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Purpose
Typical Hormone

Premarin

Scientific explorations during the first half of the 20th century led to great strides being made in understanding the human endocrine system, specifically identifying the structure and function of many hormones. Women have been beneficiaries of this work through the development of drugs for reproductive system disorders, birth control, and hormone replacement therapy to treat symptoms associated with menopause.

Premarin structure

HOT HORMONES Estrone and equilin are the two primay estrogens in Premarin and have similar biological activity as estradiol, the principal human estrogen.

One of the pioneering hormone-based drugs is Premarin, a complex mix of more than 30 estrogen compounds used for hormone replacement therapy. Premarin was introduced in 1941 by the Canadian firm Ayerst, McKenna & Harrison, which merged with American Home Products in 1943 and eventually became Wyeth. For a time, Premarin was the top-selling prescription drug in the U.S.

As the name hints, Premarin is derived from pregnant mare's urine. In the 1920s, scientists discovered that estrogens could be extracted from the human placenta and umbilical cord and used therapeutically. Ayerst, McKenna & Harrison researchers and their academic colleagues in time developed a commercial product that was a mix of several estrogens derived from the urine of pregnant women. Company researchers later learned that the estrogens in the urine of pregnant horses were the same as or similar to human estrogens. Given that horses produce a lot more urine than people do, the end result was a process to extract estrogens from horse urine, which gave birth to Premarin as a new product.

Estrogens are the family of hormones largely responsible for development and maintenance of the female reproductive system. They also help control a number of other body systems, including bone and brain cell development. The principal human estrogen is 17-estradiol, which is synthesized mainly in the ovaries and circulates along with its metabolites as sulfate ester or glucuronide derivatives (called conjugated estrogens). The two key estrogens in Premarin are estrone sulfate (50 to 60%) and equilin sulfate (22.5 to 32.5%).

During menopause, the ovaries eventually stop producing estrogens, although estrogens are still made in small amounts by other pathways. For most women, the reduction of estrogen levels isn't noticeable or causes only mild symptoms, so hormone therapy generally isn't prescribed or is needed for only a few months. But for some women, the reduction of estrogen levels can lead to very uncomfortable symptoms.

For example, one of estrogen's functions is to stimulate production of nitric oxide, which as a vasodilator helps control blood pressure and blood flow. During menopause, out-of-control dilation and contraction of skin capillaries can produce feelings of warmth or sudden intense episodes of heat and sweating--the so-called hot flashes. Hormone therapy using Premarin or other estrogen products can help the body adjust to lower estrogen levels and reduce the severity of the symptoms.

Premarin also has been clinically shown to increase bone density in patients. A combination of Premarin with medroxyprogesterone (a progestin hormone), which is sold as Wyeth's Prempro, increases bone density even more. Thus, hormone replacement therapy is used as a treatment for osteoporosis in women who have the disease or who have risk factors for it. Estrogens may also be used to treat women who have a total hysterectomy (removal of the uterus and ovaries) or an oophorectomy (removal of the ovaries) before menopause.

Originally, hormone replacement therapy was thought to help reduce the risk of heart attack, stroke, and cancer in postmenopausal women. But a 2002 report by the Women's Health Initiative (WHI) sponsored by the National Institutes of Health concluded that the opposite seems to be the case. The study found that use of estrogens at higher doses or for extended periods increases the risk of heart attack, stroke, and breast and uterine cancers. In general, hormone replacement therapy is a decision women must make based on whether the benefits outweigh these risks.

Wyeth has enjoyed an unprecedented exclusivity in marketing Premarin because of the drug's complex composition. In 1999, the Food & Drug Administration approved a second conjugated estrogen product, Cenestin, made by Duramed Pharmaceuticals. Cenestin contains nine estrogens either made synthetically or derived from plants. It's approved only for short-term use to relieve the vasodilation symptoms associated with menopause. Duramed initially wanted to market Cenestin as a generic version of Premarin. But in a controversial decision, FDA denied the generic application because the compounds in Cenestin don't match the composition of Premarin and Cenestin has not been proven to produce the same effects at the same dose.

Premarin is one of the all-time best-selling prescription drugs, and it had global sales of more than $2 billion in 2001. But the health concerns raised by the WHI study have had an impact on sales, which dropped to $880 million in 2004. Better education on appropriate low doses of the drug currently is spurring an increase in prescriptions, according to Michael S. Dey, president of Wyeth Women's Healthcare.

Protests by animal rights groups against the practice of collecting urine from pregnant horses have had a minor impact on sales. Wyeth obtains urine by contract with horse ranches, mostly located in western Canada. Collecting urine restricts the movement of horses for extended periods, which opponents of the practice consider unnecessary because synthetic and plant-derived estrogens are available. Yet given the complexity of Premarin, it may never be possible to unravel the best combination of estrogens to develop an equally effective alternative drug, Dey says.— STEVE RITTER

C&EN SPECIAL ISSUE

The Top Pharmaceuticals
That Changed The World
Vol. 83, Issue 25 (6/20/05)
Table Of Contents

Estrogens, Conjugated

CAS Registry

  • 12126-59-9

Other Names

  • Premarin

Introduced

1941 by Ayerst, McKenna & Harrison

Sales Volume

  • $880 million globally in 2004