Premarin
Encyclopedia
Premarin is the commercial name for a compound cream of vaginally administered estrogens
, consisting primarily of conjugated estrogen
s. Isolated from mare
s' urine
(PREgnant MARes' urINe), it is manufactured by Wyeth
Pharmaceuticals (part of Pfizer
since January 2009) and has been marketed since 1942. It is available in oral (0.3/ 0.45/ 0.625/ 0.9/ 1.25 mg), IV, and topical form.
(>50%), equilin
(15-25%) and equilenin
. The estrogens in Premarin are often called "conjugated equine estrogens" (CEE) because the estrogen molecule
s are generally present with hydrophilic side-groups attached such as sulfate
. Thus, estrone sulfate
is actually the major active constituent in Premarin. Estrone sulfate is easily absorbed
into the blood
after Premarin pill
s 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.
While there are some contradictory data, estrogen alone does not appear to increase the risk of coronary heart disease or breast cancer, like estrogen with progestin
does. While estrogen alone appears to decrease the risk of hip fracture for women who have had a hysterectomy, it is still 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 cancer, stroke, blood clots, and possibly 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
.
. 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 mare
s 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 six months of the year the mares are outside, where they are annually impregnated. The mares, stabled inside for the other six 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. 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 spurred 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.
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.
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.
. In 2007 the same firm tried a case in Reno, Nevada, representing three plaintiffs who were awarded roughly $17–19 million apiece in damages. Wyeth appealed this outcome, and it is currently before the Nevada Supreme Court. Wyeth has won the last four of five cases, most recently in Virginia, finding that Wyeth was not responsible for Plaintiff Georgia Torkie-Tork's breast cancer. 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 council in the case also noted that in the WHI trial, 99.62 percent of women took the drug and "did not get breast cancer."
Vaginally administered estrogens
Vaginally administered estrogens are estrogens that are delivered by intravaginal administration, thereby exerting their effects mainly in the nearby tissue, with more limited systemic effects compared to orally administered estrogens....
, consisting primarily of conjugated estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s. Isolated from mare
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...
s' urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
(PREgnant MARes' urINe), it is manufactured by Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
Pharmaceuticals (part of Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
since January 2009) and has been marketed since 1942. It is available in oral (0.3/ 0.45/ 0.625/ 0.9/ 1.25 mg), IV, and topical form.
Pharmacology
The major forms of estrogen in Premarin are estroneEstrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
(>50%), equilin
Equilin
Equilin is an estrogen from horses with the chemical name 3-hydroxyestra-1,3,5,7-tetraen-17-one. Equilin is one of the estrogens present in the mixture of estrogens isolated from horse urine and marketed as Premarin. Premarin became the most commonly used form of estrogen for hormone replacement...
(15-25%) and equilenin
Equilenin
Equilenin is a estrogenic steroid hormone obtained from the urine of pregnant mares. It is used as one of the components in Premarin.-External Links:**...
. The estrogens in Premarin are often called "conjugated equine estrogens" (CEE) because the estrogen molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s are generally present with hydrophilic side-groups attached such as sulfate
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
. Thus, estrone sulfate
Estrone sulfate
Estrone sulfate is a sulfated estrone.It has been described as a prognosis indicator for prostate cancer.It is a component of Premarin....
is actually the major active constituent in Premarin. Estrone sulfate is easily absorbed
Absorption (Pharmacokinetics)
In pharmacology , absorption is the movement of a drug into the bloodstream.Absorption involves several phases...
into the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
after Premarin pill
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
s are taken by women. Estrone sulfate is converted
Conversion (chemistry)
In chemistry, the phrase conversion has several meanings* specifically the property 'X' related to the yield 'Y' by multiplication with the selectivity 'S', i.e. the mathematical definition X * S = Y, all calculated on a molar basis; e.g...
to estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
, 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
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
. Premarin pills are used most commonly in post menopausal women who have had a hysterectomy
Hysterectomy
A hysterectomy is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total or partial...
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.
While there are some contradictory data, estrogen alone does not appear to increase the risk of coronary heart disease or breast cancer, like estrogen with progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
does. While estrogen alone appears to decrease the risk of hip fracture for women who have had a hysterectomy, it is still 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 cancer, stroke, blood clots, and possibly 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
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
conditions such as Androgen insensitivity syndrome
Androgen insensitivity syndrome
Androgen insensitivity syndrome is a condition that results in the partial or complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as...
.
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".Controversy
Premarin is the subject of some contentionContention
Contention may refer to:* The main contention, in rhetoric, the main point being argued* Resource contention, a general concept in communications and computing, is competition by users of a system for the facility at the same time:...
. Animal rights
Animal rights
Animal rights, also known as animal liberation, is the idea that the most basic interests of non-human animals should be afforded the same consideration as the similar interests of human beings...
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 mare
Mare (horse)
A mare is an adult female horse or other equine.In most cases, a mare is a female horse over the age of three, and a filly is a female horse age three and younger. However, in Thoroughbred horse racing, a mare is defined as a female horse more than four years old; in harness racing a mare is a...
s 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
Mare
Female horses are called mares.Mare is the Latin word for "sea".The word may also refer to:-People:* Ahmed Marzooq, also known as Mare, a footballer and Secretary General of Maldives Olympic Committee* Mare Winningham, American actress and singer...
and foals
Foal
A foal is an equine, particularly a horse, that is one year old or younger. More specific terms are colt for a male foal and filly for a female foal, but these terms are used until the horse is age three or four. When the foal is nursing from its dam , it may also be called a suckling...
. Some claim the numbers are more accurately in the millions.
For six months of the year the mares are outside, where they are annually impregnated. The mares, stabled inside for the other six 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. 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 spurred 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.
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.
Health effects
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 InitiativeWomen's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
sponsored by the National Institutes of Health, a large-scale clinical trial for Hormone Replacement Therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
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.
Litigation
This drug has been the subject of litigation; more than 13,000 people have sued Wyeth between 2002 and 2009. However, Wyeth and Pharmacia & Upjohn have 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 has won five summary judgments on Prempro cases and had 15 cases that were set for trial voluntarily dismissed by plaintiffs. The company has won dismissals in another 3,000 cases. 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 BoothZoe Littlepage
Zoe Littlepage is a plaintiff's lawyer whose practice specializes in defective drug litigation. She is a named partner in the joint venture law firm of Littlepage Booth and has been lead trial counsel for cases involving Rezulin, Prempro, Fen Phen diet drugs and many other prescription...
. In 2007 the same firm tried a case in Reno, Nevada, representing three plaintiffs who were awarded roughly $17–19 million apiece in damages. Wyeth appealed this outcome, and it is currently before the Nevada Supreme Court. Wyeth has won the last four of five cases, most recently in Virginia, finding that Wyeth was not responsible for Plaintiff Georgia Torkie-Tork's breast cancer. 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 council in the case also noted that in the WHI trial, 99.62 percent of women took the drug and "did not get breast cancer."
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 AdministrationFood and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) website - Menopause resource - from WyethWyethWyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
- Equine Advocates - clarification of care and fate of PMU mares and foals
- WHI Follow-up Study Confirms Health Risks of Long-Term Combination Hormone Therapy Outweigh Benefits for Postmenopausal Women NIH press release, March 4, 2008
- National Health Lung and Blood Institute's WHI website