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'''Conjugated estrogens''' ('''CEs'''), or '''conjugated equine estrogens''' ('''CEEs'''), sold under the brand name '''Premarin''' (a contraction of '''pre'''gnant '''mar'''es' ur'''in'''e) among others, is an [[estrogen (medication)|estrogen]] medication which is used in [[menopausal hormone therapy]] and for various other indications.<ref name="Martindale">{{cite book |editor=Sweetman, Sean C. |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|url=https://www.medicinescomplete.com/mc/rem/current/mono-E61.htm?q=C&t=advanced&ss=mn&p=57}}</ref><ref name="PremarinLabel">http://labeling.pfizer.com/showlabeling.aspx?id=131</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 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref><ref name="FritzSperoff2012">{{cite book|author1=Marc A. Fritz|author2=Leon Speroff|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–}}</ref> It is a [[combination drug|mixture]] of the [[sodium]] [[salt (chemistry)|salt]]s of [[estrogen conjugate]]s found in [[equine|horse]]s, such as [[estrone sulfate]] and [[equilin sulfate]].<ref name="pmid16112947" /><ref name="FritzSperoff2012" /><ref name="Martindale" /> Conjugated estrogens are available in the form of both [[natural product|natural]] preparations manufactured from the [[urine]] of [[pregnant]] [[mare]]s and fully [[chemical synthesis|synthetic]] replications of the natural preparations.<ref name="MoscouSnipe2012">{{cite book|author1=Kathy Moscou|author2=Karen Snipe|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=0-323-08578-4|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> The medication is most commonly taken [[oral administration|by mouth]], but can also be given by [[topical medication|application to the skin]] or [[vaginal administration|vagina]] as a [[cream (pharmaceutical)|cream]] or by [[intravenous injection|injection into a blood vessel]] or [[intramuscular injection|muscle]].<ref name="pmid16112947" /><ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | accessdate = 19 February 2018 | url = http://www.accessdata.fda.gov/scripts/cder/daf/}}</ref>
'''Conjugated estrogens''' ('''CEs'''), or '''conjugated equine estrogens''' ('''CEEs'''), sold under the brand name '''Premarin''' (a contraction of '''pre'''gnant '''mar'''es' ur'''in'''e) among others, is an [[estrogen (medication)|estrogen]] medication which is used in [[menopausal hormone therapy]] and for various other indications.<ref name="Martindale">{{cite book |editor=Sweetman, Sean C. |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|url=https://www.medicinescomplete.com/mc/rem/current/mono-E61.htm?q=C&t=advanced&ss=mn&p=57}}</ref><ref name="PremarinLabel">http://labeling.pfizer.com/showlabeling.aspx?id=131</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 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref><ref name="FritzSperoff2012">{{cite book|author1=Marc A. Fritz|author2=Leon Speroff|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–}}</ref> It is a [[combination drug|mixture]] of the [[sodium]] [[salt (chemistry)|salt]]s of [[estrogen conjugate]]s found in [[equine|horse]]s, such as [[estrone sulfate]] and [[equilin sulfate]].<ref name="pmid16112947" /><ref name="FritzSperoff2012" /><ref name="Martindale" /> Conjugated estrogens are available in the form of both [[natural product|natural]] preparations manufactured from the [[urine]] of [[pregnant]] [[mare]]s and fully [[chemical synthesis|synthetic]] replications of the natural preparations.<ref name="MoscouSnipe2012">{{cite book|author1=Kathy Moscou|author2=Karen Snipe|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=0-323-08578-4|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 also formulated both alone and in combination with [[progestin]]s such as [[medroxyprogesterone acetate]].<ref name="Martindale" /> The medication is most commonly taken [[oral administration|by mouth]], but can also be given by [[topical medication|application to the skin]] or [[vaginal administration|vagina]] as a [[cream (pharmaceutical)|cream]] or by [[intravenous injection|injection into a blood vessel]] or [[intramuscular injection|muscle]].<ref name="pmid16112947" /><ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | accessdate = 19 February 2018 | url = http://www.accessdata.fda.gov/scripts/cder/daf/}}</ref>


<!-- Side effects and mechanism -->
<!-- Side effects and mechanism -->
[[Side effect]]s of conjugated estrogens include [[breast pain|breast tenderness]] and [[mammoplasia|enlargement]], [[headache]], [[water retention (medicine)|fluid retention]], and [[nausea]] among others.<ref name="PremarinLabel" /><ref name="pmid16112947" /> They 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 (medication)|progesterone]].<ref name="PremarinLabel" /><ref name="pmid16112947" /> Conjugated estrogens are [[estrogen (medication)|estrogen]]s, or [[agonist]]s of the [[estrogen receptor]], the [[biological target]] of [[estrogen]]s like [[estradiol]].<ref name="pmid16112947" /><ref name="PremarinLabel" />
[[Side effect]]s of conjugated estrogens include [[breast pain|breast tenderness]] and [[mammoplasia|enlargement]], [[headache]], [[water retention (medicine)|fluid retention]], and [[nausea]] among others.<ref name="PremarinLabel" /><ref name="pmid16112947" /> 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 (medication)|progesterone]].<ref name="PremarinLabel" /><ref name="pmid16112947" /> The medication may also increase the risk of [[blood clot]]s, [[cardiovascular disease]], and, when combined with most progestogens, [[breast cancer]].<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 Opin Drug Saf | volume = 16 | issue = 8 | pages = 941–954 | date = August 2017 | pmid = 28664754 | doi = 10.1080/14740338.2017.1343298 | url = }}</ref> Conjugated estrogens are estrogens, or [[agonist]]s of the [[estrogen receptor]], the [[biological target]] of [[estrogen]]s like [[estradiol]].<ref name="pmid16112947" /><ref name="PremarinLabel" />


<!-- History, society, and culture -->
<!-- History, society, and culture -->
Premarin, the major brand of conjugated estrogens in use, is manufactured by [[Wyeth]] (now a part of [[Pfizer]]) and was first marketed in 1941 in [[Canada]] and in 1942 in the [[United States]].<ref name="FritzSperoff2012" /> It is the most widely used form of estrogen in menopausal hormone therapy.<ref name="pmid24176763" /> Conjugated estrogens are available widely throughout the world.<ref name="Martindale" /> An estrogen preparation very similar to conjugated estrogens but differing in source and composition is [[esterified estrogens]].<ref name="pmid16112947" />
Premarin, the major brand of conjugated estrogens in use, is manufactured by [[Wyeth]] (now a part of [[Pfizer]]) and was first marketed in 1941 in [[Canada]] and in 1942 in the [[United States]].<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 journal|last1=Quereda|first1=Francisco|title=Hormone Therapy (I): Estrogens, Progestogens, and Androgens|year=2017|pages=181–196|doi=10.1007/978-3-319-59318-0_11}}</ref> However, it has begun to fall out of favor relative to [[bioidentical hormone therapy|bioidentical]] [[estradiol (medication)|estradiol]], which is the most widely used form of estrogen in [[Europe]] 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 | url = }}</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 = 769–83 | date = July 2014 | pmid = 24398406 | doi = 10.1097/GME.0000000000000169 | url = }}</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 = Postgrad Med | volume = 121 | issue = 1 | pages = 73–85 | date = January 2009 | pmid = 19179815 | doi = 10.3810/pgm.2009.01.1949 | url = }}</ref> Conjugated estrogens are available widely throughout the world.<ref name="Martindale" /> An estrogen preparation very similar to conjugated estrogens but differing in source and composition is [[esterified estrogens]].<ref name="pmid16112947" />


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Revision as of 01:40, 28 February 2018

Not to be confused with Estrogen conjugate or Esterified estrogens.
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
Sodium estrone sulfateEstrogen
Sodium equilin sulfateEstrogen
Sodium 17α-dihydroequilin sulfateEstrogen
Clinical data
Trade namesCenestin, Enjuvia, Congest, C.E.S., Premarin, Prempro (with MPATooltip medroxyprogesterone acetate), Premphase (with MPA), others
Other namesCEs; Conjugated equine estrogens; CEEs; Pregnant mares' urine; Premarin; Estrogens, conjugated
AHFS/Drugs.comConsumer Drug Information
Pregnancy
category
  • X
Routes of
administration		By mouth, topical, vaginal, intravenous injection, intramuscular injection[1][2]
Drug classEstrogen
ATC code
Legal status
Legal status
  • US: WARNING[3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityVariable[4]
Protein bindingHigh (to albumin and SHBGTooltip sex hormone-binding globulin)[4][1]
MetabolismLiver[4][1]
Elimination half-lifeEstrone: 26.7 hours
Estrone (BA): 14.8 hours
Equilin: 11.4 hours[5]
ExcretionUrine[4]
Identifiers
CAS Number
PubChem CID
PubChem SID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.031.987 Edit this at Wikidata
 ☒NcheckY (what is this?)  (verify)

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.[6][4][1][7] It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate.[1][7][6] Conjugated estrogens are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations.[8][9] They are also formulated both alone and in combination with progestins such as medroxyprogesterone acetate.[6] The medication is most commonly 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 conjugated estrogens include breast tenderness and enlargement, headache, fluid retention, and nausea among others.[4][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.[4][1] The medication may also increase the risk of blood clots, cardiovascular disease, and, when combined with most progestogens, breast cancer.[10] Conjugated estrogens are estrogens, or agonists of the estrogen receptor, the biological target of estrogens like estradiol.[1][4]

Premarin, the major brand of conjugated estrogens in use, is manufactured by Wyeth (now a part of Pfizer) and was first marketed in 1941 in Canada and in 1942 in the United States.[7] 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] Conjugated estrogens are available widely throughout the world.[6] An estrogen preparation very similar to conjugated estrogens but differing in source and composition is esterified estrogens.[1]

Medical uses

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 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.[5][21][6]

Available forms

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, and vials for intravenous or intramuscular injection.[2][22][23]

Side effects

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]

Pharmacology

Pharmacodynamics

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, to a lesser extent, of estradiol.[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.[7] 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][7] 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.[6][1][7] CEEs are prodrugs of the active forms of the estrogens.[1][7][6] 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.[7] There may be as many as 230 compounds in Premarin tablets.[11]

Composition of CEEs and properties of constituents[1][11][7][6][29]
Compound Proportion (%) Relative potency
in the vagina (%)		 Relative potency
in the uterus (%)		 RBATooltip Relative binding affinity for
ERα (%)		 RBA for
ERβ (%)		 ERα / ERβ
RBA ratio
Conjugated estrogens 100 38 100 – – –
Estrone 49.1–61.5 30 32 26 52 0.50
Equilin 22.4–30.5 42 80 13 49 0.26
17α-Dihydroequilin 13.5–19.5 0.06 2.6 41 32 1.30
17α-Estradiol 2.5–9.5 0.11 3.5 19 42 0.45
Δ8-Estrone 3.5–3.9 ? ? 19 32 0.60
Equilenin 2.2–2.8 1.3 11.4 15 20–29 0.50–0.75
17β-Dihydroequilin 0.5–4.0 83 200 113 108 1.05
17α-Dihydroequilenin 1.2–1.6 0.018 1.3 20 49 0.40
17β-Estradiol 0.56–0.9 100 ? 100 100 1.00
17β-Dihydroequilenin 0.5–0.7 0.21 9.4 68 90 0.75
Δ8-17β-Estradiol Small amounts ? ? 68 72 0.94
All listed compounds are present in CEE products specifically in the form of the sodium salts of the sulfate esters (i.e., as sodium estrone sulfate, sodium equilin sulfate, etc.).[1][7]

Relative oral potency of CEEs and other estrogens[1]
Estrogen HFTooltip Hot flashes FSHTooltip Follicle-stimulating hormone HDLTooltip High-density lipoprotein-CTooltip Cholesterol SHBGTooltip Sex hormone-binding globulin CBGTooltip Corticosteroid-binding globulin AGTTooltip Angiotensinogen
Estradiol 1.0 1.0 1.0 1.0 1.0 1.0
Estriol 0.3 0.3 0.2 ? ? ?
Estrone sulfate ? 0.9 0.5 0.9 0.7 1.5
Conjugated estrogens 1.2 1.1 1.5 3.0 1.5 5.0
Equilin sulfate ? ? 6.0 7.5 6.0 7.5
Ethinylestradiol 120 120 400 500 600 350
Diethylstilbestrol ? 3.4 ? 25.6 24.5 19.5
HF = clinical relief of hot flashes; FSH = suppression of FSH levels; HDL-C, SHBG, CBG, and AGT = increase in the serum levels of these hepatic proteins.

Pharmacokinetics

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.[30] 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.[30] By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively.[30] 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),[30] 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.[31][32]

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.[6] The active forms are metabolized primarily in the liver.[6] There is some enterohepatic recirculation of CEEs.[6] 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.[5]

Plasma estradiol and estrone concentration increases with Premarin[33]
Route Dose Time E2 (↑Δ) E1 (↑Δ) Ratio Ref
Oral
 
 		 0.3 mg
0.625 mg
1.25 mg
1.25 mg
2.5 mg		 6 hours
6 hours
6 hours
1 hour
6 hours		 +20 pg/mL
+50 pg/mL
+70 pg/mL
+35–58 pg/mL
+160 pg/mL		 ND
ND
ND
110 pg/mL
ND		 ND
ND
ND
0.32–0.52
ND		 [34]
[34]
[34]
[35]
[34]
Vaginal
(cream)		 0.3 mg
0.625 mg
0.625 mg
1.25 mg
1.25 mg
2.5 mg		 ND
ND
ND
2 hours
ND
ND		 +4 pg/mL
+13–29 pg/mL
+17 pg/mL
+25 pg/mL
+27 pg/mL
+32 pg/mL		 +20 pg/mL
+29–55 pg/mL
+45 pg/mL
+50 pg/mL
+110 pg/mL
+40 pg/mL		 0.2
0.24–1.0
0.38
0.5
0.25
0.8		 [36]
[37]
[36]
[38]
[36]
[36]

Protein binding and metabolic clearance of CEEs and other estrogens[1]
Compound RBATooltip Relative binding affinity to
SHBGTooltip sex hormone-binding globulin (%)		 % bound
to SHBG		 % bound
to albumin		 MCRTooltip Metabolic clearance rate
(L/day/m2)
17β-Estradiol 50 37 61 580
Estrone 12 16 80 1050
Estriol 0.3 1 91 1110
Estrone sulfate 0 0 99 80
17β-Dihydroequilin 30 ? ? 1250
Equilin 8 26 13 2640
17β-Dihydroequilin sulfate 0 ? ? 375
Equilin sulfate 0 ? ? 175
Δ8-Estrone ? ? ? 1710
RBA to SHBG (%) is compared to 100% for testosterone.

Chemistry

See also: List of estrogens, Estrogen ester, and Estrogen conjugate

Conjugated estrogens are naturally occurring estrane steroids and analogues of estradiol.[1][7] They are in conjugate form, as the sodium salts of sulfate esters.[1][7]

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

History

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.[39] 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.[40] 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.[41] 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.[40] In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis[42] and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.[43] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.[40]

Society and culture

Generic names

Estrogens, conjugated is the generic name of the drug and its USPTooltip United States Pharmacopeia and JANTooltip Japanese Accepted Name.[44] It is also known as conjugated estrogens or as conjugated equine estrogens.[5]

Brand names

CEEs are marketed under a large number of brand names throughout the world.[6] The major brand name of the natural form of CEEs manufactured from the urine of pregnant mares is Premarin.[6] 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.[6][8][9] CEEs are also formulated in combination with progestins.[6] 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.[6][45] 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.[6] Many of the aforementioned brand names are also used in other, non-English-speaking countries.[6]

Availability

See also: List of estrogens available in the United States

CEEs are marketed and available widely throughout the world.[6][21] This includes in all English-speaking countries, Europe, Latin America, Asia, and elsewhere in the world.[6][21]

Health effects

Research starting in 1975 showed substantially increased risk of endometrial cancer.[46][47] Since 1976 the drug has carried a label warning about the risk.[48] 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.[49] 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.[50]

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.[51] 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.[52] 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.[53] 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." [54] 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."[52]

Animal welfare

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.[55]

See also

References

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  55. ^ The HRT horses (NBC)

Further reading

  • 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


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