Conjugated estrogens

Premarin is the commercial name for compound drug consisting primarily of conjugated estrogens. Isolated from mare's urine (PREgnant MARes' urINe), it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942. It is available in oral (0.3/ 0.45/ 0.625/ 0.9/ 1.25mg), IV, and topical form.

Note for vegetarians: if one seeks to avoid animal derived substances, substitution of this medication with estradiol is most common.

Pharmacology

The major forms of estrogen in Premarin are estrone (>50%), equilin (15-25%) and equilenin. The estrogens in Premarin are often called "conjugated equine estrogens" (CEE) because the estrogen molecules are generally present with hydrophilic side-groups attached such as sulfate. Thus, estrone sulfate is actually the major molecule in Premarin. Estrone sulfate is easily absorbed into the blood after Premarin pills are taken by women. Estrone sulfate is converted to estradiol, an active estrogen normally found in women. It is not clear if estrogens such as equilin that are foreign to the human body have effects in women that are significantly different from the estrogens like estradiol that are normally made in the human body.

Premarin is a form of hormone replacement therapy. Premarin pills are used most commonly in post menopausal 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 progestin pill in women who have not had a hysterectomy. For women already taking the drug it can be used to treat osteoporosis, although it is not recommended solely for this use. The most common side effects associated with Premarin use are vaginal yeast infections, vaginal spotting or bleeding, painful menses, and cramping of the legs. It is suggested that Premarin be used for the shortest period of time and at the smallest possible dose that is effective in alleviating symptoms because it can increase the risk of endometrial and breast cancers, heart attack, stroke, blood clots, and dementia. Premarin cream is only used for vaginal burning, dryness and itching.

Some of Premarin’s lesser known uses are the treatment of symptoms associated with metastatic breast cancer in men and women and prostate cancer in men. It can also be used for individuals that do not produce enough estrogen due to hypogonadism, castration, and ovarian failure, or who have certain intersex conditions such as Androgen insensitivity syndrome.

As Premarin is not a single compound, but a mixture of many naturally derived compounds, the structural diagram above does not show Premarin but its primary ingredient, Estrone in its sulfated form. Thus, Premarin cannot be characterized by the structure of just one of its many compounds.

Bioequivalance

Wyeth-Ayerst has filed petitions opposing the creation of a bioequivalent version by Duramed Pharmaceuticals. They have argued that the generic version, using synthetic steroids, "lacked an important substance that is in Premarin".

Production

Premarin is the subject of some contention. Animal rights groups and those opposing the industry claim that animal husbandry and urine collection methods used in Premarin's production cause undue stress and suffering to the mares involved. Allegations of abuse range from concern over stall size, access to water, exercise, cruel treatment, collection system and continuous breeding cycles, resulting in premature death for thousands of mares and foals. Some claim the numbers are more accurately in the millions.

For 6 months of the year the mares are outside, where they are annually impregnated. The mares, stabled inside for the other 6 months of the year, are restrained in a variety of ways, with plastic urine-collection bags in place. These bags can limit movement on their own, but many of these horses are restrained part or all of the time, further restricting natural movement. Morbidity can result, with infection and other skin injury resulting from the urine bags, and the restriction of movement can also lead to disability. Fluid (water) intake is severely restricted, as well (allowing concentration of the urine, something desired by the drug manufacturer). Most horses have a far shorter life-span in this environment than would be expected.

Some of this contention may stem from the looser standards formerly held in the industry, although accurate records are lacking. The pregnant mare urine (PMU) farms have been in existence since 1942. At that time, many farms were breeding large amounts of foals because more pregnant mares meant more urine and more income. A large number of these foals were unwanted. Many of them were out of draft mares because the larger horses could produce more urine. These foals, in many cases, were reported as being sent to slaughter.

Around the time of the turn of the century, however, the industry was cut. In part, this was from research indicating that lower doses of the drug might instead be safer. As a result, some facilities reduced the number of mares that were contained on-site, and some contend that other aspects of the industry were updated as well.

The cut spurned much controversy of its own. Many animal rights groups were (and still are) very against the industry, and so this downsizing represented a victory for them — fewer farms meant fewer animals likely to be mistreated or killed. However, it also led many of these farms to sell off large numbers of horses for slaughter, although there was an effort by rescue organizations and the general public to re-home some of these horses.

The downsizing of the industry led to another change. With a lesser quantity of urine needed for the production of Premarin, the ranchers involved in the industry were no longer limited to using only draft horses. More of a focus on breeding saleable foals has been seen, with an emphasis on selecting good quality stallions to sire the foals. Crosses now popular within the industry may include such breeds as Quarter Horses, Thoroughbreds, Hanoverians, Paints, and other such breeds, in addition to the more traditionally-used draft breeds. The ranchers rely on selling foals as much as they rely upon the urine collected from the pregnant mares. Many of these farms utilize websites and forms of promotion identical to non-Premarin related horse breeders, and, in nearly all ways, are indistinguishable from the average breeder of equines.

Currently, those in favor of the industry claim that standards on farms are strict and meticulous records must be kept, and that all ranchers must follow the “Recommended Code of Practice for the Care and Handling of Horses in PMU Operations” in order to keep their contract. They further state that ranchers are regularly inspected to ensure they are following these codes in order to ascertain well-maintained animals and facilities. However, with these operations out-of-view and inaccessible to the public, current practices cannot be verified.

Women's Health Initiative

As part of the Women's Health Initiative sponsored by the National Institutes of Health, a large-scale clinical trial for Hormone Replacement Therapy showed that long-term use of progestin and estrogen 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. The results from the study were significant enough the trials were terminated early due to a fear that the participants were at risk.

Litigation

This drug has been the subject of litigation. In 2006, Mary Daniel, in a trial in Philadelphia, PA, was awarded $1.5 million in compensatory damages as well as undisclosed punitive damages, Daniel was represented by the firm of Littlepage Booth. In 2007 the same firm tried a case in Reno, Nevada, representing three plaintiffs who were awarded roughly $17-19 million apiece in damages.

See also

• Estrogen

External links

• Information page of the manufacturer
• Premarin Vaginal Cream approved by FDA for Postmenopausal Dyspareunia (Painful Sexual Intercourse)
• Premarin information at the Food and Drug Administration (FDA) website
• Menopause resource - from Wyeth
• Facts about Premarin - from the Humane Society
• Equine Advocates - clarification of care and fate of PMU mares and foals
• NIH article on the risks of hormone therapy
• National Health Lung and Blood Institute's WHI website

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