|Sodium estrone sulfate||Estrogen|
|Sodium equilin sulfate||Estrogen|
|Sodium 17α-dihydroequilin sulfate||Estrogen|
|Synonyms||Conjugated equine estrogens; CEEs; Pregnant mares' urine|
|AHFS/Drugs.com||Consumer Drug Information|
|By mouth, topical, intravenous|
|Biological half-life||~12 hours|
|(what is this?)|
Premarin is the brand name for an estrogen medication that consists of conjugated estrogens isolated from the urine of pregnant mares (pregnant mares' urine). It is manufactured by Wyeth (now a part of Pfizer), and was first marketed in 1941 and 1942 in Canada and the United States, respectively, for the treatment of menopausal symptoms.
Premarin is a form of hormone therapy used in women. 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. It can also be used in conjunction with a progestogen in women who have not had a hysterectomy. For women already taking the medication, it can be used to treat osteoporosis, although it is not recommended solely for this use. Some lesser known uses are the treatment of breast cancer in both men and women and the treatment of prostate cancer in men.
The most common side effects associated with Premarin use 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.
Premarin is a combination of estrogens, or agonists of the estrogen receptors. The major estrogen in Premarin, sodium estrone sulfate, itself is inactive, and rather serves as a prodrug to estrone and, to a lesser extent, estradiol. The transformation of estrone sulfate to estrone is catalyzed by estrone sulfatase. Premarin and estrone have been found to be equivalent in potency in an animal model of estrogenic activity. 17β-Dihydroequilenin, the active form of sodium 17β-dihydroequilenin sulfate, 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.
Differences from estradiol
|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.|
Similarly to the synthetic estrogens ethinylestradiol and diethylstilbestrol, Premarin has disproportionate effects on hepatic protein production relative to bioidentical estradiol, although to a lesser extent (see the table).
Oral Premarin, at a daily dosage of 0.625 mg, achieves 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. The oral ingestion of 10 mg Premarin, 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 1400 pg/mL and 560 pg/mL within 3 and 5 hours, respectively. By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively. Oral Premarin 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), although this does not account for equilin and other equine estrogens involved in the effects of Premarin, which may be significantly more potent in comparison to estrone.
The pharmacokinetics of Premarin have been reviewed.
Premarin consists of conjugated equine estrogens (CEEs), or, more exactly, the sodium salts of the sulfate esters of equine estrogens. The exact composition of Premarin is as follows: sodium estrone sulfate (49.3%), sodium equilin sulfate (22.4%), sodium 17α-dihydroequilin sulfate (13.8%), sodium 17α-estradiol sulfate (4.5%), sodium 8,9-dehydroestrone sulfate (3.5%), sodium equilenin sulfate (2.2%), sodium 17β-dihydroequilin sulfate (1.7%), sodium 17α-dihydroequilenin sulfate (1.2%), sodium 17β-estradiol sulfate (0.9%), sodium 17β-dihydroequilenin sulfate (0.5%), and sodium 8,9-dehydroestradiol sulfate (small amounts), as well as hippulin (also small amounts). There are many different steroids in Premarin, even androgens and progestogens, but only the above-mentioned estrogens are present in sufficient amounts to produce clinically-relevant effects.
Emmenin, which was an extract of the urine of pregnant women, was the predecessor of Premarin, and Progynon was a competing product. Both of these products contained conjugated estrogens similarly to Premarin, but the composition differed. The major active ingredient of 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. 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. 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. 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. In 1984 an NIH consensus panel found that estrogens were effective for preventing osteoporosis and 1986 the FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis. This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.
Society and culture
Research starting in 1975 showed substantially increased risk of endometrial cancer. Since 1976 the drug has carried a label warning about the risk. 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. 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.
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. 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. 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. 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."  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."
Animal welfare groups claim that animal husbandry and urine collection methods used in the production of Premarin 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 Premarin HRT industry a model of self-regulation.
- Esterified estrogens
- Estrogen conjugate
- Estrogen ester
- High-dose estrogen
- List of steroidal estrogens
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- The HRT horses (NBC)
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