Conjugated estrogens

Source: Wikipedia, the free encyclopedia.
Not to be confused with Estrogen conjugate or Esterified estrogens.

Conjugated estrogens
intravenous injection, intramuscular injection[1][2]
Drug classEstrogen
ATC code
Legal status
Legal status
  • US: WARNING[3]
  • In general: ℞ (Prescription only)
ECHA InfoCard
100.031.987 Edit this at Wikidata
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Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an

injection into a blood vessel or muscle.[1][2]

blood clots, cardiovascular disease, and, when combined with most progestogens, breast cancer.[10] CEEs are estrogens, or agonists of the estrogen receptor, the biological target of estrogens like estradiol.[1][4] 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 problems with CEEs relative to estradiol.[1][11]

Premarin, the major brand of CEEs in use, is manufactured by

bioidentical estradiol, which is the most widely used form of estrogen in Europe for menopausal hormone therapy.[13][14][15][16] CEEs are available widely throughout the world.[6] An estrogen preparation very similar to CEEs but differing in source and composition is esterified estrogens.[1] In 2020, it was the 283rd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[17][18]

Medical uses

CEEs are a form 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.[22][23] It has been used at a dosage of 2.5 mg three times per day (7.5 mg/day total) for prostate cancer.[24][25]

CEEs are specifically approved in countries such as the

dysfunctional uterine bleeding.[2][27]: 318 [28]
: 60 

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 2.5–10 μg/day 5–20 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
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.

Available forms

See also:
Conjugated estrogens/bazedoxifene

Natural CEEs, as Premarin, are available in the form of

intravenous or intramuscular injection (25 mg/vial).[2][29] Synthetic CEEs, such as Cenestin (Synthetic A), Enjuvia (Synthetic B), and generic formulations, are available in the form of oral tablets (0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, or 1.25 mg) and creams for topical or vaginal administration (0.625 mg/g).[2][30]

Contraindications

See also: Estrogen (medication) § Contraindications

venous thromboembolism, among others.[citation needed
]

Side effects

The most common

venous thromboembolism risk with oral CEEs plus medroxyprogesterone acetate and oral estradiol plus norethisterone acetate was found to be equivalent (RRTooltip Relative risk = 4.0 and 3.9, respectively).[35][36] As of present, there are no randomized controlled trials that would allow for unambiguous conclusions.[32]

Results of the Women's Health Initiative (WHI) menopausal hormone therapy randomized controlled trials
Clinical outcome Hypothesized
effect on risk 		Estrogen and progestogen
(CEsTooltip conjugated estrogens 0.625 mg/day p.o. + MPATooltip medroxyprogesterone acetate 2.5 mg/day p.o.)
(n = 16,608, with uterus, 5.2–5.6 years follow up) 		Estrogen alone
(CEsTooltip Conjugated estrogens 0.625 mg/day p.o.)
(n = 10,739, no uterus, 6.8–7.1 years follow up)
HRTooltip Hazard ratio 95% CITooltip Confidence interval
AR
Tooltip Attributable risk 		HRTooltip Hazard ratio 95% CITooltip Confidence interval
AR
Tooltip Attributable risk
Coronary heart disease
 Decreased 1.24 1.00–1.54 +6 / 10,000 PYs 0.95 0.79–1.15 −3 / 10,000 PYs
Stroke Decreased 1.31 1.02–1.68 +8 / 10,000 PYs 1.37 1.09–1.73 +12 / 10,000 PYs
Pulmonary embolism Increased 2.13 1.45–3.11 +10 / 10,000 PYs 1.37 0.90–2.07 +4 / 10,000 PYs
Venous thromboembolism
 Increased 2.06 1.57–2.70 +18 / 10,000 PYs 1.32 0.99–1.75 +8 / 10,000 PYs
Breast cancer Increased 1.24 1.02–1.50 +8 / 10,000 PYs 0.80 0.62–1.04 −6 / 10,000 PYs
Colorectal cancer Decreased 0.56 0.38–0.81 −7 / 10,000 PYs 1.08 0.75–1.55 +1 / 10,000 PYs
Endometrial cancer – 0.81 0.48–1.36 −1 / 10,000 PYs – – –
Hip fractures Decreased 0.67 0.47–0.96 −5 / 10,000 PYs 0.65 0.45–0.94 −7 / 10,000 PYs
Total fractures Decreased 0.76 0.69–0.83 −47 / 10,000 PYs 0.71 0.64–0.80 −53 / 10,000 PYs
Total mortality Decreased 0.98 0.82–1.18 −1 / 10,000 PYs 1.04 0.91–1.12 +3 / 10,000 PYs
Global index – 1.15 1.03–1.28 +19 / 10,000 PYs 1.01 1.09–1.12 +2 / 10,000 PYs
Diabetes – 0.79 0.67–0.93 0.88 0.77–1.01
Gallbladder disease Increased 1.59 1.28–1.97 1.67 1.35–2.06
Stress incontinence – 1.87 1.61–2.18 2.15 1.77–2.82
Urge incontinence
 – 1.15 0.99–1.34 1.32 1.10–1.58
Peripheral artery disease – 0.89 0.63–1.25 1.32 0.99–1.77
Probable dementia Decreased 2.05 1.21–3.48 1.49 0.83–2.66
Abbreviations: CEs = conjugated estrogens. MPA =
coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen plus progestogen group only), hip fractures, and death
from other causes. Sources: See template.
Risk of venous thromboembolism (VTE) with hormone therapy and birth control (QResearch/CPRD)
Type Route Medications Odds ratio (95% CITooltip confidence interval)
Menopausal hormone therapy
 Oral Estradiol alone
    ≤1 mg/day
    >1 mg/day		 1.27 (1.16–1.39)*
1.22 (1.09–1.37)*
1.35 (1.18–1.55)*
Conjugated estrogens alone
    ≤0.625 mg/day
    >0.625 mg/day		 1.49 (1.39–1.60)*
1.40 (1.28–1.53)*
1.71 (1.51–1.93)*
Estradiol/medroxyprogesterone acetate 1.44 (1.09–1.89)*
Estradiol/dydrogesterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.18 (0.98–1.42)
1.12 (0.90–1.40)
1.34 (0.94–1.90)
Estradiol/norethisterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.68 (1.57–1.80)*
1.38 (1.23–1.56)*
1.84 (1.69–2.00)*
Estradiol/norgestrel or estradiol/drospirenone
 1.42 (1.00–2.03)
Conjugated estrogens/medroxyprogesterone acetate 2.10 (1.92–2.31)*
Conjugated estrogens/norgestrel
    ≤0.625 mg/day CEEs
    >0.625 mg/day CEEs		 1.73 (1.57–1.91)*
1.53 (1.36–1.72)*
2.38 (1.99–2.85)*
Tibolone alone 1.02 (0.90–1.15)
Raloxifene alone 1.49 (1.24–1.79)*
Transdermal
 Estradiol alone
   ≤50 μg/day
   >50 μg/day		 0.96 (0.88–1.04)
0.94 (0.85–1.03)
1.05 (0.88–1.24)
Estradiol/progestogen 0.88 (0.73–1.01)
Vaginal
 Estradiol alone 0.84 (0.73–0.97)
Conjugated estrogens alone 1.04 (0.76–1.43)
Combined birth control
 Oral Ethinylestradiol/norethisterone 2.56 (2.15–3.06)*
Ethinylestradiol/levonorgestrel 2.38 (2.18–2.59)*
Ethinylestradiol/norgestimate
 2.53 (2.17–2.96)*
Ethinylestradiol/desogestrel 4.28 (3.66–5.01)*
Ethinylestradiol/gestodene 3.64 (3.00–4.43)*
Ethinylestradiol/drospirenone 4.12 (3.43–4.96)*
Ethinylestradiol/cyproterone acetate 4.27 (3.57–5.11)*
Notes: (1)
Bioidentical progesterone was not included, but is known to be associated with no additional risk relative to estrogen alone. Footnotes: * = Statistically significant
(p < 0.01). Sources: See template.

Overdose

See also: Estrogen (medication) § Overdose

Estrogens, including CEEs, are relatively safe in acute

overdose.[citation needed
]

Interactions

See also: Estrogen (medication) § Interactions

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

Pharmacology

Pharmacodynamics

See also: Pharmacodynamics of estradiol
Estradiol, the main active form of estrone sulfate and the major active estrogen with CEEs[1]
equilin sulfate and the second major active estrogen with CEEs[1]

CEEs are a combination of

cardiovascular system were observed but proliferative responses in breast or endometrium were not seen, although the clinical significance of this is unknown.[40]

CEEs consists of the

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.[7][41][12]

A dosage of 0.625 mg/day oral CEEs has been found to increase SHBG levels by 100%.[41][42] For comparison, 1 mg/day oral estradiol increased SHBG levels by 45%, while 50 µg/day transdermal estradiol increased SHBG levels by 12%.[41][42] 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.[41]

Composition of conjugated estrogens and properties of constituents
Compound Synonym Proportion (%) Relative potency
in the vagina (%)		 Relative potency
in the uterus (%)
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.
Potencies of oral estrogens[data sources 1]
Compound Dosage for specific uses (mg usually)[a]
ETD[b] EPD[b] MSD[b] MSD[c] OID[c] TSD[c]
Estradiol (non-micronized) 30 ≥120–300 120 6 - -
Estradiol (micronized) 6–12 60–80 14–42 1–2 >5 >8
Estradiol valerate 6–12 60–80 14–42 1–2 - >8
Estradiol benzoate - 60–140 - - - -
Estriol ≥20 120–150[d] 28–126 1–6 >5 -
Estriol succinate - 140–150[d] 28–126 2–6 - -
Estrone sulfate 12 60 42 2 - -
Conjugated estrogens 5–12 60–80 8.4–25 0.625–1.25 >3.75 7.5
Ethinylestradiol 200 μg 1–2 280 μg 20–40 μg 100 μg 100 μg
Mestranol 300 μg 1.5–3.0 300–600 μg 25–30 μg >80 μg -
Quinestrol 300 μg 2–4 500 μg 25–50 μg - -
Methylestradiol - 2 - - - -
Diethylstilbestrol 2.5 20–30 11 0.5–2.0 >5 3
DES dipropionate - 15–30 - - - -
Dienestrol 5 30–40 42 0.5–4.0 - -
Dienestrol diacetate 3–5 30–60 - - - -
Hexestrol - 70–110 - - - -
Chlorotrianisene - >100 - - >48 -
Methallenestril - 400 - - - -
Sources and footnotes:
  1. ^ [43][44][45][46][47][48] [49][50][51][52] [53][54][55][56][57][58][59][60][61]
  1. ^ Dosages are given in milligrams unless otherwise noted.
  2. ^ a b c Dosed every 2 to 3 weeks
  3. ^ a b c Dosed daily
  4. ^ a b In divided doses, 3x/day; irregular and atypical proliferation.
Relative oral potencies of estrogens
Estrogen
HF
Tooltip Hot flashes		 VETooltip Vaginal epithelium UCaTooltip Urinary calcium FSHTooltip Follicle-stimulating hormone LHTooltip Luteinizing hormone HDLTooltip High-density lipoprotein-CTooltip Cholesterol SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid-binding globulin
AGT
Tooltip Angiotensinogen		 Liver
Estradiol 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Estrone ? ? ? 0.3 0.3 ? ? ? ? ?
Estriol 0.3 0.3 0.1 0.3 0.3 0.2 ? ? ? 0.67
Estrone sulfate ? 0.9 0.9 0.8–0.9 0.9 0.5 0.9 0.5–0.7 1.4–1.5 0.56–1.7
Conjugated estrogens 1.2 1.5 2.0 1.1–1.3 1.0 1.5 3.0–3.2 1.3–1.5 5.0 1.3–4.5
Equilin sulfate
 ? ? 1.0 ? ? 6.0 7.5 6.0 7.5 ?
Ethinylestradiol 120 150 400 60–150 100 400 500–600 500–600 350 2.9–5.0
Diethylstilbestrol ? ? ? 2.9–3.4 ? ? 26–28 25–37 20 5.7–7.5
Sources and footnotes
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations: HF = Clinical relief of
liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins
). Sources: See template.

Antigonadotropic effects

Testosterone levels with no treatment and with various estrogens in men with prostate cancer.[62] Determinations were made with an early radioimmunoassay (RIA).[62]

A preliminary study of ovulation inhibition in women found that oral CEEs was 33% effective at 1.25 mg/day and 94% at 3.75 mg/day.[63][64] 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).[65]

Pharmacokinetics

See also: Pharmacokinetics of estradiol

CEEs are

absorption, they are resulfated mainly in the liver also during the first pass.[66] Following this, they serve as a circulating reservoir and are slowly rehydrolyzed into their unconjugated active forms.[66]

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.

first-pass metabolism),[67] 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.[68][69] The pharmacokinetics of vaginal CEEs[70] and of intravenous CEEs have been studied as well.[71]

Eoncentrations of equilin that are very high relative to those of other estrogens are produced by typical clinical doses of CEEs.[72] With a dosage of 1.25 mg oral CEEs, equilin levels of 1,082 to 2,465 pg/mL have been observed.[72] The clinical significance of these levels of equilin is unknown.[72]

The active forms are

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][unreliable medical source?
]

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
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
a		 20 mg 5 min
30 min
60 min
120 min		 800 pg/mL
3000 pg/mL
3500 pg/mL
3100 pg/mL		 4500 pg/mL
24000 pg/mL
19000 pg/mL
10500 pg/mL		 1:5.3
1:8.1
1:5.5
1:3.4
Notes: a = Absolute levels, not change. Sources: See template.
Protein binding and metabolic clearance rates of estrogens
Compound
RBATooltip Relative binding affinity to
SHBG
Tooltip sex hormone-binding globulin (%)		 Bound to
SHBG (%)		 Bound to
albumin (%)		 Total
bound (%)
MCR
Tooltip Metabolic clearance rate
(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

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

CEEs are

17α-dihydroequilin.[1][7]

Chemical structures of equine estrogens[12][73]
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

Conjugated estriol, an extract of the urine of pregnant women and sold under the brand names Progynon and Emmenin in the 1930s, was the predecessor of Premarin.[74] Both of these products contained conjugated estrogens similarly to Premarin, but the estrogens were human estrogens as opposed to equine estrogens and the composition differed. The major active ingredient in Progynon and Emmenin was estriol glucuronide.

Estrone sulfate was first isolated from the urine of pregnant mares in the late 1930s by researchers in the Department of Biochemistry at

Kefauver Harris Amendment the FDA had its efficacy reviewed, and in 1972 found it effective for menopausal symptoms and probably effective for osteoporosis.[77] 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.[76] In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis[78] and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.[79] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.[76]

Conjugated estrogens was introduced for medical use under the brand name Premarin in Canada in 1941, in the United States in 1942, and in the United Kingdom in 1956.[80]

The manufacturer of Premarin secretly paid

gynecologist Robert A. Wilson to promote its use by menopausal women in his 1966 book, Feminine Forever, leading to increased sales.[81]

Society and culture

Names

Estrogens, conjugated is the

generic name of the drug and its USPTooltip United States Pharmacopeia and JANTooltip Japanese Accepted Name.[82] It is also known as conjugated estrogens or as conjugated equine estrogens.[5][unreliable medical source?] The brand name Premarin is a contraction of "pregnant mares' urine".[83][84][85]

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 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.[6][86] 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][26] This includes in all English-speaking countries, throughout the European Union, Latin America, Asia, and elsewhere in the world.[6][26]

Health effects

Research starting in 1975 showed substantially increased risk of

blood clots, and breast cancer.[90] 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.[91]

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.[92] 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.[93] 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.[94] 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."[95] 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."[93]

Animal welfare

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.[96]

Notes

References

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    S2CID 24616324
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  2. ^ a b c d e "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 19 February 2018.
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  4. ^ 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 3 June 2019.
  5. ^ a b c d "Conjugated estrogens".
  6. ^
    ISBN 978-0-85369-840-1
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    ISBN 978-1-4511-4847-3
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  17. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  18. ^ "Estrogens, Conjugated - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
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Further reading

External links
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