Conjugated estrogens

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Conjugated estrogens
Estrone sulfate.svg
Estrone sulfate, the primary active component in conjugated estrogens (constitutes about 50 to 70% of total content).
Equilin sulfate.svg
Equilin sulfate, the second most major active component in conjugated estrogens (constitutes about 20 to 30% of total content).
Combination of
Sodium estrone sulfate Estrogen
Sodium equilin sulfate Estrogen
Sodium 17α-dihydroequilin sulfate Estrogen
Clinical data
Trade names Cenestin, Enjuvia, Congest, C.E.S., Premarin, Prempro (with MPA), Premphase (with MPA), others
Synonyms CEs; Conjugated equine estrogens; CEEs; Pregnant mares' urine; Premarin; Estrogens, conjugated
AHFS/ Consumer Drug Information
  • X
Routes of
By mouth, topical, vaginal, intravenous injection, intramuscular injection[1][2]
Drug class Estrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Variable[3]
Protein binding High (to albumin and SHBG)[3][1]
Metabolism Liver[3][1]
Elimination half-life Estrone: 26.7 hours
Estrone (BA): 14.8 hours
Equilin: 11.4 hours[4]
Excretion Urine[3]
CAS Number
PubChem CID
PubChem SID
ECHA InfoCard 100.006.475 Edit this at Wikidata

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin (a contraction of "pregnant mares' urine") among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications.[5][3][1][6] It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate.[1][6][5] CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations.[7][8] They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate.[5] CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.[1][2]

Side effects of CEEs include breast tenderness and enlargement, headache, fluid retention, and nausea among others.[3][1] It may increase the risk of endometrial hyperplasia and endometrial cancer in women with an intact uterus if it is not taken together with a progestogen like progesterone.[3][1] The medication may also increase the risk of blood clots, cardiovascular disease, and, when combined with most progestogens, breast cancer.[9] CEEs are estrogens, or agonists of the estrogen receptor, the biological target of estrogens like estradiol.[1][3] 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 liver.[1] This results in an increased risk of blood clots and cardiovascular disease with CEEs relative to estradiol.[1][10]

Premarin, the major brand of CEEs in use, is manufactured by Wyeth and was first marketed in 1941 in Canada and in 1942 in the United States.[6] It is the most commonly used form of estrogen in menopausal hormone therapy in the United States.[11][12] However, it has begun to fall out of favor relative to bioidentical estradiol, which is the most widely used form of estrogen in Europe for menopausal hormone therapy.[12][13][14][15] CEEs are available widely throughout the world.[5] An estrogen preparation very similar to CEEs but differing in source and composition is esterified estrogens.[1]

Medical uses[edit]

CEEs are a form of hormone therapy used in women.[16] 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.[17] It must be used in combination with a progestogen in women who have not had a hysterectomy.[1] For women already taking the medication, it can be used to treat osteoporosis, although it is not recommended solely for this use.[18] Some lesser known uses are as a means of high-dose estrogen therapy in the treatment of breast cancer in both men and women and the treatment of prostate cancer in men.[19][20]

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.[4][21][5]

Available forms[edit]

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).[2][22] Synthetic CEEs, such as Cenestin, Enjuvia, 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][23]


Side effects[edit]

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.[24]





CEEs are a combination of estrogens, or agonists of the estrogen receptors.[1] The major estrogen in CEEs, sodium estrone sulfate, itself is inactive, and rather serves as a prodrug of estrone and, to a lesser extent, of estradiol.[1][25][26] The transformation of estrone sulfate to estrone is catalyzed by estrone sulfatase.[27] CEEs, as Premarin, and estrone have been found to be equivalent in potency in an animal model of estrogenic activity.[6] The active forms of the equine-specific 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.[1] This results in disproportionate effects on liver protein production compared to estradiol, although to a lesser extent than ethinylestradiol and diethylstilbestrol (see the table).[1] In addition, 17β-dihydroequilenin has unexpectedly 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 noted but proliferative responses in breast or endometrium were not observed.[28]

CEEs consists of the sodium salts of the sulfate esters of equine estrogens in a specific and consistent composition (see the table).[1][6] The major estrogens in CEEs are sodium estrone sulfate and sodium equilin sulfate, which together account for approximately 71.5 to 92.0% of the total content of CEEs.[5][1][6] CEEs are prodrugs of the active forms of the estrogens.[1][6][5] There are many different steroids in natural CEE products like Premarin, even androgens and progestogens, but only the estrogens are present in sufficient amounts to produce clinically-relevant effects.[6][29] There may be as many as 230 compounds in Premarin tablets.[11]

A dosage of 0.625 mg/day oral CEEs has been found to increase SHBG levels by 100%.[29][30] For comparison, 1 mg/day oral estradiol increased SHBG levels by 45%, while 50 µg/day transdermal estradiol increased SHBG levels by 12%.[29][30] Ethinylestradiol is more potent in its effects on hepatic protein synthesis than either CEEs or estradiol.[29] In terms of effects on hepatic protein synthesis, 10 µg/day oral ethinylestradiol has been found to be equivalent in potency to 1.25 mg/day CEEs.[29]


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.[32] 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 3 and 5 hours, respectively.[32] By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively.[32] 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),[32] 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.[33][34]

When taken orally, CEEs are hydroylzed in the intestines by enzymes that remove the sulfate group and allow for absorption of the unconjugated, active forms of the estrogens.[5] The active forms are metabolized primarily in the liver.[5] There is some enterohepatic recirculation of CEEs.[5] 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.[4]


Conjugated estrogens are naturally occurring estrane steroids and analogues of estradiol.[1][6] They are in conjugate form, as the sodium salts of sulfate esters.[1][6]

Chemical structures of equine estrogens. The active forms of conjugated equine estrogens are shown.


Emmenin, which was an extract of the urine of pregnant women, was the predecessor of Premarin, and Progynon was a very similar competing product. 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 Emmenin and Progynon 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.[41] Premarin was first introduced in 1941 by Wyeth Ayerst as a treatment for hot flushes and other symptoms of menopause; at that time, Wyeth Ayerst only had to prove its safety, and not its efficacy.[42] 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.[43] 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.[42] In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis[44] and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.[45] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.[42]

Society and culture[edit]

Generic names[edit]

Estrogens, conjugated is the generic name of the drug and its USP and JAN.[46] It is also known as conjugated estrogens or as conjugated equine estrogens.[4]

Brand names[edit]

CEEs are marketed under a large number of brand names throughout the world.[5] The major brand name of the natural form of CEEs manufactured from the urine of pregnant mares is Premarin.[5] 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.[5][7][8] CEEs are also formulated in combination with progestins.[5] Major brand names of CEEs in combination with medroxyprogesterone acetate include Premphase and Prempro 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.[5][47] 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.[5] Many of the aforementioned brand names are also used in other, non-English-speaking countries.[5]


CEEs are marketed and available widely throughout the world.[5][21] This includes in all English-speaking countries, Europe, Latin America, Asia, and elsewhere in the world.[5][21]

Health effects[edit]

Research starting in 1975 showed substantially increased risk of endometrial cancer.[48][49] Since 1976 the drug has carried a label warning about the risk.[50] 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.[51] 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.[52]


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.[53] 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.[54] 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.[55] 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." [56] Wyeth's counsel in the case also noted that in the WHI trial, 99.62 percent of women took the drug and "did not get breast cancer."[54]

Animal welfare[edit]

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.[57]

See also[edit]


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Further reading[edit]

  • Ansbacher R (April 1993). "Bioequivalence of conjugated estrogen products". Clin Pharmacokinet. 24 (4): 271–4. doi:10.2165/00003088-199324040-00001. PMID 8387902. 
  • O'Connell MB (September 1995). "Pharmacokinetic and pharmacologic variation between different estrogen products". J Clin Pharmacol. 35 (9 Suppl): 18S–24S. PMID 8530713. 
  • Egarter C, Geurts P, Boschitsch E, Speiser P, Huber J (April 1996). "The effects of estradiol valerate plus medroxyprogesterone acetate and conjugated estrogens plus medrogestone on climacteric symptoms and metabolic variables in perimenopausal women". Acta Obstet Gynecol Scand. 75 (4): 386–93. PMID 8638462. 
  • Bhavnani BR (January 1998). "Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism". Proc. Soc. Exp. Biol. Med. 217 (1): 6–16. PMID 9421201. 
  • Gruber DM, Huber JC (December 1999). "Conjugated estrogens--the natural SERMs". Gynecol. Endocrinol. 13 Suppl 6: 9–12. PMID 10862263. 
  • Campagnoli C, Ambroggio S, Biglia N, Sismondi P (December 1999). "Conjugated estrogens and breast cancer risk". Gynecol. Endocrinol. 13 Suppl 6: 13–9. PMID 10862264. 
  • Bhavnani BR (June 2003). "Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's". J. Steroid Biochem. Mol. Biol. 85 (2-5): 473–82. PMID 12943738. 
  • Ortmann J, Traupe T, Vetter W, Barton M (May 2004). "[Postmenopausal hormone replacement therapy and cardiovascular risk: role of conjugated equine estrogens and medroxyprogesterone acetate]". Praxis (Bern 1994) (in German). 93 (21): 904–14. doi:10.1024/0369-8394.93.21.904. PMID 15216975. 
  • Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. 
  • Kurabayashi T (November 2007). "[New evidence of conjugated estrogen and 17beta-estradiol for treatment and prevention of osteoporosis]". Nippon Rinsho (in Japanese). 65 Suppl 9: 369–73. PMID 18161134. 
  • Lamba G, Kaur H, Adapa S, Shah D, Malhotra BK, Rafiyath SM, Thakar K, Fernandez AC (June 2013). "Use of conjugated estrogens in life-threatening gastrointestinal bleeding in hemodialysis patients--a review". Clin. Appl. Thromb. Hemost. 19 (3): 334–7. doi:10.1177/1076029612437575. PMID 22411999. 
  • Mirkin S, Komm BS, Pickar JH (January 2014). "Conjugated estrogens for the treatment of menopausal symptoms: a review of safety data". Expert Opin Drug Saf. 13 (1): 45–56. doi:10.1517/14740338.2013.824965. PMID 23919270. 
  • Bhavnani BR, Stanczyk FZ (July 2014). "Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action". J. Steroid Biochem. Mol. Biol. 142: 16–29. doi:10.1016/j.jsbmb.2013.10.011. PMID 24176763. 
  • Mattison DR, Karyakina N, Goodman M, LaKind JS (2014). "Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps". Crit. Rev. Toxicol. 44 (8): 696–724. doi:10.3109/10408444.2014.930813. PMID 25099693. 

External links[edit]