = Estrone sulfate
			| component2 = Equilin sulfate
	| class1 = Estrogen
			| class2 = ]
	| component2 = Equilin sulfate
			| component3 = 17α-Dihydro-equilin sulfate
	| class2 = Estrogen
			| class3 = ]
	| component3 = Equilenin sulfate
	| class3 = Estrogen
	<!--Clinical data-->		<!-- Clinical data -->
	| tradename =		| tradename = Cenestin, Enjuvia, Premarin, others
	| Drugs.com = {{drugs.com|CDI|premarin}}		| Drugs.com = {{drugs.com|mtm|conjugated-estrogens-vaginal}}
			| pregnancy_category =
	| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
			| routes_of_administration = ], ], ], ], ]<ref name="pmid16112947" /><ref name="Drugs@FDA" />
	| pregnancy_US = <!-- A / B / C / D / X -->
			| class = ]
	| pregnancy_category = X
			| ATC_prefix = G03
	| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
			| ATC_suffix = CA57
	| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
	| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
	| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
	| legal_status = Rx-only
	| routes_of_administration = ], ]
			| legal_status = Rx-only
	<!--Pharmacokinetic data-->
	| protein_bound = >90%
	| elimination_half-life = 7.2 hours
	| excretion = renal
	<!--Identifiers-->		<!-- Pharmacokinetic data -->
			| bioavailability = Variable<ref name="PremarinLabel" />
	| CAS_number = 12126-59-9
			| protein_bound = High (to ] and {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="PremarinLabel" /><ref name="pmid16112947" />
	| ATC_prefix = G03
			| metabolism = ]<ref name="PremarinLabel" /><ref name="pmid16112947" />
	| ATC_suffix = CA57
			| elimination_half-life = ]: 26.7 hours<br />Estrone ({{abbr|BA|baseline-adjusted}}): 14.8 hours<br />]: 11.4 hours<ref name="DrugBank" />{{Unreliable medical source|date=March 2024}}
	| PubChem = 656613
			| excretion = ]<ref name="PremarinLabel" />
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 570974
	| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = IU5QR144QX
	<!--Chemical data-->		<!-- Identifiers -->
			| CAS_number_Ref = {{cascite|correct|CAS}}
	| smiles = .S(=O)(=O)Oc1ccc2c(c1)C/C=C3\2CC4(C(=O)CC34)C
			| CAS_number = 12126-59-9
	| InChI = 1/C18H20O5S.Na/c1-18-9-8-14-13-5-3-12(23-24(20,21)22)10-11(13)2-4-15(14)16(18)6-7-17(18)19;/h3-5,10,14,16H,2,6-9H2,1H3,(H,20,21,22);/q;+1/p-1/t14-,16+,18+;/m1./s1
			| PubChem = 656613
	| InChIKey = QTTMOCOWZLSYSV-ASRZMYKCBJ
			| DrugBank = DB00286
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| StdInChI = 1S/C18H20O5S.Na/c1-18-9-8-14-13-5-3-12(23-24(20,21)22)10-11(13)2-4-15(14)16(18)6-7-17(18)19;/h3-5,10,14,16H,2,6-9H2,1H3,(H,20,21,22);/q;+1/p-1/t14-,16+,18+;/m1./s1
			| ChemSpiderID = 570974
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
			| UNII_Ref = {{fdacite|correct|FDA}}
	| StdInChIKey = QTTMOCOWZLSYSV-QWAPEVOJSA-M
			| UNII = IU5QR144QX
	| synonyms = conjugated estrogens
			| KEGG = D04070
			| ChEBI = 8389
			| ChEMBL = 1201649
			| synonyms = CEs; Conjugated equine estrogens; CEEs; Pregnant mares' urine; Estrogens, conjugated
	}}		}}
			<!-- Definition and medical uses -->
			'''Conjugated estrogens''' ('''CEs'''), or '''conjugated equine estrogens''' ('''CEEs'''), sold under the brand name '''Premarin''' among others, is an ] medication which is used in ] and for various other indications.<ref name="Martindale">{{cite book | veditors = Sweetman SC |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |page=2087 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1|chapter-url=https://www.medicinescomplete.com/mc/rem/current/mono-E61.htm?q=C&t=advanced&ss=mn&p=57}}</ref><ref name="PremarinLabel">{{cite web|url=http://labeling.pfizer.com/showlabeling.aspx?id=131 |title=PREMARIN- estrogens, conjugated tablet, film coated Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. |website=labeling.pfizer.com |access-date=3 June 2019}}</ref><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="FritzSperoff2012">{{cite book| vauthors = Fritz MA, Speroff L |title=Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=KZLubBxJEwEC&pg=PA751|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4847-3|pages=751–3}}</ref> It is a ] of the ] ]s of ]s found in ]s, such as ] and ].<ref name="pmid16112947" /><ref name="FritzSperoff2012"/><ref name="Martindale" /> CEEs are available in the form of both ] preparations manufactured from the ] of ] ]s and fully ] replications of the natural preparations.<ref name="MoscouSnipe2012">{{cite book | vauthors = Moscou K, Snipe K |title=Pharmacology for Pharmacy Technicians Pageburst E-Book on VitalSource2: Pharmacology for Pharmacy Technicians Pageburst E-Book on VitalSource|url=https://books.google.com/books?id=1nvESqVnxc0C&pg=PA573|date=1 December 2012|publisher=Elsevier Health Sciences|isbn=978-0-323-08578-6|pages=573–}}</ref><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=PA378|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=378–}}</ref> They are formulated both alone and in combination with ]s such as ].<ref name="Martindale" /> CEEs are usually taken ], but can also be given by ] or ] as a ] or by ] or ].<ref name="pmid16112947" /><ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 19 February 2018 | url = http://www.accessdata.fda.gov/scripts/cder/daf/}}</ref>
	'''Premarin''' is the commercial name for compound drug consisting primarily of conjugated ]s. Isolated from ] ] ('''PRE'''gnant '''MAR'''es' ur'''IN'''e), it is manufactured by ] ]s (part of ] since January 2009) and has been marketed since 1942. It is available in oral (0.3/ 0.45/ 0.625/ 0.9/ 1.25&nbsp;mg), IV, and topical form.
			<!-- Side effects and mechanism of action -->
			]s of CEEs include ] and ], ], ], and ] among others.<ref name="PremarinLabel" /><ref name="pmid16112947" /> It may increase the risk of ] and ] in women with an intact ] if it is not taken together with a ] like ].<ref name="PremarinLabel" /><ref name="pmid16112947" /> The medication may also increase the risk of ]s, ], and, when combined with most progestogens, ].<ref name="pmid28664754">{{cite journal | vauthors = Pickar JH, Archer DF, Kagan R, Pinkerton JV, Taylor HS | title = Safety and benefit considerations for menopausal hormone therapy | journal = Expert Opinion on Drug Safety | volume = 16 | issue = 8 | pages = 941–954 | date = August 2017 | pmid = 28664754 | doi = 10.1080/14740338.2017.1343298 | s2cid = 24155838 }}</ref> CEEs are estrogens, or ]s of the ], the ] of ]s like ].<ref name="pmid16112947" /><ref name="PremarinLabel" /> Compared to estradiol, certain estrogens in CEEs are more resistant to metabolism, and the medication shows relatively increased effects in certain parts of the body like the ].<ref name="pmid16112947" /> This results in an increased risk of blood clots and cardiovascular problems with CEEs relative to estradiol.<ref name="pmid16112947" /><ref name="pmid25223916">{{cite journal | vauthors = Scarabin PY | title = Hormones and venous thromboembolism among postmenopausal women | journal = Climacteric | volume = 17 | issue = Suppl 2 | pages = 34–37 | date = December 2014 | pmid = 25223916 | doi = 10.3109/13697137.2014.956717 | s2cid = 5084606 }}</ref>
			<!-- History, society, and culture -->
			Premarin, the major brand of CEEs in use, is manufactured by ] and was first marketed in 1941 in ] and in 1942 in the ].<ref name="FritzSperoff2012"/> It is the most commonly used form of estrogen in menopausal hormone therapy in the United States.<ref name="pmid24176763" /><ref name="Quereda2017">{{cite book| vauthors = Quereda F |title=Menopause|year=2017|pages=181–196|doi=10.1007/978-3-319-59318-0_11|isbn=978-3-319-59317-3|chapter=Hormone Therapy (I): Estrogens, Progestogens, and Androgens|publisher=Springer }}</ref> However, it has begun to fall out of favor relative to ] ], which is the most widely used form of estrogen in ] for menopausal hormone therapy.<ref name="Quereda2017" /><ref name="pmid28301216">{{cite journal | vauthors = L'Hermite M | title = Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal | journal = Climacteric | volume = 20 | issue = 4 | pages = 331–338 | date = August 2017 | pmid = 28301216 | doi = 10.1080/13697137.2017.1291607 | s2cid = 4771048 }}</ref><ref name="pmid24398406">{{cite journal | vauthors = Simon JA | title = What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead? | journal = Menopause | volume = 21 | issue = 7 | pages = 769–783 | date = July 2014 | pmid = 24398406 | doi = 10.1097/GME.0000000000000169 | s2cid = 30292136 }}</ref><ref name="pmid19179815">{{cite journal | vauthors = Holtorf K | title = The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? | journal = Postgraduate Medicine | volume = 121 | issue = 1 | pages = 73–85 | date = January 2009 | pmid = 19179815 | doi = 10.3810/pgm.2009.01.1949 | s2cid = 2060730 }}</ref> CEEs are available widely throughout the world.<ref name="Martindale" /> An estrogen preparation very similar to CEEs but differing in source and composition is ].<ref name="pmid16112947" /> In 2020, it was the 283rd most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref name="DrugStats2017">{{cite web | title = The Top 300 of 2020 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date = 7 October 2022}}</ref><ref>{{cite web | title = Estrogens, Conjugated - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EstrogensConjugated | access-date = 7 October 2022}}</ref>
			{{TOC limit}}
			==Medical uses==
			CEEs are a form of ] used in women.<ref>{{cite book |title = Women's vascular health |url=https://books.google.com/books?id=GsPie79hwsIC&pg=PA222 |publisher = CRC Press |date =29 December 2006 |isbn=978-0-340-80997-6 |language = en | vauthors = Greer IA, Ginsberg J, Forbes C }}</ref> It is used most commonly in ] women who have had a ] to treat ]es, and burning, itching, and dryness of the vagina and surrounding areas.<ref>{{cite book |title =Nezhat's Operative gynecologic laparoscopy and hysteroscopy |url = https://books.google.com/books?id=Z0gYy2hdn3QC&pg=PA266 |publisher = Cambridge University Press |date = 7 July 2008 |access-date = 7 May 2015 |isbn = 978-1-139-47200-5 | language = en| vauthors = Nezhat C, Nezhat F, Nezhat C }}</ref> It must be used in combination with a ] in women who have not had a ].<ref name="pmid16112947" /> For women already taking the medication, it can be used to treat ], although it is not recommended solely for this use.<ref>{{cite journal | vauthors = Maeda SS, Lazaretti-Castro M | title = An overview on the treatment of postmenopausal osteoporosis | journal = Arquivos Brasileiros de Endocrinologia e Metabologia | volume = 58 | issue = 2 | pages = 162–171 | date = March 2014 | pmid = 24830593 | doi = 10.1590/0004-2730000003039 | doi-access = free }}</ref> Some lesser known uses are as a means of ] therapy in the treatment of ] in both women and men and in the treatment of ] in men.<ref>{{cite journal | vauthors = Majeed W, Aslam B, Javed I, Khaliq T, Muhammad F, Ali A, Raza A | title = Breast cancer: major risk factors and recent developments in treatment | journal = Asian Pacific Journal of Cancer Prevention | volume = 15 | issue = 8 | pages = 3353–3358 | date = 2014 | pmid = 24870721 | doi = 10.7314/apjcp.2014.15.8.3353 | doi-access = free }}</ref><ref>{{cite book|title = 2015 Nurse's Drug Handbook|url = https://books.google.com/books?id=o_vPBgAAQBAJ&q=premarin+prostate+cancer&pg=PA448|publisher = Jones & Bartlett Publishers|date = 14 January 2015|access-date = 7 May 2015|isbn = 978-1-284-09137-3|language = en }}</ref> It has been used at a dosage of 2.5&nbsp;mg three times per day (7.5&nbsp;mg/day total) for prostate cancer.<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=PA540|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=540–}}</ref><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>
			CEEs are specifically approved in countries such as the ] and ] for the treatment of moderate to severe ] ]s (hot flashes) and ] (atrophic vaginitis, atrophic urethritis) associated with ], ] due to ], ], or ], ], the ] treatment of ] in women, the palliative treatment of ] ] ] in men, and the prevention of ] ].<ref name="DrugBank" /><ref name="Drugs.com-Premarin">{{cite web | url=https://www.drugs.com/international/premarin.html | title=Premarin}}</ref><ref name="Martindale" /> The intravenous formulation of CEEs is specifically used to rapidly ] in women with ] due to ].<ref name="Drugs@FDA" /><ref name="HorskyPresl1981e">{{cite book | vauthors = Horský J, Presl J | title=Ovarian Function and its Disorders | chapter=Hormonal Treatment of Disorders of the Menstrual Cycle | series=Developments in Obstetrics and Gynecology | pages = 309–332 | doi = 10.1007/978-94-009-8195-9_11 | veditors = Horsky J, Presl J | chapter-url = https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA310 | date = 1981 | publisher = Springer Science & Business Media | isbn = 978-94-009-8195-9}}</ref>{{Rp|318}}<ref name="Piersol1975">{{cite book| vauthors = Piersol GM |title=The Cyclopedia of Medicine, Surgery, Specialties|url=https://books.google.com/books?id=RiE9K5bgKcsC|year=1975|publisher=F. A. Davis Company}}</ref>{{RP|60}}
			{{Estrogen dosages for menopausal hormone therapy}}
			===Available forms===
			{{See also|Conjugated estrogens/medroxyprogesterone acetate|Conjugated estrogens/norgestrel|Conjugated estrogens/methyltestosterone|Conjugated estrogens/bazedoxifene}}
			Natural CEEs, as Premarin, are available in the form of ] ]s (0.3&nbsp;mg, 0.625&nbsp;mg, 0.9&nbsp;mg, 1.25&nbsp;mg, or 2.5&nbsp;mg), ]s for ] or ] (0.625&nbsp;mg/g), and ]s for ] or ] (25&nbsp;mg/vial).<ref name="Drugs@FDA" /><ref name="MorleyBerg1999">{{cite book | vauthors = Morley JE, van den Berg L |title=Endocrinology of Aging|url=https://books.google.com/books?id=hGD0BwAAQBAJ&pg=PA172|date=5 November 1999|publisher=Springer Science & Business Media|isbn=978-1-59259-715-4|pages=172–}}</ref> Synthetic CEEs, such as Cenestin (Synthetic A), Enjuvia (Synthetic B), and generic formulations, are available in the form of oral tablets (0.3&nbsp;mg, 0.45&nbsp;mg, 0.625&nbsp;mg, 0.9&nbsp;mg, or 1.25&nbsp;mg) and creams for topical or vaginal administration (0.625&nbsp;mg/g).<ref name="Drugs@FDA" /><ref name="Shorr2007">{{cite book| vauthors = Shorr RI |title=Drugs for the Geriatric Patient E-Book: Text with BONUS Handheld Software|url=https://books.google.com/books?id=-gmjBQAAQBAJ&pg=PA462|date=11 April 2007|publisher=Elsevier Health Sciences|isbn=978-1-4377-1035-9|pages=462–}}</ref>
			==Contraindications==
			{{See also|Estrogen (medication)#Contraindications}}
			]s of CEEs include ] and a history of ], among others.{{Citation needed|date=July 2018}}
			==Side effects==
			The most common ]s associated with CEEs are vaginal ]s, ], ], and ]ing of the legs. While there are some contradictory data, estrogen alone does not appear to increase the risk of ] or breast cancer, unlike the case of estrogen in combination with certain ]s such as ] or ].<ref>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121062.htm |title=Premarin (Conjugated estrogens) Vaginal Cream |website=] |access-date=20 February 2018 |archive-url=https://web.archive.org/web/20161026041953/https://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121062.htm |archive-date=26 October 2016 |url-status=dead }}</ref> Only a few clinical studies have assessed differences between oral CEEs and oral estradiol in terms of health parameters.<ref name="pmid26327865">{{cite journal | vauthors = Bińkowska M | title = Menopausal hormone therapy and venous thromboembolism | journal = Przeglad Menopauzalny = Menopause Review | volume = 13 | issue = 5 | pages = 267–272 | date = October 2014 | pmid = 26327865 | pmc = 4520375 | doi = 10.5114/pm.2014.46468 }}</ref> Oral CEEs have been found to possess a significantly greater risk of ] and ] complications than oral estradiol ({{abbrlink|OR|Odds ratio}} = 2.08) and oral ] ({{abbrlink|OR|Odds ratio}} = 1.78).<ref name="pmid26327865" /><ref name="pmid24081194">{{cite journal | vauthors = Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS, Hwang M, Bis JC, McKnight B, Rice KM, Lumley T, Rosendaal FR, Heckbert SR, Psaty BM | title = Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens | journal = JAMA Internal Medicine | volume = 174 | issue = 1 | pages = 25–31 | date = January 2014 | pmid = 24081194 | pmc = 4636198 | doi = 10.1001/jamainternmed.2013.11074 }}</ref><ref name="pmid15467060">{{cite journal | vauthors = Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM | title = Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis | journal = JAMA | volume = 292 | issue = 13 | pages = 1581–1587 | date = October 2004 | pmid = 15467060 | doi = 10.1001/jama.292.13.1581 | doi-access = free | hdl = 1887/5083 | hdl-access = free }}</ref> However, in another study, the increase in ] risk with oral CEEs plus medroxyprogesterone acetate and oral estradiol plus ] was found to be equivalent ({{abbrlink|RR|Relative risk}} = 4.0 and 3.9, respectively).<ref name="pmid27998619">{{cite journal | vauthors = Lekovic D, Miljic P, Dmitrovic A, Thachil J | title = How do you decide on hormone replacement therapy in women with risk of venous thromboembolism? | journal = Blood Reviews | volume = 31 | issue = 3 | pages = 151–157 | date = May 2017 | pmid = 27998619 | doi = 10.1016/j.blre.2016.12.001 }}</ref><ref name="pmid23136837">{{cite journal | vauthors = Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A | title = The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy | journal = Journal of Thrombosis and Haemostasis | volume = 11 | issue = 1 | pages = 124–131 | date = January 2013 | pmid = 23136837 | doi = 10.1111/jth.12060 | s2cid = 22306721 | doi-access = }}</ref> As of present, there are no ]s that would allow for unambiguous conclusions.<ref name="pmid26327865" />
			{{Results of the Women's Health Initiative menopausal hormone therapy randomized controlled trials}}
			{{Risk of venous thromboembolism with hormone therapy and birth control pills (QResearch/CPRD)}}
			==Overdose==
			{{See also|Estrogen (medication)#Overdose}}
			Estrogens, including CEEs, are relatively safe in acute ].{{Citation needed|date=July 2018}}
			== Interactions ==
			{{See also|Estrogen (medication)#Interactions}}
			]s and ]s of ] ]s may ] with CEEs.{{Citation needed|date=July 2018}}
	==Pharmacology==		==Pharmacology==
			===Pharmacodynamics===
	The major forms of estrogen in Premarin are ] (>50%), ] (15-25%) and ]. The estrogens in Premarin are often called "conjugated equine estrogens" (CEE) because the estrogen ]s are generally present with ] side-groups attached such as ]. Thus, ] is actually the major active constituent in Premarin. Estrone sulfate is easily ] into the ] after Premarin ]s are taken by ]. Estrone sulfate is ] to ], an active estrogen normally found in women. It is not clear if estrogens such as equilin that are foreign to the human body have effects in women that are significantly different from the estrogens like estradiol that are normally made in the human body.
			{{See also|Pharmacodynamics of estradiol}}
	<gallery>
	File:estrone sulfate.svg|Estrone sulfate
	File:equilin sulfate.svg|Equilin sulfate
	File:equilenin sulfate.svg|Equilenin sulfate
	</gallery>
			], the main ] of ] and the major active estrogen with CEEs<ref name="pmid16112947" />]]
	Premarin is a form of ]. Premarin pills are used most commonly in post menopausal women who have had a ] to treat hot flashes, and burning, itching, and dryness of the vagina and surrounding areas. It can also be used in conjunction with a progestin pill in women who have not had a hysterectomy. For women already taking the drug it can be used to treat osteoporosis, although it is not recommended solely for this use. The most common side effects associated with Premarin use are vaginal yeast infections, vaginal spotting or bleeding, painful menses, and cramping of the legs.
			], the main ] of ] and the second major active estrogen with CEEs<ref name="pmid16112947" />]]
	While there are some contradictory data, estrogen alone does not appear to increase the risk of coronary heart disease or breast cancer, like estrogen with ] does.<ref>http://www.nhlbi.nih.gov/whi/estro_alone.htm NHLBI Women's Health Initiative Estrogen Alone Study</ref> While estrogen alone appears to decrease the risk of hip fracture for women who have had a hysterectomy, it is still suggested that Premarin be used for the shortest period of time and at the smallest possible dose that is effective in alleviating symptoms because it can increase the risk of endometrial cancer, stroke, blood clots, and possibly dementia. Premarin cream is only used for vaginal burning, dryness and itching.
			CEEs are a combination of ]s, or ]s of the ]s.<ref name="pmid16112947" /> The major estrogen in CEEs, ], itself is inactive, and rather serves as a ] of ] and then of ].<ref name="pmid16112947" /><ref name="Buchsbaum2012">{{cite book| vauthors = Buchsbaum HJ |title=The Menopause |url=https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA64|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5525-3|pages=64–}}</ref><ref name="FalconeHurd2013">{{cite book| vauthors = Falcone T, Hurd WW |title=Clinical Reproductive Medicine and Surgery: A Practical Guide|url=https://books.google.com/books?id=TAYnR1b8jRkC&pg=PA5|date=22 May 2013|publisher=Springer Science & Business Media |isbn=978-1-4614-6837-0|pages=5–6}}</ref> The transformation of estrone sulfate to estrone is catalyzed by ], and of estrone into estradiol by ].<ref name="pmid16112947" /><ref name="Sanfilippo1998">{{cite book| vauthors = Sanfilippo JS |title=Primary Care in Obstetrics and Gynecology: A Handbook for Clinicians|url=https://books.google.com/books?id=jfmB3aNSGfoC&pg=PA227|date=January 1998|publisher=Springer Science & Business Media|isbn=978-0-387-94739-6|pages=220, 227|quote=Conjugated estrogens are absorbed with peak levels at 4 hours and a half-life of approximately 12 hours.}}</ref> CEEs (as Premarin) and estrone have been found to be equivalent in ] in an ] of estrogenic activity.<ref name="FritzSperoff2012"/> On the other hand, the active forms of the equine estrogens in CEEs, such as ] and ], have greater ] in the ] relative to ] ], similarly to ] estrogens like ] and ].<ref name="pmid16112947" /> This results in disproportionate effects on ] compared to estradiol, although to a lesser extent than ethinylestradiol and diethylstilbestrol.<ref name="pmid16112947" /> In addition, ] has shown a ] (SERM)-like profile of estrogenic activity in studies with monkeys, in which beneficial effects on ] and the ] system were observed but ] responses in ] or ] were not seen, although the clinical significance of this is unknown.<ref name="pmid17443713">{{cite journal | vauthors = Cline JM | title = Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors | journal = Birth Defects Research. Part B, Developmental and Reproductive Toxicology | volume = 80 | issue = 2 | pages = 126–146 | date = April 2007 | pmid = 17443713 | doi = 10.1002/bdrb.20112 }}</ref>
	Some of Premarin’s lesser known uses are the treatment of symptoms associated with metastatic breast cancer in men and women and prostate cancer in men. It can also be used for individuals that do not produce enough estrogen due to hypogonadism, castration, and ovarian failure, or who have certain ] conditions such as ].
			CEEs consists of the ] ]s of the ] ]s of equine estrogens in a specific and consistent composition (see the table).<ref name="pmid16112947" /><ref name="FritzSperoff2012"/> The major estrogens in CEEs are ] and ], which together account for approximately 71.5–92.0% of the total content of CEEs.<ref name="Martindale" /><ref name="pmid16112947" /><ref name="FritzSperoff2012"/> CEEs are ]s of the active forms of the estrogens.<ref name="pmid16112947" /><ref name="FritzSperoff2012"/><ref name="Martindale" /> Sodium estrone sulfate is a prodrug of ], which in turn is a prodrug of ], while sodium equilin sulfate is a prodrug of ] and then of 17β-dihydroequilin.<ref name="pmid16112947" /> As such, the major active estrogens with CEEs are estradiol and 17β-dihydroequilin, which have ] estrogenic activity and account for most of the effects of CEEs.<ref name="pmid16112947" /> The 17α-estrogens in CEEs such as ] and ] have low estrogenicity and are thought to contribute minimally to its effects.<ref name="pmid16112947" /> There are many different ]s in natural CEE products like Premarin, as many as 230&nbsp;compounds and including even ]s and ]s, but only the estrogens are present in sufficient amounts to produce clinically-relevant effects.<ref name="FritzSperoff2012"/><ref name="pmid16915215" /><ref name="pmid24176763" />
	==Bioequivalance==
	] has filed petitions opposing the creation of a bioequivalent version by ]. They have argued that the generic version, using synthetic steroids, "lacked an important substance that is in Premarin".<ref>{{cite news |first= |last= |authorlink= |coauthors= |title=F.D.A. Makes No Recommendation on Generic Estrogen Drug |url=http://www.nytimes.com/1995/07/30/us/fda-makes-no-recommendation-on-generic-estrogen-drug.html |quote=Wyeth-Ayerst filed a petition opposing that request, arguing that the generic compound, which uses synthetic ingredients, lacked an important substance that is in Premarin, a drug refined from the urine of pregnant mares. ... A generic form of the drug proposed by Duramed Pharmaceuticals followed the five-estrogen formula. In its petition, Wyeth-Ayerst claimed that DHES was an important component and that there was uncertainty about whether an estrogen replacement pill without DHES would have the same beneficial effects as its Premarin. |work=] |accessdate=2009-04-29 | date=1995-07-30}}</ref>
			A dosage of 0.625&nbsp;mg/day oral CEEs has been found to increase SHBG levels by 100%.<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 | pages = 85 | date = March 2006 | pmid = 16915215 | pmc = 1682006 }}</ref><ref name="pmid10914617">{{cite journal | vauthors = Nachtigall LE, Raju U, Banerjee S, Wan L, Levitz M | title = Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels | journal = Menopause | volume = 7 | issue = 4 | pages = 243–250 | date = 2000 | pmid = 10914617 | doi = 10.1097/00042192-200007040-00006 | s2cid = 3076514 }}</ref> For comparison, 1&nbsp;mg/day oral estradiol increased SHBG levels by 45%, while 50&nbsp;μg/day transdermal estradiol increased SHBG levels by 12%.<ref name="pmid16915215" /><ref name="pmid10914617" /> ] is more potent in its effects on liver protein synthesis than either CEEs or estradiol, with 10&nbsp;μg/day oral ethinylestradiol having been found to be approximately equivalent to 1.25&nbsp;mg/day CEEs.<ref name="pmid16915215" />
	==Controversy==
	{{Refimprove section|date=June 2011}}
	{{Unbalanced section|date=December 2010}}
	{{Weasel|date=June 2011}}
	Premarin is the subject of some ]. ] groups and those opposing the industry claim that animal husbandry and urine collection methods used in Premarin's production cause undue stress and suffering to the ]s involved.<ref>, a part of equinerescue.net</ref> Allegations of abuse range from concern over stall size, access to water, exercise, cruel treatment, collection system and continuous breeding cycles, resulting in premature death for thousands of ] and ]. Some claim the numbers are more accurately in the millions.<ref></ref>
			{{Composition of conjugated estrogens and properties of constituents}}
	For six months of the year the mares are outside, where they are annually impregnated. The mares, stabled inside for the other six months of the year, are restrained in a variety of ways, with plastic urine-collection bags in place. These bags can limit movement on their own, but many of these horses are restrained part or all of the time, further restricting natural movement. Morbidity can result, with infection and other skin injury resulting from the urine bags, and the restriction of movement can also lead to disability. Fluid (water) intake is severely restricted, as well. {{fact|date=February 2011}} Most horses have a far shorter life-span in this environment than would be expected.
			{{Oral potencies of estrogens}}
	Some of this contention may stem from the looser standards formerly held in the industry, although accurate records are lacking. The pregnant mare urine (PMU) farms have been in existence since 1942. At that time, many farms were breeding large amounts of foals because more pregnant mares meant more urine and more income. A large number of these foals were unwanted. Many of them were out of draft mares because the larger horses could produce more urine. These foals, in many cases, were reported as being sent to slaughter.
			{{Relative oral potencies of estrogens}}
	Around the time of the turn of the century, however, the industry was cut. In part, this was from research indicating that lower doses of the drug might instead be safer. As a result, some facilities reduced the number of mares that were contained on-site, and some contend that other aspects of the industry were updated as well.
			====Antigonadotropic effects====
	The cut spurred much controversy of its own. Many animal rights groups were (and still are) very against the industry, and so this downsizing represented a victory for them — fewer farms meant fewer animals likely to be mistreated or killed. However, it also led many of these farms to sell off large numbers of horses for slaughter.
			] (RIA).<ref name="pmid4359746" />]]
			A preliminary study of ] inhibition in women found that oral CEEs was 33% effective at 1.25&nbsp;mg/day and 94% at 3.75&nbsp;mg/day.<ref name="Greenblatt1966e">{{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="HerrRevesz19702">{{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|publisher=Springer |doi=10.1007/978-3-642-49793-3_8|doi-broken-date=1 November 2024 |isbn=978-3-642-49506-9}}</ref> A dosage of oral CEEs of 2.5&nbsp;mg three times daily (7.5&nbsp;mg/day total) has been found to suppress total testosterone levels in men to an equivalent extent as 3&nbsp;mg/day oral ], which is the minimum dosage of diethylstilbestrol required to consistently suppress total testosterone levels into the castrate range (<50&nbsp;ng/dL).<ref name="pmid29603164e">{{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 downsizing of the industry led to another change. With a lesser quantity of urine needed for the production of Premarin, the ranchers involved in the industry were no longer limited to using only draft horses. More of a focus on breeding saleable foals has been seen, with an emphasis on selecting good quality stallions to sire the foals. Crosses now popular within the industry may include such breeds as Quarter Horses, Thoroughbreds, Hanoverians, Paints, and other such breeds, in addition to the more traditionally-used draft breeds. The ranchers rely on selling foals as much as they rely upon the urine collected from the pregnant mares. Many of these farms utilize websites and forms of promotion identical to non-Premarin related horse breeders, and, in nearly all ways, are indistinguishable from the average breeder of equines.
			===Pharmacokinetics===
	Currently, those in favor of the industry claim that standards on farms are strict and meticulous records must be kept, and that all ranchers must follow the “Recommended Code of Practice for the Care and Handling of Horses in PMU Operations” in order to keep their contract. They further state that ranchers are regularly inspected to ensure they are following these codes in order to ascertain well-maintained animals and facilities.
			{{See also|Pharmacokinetics of estradiol}}
			CEEs are ] in the ]s during first-pass metabolism upon ].<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><ref name="Martindale" /> Following their ], they are ] mainly in the ] also during the first pass.<ref name="pmid8842581" /> Following this, they serve as a circulating reservoir and are slowly rehydrolyzed into their unconjugated active forms.<ref name="pmid8842581" />
	==Health effects==
	Research starting in 1975 showed substantially increased risk of endometrial cancer.<ref>{{cite journal | journal=New England Journal of Medicine| title=Increased risk of endometrial carcinoma among users of conjugated estrogens. | author=Ziel HK, Finkle WD| volume = 293 | pages=1167–1170 | pmid=171569 | doi=10.1056/NEJM197512042932303}}</ref><ref>{{cite journal| title=Exogenous estrogen and endometrial carcinoma: case-control and incidence study. | author=McDonald, TW et al.| journal=American J Obstet Gynecol | volume = 127 | pages = 572–580 | pmid=190887}}</ref> Since 1976 the drug has carried a label warning about the risk.<ref name=Singer>{{cite news| url=http://www.nytimes.com/2009/12/13/business/13drug.html| title=Menopause, as Brought to You by Big Pharma | author=Natasha Singer and Duff Wilson | date=2009-12-12 | publisher=New York Times}}</ref> As part of the ] sponsored by the National Institutes of Health, a large-scale clinical trial for ] showed that long-term use of progestin and estrogen may increase the risk of strokes, heart attacks, blood clots, and breast cancer.<ref name=Brunner>{{cite journal| title=Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative Randomized Clinical Trial. | author=Brunner, RL et al; Womens Health Initiative Investigators | journal=Archives of Internal Medicine| volume = 165 | pages = 1976–1986 | pmid=16186467 | year=2005 | url=http://archinte.ama-assn.org/cgi/content/full/165/17/1976 | issue=17 | doi=10.1001/archinte.165.17.1976}}</ref>
	Following these results, Wyeth experienced a significant decline in its sales of Premarin, Prempro (conjugated equine estrogens) and related hormones, from over $2 billion in 2002 to just over $1 billion in 2006.<ref></ref>
			Oral CEEs, at a daily dosage of 0.625&nbsp;mg, achieve estrone and estradiol levels of 150&nbsp;pg/mL and 30–50&nbsp;pg/mL, respectively, while a daily oral dosage of 1.25&nbsp;mg achieves levels of 120–200&nbsp;pg/mL and 40–60&nbsp;pg/mL of estrone and estradiol, respectively.<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=HB2XO5MhKakC&pg=PA771|date=5 June 2007|publisher=Academic Press|isbn=978-0-08-055309-2|pages=771–}}</ref> The oral ingestion of 10&nbsp;mg&nbsp;CEEs, which contains about 4.5&nbsp;mg sodium estrone sulfate and 2.5&nbsp;mg sodium equilin sulfate, produces maximal plasma concentrations of estrone and equilin of 1,400&nbsp;pg/mL and 560&nbsp;pg/mL within three and five&nbsp;hours, respectively.<ref name="Lobo2007" /> By 24&nbsp;hours post-dose of 10&nbsp;mg, the levels of estrone and equilin fall to 280&nbsp;pg/mL and 125&nbsp;pg/mL, respectively.<ref name="Lobo2007" /> Oral CEEs 1.25&nbsp;mg/daily and oral micronized estradiol 1&nbsp;mg/daily result in similar plasma concentrations of estrone and estradiol (150–300&nbsp;pg/mL and 30–50&nbsp;pg/mL for micronized estradiol, respectively) (oral estradiol is extensively metabolized into estrone during ] ]),<ref name="Lobo2007" /> although this does not account for equilin and other equine estrogens involved in the effects of CEEs, which may be significantly more potent in comparison to estrone.<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><ref name="Seidel1974">{{cite book| vauthors = Seidel GE |title=Gonadotrophins: Current Research|url=https://books.google.com/books?id=s21mXv6g5NkC&pg=PA157|year=1974|publisher=Ardent Media|isbn=978-0-8422-7205-6|pages=157–}}</ref> The ] of vaginal CEEs<ref name="pmid7231202">{{cite journal | vauthors = Punnonen R, Vilska S, Grönroos M, Rauramo L | title = The vaginal absorption of oestrogens in post-menopausal women | journal = Maturitas | volume = 2 | issue = 4 | pages = 321–326 | date = December 1980 | pmid = 7231202 | doi = 10.1016/0378-5122(80)90034-1 }}</ref> and of intravenous CEEs have been studied as well.<ref name="pmid3653846">{{cite journal | vauthors = Honjo H, Kitawaki J, Itoh M, Yasuda J, Iwasaku K, Urabe M, Naitoh K, Yamamoto T, Okada H, Ohkubo T | title = Serum and urinary estrone sulfate during the menstrual cycle, measured by a direct radioimmunoassay, and fate of exogenously injected estrone sulfate | journal = Hormone Research | volume = 27 | issue = 2 | pages = 61–68 | date = 1987 | pmid = 3653846 | doi = 10.1159/000180788 | doi-broken-date = 2 November 2024 }}</ref>
	==Litigation==
	This drug has been the subject of litigation; more than 13,000 people have sued Wyeth between 2002 and 2009. However, Wyeth and Pharmacia & Upjohn have prevailed in the vast majority of hormone therapy cases previously set for trial through a combination of rulings by judges, verdicts by juries, and dismissals by plaintiffs themselves.<ref>Pfizer Statement on Prempro, Indy News Channel: http://www.theindychannel.com/health/21716786/detail.html</ref> Of the company’s losses, two of the jury verdicts were reversed post-trial and others are being challenged on appeal. Wyeth also has won five summary judgments on Prempro cases and had 15 cases that were set for trial voluntarily dismissed by plaintiffs. The company has won dismissals in another 3,000 cases.<ref name="Bloomberg 2010">Bloomberg: Pfizer Wins Trial Over Claim Prempro Caused Cancer, February 24, 2010, Jef Feeley</ref> In 2006, Mary Daniel, in a trial in Philadelphia, PA, was awarded $1.5 million in compensatory damages as well as undisclosed punitive damages,<ref> 2007-01-29 Associated press</ref> Daniel was represented by the firm of ]. In 2007 the same firm tried a case in Reno, Nevada, representing three plaintiffs who were awarded roughly $17–19 million apiece in damages.<ref> Lawyers USA 2007-10-22 Gertner, Reni</ref> Wyeth appealed this outcome, and it is currently before the Nevada Supreme Court.<ref>Las Vegas Sun: Drug Company Attorney asks for New Trial in $58 Million Judgment. http://www.lasvegassun.com/news/2010/may/03/drug-company-attorney-asks-new-trial-58-million-ju/</ref> Wyeth has won the last four of five cases, most recently in Virginia, finding that Wyeth was not responsible for Plaintiff Georgia Torkie-Tork's breast cancer<ref>Pfizer Properly Warned About Prempro Risks, Jury Finds http://www.bloomberg.com/news/2010-12-03/pfizer-properly-warned-about-prempro-health-risks-jury-finds.html</ref>. Wyeth has been quoted as saying "many risk factors associated with breast cancer have been identified, but science cannot establish what role any particular risk factor or combination play in any individual woman's breast cancer." <ref>Legal Intelligencer: Philadelphia Jury Returns Defense Verdict in HRT Case, Amaris Elliott Engel http://www.law.com/jsp/article.jsp?id=1202444500915.</ref> Wyeth's council in the case also noted that in the WHI trial, 99.62 percent of women took the drug and "did not get breast cancer."<ref name="Bloomberg 2010"/>
			Eoncentrations of equilin that are very high relative to those of other estrogens are produced by typical clinical doses of CEEs.<ref name="WallachHammond1982">{{cite journal | vauthors = Hammond CB, Maxson WS | title = Current status of estrogen therapy for the menopause | journal = Fertility and Sterility | volume = 37 | issue = 1 | pages = 5–25 | date = January 1982 | pmid = 6277697 | doi = 10.1016/S0015-0282(16)45970-4 | doi-access = }}</ref> With a dosage of 1.25&nbsp;mg oral CEEs, equilin levels of 1,082 to 2,465&nbsp;pg/mL have been observed.<ref name="WallachHammond1982" /> The clinical significance of these levels of equilin is unknown.<ref name="WallachHammond1982" />
	==See also==
	* ]
			The active forms are ] primarily in the liver.<ref name="Martindale" /> There is some ] of CEEs.<ref name="Martindale" /> Following a single oral dose of 0.625&nbsp;CEEs, the ] of estrone was 26.7&nbsp;hours, of baseline-adjusted estrone was 14.8&nbsp;hours, and of equilin was 11.4&nbsp;hours.<ref name="DrugBank" />{{Unreliable medical source|date=March 2024}}
	==References==
			{{Plasma estrogen levels after a single dose of conjugated estrogens by different routes}}
			{{Protein binding and metabolic clearance rates of estrogens}}
			==Chemistry==
			{{See also|List of estrogens|Estrogen ester|Estrogen conjugate}}
			CEEs are ] ] ]s.<ref name="pmid16112947" /><ref name="FritzSperoff2012"/> They are in ] form, as the ] ]s of the C17β ] ]s.<ref name="pmid16112947" /><ref name="FritzSperoff2012"/> The estrogens in CEEs, in their unconjugated active forms, include ] human estrogens like ] and ] as well as ]s such as ] and ].<ref name="pmid16112947" /><ref name="FritzSperoff2012"/> The equine estrogens differ from human estrogens in that they have additional ]s in the B ] of the steroid ].<ref name="pmid16112947"/><ref name="FritzSperoff2012"/> CEEs contain both 17β-estrogens like estradiol and 17β-dihydroequilin and the C17α ]s like ] and ].<ref name="pmid16112947" /><ref name="FritzSperoff2012"/>
			{{Chemical structures of equine estrogens|align=center|caption=This diagram illustrates the chemical structures of the active/unconjugated forms of the equine estrogens present in conjugated estrogens.}}
			== History ==
			], an ] of the ] of ] women and sold under the brand names Progynon and Emmenin in the 1930s, was the predecessor of Premarin.<ref name="FeldbergLadd-Taylor2003">{{cite book| vauthors = Feldberg GD, Ladd-Taylor M, Li A |title=Women, Health and Nation: Canada and the United States Since 1945|url=https://books.google.com/books?id=CRjtHlq1INcC&pg=PA103|year=2003|publisher=McGill-Queen's Press - MQUP|isbn=978-0-7735-2501-6|pages=103–}}</ref> Both of these products contained conjugated estrogens similarly to Premarin, but the estrogens were human estrogens as opposed to equine estrogens and the composition differed. The major active ingredient in Progynon and Emmenin was ].
			Estrone sulfate was first isolated from the urine of pregnant mares in the late 1930s by researchers in the Department of Biochemistry at ].<ref name="SchachterMarrian1938">{{cite journal| vauthors = Schachter B, Marrian GF |title=The isolation of estrone sulfate from the urine of pregnant mares|journal=Journal of Biological Chemistry|volume=126|year=1938|issue=2|pages=663–669|doi=10.1016/S0021-9258(18)73874-X|doi-access=free}}</ref> Premarin was first introduced in 1941 by Wyeth Ayerst as a treatment for ] and other symptoms of menopause; at that time, Wyeth Ayerst only had to prove its safety, and not its efficacy.<ref name=MDD>{{cite journal | vauthors = Kling J | date = October 2000 | url = http://pubs.acs.org/subscribe/archive/mdd/v03/i08/html/kling.html | title = The Strange Case of Premarin | journal = Modern Drug Discovery | volume = 3 | issue = 8 | pages = 46–52 }}</ref> In response to the 1962 ] the FDA had its efficacy reviewed, and in 1972 found it effective for menopausal symptoms and probably effective for osteoporosis.<ref>{{cite web|url=https://archive.org/details/federalregister37gunit|title=Federal register |date=3 June 1972|publisher=Washington : |via=Internet Archive}}</ref> The review also determined that two estrogens – estrone sulfate and equilin sulfate – were primarily responsible for the activity of Premarin, and it laid the groundwork for Abbreviated New Drug Application (ANDA) submissions of generic versions.<ref name=MDD/> In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis<ref>National Institutes of Health Consensus Development Conference Statement. 2–4 April 1984 {{Webarchive|url=https://web.archive.org/web/20051121042455/http://consensus.nih.gov/1984/1984Osteoporosis043html.htm |date=21 November 2005 }}</ref> and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.<ref name=Woodcock1997>Food and Drug Administration. 5 May 1997 </ref> This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.<ref name=MDD/>
			Conjugated estrogens was introduced for medical use under the brand name Premarin in ] in 1941, in the ] in 1942, and in the ] in 1956.<ref name="PanayBriggs2015">{{cite book| vauthors = Panay N, Briggs P, Kovacs G |title=Managing the Menopause|url=https://books.google.com/books?id=l0pLCgAAQBAJ&pg=PA118|date=20 August 2015|publisher=Cambridge University Press|isbn=978-1-107-45182-7|pages=118–|quote=Premarin (Pregnant Mares Urine) was introduced in Canada in 1941, in the USA in 1942 and in the UK in 1956.}}</ref>
			The manufacturer of Premarin secretly paid ] ] to promote its use by ] women in his 1966 book, '']'', leading to increased sales.<ref name="Dominus2023">{{cite news | vauthors = Dominus S |date=1 February 2023 |title=Women Have Been Misled About Menopause |language=en-US |work=The New York Times |url=https://www.nytimes.com/2023/02/01/magazine/menopause-hot-flashes-hormone-therapy.html |access-date=7 February 2023 |issn=0362-4331 |quote=Every woman has the right — indeed the duty — to counteract the chemical castration that befalls her during her middle years," the gynecologist Robert Wilson wrote in 1966. The U.S. Food and Drug Administration approved the first hormone-therapy drug in 1942, but Wilson's blockbuster book, "Feminine Forever," can be considered a kind of historical landmark...Within a decade of the book's publication, Premarin — a mix of estrogens derived from the urine of pregnant horses — was the fifth-most-prescribed drug in the United States. (Decades later, it was revealed that Wilson received funding from the pharmaceutical company that sold Premarin.)}}</ref>
			==Society and culture==
			===Names===
			''Estrogens, conjugated'' is the ] of the drug and its {{abbrlink|USP|United States Pharmacopeia}} and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="ChemIDplus">{{cite web | url=https://chem.nlm.nih.gov/chemidplus/rn/12126-59-9 | title=ChemIDplus - 12126-59-9 - QTTMOCOWZLSYSV-QWAPEVOJSA-M - Estrogens, conjugated - Similar structures search, synonyms, formulas, resource links, and other chemical information}}</ref> It is also known as ''conjugated estrogens'' or as ''conjugated equine estrogens''.<ref name="DrugBank">{{cite web | url=https://www.drugbank.ca/drugs/DB00286 | title=Conjugated estrogens}}</ref>{{Unreliable medical source|date=March 2024}} The brand name Premarin is a contraction of "'''pre'''gnant '''mar'''es' ur'''in'''e".<ref name="pmid23217066">{{cite journal | vauthors = Alexander IM | title = The history of hormone therapy use and recent controversy related to heart disease and breast cancer arising from prevention trial outcomes | journal = Journal of Midwifery & Women's Health | volume = 57 | issue = 6 | pages = 547–557 | date = 2012 | pmid = 23217066 | doi = 10.1111/j.1542-2011.2012.00247.x }}</ref><ref name="pmid15845914">{{cite journal | vauthors = Davis SR, Dinatale I, Rivera-Woll L, Davison S | title = Postmenopausal hormone therapy: from monkey glands to transdermal patches | journal = The Journal of Endocrinology | volume = 185 | issue = 2 | pages = 207–222 | date = May 2005 | pmid = 15845914 | doi = 10.1677/joe.1.05847 | doi-access = free }}</ref><ref name="pmid21189221">{{cite journal | vauthors = Smith AL, Wein AJ | title = Estrogen replacement therapy for the treatment of postmenopausal genitourinary tract dysfunction | journal = Discovery Medicine | volume = 10 | issue = 55 | pages = 500–510 | date = December 2010 | pmid = 21189221 | doi = }}</ref>
			CEEs are marketed under a large number of brand names throughout the world.<ref name="Martindale" /> The major brand name of the natural form of CEEs manufactured from the urine of pregnant mares is Premarin.<ref name="Martindale" /> Major brand names of fully synthetic versions of CEEs include Cenestin and Enjuvia in the ] and C.E.S. and Congest in ].<ref name="Martindale" /><ref name="MoscouSnipe2012" /><ref name="HumansOrganization2007" /> CEEs are also formulated in combination with progestins.<ref name="Martindale" /> Major brand names of CEEs in combination with ] include Prempro and Premphase in the United States, Premplus in Canada, Premique in the ] and ], Premia in ] and ], and Premelle in ].<ref name="Martindale" /><ref name="HochadelAvorn2007">{{cite book| vauthors = Hochadel MA, Avorn J |title=The AARP Guide to Pills: Essential Information on More Than 1,200 Prescription and Nonprescription Medications, Including Generics|url=https://books.google.com/books?id=_OvwGMswS6gC&pg=PA235|date=1 January 2007|publisher=Sterling Publishing Company Incorporated|isbn=978-1-4027-4446-4|pages=235–}}</ref> Prempak-C is a combination of CEEs and ] which is used in the United Kingdom and Ireland, and Prempak N is a combination of CEEs and ] which is used in South Africa.<ref name="Martindale" /> Many of the aforementioned brand names are also used in other, non-English-speaking countries.<ref name="Martindale" />
			===Availability===
			{{See also|List of estrogens available in the United States}}
			CEEs are marketed and available widely throughout the world.<ref name="Martindale" /><ref name="Drugs.com-Premarin" /> This includes in all English-speaking countries, throughout the European Union, Latin America, Asia, and elsewhere in the world.<ref name="Martindale" /><ref name="Drugs.com-Premarin" />
			===Health effects===
			Research starting in 1975 showed substantially increased risk of ].<ref>{{cite journal | vauthors = Ziel HK, Finkle WD | title = Increased risk of endometrial carcinoma among users of conjugated estrogens | journal = The New England Journal of Medicine | volume = 293 | issue = 23 | pages = 1167–1170 | date = December 1975 | pmid = 171569 | doi = 10.1056/NEJM197512042932303 }}</ref><ref>{{cite journal | vauthors = McDonald TW, Annegers JF, O'Fallon WM, Dockerty MB, Malkasian GD, Kurland LT | title = Exogenous estrogen and endometrial carcinoma: case-control and incidence study | journal = American Journal of Obstetrics and Gynecology | volume = 127 | issue = 6 | pages = 572–580 | date = March 1977 | pmid = 190887 | doi = 10.1016/0002-9378(77)90351-9 }}</ref> Since 1976, the drug has carried a label warning about the risk.<ref name=Singer>{{cite news| url=https://www.nytimes.com/2009/12/13/business/13drug.html| title=Menopause, as Brought to You by Big Pharma | vauthors = Singer N, Wilson D | date=12 December 2009 | work=New York Times}}</ref> As part of the ] sponsored by the ], a large-scale ] of menopausal HRT showed that long-term use of estrogen and a progestin may increase the risk of ]s, ]s, ]s, and breast cancer.<ref name=Brunner>{{cite journal | vauthors = Brunner RL, Gass M, Aragaki A, Hays J, Granek I, Woods N, Mason E, Brzyski R, Ockene J, Assaf A, LaCroix A, Matthews K, Wallace R | title = Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative Randomized Clinical Trial | journal = Archives of Internal Medicine | volume = 165 | issue = 17 | pages = 1976–1986 | date = September 2005 | pmid = 16186467 | doi = 10.1001/archinte.165.17.1976 | collaboration = Womens Health Initiative Investigators | doi-access = free | url = https://escholarship.org/content/qt1279619t/qt1279619t.pdf?t=ptra6f }}</ref> Following these results, Wyeth experienced a significant decline in its sales of Premarin, Prempro (CEEs and ]), and related products, from over $2 billion in 2002 to just over $1 billion in 2006.<ref>{{cite press release |title=Earnings Results for the 2006 Fourth Quarter and Full Year |publisher=Wyeth |url=http://www.wyeth.com/irj/servlet/prt/portal/prtroot/com.sap.km.cm.docs/wyeth_xml/home/news/announcements/1170158273391.pdf |access-date=20 February 2018 |archive-url=https://web.archive.org/web/20071127184549/http://www.wyeth.com/irj/servlet/prt/portal/prtroot/com.sap.km.cm.docs/wyeth_xml/home/news/announcements/1170158273391.pdf |archive-date=27 November 2007 |url-status=dead }}</ref>
			===Litigation===
			This drug has been the subject of litigation; more than 13,000 people have sued Wyeth between 2002 and 2009. Wyeth and Pharmacia & Upjohn prevailed in the vast majority of hormone therapy cases previously set for trial through a combination of rulings by judges, verdicts by juries, and dismissals by plaintiffs themselves.<ref>{{cite web|title=Pfizer Statement on Prempro |publisher=Indy News Channel |url=http://www.theindychannel.com/health/21716786/detail.html |url-status=dead |archive-url=https://web.archive.org/web/20120223141331/http://www.theindychannel.com/health/21716786/detail.html |archive-date=23 February 2012 |date=24 November 2009 }}</ref> Of the company's losses, two of the jury verdicts were reversed post-trial and others are being challenged on appeal. Wyeth also won five summary judgments on Prempro cases and had 15 cases voluntarily dismissed by plaintiffs. The company won dismissals in another 3,000 cases.<ref name="Bloomberg 2010">{{cite news |publisher=Bloomberg |title=Pfizer wins trial over claim Prempro caused cancer |date=24 February 2010 | vauthors = Feeley J }}</ref> In 2006, Mary Daniel, in a trial in Philadelphia, was awarded $1.5 million in compensatory damages as well as undisclosed punitive damages. As of 2010, Wyeth had won the last four of five cases, most recently in Virginia, finding that they were not responsible for the breast cancer of plaintiff Georgia Torkie-Tork.<ref>{{cite news |title=Pfizer properly warned about Prempro risks, jury finds |url=https://www.bloomberg.com/news/2010-12-03/pfizer-properly-warned-about-prempro-health-risks-jury-finds.html |date=3 December 2010}}</ref> Wyeth has been quoted as saying "many risk factors associated with breast cancer have been identified, but science cannot establish what role any particular risk factor or combination play in any individual woman's breast cancer."<ref>{{cite web |title=Legal Intelligencer: Philadelphia jury returns defense verdict in HRT case, Amaris Elliott Engel |url=http://www.law.com/jsp/article.jsp?id=1202444500915 }}</ref> Wyeth's counsel in the case also noted that in the WHI trial, 99.62% of women took the drug and "did not get breast cancer".<ref name="Bloomberg 2010"/>
			===Animal welfare===
			] groups claim that animal husbandry and urine collection methods used in the production of CEEs cause undue stress and suffering to the ]s involved. Animal activists have made claims of abuses ranging from inadequate stall size, long periods of confinement, cumbersome urine collection, and continuous breeding cycles. After reaching advanced age, many of the mares are adopted for recreation use, while some are sent to feed lots for slaughter. Despite the controversy, the USDA called the CEEs HRT industry a model of self-regulation.<ref>{{cite web|url=https://www.nbcnews.com/id/wbna3995076|title=The HRT horses| vauthors = Morrison K |date=19 January 2004|website=msnbc.com}}</ref>
			==Notes==
			{{Notelist}}
			{{Notefoot}}
			== References ==
	{{Reflist}}		{{Reflist}}
			== Further reading ==
	==External links==
			{{refbegin|30em}}
	*
			* {{cite journal | vauthors = Bhavnani BR | title = The saga of the ring B unsaturated equine estrogens | journal = Endocrine Reviews | volume = 9 | issue = 4 | pages = 396–416 | date = November 1988 | pmid = 3065072 | doi = 10.1210/edrv-9-4-396 }}
	*
			* {{cite journal | vauthors = Ansbacher R | title = Bioequivalence of conjugated estrogen products | journal = Clinical Pharmacokinetics | volume = 24 | issue = 4 | pages = 271–274 | date = April 1993 | pmid = 8387902 | doi = 10.2165/00003088-199324040-00001 | s2cid = 7681617 }}
	* at the ] (FDA) website
			* {{cite journal | vauthors = O'Connell MB | title = Pharmacokinetic and pharmacologic variation between different estrogen products | journal = Journal of Clinical Pharmacology | volume = 35 | issue = 9S | pages = 18S–24S | date = September 1995 | pmid = 8530713 | doi = 10.1002/j.1552-4604.1995.tb04143.x | s2cid = 10159196 }}
	* - from ]
			* {{cite journal | vauthors = Egarter C, Geurts P, Boschitsch E, Speiser P, Huber J | title = The effects of estradiol valerate plus medroxyprogesterone acetate and conjugated estrogens plus medrogestone on climacteric symptoms and metabolic variables in perimenopausal women | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 75 | issue = 4 | pages = 386–393 | date = April 1996 | pmid = 8638462 | doi = 10.3109/00016349609033337 | s2cid = 44498140 }}
	* - clarification of care and fate of PMU mares and foals
			* {{cite journal | vauthors = Bhavnani BR | title = Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 217 | issue = 1 | pages = 6–16 | date = January 1998 | pmid = 9421201 | doi = 10.3181/00379727-217-44199 | s2cid = 45177839 }}
	* NIH press release, March 4, 2008
			* {{cite journal | vauthors = Gruber DM, Huber JC | title = Conjugated estrogens--the natural SERMs | journal = Gynecological Endocrinology | volume = 13 | issue = Suppl 6 | pages = 9–12 | date = December 1999 | pmid = 10862263 }}
	*
			* {{cite journal | vauthors = Campagnoli C, Ambroggio S, Biglia N, Sismondi P | title = Conjugated estrogens and breast cancer risk | journal = Gynecological Endocrinology | volume = 13 | issue = Suppl 6 | pages = 13–19 | date = December 1999 | pmid = 10862264 }}
			* {{cite journal | vauthors = Bhavnani BR | title = Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 85 | issue = 2–5 | pages = 473–482 | date = June 2003 | pmid = 12943738 | doi = 10.1016/S0960-0760(03)00220-6 | s2cid = 45552896 }}
			* {{cite journal | vauthors = Ortmann J, Traupe T, Vetter W, Barton M | title = | language = de | journal = Praxis | volume = 93 | issue = 21 | pages = 904–914 | date = May 2004 | pmid = 15216975 | doi = 10.1024/0369-8394.93.21.904 }}
			* {{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 = Kurabayashi T | title = | language = ja | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 65 | issue = Suppl 9 | pages = 369–373 | date = November 2007 | pmid = 18161134 }}
			* {{cite journal | vauthors = Lamba G, Kaur H, Adapa S, Shah D, Malhotra BK, Rafiyath SM, Thakar K, Fernandez AC | title = Use of conjugated estrogens in life-threatening gastrointestinal bleeding in hemodialysis patients--a review | journal = Clinical and Applied Thrombosis/Hemostasis | volume = 19 | issue = 3 | pages = 334–337 | date = June 2013 | pmid = 22411999 | doi = 10.1177/1076029612437575 | s2cid = 30468265 }}
			* {{cite journal | vauthors = Mirkin S, Komm BS, Pickar JH | title = Conjugated estrogens for the treatment of menopausal symptoms: a review of safety data | journal = Expert Opinion on Drug Safety | volume = 13 | issue = 1 | pages = 45–56 | date = January 2014 | pmid = 23919270 | doi = 10.1517/14740338.2013.824965 | s2cid = 24379298 }}
			* {{cite journal | vauthors = Bhavnani BR, Stanczyk FZ | title = Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 142 | pages = 16–29 | date = July 2014 | pmid = 24176763 | doi = 10.1016/j.jsbmb.2013.10.011 | s2cid = 1360563 }}
			* {{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}}
			== External links ==
	{{Sex hormones}}
			* NIH press release, 4 March 2008
			{{Estradiol}}
	]
			{{Estrogens and antiestrogens}}
			{{Estrogen receptor modulators}}
			{{Portal bar | Medicine}}
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