Conjugated estrogens

Estrone sulfate, the primary active component in conjugated estrogens (constitutes about 50 to 70% of total content)
Equilin sulfate, the second most major active component in conjugated estrogens (constitutes about 20 to 30% of total content)
Combination of
Estrone sulfate	Estrogen
Equilin sulfate	Estrogen
17α-Dihydro-equilin sulfate	Estrogen
Clinical data
Trade names	Cenestin, Enjuvia, Premarin, others
Other names	CEs; Conjugated equine estrogens; CEEs; Pregnant mares' urine; Estrogens, conjugated
AHFS/Drugs.com	Multum Consumer Information
Routes of administration	By mouth,topical,vaginal,intravenous injection,intramuscular injection[1][2]
Drug class	Estrogen
ATC code	G03CA57 (WHO)
Legal status
Legal status	CA: ℞-only[3][4][5] US: ℞-only[6][7][8] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Variable[6]
Protein binding	High (toalbumin andSHBGTooltip sex hormone-binding globulin)[6][1]
Metabolism	Liver[6][1]
Eliminationhalf-life	Estrone: 26.7 hours Estrone (BA): 14.8 hours Equilin: 11.4 hours[9][unreliable medical source?]
Excretion	Kidney[6]
Identifiers
CAS Number	12126-59-9 Y
PubChemCID	656613
DrugBank	DB00286
ChemSpider	570974 Y
UNII	IU5QR144QX
KEGG	D04070
ChEBI	CHEBI:8389
ChEMBL	ChEMBL1201649
CompTox Dashboard(EPA)	DTXSID9021186
ECHA InfoCard	100.031.987
(verify)

Conjugated estrogens (CEs), orconjugated equine estrogens (CEEs), sold under the brand namePremarin among others, is anestrogen medication which is used inmenopausal hormone therapy and for various other indications.^{[10][6][1][11]} It is amixture of thesodiumsalts ofestrogen conjugates found inhorses, such asestrone sulfate andequilin sulfate.^[1][11][10] CEEs are available in the form of bothnatural preparations manufactured from theurine ofpregnantmares and fullysynthetic replications of the natural preparations.^[12][13] They are formulated both alone and in combination withprogestins such asmedroxyprogesterone acetate.^[10] CEEs are usually takenby mouth, but can also be given byapplication to the skin orvagina as acream or byinjection into a blood vessel ormuscle.^[1][2]

Side effects of CEEs includebreast tenderness andenlargement,headache,fluid retention, andnausea among others.^[6][1] It may increase the risk ofendometrial hyperplasia andendometrial cancer in women with an intactuterus if it is not taken together with aprogestogen likeprogesterone.^[6][1] The medication may also increase the risk ofblood clots,cardiovascular disease, and, when combined with most progestogens,breast cancer.^[14] CEEs are estrogens, oragonists of theestrogen receptor, thebiological target ofestrogens likeestradiol.^[1][6] 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 theliver.^[1] This results in an increased risk of blood clots and cardiovascular problems with CEEs relative to estradiol.^[1][15]

Premarin, the major brand of CEEs in use, is manufactured byPfizer and was first marketed in 1941 inCanada and in 1942 in theUnited States.^[11] It is the most commonly used form of estrogen in menopausal hormone therapy in the United States.^[16][17] However, it has begun to fall out of favor relative tobioidenticalestradiol, which is the most widely used form of estrogen inEurope for menopausal hormone therapy.^{[17][18][19][20]} CEEs are available widely throughout the world.^[10] An estrogen preparation very similar to CEEs but differing in source and composition isesterified estrogens.^[1] In 2020, it was the 283rd most commonly prescribed medication in the United States, with more than 1 million prescriptions.^[21][22]

CEEs are a form ofhormone therapy used in women.^[23] It is used most commonly inpostmenopausal women who have had ahysterectomy to treathot flashes, and burning, itching, and dryness of the vagina and surrounding areas.^[24] It must be used in combination with aprogestogen in women who have not had ahysterectomy.^[1] For women already taking the medication, it can be used to treatosteoporosis, although it is not recommended solely for this use.^[25] Some lesser known uses are as a means ofhigh-dose estrogen therapy in the treatment ofbreast cancer in both women and men and in the treatment ofprostate cancer in men.^[26][27] It has been used at a dosage of 2.5 mg three times per day (7.5 mg/day total) for prostate cancer.^[28][29]

CEEs are specifically approved in countries such as theUnited States andCanada for the treatment of moderate to severevasomotorsymptoms (hot flashes) andvulvovaginal atrophy (atrophic vaginitis, atrophic urethritis) associated withmenopause,hypoestrogenism due tohypogonadism,ovariectomy, orprimary ovarian failure,abnormal uterine bleeding, thepalliative treatment ofmetastatic breast cancer in women, the palliative treatment ofadvancedandrogen-dependentprostate cancer in men, and the prevention ofpostmenopausalosteoporosis.^{[9][unreliable medical source?][30][10]} The intravenous formulation of CEEs is specifically used to rapidlylimit bleeding in women withhemorrhage due todysfunctional uterine bleeding.^{[2][31]: 318 [32]: 60}

Natural CEEs, as Premarin, are available in the form oforaltablets (0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg, or 2.5 mg),creams fortopical orvaginal administration (0.625 mg/g), andvials forintravenous orintramuscular injection (25 mg/vial).^[2][33] 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).^[2][34]

Contraindications of CEEs includebreast cancer and a history ofvenous thromboembolism, among others.^{[citation needed]}

The most commonside effects associated with CEEs are vaginalyeast infections,vaginal spotting or bleeding,painful menses, andcramping of the legs. While there are some contradictory data, estrogen alone does not appear to increase the risk ofcoronary heart disease or breast cancer, unlike the case of estrogen in combination with certainprogestins such aslevonorgestrel ormedroxyprogesterone acetate.^[35] Only a few clinical studies have assessed differences between oral CEEs and oral estradiol in terms of health parameters.^[36] Oral CEEs have been found to possess a significantly greater risk ofthromboembolic andcardiovascular complications than oral estradiol (ORTooltip Odds ratio = 2.08) and oralesterified estrogens (ORTooltip Odds ratio = 1.78).^[36][37][38] However, in another study, the increase invenous thromboembolism risk with oral CEEs plus medroxyprogesterone acetate and oral estradiol plusnorethisterone acetate was found to be equivalent (RRTooltip Relative risk = 4.0 and 3.9, respectively).^[39][40] As of present, there are norandomized controlled trials that would allow for unambiguous conclusions.^[36]

Estrogens, including CEEs, are relatively safe in acuteoverdose.^{[citation needed]}

Inhibitors andinducers ofcytochrome P450enzymes mayinteract with CEEs.^{[citation needed]}

CEEs are a combination ofestrogens, oragonists of theestrogen receptors.^[1] The major estrogen in CEEs,sodium estrone sulfate, itself is inactive, and rather serves as aprodrug ofestrone and then ofestradiol.^[1][41][42] The transformation of estrone sulfate to estrone is catalyzed bysteroid sulfatase, and of estrone into estradiol by17β-hydroxysteroid dehydrogenase.^[1][43] CEEs (as Premarin) and estrone have been found to be equivalent inpotency in ananimal model of estrogenic activity.^[11] On the other hand, the active forms of the equine estrogens in CEEs, such asequilin and17β-dihydroequilin, have greaterpotency in theliver relative tobioidenticalestradiol, similarly tosynthetic estrogens likeethinylestradiol anddiethylstilbestrol.^[1] This results in disproportionate effects onliver protein production compared to estradiol, although to a lesser extent than ethinylestradiol and diethylstilbestrol.^[1] In addition,17β-dihydroequilenin has shown aselective estrogen receptor modulator (SERM)-like profile of estrogenic activity in studies with monkeys, in which beneficial effects onbone and thecardiovascular system were observed butproliferative responses inbreast orendometrium were not seen, although the clinical significance of this is unknown.^[44]

CEEs consists of thesodiumsalts of thesulfateesters of equine estrogens in a specific and consistent composition (see the table).^[1][11] The major estrogens in CEEs aresodium estrone sulfate andsodium equilin sulfate, which together account for approximately 71.5–92.0% of the total content of CEEs.^[10][1][11] CEEs areprodrugs of the active forms of the estrogens.^[1][11][10] Sodium estrone sulfate is a prodrug ofestrone, which in turn is a prodrug ofestradiol, while sodium equilin sulfate is a prodrug ofequilin and then of 17β-dihydroequilin.^[1] As such, the major active estrogens with CEEs are estradiol and 17β-dihydroequilin, which havepotent estrogenic activity and account for most of the effects of CEEs.^[1] The 17α-estrogens in CEEs such as17α-estradiol and17α-dihydroequilin have low estrogenicity and are thought to contribute minimally to its effects.^[1] There are many differentsteroids in natural CEE products like Premarin, as many as 230 compounds and including evenandrogens andprogestogens, but only the estrogens are present in sufficient amounts to produce clinically-relevant effects.^[11][45][16]

A dosage of 0.625 mg/day oral CEEs has been found to increase SHBG levels by 100%.^[45][46] For comparison, 1 mg/day oral estradiol increased SHBG levels by 45%, while 50 μg/day transdermal estradiol increased SHBG levels by 12%.^[45][46]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.^[45]

A preliminary study ofovulation inhibition in women found that oral CEEs was 33% effective at 1.25 mg/day and 94% at 3.75 mg/day.^[67][68] 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 oraldiethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress total testosterone levels into the castrate range (<50 ng/dL).^[69]

CEEs arehydrolyzed in theintestines during first-pass metabolism uponoral administration.^[70][10] Following theirabsorption, they areresulfated mainly in theliver also during the first pass.^[70] Following this, they serve as a circulating reservoir and are slowly rehydrolyzed into their unconjugated active forms.^[70]

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.^[71] 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.^[71] By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively.^[71] 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 duringhepaticfirst-pass metabolism),^[71] 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.^[72][73] Thepharmacokinetics of vaginal CEEs^[74] and of intravenous CEEs have been studied as well.^[75]

Eoncentrations of equilin that are very high relative to those of other estrogens are produced by typical clinical doses of CEEs.^[76] With a dosage of 1.25 mg oral CEEs, equilin levels of 1,082 to 2,465 pg/mL have been observed.^[76] The clinical significance of these levels of equilin is unknown.^[76]

The active forms aremetabolized primarily in the liver.^[10] There is someenterohepatic recirculation of CEEs.^[10] Following a single oral dose of 0.625 CEEs, thebiological half-life of estrone was 26.7 hours, of baseline-adjusted estrone was 14.8 hours, and of equilin was 11.4 hours.^{[9][unreliable medical source?]}

CEEs arenaturally occurringestranesteroids.^[1][11] They are inconjugate form, as thesodiumsalts of the C17βsulfateesters.^[1][11] The estrogens in CEEs, in their unconjugated active forms, includebioidentical human estrogens likeestradiol andestrone as well asequine-specific estrogens such asequilin and17β-dihydroequilin.^[1][11] The equine estrogens differ from human estrogens in that they have additionaldouble bonds in the Bring of the steroidnucleus.^[1][11] CEEs contain both 17β-estrogens like estradiol and 17β-dihydroequilin and the C17αepimers like17α-estradiol and17α-dihydroequilin.^[1][11]

v t e Chemical structures of equine estrogens[16][77] Estrone 17β-Estradiol 17α-Estradiol Equilin 17β-Dihydroequilin 17α-Dihydroequilin Equilenin 17β-Dihydroequilenin 17α-Dihydroequilenin Δ8-Estrone Δ8-17β-Estradiol This diagram illustrates the chemical structures of the active/unconjugated forms of the equine estrogens present in conjugated estrogens.

Conjugated estriol, anextract of theurine ofpregnant women and sold under the brand names Progynon and Emmenin in the 1930s, was the predecessor of Premarin.^[78] 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 wasestriol glucuronide.

Estrone sulfate was first isolated from the urine of pregnant mares in the late 1930s by researchers in the Department of Biochemistry atUniversity of Toronto.^[79] Premarin was first introduced in 1941 by Wyeth Ayerst as a treatment forhot flashes and other symptoms of menopause; at that time, Wyeth Ayerst only had to prove its safety, and not its efficacy.^[80] In response to the 1962Kefauver Harris Amendment the FDA had its efficacy reviewed, and in 1972 found it effective for menopausal symptoms and probably effective for osteoporosis.^[81] 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.^[80] In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis^[82] and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.^[83] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.^[80]

Conjugated estrogens was introduced for medical use under the brand name Premarin inCanada in 1941, in theUnited States in 1942, and in theUnited Kingdom in 1956.^[84]

The manufacturer of Premarin secretly paidgynecologistRobert A. Wilson to promote its use bymenopausal women in his 1966 book,Feminine Forever, leading to increased sales.^[85]

Estrogens, conjugated is thegeneric name of the drug and itsUSPTooltip United States Pharmacopeia andJANTooltip Japanese Accepted Name.^[86] It is also known asconjugated estrogens or asconjugated equine estrogens.^{[9][unreliable medical source?]} The brand name Premarin is a contraction of "pregnantmares' urine".^[87][88][89]

CEEs are marketed under a large number of brand names throughout the world.^[10] The major brand name of the natural form of CEEs manufactured from the urine of pregnant mares is Premarin.^[10] Major brand names of fully synthetic versions of CEEs include Cenestin and Enjuvia in theUnited States and C.E.S. and Congest inCanada.^[10][12][13] CEEs are also formulated in combination with progestins.^[10] Major brand names of CEEs in combination withmedroxyprogesterone acetate include Prempro and Premphase in the United States, Premplus in Canada, Premique in theUnited Kingdom andIreland, Premia inAustralia andNew Zealand, and Premelle inSouth Africa.^[10][90] Prempak-C is a combination of CEEs andnorgestrel which is used in the United Kingdom and Ireland, and Prempak N is a combination of CEEs andmedrogestone which is used in South Africa.^[10] Many of the aforementioned brand names are also used in other, non-English-speaking countries.^[10]

CEEs are marketed and available widely throughout the world.^[10][30] This includes in all English-speaking countries, throughout the European Union, Latin America, Asia, and elsewhere in the world.^[10][30]

Research starting in 1975 showed substantially increased risk ofendometrial cancer.^[91][92] Since 1976, the drug has carried a label warning about the risk.^[93] As part of theWomen's Health Initiative sponsored by theNational Institutes of Health, a large-scaleclinical trial of menopausal HRT showed that long-term use of estrogen and a progestin may increase the risk ofstrokes,heart attacks,blood clots, and breast cancer.^[94] Following these results, Wyeth experienced a significant decline in its sales of Premarin, Prempro (CEEs andmedroxyprogesterone acetate), and related products, from over $2 billion in 2002 to just over $1 billion in 2006.^[95]

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.^[96] 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.^[97] 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.^[98] 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."^[99] 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".^[97]

Animal welfare groups claim that animal husbandry and urine collection methods used in the production of CEEs cause undue stress and suffering to themares 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.^[100]

• 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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