Conjugated estrogens

CEEs are a form of hormone therapy used in women.{{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 }} It is used most commonly in postmenopausal women who have had a hysterectomy to treat hot flashes, and burning, itching, and dryness of the vagina and surrounding areas.{{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 }} It must be used in combination with a progestogen in women who have not had a hysterectomy. For women already taking the medication, it can be used to treat osteoporosis, although it is not recommended solely for this use.{{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 }} Some lesser known uses are as a means of high-dose estrogen therapy in the treatment of breast cancer in both women and men and in the treatment of prostate cancer in men.{{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 }}{{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 }} It has been used at a dosage of 2.5 mg three times per day (7.5 mg/day total) for prostate cancer.{{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–}}{{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–}}

CEEs are specifically approved in countries such as the United States and Canada for the treatment of moderate to severe vasomotor symptoms (hot flashes) and vulvovaginal atrophy (atrophic vaginitis, atrophic urethritis) associated with menopause, hypoestrogenism due to hypogonadism, ovariectomy, or primary ovarian failure, abnormal uterine bleeding, the palliative treatment of metastatic breast cancer in women, the palliative treatment of advanced androgen-dependent prostate cancer in men, and the prevention of postmenopausal osteoporosis.{{Unreliable medical source|date=March 2024}}{{cite web | url=https://www.drugs.com/international/premarin.html | title=Premarin}} The intravenous formulation of CEEs is specifically used to rapidly limit bleeding in women with hemorrhage due to dysfunctional uterine bleeding.{{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}}{{Rp|318}}{{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}}{{RP|60}}

{{Estrogen dosages for menopausal hormone therapy}}

{{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 oral tablets (0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg, or 2.5 mg), creams for topical or vaginal administration (0.625 mg/g), and vials for intravenous or intramuscular injection (25 mg/vial).{{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–}} Synthetic CEEs, such as Cenestin (Synthetic A), Enjuvia (Synthetic B), and generic formulations, are available in the form of oral tablets (0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, or 1.25 mg) and creams for topical or vaginal administration (0.625 mg/g).{{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–}}

{{See also|Estrogen (medication)#Contraindications}}

Contraindications of CEEs include breast cancer and a history of venous thromboembolism, among others.{{Citation needed|date=July 2018}}

The most common side effects associated with CEEs are vaginal yeast infections, vaginal spotting or bleeding, painful menses, and cramping of the legs. While there are some contradictory data, estrogen alone does not appear to increase the risk of coronary heart disease or breast cancer, unlike the case of estrogen in combination with certain progestins such as levonorgestrel or medroxyprogesterone acetate.{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121062.htm |title=Premarin (Conjugated estrogens) Vaginal Cream |website=Food and Drug Administration |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 }} Only a few clinical studies have assessed differences between oral CEEs and oral estradiol in terms of health parameters.{{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 }} Oral CEEs have been found to possess a significantly greater risk of thromboembolic and cardiovascular complications than oral estradiol ({{abbrlink|OR|Odds ratio}} = 2.08) and oral esterified estrogens ({{abbrlink|OR|Odds ratio}} = 1.78).{{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 }}{{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 }} However, in another study, the increase in venous thromboembolism risk with oral CEEs plus medroxyprogesterone acetate and oral estradiol plus norethisterone acetate was found to be equivalent ({{abbrlink|RR|Relative risk}} = 4.0 and 3.9, respectively).{{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 }}{{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 = }} As of present, there are no randomized controlled trials that would allow for unambiguous conclusions.

{{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)}}

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

Estrogens, including CEEs, are relatively safe in acute overdose.{{Citation needed|date=July 2018}}

{{See also|Estrogen (medication)#Interactions}}

Inhibitors and inducers of cytochrome P450 enzymes may interact with CEEs.{{Citation needed|date=July 2018}}

{{See also|Pharmacodynamics of estradiol}}

File:Estradiol.svg, the main active form of estrone sulfate and the major active estrogen with CEEs]]

File:17β-Dihydroequilin.svg, the main active form of equilin sulfate and the second major active estrogen with CEEs]]

CEEs are a combination of estrogens, or agonists of the estrogen receptors. The major estrogen in CEEs, sodium estrone sulfate, itself is inactive, and rather serves as a prodrug of estrone and then of estradiol.{{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–}}{{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}} The transformation of estrone sulfate to estrone is catalyzed by steroid sulfatase, and of estrone into estradiol by 17β-hydroxysteroid dehydrogenase.{{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.}} CEEs (as Premarin) and estrone have been found to be equivalent in potency in an animal model of estrogenic activity. On the other hand, the active forms of the equine estrogens in CEEs, such as equilin and 17β-dihydroequilin, have greater potency in the liver relative to bioidentical estradiol, similarly to synthetic estrogens like ethinylestradiol and diethylstilbestrol. This results in disproportionate effects on liver protein production compared to estradiol, although to a lesser extent than ethinylestradiol and diethylstilbestrol. In addition, 17β-dihydroequilenin has shown a selective estrogen receptor modulator (SERM)-like profile of estrogenic activity in studies with monkeys, in which beneficial effects on bone and the cardiovascular system were observed but proliferative responses in breast or endometrium were not seen, although the clinical significance of this is unknown.{{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 }}

CEEs consists of the sodium salts of the sulfate esters of equine estrogens in a specific and consistent composition (see the table). The major estrogens in CEEs are sodium estrone sulfate and sodium equilin sulfate, which together account for approximately 71.5–92.0% of the total content of CEEs. CEEs are prodrugs of the active forms of the estrogens. Sodium estrone sulfate is a prodrug of estrone, which in turn is a prodrug of estradiol, while sodium equilin sulfate is a prodrug of equilin and then of 17β-dihydroequilin. As such, the major active estrogens with CEEs are estradiol and 17β-dihydroequilin, which have potent estrogenic activity and account for most of the effects of CEEs. The 17α-estrogens in CEEs such as 17α-estradiol and 17α-dihydroequilin have low estrogenicity and are thought to contribute minimally to its effects. There are many different steroids in natural CEE products like Premarin, as many as 230 compounds and including even androgens and progestogens, but only the estrogens are present in sufficient amounts to produce clinically-relevant effects.

A dosage of 0.625 mg/day oral CEEs has been found to increase SHBG levels by 100%.{{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 }}{{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 }} For comparison, 1 mg/day oral estradiol increased SHBG levels by 45%, while 50 μg/day transdermal estradiol increased SHBG levels by 12%. Ethinylestradiol is more potent in its effects on liver protein synthesis than either CEEs or estradiol, with 10 μg/day oral ethinylestradiol having been found to be approximately equivalent to 1.25 mg/day CEEs.

{{Composition of conjugated estrogens and properties of constituents}}

{{Oral potencies of estrogens}}

{{Relative oral potencies of estrogens}}

File:Testosterone levels with different estrogen therapies in men with prostate cancer.png (RIA).]]

A preliminary study of ovulation inhibition in women found that oral CEEs was 33% effective at 1.25 mg/day and 94% at 3.75 mg/day.{{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}}{{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}} A dosage of oral CEEs of 2.5 mg three times daily (7.5 mg/day total) has been found to suppress total testosterone levels in men to an equivalent extent as 3 mg/day oral diethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress total testosterone levels into the castrate range (<50 ng/dL).{{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 }}

{{See also|Pharmacokinetics of estradiol}}

CEEs are hydrolyzed in the intestines during first-pass metabolism upon oral administration.{{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 }} Following their absorption, they are resulfated mainly in the liver also during the first pass. Following this, they serve as a circulating reservoir and are slowly rehydrolyzed into their unconjugated active forms.

Oral CEEs, at a daily dosage of 0.625 mg, achieve estrone and estradiol levels of 150 pg/mL and 30–50 pg/mL, respectively, while a daily oral dosage of 1.25 mg achieves levels of 120–200 pg/mL and 40–60 pg/mL of estrone and estradiol, respectively.{{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–}} The oral ingestion of 10 mg CEEs, which contains about 4.5 mg sodium estrone sulfate and 2.5 mg sodium equilin sulfate, produces maximal plasma concentrations of estrone and equilin of 1,400 pg/mL and 560 pg/mL within three and five hours, respectively. By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively. Oral CEEs 1.25 mg/daily and oral micronized estradiol 1 mg/daily result in similar plasma concentrations of estrone and estradiol (150–300 pg/mL and 30–50 pg/mL for micronized estradiol, respectively) (oral estradiol is extensively metabolized into estrone during hepatic first-pass metabolism), 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.{{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–}}{{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–}} The pharmacokinetics of vaginal CEEs{{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 }} and of intravenous CEEs have been studied as well.{{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 }}

Eoncentrations of equilin that are very high relative to those of other estrogens are produced by typical clinical doses of CEEs.{{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 = }} With a dosage of 1.25 mg oral CEEs, equilin levels of 1,082 to 2,465 pg/mL have been observed. The clinical significance of these levels of equilin is unknown.

The active forms are metabolized primarily in the liver. There is some enterohepatic recirculation of CEEs. Following a single oral dose of 0.625 CEEs, the biological half-life of estrone was 26.7 hours, of baseline-adjusted estrone was 14.8 hours, and of equilin was 11.4 hours.{{Unreliable medical source|date=March 2024}}

{{Plasma estrogen levels after a single dose of conjugated estrogens by different routes}}

{{Protein binding and metabolic clearance rates of estrogens}}

{{See also|List of estrogens|Estrogen ester|Estrogen conjugate}}

CEEs are naturally occurring estrane steroids. They are in conjugate form, as the sodium salts of the C17β sulfate esters. The estrogens in CEEs, in their unconjugated active forms, include bioidentical human estrogens like estradiol and estrone as well as equine-specific estrogens such as equilin and 17β-dihydroequilin. The equine estrogens differ from human estrogens in that they have additional double bonds in the B ring of the steroid nucleus. CEEs contain both 17β-estrogens like estradiol and 17β-dihydroequilin and the C17α epimers like 17α-estradiol and 17α-dihydroequilin.

{{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.}}

Conjugated estriol, an extract of the urine of pregnant women and sold under the brand names Progynon and Emmenin in the 1930s, was the predecessor of Premarin.{{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–}} 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 estriol glucuronide.

Estrone sulfate was first isolated from the urine of pregnant mares in the late 1930s by researchers in the Department of Biochemistry at University of Toronto.{{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}} Premarin was first introduced in 1941 by Wyeth Ayerst as a treatment for hot flashes and other symptoms of menopause; at that time, Wyeth Ayerst only had to prove its safety, and not its efficacy.{{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 }} In response to the 1962 Kefauver Harris Amendment the FDA had its efficacy reviewed, and in 1972 found it effective for menopausal symptoms and probably effective for osteoporosis.{{cite web|url=https://archive.org/details/federalregister37gunit|title=Federal register [microform]|date=3 June 1972|publisher=Washington : [Office of the Federal Register, National Archives and Records Service, General Services Administration : Distributed by the Supt. of Docs., U.S. G.P.O.]|via=Internet Archive}} 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. In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosisNational Institutes of Health Consensus Development Conference Statement. 2–4 April 1984 [http://consensus.nih.gov/1984/1984Osteoporosis043html.htm Osteoporosis] {{Webarchive|url=https://web.archive.org/web/20051121042455/http://consensus.nih.gov/1984/1984Osteoporosis043html.htm |date=21 November 2005 }} and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.Food and Drug Administration. 5 May 1997 [https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm168836.htm Conjugated Estrogens - Letter from Dr. Janet Woodcock: Approvability of a Synthetic Generic Version of Premarin] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.

Conjugated estrogens was introduced for medical use under the brand name Premarin in Canada in 1941, in the United States in 1942, and in the United Kingdom in 1956.{{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.}}

The manufacturer of Premarin secretly paid gynecologist Robert A. Wilson to promote its use by menopausal women in his 1966 book, Feminine Forever, leading to increased sales.{{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.)}}

Estrogens, conjugated is the generic name of the drug and its {{abbrlink|USP|United States Pharmacopeia}} and {{abbrlink|JAN|Japanese Accepted Name}}.{{cite web | url=https://chem.nlm.nih.gov/chemidplus/rn/12126-59-9 | title=ChemIDplus - 12126-59-9 - QTTMOCOWZLSYSV-QWAPEVOJSA-M - Estrogens, conjugated [USP:JAN] - Similar structures search, synonyms, formulas, resource links, and other chemical information}} It is also known as conjugated estrogens or as conjugated equine estrogens.{{cite web | url=https://www.drugbank.ca/drugs/DB00286 | title=Conjugated estrogens}}{{Unreliable medical source|date=March 2024}} The brand name Premarin is a contraction of "pregnant mares' urine".{{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 }}{{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 }}{{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 = }}

CEEs are marketed under a large number of brand names throughout the world. The major brand name of the natural form of CEEs manufactured from the urine of pregnant mares is Premarin. Major brand names of fully synthetic versions of CEEs include Cenestin and Enjuvia in the United States and C.E.S. and Congest in Canada. CEEs are also formulated in combination with progestins. Major brand names of CEEs in combination with medroxyprogesterone acetate include Prempro and Premphase in the United States, Premplus in Canada, Premique in the United Kingdom and Ireland, Premia in Australia and New Zealand, and Premelle in South Africa.{{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–}} Prempak-C is a combination of CEEs and norgestrel which is used in the United Kingdom and Ireland, and Prempak N is a combination of CEEs and medrogestone which is used in South Africa. Many of the aforementioned brand names are also used in other, non-English-speaking countries.

{{See also|List of estrogens available in the United States}}

CEEs are marketed and available widely throughout the world. This includes in all English-speaking countries, throughout the European Union, Latin America, Asia, and elsewhere in the world.

Research starting in 1975 showed substantially increased risk of endometrial cancer.{{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 }}{{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 }} Since 1976, the drug has carried a label warning about the risk.{{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}} As part of the Women's Health Initiative sponsored by the National Institutes of Health, a large-scale clinical trial of menopausal HRT showed that long-term use of estrogen and a progestin may increase the risk of strokes, heart attacks, blood clots, and breast cancer.{{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 }} Following these results, Wyeth experienced a significant decline in its sales of Premarin, Prempro (CEEs and medroxyprogesterone acetate), and related products, from over $2 billion in 2002 to just over $1 billion in 2006.{{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 }}

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.{{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 }} 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.{{cite news |publisher=Bloomberg |title=Pfizer wins trial over claim Prempro caused cancer |date=24 February 2010 | vauthors = Feeley J }} 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.{{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}} 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."{{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 }} 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".

Animal welfare groups claim that animal husbandry and urine collection methods used in the production of CEEs cause undue stress and suffering to the mares 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.{{cite web|url=https://www.nbcnews.com/id/wbna3995076|title=The HRT horses| vauthors = Morrison K |date=19 January 2004|website=msnbc.com}}

{{Notelist}}

{{Notefoot}}

{{Reflist}}

{{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 }}
• {{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 }}
• {{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 }}
• {{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 }}
• {{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 = [Postmenopausal hormone replacement therapy and cardiovascular risk: role of conjugated equine estrogens and medroxyprogesterone acetate] | 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 = [New evidence of conjugated estrogen and 17beta-estradiol for treatment and prevention of osteoporosis] | 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}}

• [https://web.archive.org/web/20081218203608/http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2554 WHI Follow-up Study Confirms Health Risks of Long-Term Combination Hormone Therapy Outweigh Benefits for Postmenopausal Women] NIH press release, 4 March 2008

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