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
Estrone sulfateEstrogen
Equilin sulfateEstrogen
17α-Dihydro-equilin sulfateEstrogen
Clinical data
Trade namesCenestin, Enjuvia, Congest, C.E.S., Premarin, Prempro (with MPA), Premphase (with MPA), others
SynonymsCEs; 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
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityVariable[3]
Protein bindingHigh (to albumin and SHBG)[3][1]
MetabolismLiver[3][1]
Elimination half-lifeEstrone: 26.7 hours
Estrone (BA): 14.8 hours
Equilin: 11.4 hours[4]
ExcretionUrine[3]
Identifiers
CAS Number
PubChem CID
PubChem SID
ChemSpider
UNII
KEGG
ECHA InfoCard100.006.475 Edit this at Wikidata
  (verify)

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin 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] In 2016 it was the 149th most prescribed medication in the United States with more than 4 million prescriptions.[16]

Medical uses[edit]

CEEs are a form of hormone therapy used in women.[17] 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.[18] 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.[19] 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.[20][21] It has been used at a dosage of 2.5 mg three times per day (7.5 mg/day total) for prostate cancer.[22][23]

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][24][5]

Estrogen dosages for menopausal hormone therapy

Route/form Estrogen Low Standard High
Oral Estradiol 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol valerate 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day 0.9–1.8 mg/day 1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Estropipate 0.75 mg/day 1.5 mg/day 3 mg/day
Estriol 1–2 mg/day 2–4 mg/day 4–8 mg/day
Ethinylestradiola 5–10 μg/day
Nasal spray Estradiol 150 μg/day 300 μg/day 600 μg/day
Transdermal patch Estradiol 25 μg/dayb 50 μg/dayb 100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day 1–1.5 mg/day 2–3 mg/day
Vaginal Estradiol 25 μg/day
Estriol 30 μg/day 0.5 mg 2x/week 0.5 mg/day
IM or SC injection Estradiol valerate 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks 3 mg 1x/3–4 weeks 5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week 1 mg 1x/week 1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months 50 mg 1x/6 months 100 mg 1x/6 months
Footnotes: a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.

Estrogen dosages for breast cancer

Route/form Estrogen Dosage
Oral Estradiol 10 mg 3x/day
AI-resistant: 2 mg 1–3x/day
Estradiol valerate AI-resistant: 2 mg 1–3x/day
Conjugated estrogens 10 mg 3x/day
Ethinylestradiol 0.5–1 mg 3x/day
Diethylstilbestrol 5 mg 3x/day
Dienestrol 5 mg 3x/day
IM or SC injection Estradiol benzoate 5 mg 2–3x/week
Estradiol dipropionate 5 mg 2–3x/week
Estradiol valerate 30 mg 1x/2 weeks
Polyestradiol phosphate 40–80 mg 1x/4 weeks
Estrone 5 mg ≥3x/week
Notes: (1) Only in women who are at least 5 years postmenopausal. (2) Dosages are not necessarily equivalent. Sources: See template.

Estrogen dosages for prostate cancer

Route/form Estrogen Dosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–2 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 120–480 mg 1–3x/day
Chlorotrianisene 12–24 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IM or SC injection Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

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][25] 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][26]

Contraindications[edit]

Contraindications of CEEs include breast cancer and a history of venous thromboembolism, among others.[citation needed]

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.[27] Only a few clinical studies have assessed differences between oral CEEs and oral estradiol in terms of health parameters.[28] Oral CEEs have been found to possess a significantly greater risk of thromboembolic and cardiovascular complications than oral estradiol (OR = 2.08) and oral esterified estrogens (OR = 1.78).[28][29][30] 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 (RR = 4.0 and 3.9, respectively).[31][32] As of present, there are no randomized controlled trials that would allow for unambiguous conclusions.[28]

Health risks in the CEEs/MPA substudy of the Women's Health Initiative

Event Relative Risk CEEs/MPA vs. placebo at 5.2 years (95% CI[note 1]) Placebo
(n = 8102)
CEEs/MPA
(n = 8506)
Absolute Risk per 10,000 Women-Years
Coronary heart disease events
( non-fatal myocardial infarction, death)
1.29 (1.02–1.63)
1.32 (1.02–1.72)
1.18 (0.70–1.97)
30
23
6
37
30
7
Invasive breast cancer[a] 1.26 (1.00–1.59) 30 38
Stroke 1.41 (1.07–1.85) 21 29
Pulmonary embolism 2.13 (1.39–3.25) 8 16
Colorectal cancer 0.63 (0.43–0.92) 16 10
Endometrial cancer 0.83 (0.47–1.47) 6 5
Hip fracture 0.66 (0.45–0.98) 15 10
Death due to causes other than above 0.92 (0.74–1.14) 40 37
Global Index[b] 1.15 (1.03–1.28) 151 170
Deep vein thrombosis[c] 2.07 (1.49–2.87) 13 26
Vertebral fractures[c] 0.66 (0.44–0.98) 15 9
Other osteoporotic fractures[c] 0.77 (0.69–0.86) 170 131
Sources: See template.

Overdose[edit]

Estrogens, including CEEs, are relatively safe in acute overdose.[citation needed]

Interactions[edit]

Inhibitors and inducers of cytochrome P450 enzymes may interact with CEEs.[citation needed]

Pharmacology[edit]

Pharmacodynamics[edit]

Estradiol, the main active form of estrone sulfate and the major active estrogen with CEEs.[1]
17β-Dihydroequilin, the main active form of equilin sulfate and the second major active estrogen with CEEs.[1]

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 then of estradiol.[1][33][34] The transformation of estrone sulfate to estrone is catalyzed by steroid sulfatase, and of estrone into estradiol by 17β-hydroxysteroid dehydrogenase.[1][35] CEEs (as Premarin) and estrone have been found to be equivalent in potency in an animal model of estrogenic activity.[6] 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.[1] This results in disproportionate effects on liver protein production compared to estradiol, although to a lesser extent than ethinylestradiol and diethylstilbestrol.[1] 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.[36]

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] 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.[1] 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.[1] The 17α-estrogens in CEEs such as 17α-estradiol and 17α-dihydroequilin have low estrogenicity and are thought to contribute minimally to its effects.[1] 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.[6][37][11]

A dosage of 0.625 mg/day oral CEEs has been found to increase SHBG levels by 100%.[37][38] For comparison, 1 mg/day oral estradiol increased SHBG levels by 45%, while 50 µg/day transdermal estradiol increased SHBG levels by 12%.[37][38] 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.[37]

Composition of conjugated estrogens and properties of constituents

Compound Synonym Proportion (%) Relative potency
in the vagina (%)
Relative potency
in the uterus (%)
RBA 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 Δ7-Estrone 22.4–30.5 42 80 13 49 0.26
17α-Dihydroequilin Δ7-17α-Estradiol 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 Δ6,8-Estrone 2.2–2.8 1.3 11.4 15 20–29 0.50–0.75
17β-Dihydroequilin Δ7-17β-Estradiol 0.5–4.0 83 200 113 108 1.05
17α-Dihydroequilenin Δ6,8-17α-Estradiol 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 Δ6,8-17β-Estradiol 0.5–0.7 0.21 9.4 68 90 0.75
Δ8-17β-Estradiol Small amounts ? ? 68 72 0.94
Notes: All listed compounds are present in conjugated estrogen products specifically in the form of the sodium salts of the sulfate esters (i.e., as sodium estrone sulfate, sodium equilin sulfate, etc.). Sources: See template.

Oral potencies of estrogens

Estrogen Type Class ETD
(mg/14 days)
EPD
(mg/14 days)
EPD
(mg/day)
MSD
(mg/14 days)
MSD
(mg/day)
TSD
(mg/day)
Estradiol (micronized) Bioidentical Steroidal ? 60–80 4.3 14–28 1.0–2.0 >8
Estradiol valerate Bioidentical Steroidal 6–10 60–80 4.3 14–28 1.0–2.0 >8
Estriol Bioidentical Steroidal 20a 120–150b 10.0–10.7b 28–84 1.0–6.0 ?
Estriol succinate Bioidentical Steroidal ? 140–150b 10.0–10.7b 28–84 2.0–6.0 ?
Conjugated estrogens Natural Steroidal 5–12 60–80 4.3 8.4–17.5 0.625–1.25 7.5
Ethinylestradiol Synthetic Steroidal 0.2 1.0–2.0 0.071–0.11 0.28 0.02 0.1
Mestranol Synthetic Steroidal 0.3 1.5–3.0 0.11–0.13 0.3–0.5 0.025 ?
Quinestrol Synthetic Steroidal 0.3 2.0–4.0 0.14–0.29 ? 0.025–0.05 ?
Methylestradiol Synthetic Steroidal ? 2.0 ? ? ? ?
Diethylstilbestrol Synthetic Nonsteroidal 2.5 20–30 1.4–2.1 ? 0.5–2.0 3
Diethylstilbestrol dipropionate Synthetic Nonsteroidal ? 15–30 1.1–1.4 ? ? ?
Dienestrol Synthetic Nonsteroidal ? 30 ? ? 0.5–4.0 ?
Dienestrol diacetate Synthetic Nonsteroidal 3–5 30–60 2.9–4.3 ? ? ?
Hexestrol Synthetic Nonsteroidal ? 70–110 ? ? ? ?
Hexestrol diacetate Synthetic Nonsteroidal ? 45 ? ? ? ?
Chlorotrianisene Synthetic Nonsteroidal ? >100 ? ? ? ?
Methallenestril Synthetic Nonsteroidal ? 400 ? ? ? ?
Note: The OID of EE is 0.1 mg/day. Footnotes: a = Very variable, often higher. b = In divided doses, 3x/day; irregular and atypical proliferation. Sources: See template.

Relative oral potencies of estrogens

Estrogen Type HF VE UCa FSH LH HDL-C SHBG CBG AGT Liver
Estradiol Bioidentical 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Estrone Bioidentical ? ? ? 0.3 0.3 ? ? ? ? ?
Estriol Bioidentical 0.3 0.3 0.1 0.3 0.3 0.2 ? ? ? 0.67
Estrone sulfate Bioidentical ? 0.9 0.9 0.9 0.9 0.5 0.9 0.7 1.5 0.56–1.7
Conjugated estrogens Natural 1.2 1.5 2.0 1.1 1.0 1.5 3.0 1.5 5.0 1.3–4.5
Equilin sulfate Natural ? ? 1.0 ? ? 6.0 7.5 6.0 7.5 ?
Ethinylestradiol Synthetic 120 150 400 120 100 400 500 600 350 2.9–5.0
Diethylstilbestrol Synthetic ? ? ? 3.4 ? ? 25.6 24.5 19.5 5.7–7.5
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations: HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCa. FSH = Suppression of FSH levels. LH = Suppression of LH levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (specifically hot flashes relief and gonadotropin suppression). Type: Bioidentical = Identical to those found in humans. Natural = Naturally occurring but not identical to those found in humans (e.g., estrogens of other species). Synthetic = Man-made, does not occur naturally in animals or in the environment. Sources: See template.

Antigonadotropic effects[edit]

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).[39]

Pharmacokinetics[edit]

CEEs are hydrolyzed in the intestines during first-pass metabolism upon oral administration.[40][5] Following their absorption, they are resulfated mainly in the liver also during the first pass.[40] Following this, they serve as a circulating reservoir and are slowly rehydrolyzed into their unconjugated active forms.[40]

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.[41] 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.[41] By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively.[41] 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),[41] 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.[42][43] The pharmacokinetics of vaginal CEEs have been studied as well.[44]

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]

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

Route Dose Time E2 (↑Δ) E1 (↑Δ) Ratio
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
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
Intravenous 25 mg ND ND ND ND
Sources: See template.

Endogenous estradiol production rates and plasma estrogen levels

Group E2 (prod) E2 (levels) E1 (levels) Ratio
Pubertal girlsa
  Tanner stage I (childhood)
  Tanner stage II (ages 8–12)
  Tanner stage III (ages 10–13)
  Tanner stage IV (ages 11–14)
  Tanner stage V (ages 12–15)
    Follicular (days 1–14)
    Luteal (days 15–28)
 
?
?
?
?
 
?
?
 
9 (<9–20) pg/mL
15 (<9–30) pg/mL
27 (<9–60) pg/mL
55 (16–85) pg/mL
 
50 (30–100) pg/mL
130 (70–300) pg/mL
 
13 (<9–23) pg/mL
18 (10–37) pg/mL
26 (17–58) pg/mL
36 (23–69) pg/mL
 
44 (30–89) pg/mL
75 (39–160) pg/mL
 
?
?
?
?
 
?
?
Prepubertal boys ? 2–8 pg/mL ? ?
Premenopausal women
  Early follicular phase (days 1–4)
  Mid follicular phase (days 5–9)
  Late follicular phase (days 10–14)
  Luteal phase (days 15–28)
  Oral contraceptive (anovulatory)
 
30–100 µg/day
100–160 µg/day
320–640 µg/day
300 µg/day
?
 
40–60 pg/mL
60–100 pg/mL
200–400 pg/mL
190 pg/mL
12–50 pg/mL
 
40–60 pg/mL
?
170–200 pg/mL
100–150 pg/mL
?
 
0.5–1
?
1–2
1.5
?
Postmenopausal women 18 µg/day 5–20 pg/mL 30–70 pg/mL 0.3–0.8
Pregnant women
  First trimester (weeks 1–12)
  Second trimester (weeks 13–26)
  Third trimester (weeks 27–40)
 
?
?
?
 
1,000–5,000 pg/mL
5,000–15,000 pg/mL
10,000–40,000 pg/mL
 
?
?
?
 
?
?
?
Mena 20–60 µg/day 27 (20–55) pg/mL 20–90 pg/mL 0.4–0.6
Footnotes: a = Format is "Mean value (range)". Sources: See template.

Protein binding and metabolic clearance rates of estrogens

Compound RBA to
SHBG (%)
Bound to
SHBG (%)
Bound to
albumin (%)
Total
bound
(%)
MCR
(L/day/m2)
17β-Estradiol 50 37 61 98 580
Estrone 12 16 80 96 1050
Estriol 0.3 1 91 92 1110
Estrone sulfate 0 0 99 99 80
17β-Dihydroequilin 30 ? ? ? 1250
Equilin 8 26 13 ? 2640
17β-Dihydroequilin sulfate 0 ? ? ? 375
Equilin sulfate 0 ? ? ? 175
Δ8-Estrone ? ? ? ? 1710
Notes: RBA for SHBG (%) is compared to 100% for testosterone. Sources: See template.

Chemistry[edit]

CEEs are naturally occurring estrane steroids.[1][6] They are in conjugate form, as the sodium salts of the C17β sulfate esters.[1][6] 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.[1][6] The equine estrogens differ from human estrogens in that they have additional double bonds in the B ring of the steroid nucleus.[1][6] CEEs contain both 17β-estrogens like estradiol and 17β-dihydroequilin and the C17α epimers like 17α-estradiol and 17α-dihydroequilin.[1][6]

Chemical structures of equine estrogens[11][45]
The image above contains clickable links
This diagram illustrates the chemical structures of the active/unconjugated forms of the equine estrogens present in conjugated estrogens.

History[edit]

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.[46] 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.[47] 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.[48] 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.[47] In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis[49] and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.[50] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.[47]

Society and culture[edit]

Names[edit]

Estrogens, conjugated is the generic name of the drug and its USP and JAN.[51] It is also known as conjugated estrogens or as conjugated equine estrogens.[4] The brand name Premarin is a contraction of "pregnant mares' urine".

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 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.[5][52] 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]

Availability[edit]

CEEs are marketed and available widely throughout the world.[5][24] This includes in all English-speaking countries, throughout Europe, Latin America, Asia, and elsewhere in the world.[5][24]

Usage[edit]

Besides ethinylestradiol used in birth control pills, CEEs were the second most used estrogen in the U.S. in 2016, with 4.2 million total prescriptions filled.[16] The first most used estrogen was estradiol, with 13.4 million total prescriptions filled.[16] CEEs were the 149th most prescribed medication in the U.S. that year.[16]

Health effects[edit]

Research starting in 1975 showed substantially increased risk of endometrial cancer.[53][54] Since 1976 the drug has carried a label warning about the risk.[55] 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.[56] 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.[57]

Litigation[edit]

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.[58] 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.[59] 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.[60] 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." [61] 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."[59]

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.[62]

See also[edit]

Notes[edit]

  1. ^ Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.
  2. ^ A subset of the events was combined in a "global index", defined as the earliest occurrence of coronary heart disease events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.
  3. ^ a b c Not included in Global Index.
  1. ^ Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

References[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae 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.
  2. ^ a b c d "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 19 February 2018.
  3. ^ a b c d e f g h "PREMARIN- estrogens, conjugated tablet, film coated Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc". labeling.pfizer.com. Retrieved 2019-06-03.
  4. ^ a b c d "Conjugated estrogens".
  5. ^ a b c d e f g h i j k l m n o p q r s Sweetman, Sean C., ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2087. ISBN 978-0-85369-840-1.
  6. ^ a b c d e f g h i j k l m Marc A. Fritz; Leon Speroff (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 751–3. ISBN 978-1-4511-4847-3.
  7. ^ a b Kathy Moscou; Karen Snipe (1 December 2012). Pharmacology for Pharmacy Technicians Pageburst E-Book on VitalSource2: Pharmacology for Pharmacy Technicians Pageburst E-Book on VitalSource. Elsevier Health Sciences. pp. 573–. ISBN 978-0-323-08578-6.
  8. ^ a b IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 378–. ISBN 978-92-832-1291-1.
  9. ^ Pickar JH, Archer DF, Kagan R, Pinkerton JV, Taylor HS (August 2017). "Safety and benefit considerations for menopausal hormone therapy". Expert Opin Drug Saf. 16 (8): 941–954. doi:10.1080/14740338.2017.1343298. PMID 28664754.
  10. ^ Scarabin PY (December 2014). "Hormones and venous thromboembolism among postmenopausal women". Climacteric. 17 Suppl 2: 34–7. doi:10.3109/13697137.2014.956717. PMID 25223916.
  11. ^ a b c 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.
  12. ^ a b Quereda, Francisco (2017). "Hormone Therapy (I): Estrogens, Progestogens, and Androgens". Menopause. pp. 181–196. doi:10.1007/978-3-319-59318-0_11. ISBN 978-3-319-59317-3.
  13. ^ L'Hermite M (August 2017). "Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal". Climacteric. 20 (4): 331–338. doi:10.1080/13697137.2017.1291607. PMID 28301216.
  14. ^ Simon JA (July 2014). "What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead?". Menopause. 21 (7): 769–83. doi:10.1097/GME.0000000000000169. PMID 24398406.
  15. ^ Holtorf K (January 2009). "The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?". Postgrad Med. 121 (1): 73–85. doi:10.3810/pgm.2009.01.1949. PMID 19179815.
  16. ^ a b c d "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
  17. ^ Greer, Iain A.; Ginsberg, Jeff; Forbes, Charles (29 December 2006). Women's vascular health. CRC Press. ISBN 9780340809976.
  18. ^ Nezhat, Camran; Nezhat, Farr; Nezhat, Ceana (7 July 2008). Nezhat's Operative gynecologic laparoscopy and hysteroscopy. Cambridge University Press. ISBN 9781139472005. Retrieved 7 May 2015.
  19. ^ Maeda, Sergio Setsuo; Lazaretti-Castro, Marise; Maeda, Sergio Setsuo; Lazaretti-Castro, Marise (2014). "An overview on the treatment of postmenopausal osteoporosis". Arquivos Brasileiros de Endocrinologia & Metabologia. 58 (2): 162–171. doi:10.1590/0004-2730000003039. ISSN 0004-2730.
  20. ^ Majeed, W.; Aslam, B.; Javed, I.; Khaliq, T.; Muhammad, F.; Ali, A.; Raza, A. (2014). "Breast cancer: major risk factors and recent developments in treatment". Asian Pac J Cancer Prev. 15 (8): 3353–8. doi:10.7314/apjcp.2014.15.8.3353. PMID 24870721.
  21. ^ Learning, Jones & Bartlett (2015-01-14). 2015 Nurse's Drug Handbook. Jones & Bartlett Publishers. ISBN 9781284091373. Retrieved 2015-05-07.
  22. ^ Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 540–. ISBN 978-3-642-60107-1.
  23. ^ Louis J Denis; Keith Griffiths; Amir V Kaisary; Gerald P Murphy (1 March 1999). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 297–. ISBN 978-1-85317-422-3.
  24. ^ a b c "Premarin".
  25. ^ John E. Morley; Lucretia van den Berg (5 November 1999). Endocrinology of Aging. Springer Science & Business Media. pp. 172–. ISBN 978-1-59259-715-4.
  26. ^ Ronald I. Shorr (11 April 2007). Drugs for the Geriatric Patient E-Book: Text with BONUS Handheld Software. Elsevier Health Sciences. pp. 462–. ISBN 978-1-4377-1035-9.
  27. ^ "Archived copy". Archived from the original on 2016-10-26. Retrieved 2018-02-20.CS1 maint: Archived copy as title (link)
  28. ^ a b c Bińkowska M (October 2014). "Menopausal hormone therapy and venous thromboembolism". Prz Menopauzalny. 13 (5): 267–72. doi:10.5114/pm.2014.46468. PMC 4520375. PMID 26327865.
  29. ^ 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 (January 2014). "Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens". JAMA Intern Med. 174 (1): 25–31. doi:10.1001/jamainternmed.2013.11074. PMC 4636198. PMID 24081194.
  30. ^ Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM (October 2004). "Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis". JAMA. 292 (13): 1581–7. doi:10.1001/jama.292.13.1581. PMID 15467060.
  31. ^ Lekovic D, Miljic P, Dmitrovic A, Thachil J (May 2017). "How do you decide on hormone replacement therapy in women with risk of venous thromboembolism?". Blood Rev. 31 (3): 151–157. doi:10.1016/j.blre.2016.12.001. PMID 27998619.
  32. ^ Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A (January 2013). "The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy". J. Thromb. Haemost. 11 (1): 124–31. doi:10.1111/jth.12060. PMID 23136837.
  33. ^ H.J. Buchsbaum (6 December 2012). The Menopause. Springer Science & Business Media. pp. 64–. ISBN 978-1-4612-5525-3.
  34. ^ Tommaso Falcone; William W. Hurd (22 May 2013). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer Science & Business Media. pp. 5–6. ISBN 978-1-4614-6837-0.
  35. ^ Joseph S. Sanfilippo (January 1998). Primary Care in Obstetrics and Gynecology: A Handbook for Clinicians. Springer Science & Business Media. pp. 220, 227. ISBN 978-0-387-94739-6. Conjugated estrogens are absorbed with peak levels at 4 hours and a half-life of approximately 12 hours.
  36. ^ Cline JM (2007). "Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors". Birth Defects Res. B Dev. Reprod. Toxicol. 80 (2): 126–46. doi:10.1002/bdrb.20112. PMID 17443713.
  37. ^ a b c d Notelovitz M (March 2006). "Clinical opinion: the biologic and pharmacologic principles of estrogen therapy for symptomatic menopause". MedGenMed. 8 (1): 85. PMC 1682006. PMID 16915215.
  38. ^ a b Nachtigall LE, Raju U, Banerjee S, Wan L, Levitz M (2000). "Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels". Menopause. 7 (4): 243–50. doi:10.1097/00042192-200007040-00006. ISSN 1072-3714. PMID 10914617.
  39. ^ Scott WW, Menon M, Walsh PC (April 1980). "Hormonal Therapy of Prostatic Cancer". Cancer. 45 Suppl 7: 1929–1936. doi:10.1002/cncr.1980.45.s7.1929. PMID 29603164.
  40. ^ a b c Fotherby K (August 1996). "Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy". Contraception. 54 (2): 59–69. doi:10.1016/0010-7824(96)00136-9. PMID 8842581.
  41. ^ a b c d Rogerio A. Lobo (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 771–. ISBN 978-0-08-055309-2.
  42. ^ M. Notelovitz; P.A. van Keep (6 December 2012). The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28–November 2, 1984. Springer Science & Business Media. pp. 395–. ISBN 978-94-009-4145-8.
  43. ^ G. E. Seidel (1974). Gonadotrophins: Current Research. Ardent Media. pp. 157–. ISBN 978-0-8422-7205-6.
  44. ^ Punnonen R, Vilska S, Grönroos M, Rauramo L (December 1980). "The vaginal absorption of oestrogens in post-menopausal women". Maturitas. 2 (4): 321–6. doi:10.1016/0378-5122(80)90034-1. PMID 7231202.
  45. ^ Bhavnani BR, Tam SP, Lu X (October 2008). "Structure activity relationships and differential interactions and functional activity of various equine estrogens mediated via estrogen receptors (ERs) ERalpha and ERbeta". Endocrinology. 149 (10): 4857–70. doi:10.1210/en.2008-0304. PMID 18599548.
  46. ^ Schachter, B.; Marrian, G. F. (1938). "The isolation of estrone sulfate from the urine of pregnant mares". Journal of Biological Chemistry. 126: 663–669.
  47. ^ a b c Jim Kling October 2000 The Strange Case of Premarin Modern Drug Discovery (3):8 46–52
  48. ^ "Federal register [microform]". 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.] 3 June 1972 – via Internet Archive.
  49. ^ National Institutes of Health Consensus Development Conference Statement. April 2–4, 1984 Osteoporosis
  50. ^ Food and Drug Administration. May 5, 1997 Conjugated Estrogens - Letter from Dr. Janet Woodcock: Approvability of a Synthetic Generic Version of Premarin
  51. ^ "ChemIDplus - 12126-59-9 - QTTMOCOWZLSYSV-QWAPEVOJSA-M - Estrogens, conjugated [USP:JAN] - Similar structures search, synonyms, formulas, resource links, and other chemical information".
  52. ^ MaryAnne Hochadel; Jerry Avorn (1 January 2007). The AARP Guide to Pills: Essential Information on More Than 1,200 Prescription and Nonprescription Medications, Including Generics. Sterling Publishing Company Incorporated. pp. 235–. ISBN 978-1-4027-4446-4.
  53. ^ Ziel HK, Finkle WD (4 December 1975). "Increased risk of endometrial carcinoma among users of conjugated estrogens". New England Journal of Medicine. 293 (23): 1167–1170. doi:10.1056/NEJM197512042932303. PMID 171569.
  54. ^ McDonald TW, et al. (15 March 1977). "Exogenous estrogen and endometrial carcinoma: case-control and incidence study". Am J Obstet Gynecol. 127 (6): 572–580. doi:10.1016/0002-9378(77)90351-9. PMID 190887.
  55. ^ Natasha Singer and Duff Wilson (12 December 2009). "Menopause, as Brought to You by Big Pharma". New York Times.
  56. ^ Brunner RL et al; Womens Health Initiative Investigators (26 September 2005). "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". Archives of Internal Medicine. 165 (17): 1976–1986. doi:10.1001/archinte.165.17.1976. PMID 16186467.
  57. ^ "Earnings Results for the 2006 Fourth Quarter and Full Year" (PDF) (Press release). Wyeth. Archived from the original (PDF) on 2007-11-27. Retrieved 2018-02-20.
  58. ^ "Pfizer Statement on Prempro". Indy News Channel. 2009-11-24. Archived from the original on February 23, 2012.
  59. ^ a b Jef Feeley (February 24, 2010). "Pfizer wins trial over claim Prempro caused cancer". Bloomberg.
  60. ^ "Pfizer properly warned about Prempro risks, jury finds". 3 December 2010.
  61. ^ "Legal Intelligencer: Philadelphia jury returns defense verdict in HRT case, Amaris Elliott Engel".
  62. ^ News, Keith Morrison NBC (19 January 2004). "The HRT horses". msnbc.com.

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. doi:10.1002/j.1552-4604.1995.tb04143.x. 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. doi:10.3109/00016349609033337. 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. doi:10.3181/00379727-217-44199. 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. doi:10.1016/S0960-0760(03)00220-6. 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]