Issues

Hormone Replacement Therapy

Hormone "Replacement" Therapy or "HT" is an umbrella term that is used to refer to either the use of the combination of conjugated estrogens (estrogen) and progesterone (progestin), or the use of estrogen by itself.

A major focus of this litigation is the combination use of estrogen and progestin. The combination's use became popular in the 1980s. Progestin is synthetic progesterone. Its chemical name is MedroxyProgesterone Acetate or MPA. The drug Prempro contains both Premarin (estrogen derived from the urine of pregnant mares) and MPA. Before Prempro was marketed, women were given Premarin and MPA in separate doses at the same time.

How does the female reproductive hormone cycle work?

Beginning at puberty, a woman's ovaries produce natural hormones estrogen and progesterone. The hypothalamus and pituitary glands send messages to the follicle (eggs encased in their sacs) to produce hormones.

The production of hormones slows over time. By age 35, a woman's hormone production has dropped considerably. Progesterone, often called the "feel good" hormone, is the first hormone to decline and drops 120 times more rapidly than estrogen.

Menopause is a life phase through which all women pass. It is the body's process of phasing out the reproductive cycle by reducing natural estrogen. During menopause, a woman's estrogen level drops sharply. Hot flashes are a common condition of menopause. For some women, hot flashes are just a vague feeling of warmth. For others, the skin suddenly flushes and beads with sweat, while the pulse races. When estrogen levels decline, so does calcium in the skeleton. As a result, the risk of osteoporosis and spine, hip and other fractures goes up.

How Wyeth created a demand for its hormone therapy products

Menopause was first described in the published medical literature in the late 1800s. The dawn of the 20th century saw a growing quest for treatment to maintain the youthfulness, sexual health and vitality of women. As awareness of the effects of menopause increased, so did the desire for a magic "cure". In 1942, Wyeth's predecessor Ayerst received approval for the patent of Premarin. Ayerst received FDA approval to market Premarin the same year. Premarin was approved initially as a "replacement" therapy, to "replace" the estrogens that began to disappear from a woman's body. In other words, the FDA approved Premarin only to relieve menopausal symptoms like hot flashes, vaginal atrophy and osteoporosis. Nevertheless, Wyeth boasted additional benefits for Premarin (and later Prempro) beyond FDA-approved uses.

Wyeth created a demand for Premarin by overpromoting it through the press.

In 1962, Dr. Robert Wilson, a New York gynecologist, wrote an article published in the Journal of the American Medical Association (JAMA), which claimed that taking estrogen during menopause reduces breast and genital cancers. Later, in 1966, Dr. Wilson authored a bestseller entitled Feminine Forever. Wilson denied that menopause is a phase of life. Instead he characterized it as a disease. Wilson claimed that estrogen was the cure for "the tragedy of women." Menopause, he declared, caused women to lose their youthful appearance and lose their sexuality as if they were castrated. Not only was menopause curable, but it was "completely preventable" if women would take estrogen before entering menopause and continuing for the rest of their lives. The following quotes illustrate how Wilson's book sold the estrogen concept to naïve physicians and a susceptible generation of women:

• "Multiplied by millions, [the menopausal woman] is a focus of bitterness and discontent in the whole fabric of our civilization."
• "To watch a pleasant energetic woman turn into a dull-minded but sharp-tongued caricature of her former self is one of the saddest of human spectacles."
• "[With hormone medications,] breasts and genital organs will not shrivel. Such women will be much more pleasant to live with and will not become dull and unattractive."

Dr. Wilson did not divulge in his book that Wyeth paid him to write Feminine Forever. Wyeth also paid Wilson to lecture to women's groups about his book and poured thousands of dollars into his research. Wyeth purchased thousands of copies of the book - so many copies that Feminine Forever made it onto the Bestseller List. Wyeth's sales force then distributed copies to physicians throughout the country. As a result, Wyeth's sales of Premarin quadrupled.

Wyeth saw enormous profit in the notion that it could convince doctors to prescribe Premarin to every middle-aged woman in civilized society for the rest of their lives. Wyeth ran ads in medical journals urging physicians, "Treat her with Premarin. Keep her on Premarin."

In 1975, Wyeth ran an advertisement in JAMA, claiming that Premarin would relieve "tension, irritability, headaches, undue fatigue, depression and insomnia" caused by declining hormone levels. In bold large, letters, Wyeth advised doctors, "Almost any tranquilizer will calm her down ... but at her age, estrogen may be what she really needs."

Wyeth's plan worked. By the mid-1970s, doctors wrote more than 30 million prescriptions for Premarin every year. Over time, Premarin became the fifth most frequently prescribed drug in the United States.

Despite cancer side effects, Wyeth found ways to keep promoting Premarin.

Just as Wyeth's Premarin profits peaked, new studies showed a link between menopausal use of estrogen and endometrial (uterine) cancer. Estrogen sales plummeted.

Wyeth needed a new justification for women to keep taking Premarin. In 1980, Wyeth found it: An article by Dr. Don Gambrell published in Obstetrics and Gynecology reported that adding progestin to estrogen led to a decline in endometrial cancer. Thus, Wyeth, through its sales representatives, convinced doctors that adding progestin (MPA) to estrogen hormone therapy would protect the uterus from cancer.

In 1985, Wyeth developed another marketing spin to promote hormone therapy drugs: HT could prevent osteoporosis, or bone loss. But in order to generate sales, Wyeth had to recast osteoporosis into a terrible, debilitating disease that targeted and struck down menopausal women. Wyeth embarked on a major PR campaign, including funding a National Osteoporosis Week, and later, the National Osteoporosis Foundation. Wyeth cleverly used these organizations to promote Premarin as a cure for bone loss in older women.

At around the same time, Wyeth also wanted to claim that HT prevented cardiovascular disease. Wyeth knew that if it could make the claim that its drugs protected against the biggest killer of all, it could promote Premarin as a recommended treatment for all women. Despite what Wyeth claimed to be clear scientific results, the FDA refused to allow the cardio-preventive label.

By the late 1990s, Wyeth touted Prempro as effective treatment for myriad diseases, including Alzheimer's, vision problems, tooth loss, heart disease and colon cancer. Yet the FDA had not approved Prempro for treatment of any of these conditions.

Wyeth needed a new HT drug to make up for the loss of Premarin's patent

In 1995, the FDA began to receive applications for several synthetic conjugated estrogens. Faced with the threat of a shrinking market, Wyeth developed a single combination therapy pill that would combine Premarin with progestin (MPA). Before then, Wyeth had little success marketing Cycrin, its own brand of MPA compared with its better-known competitor Provera, manufactured by Pfizer. By combining both Premarin and MPA into a single pill offered convenience and guaranteed a new long patent life for Wyeth's HT product line.

Prempro's big clinical study goes South on Wyeth

Soon after introducing Prempro, Wyeth began funding a 4-year heart disease prevention trial known as HERS (Heart and Estrogen/Progestin Replacement Study). Wyeth had high hopes that HERS would show that HT prevents heart disease in high-risk women. If so, Wyeth could then receive FDA approval to market Prempro for heart disease. In 1998, Wyeth's hopes were dashed. That year, the HERS investigators reported that HT did not reduce the rate of coronary adverse events in women with pre-existing heart disease. The fate of Prempro for treatment of heart disease lay in another study already underway, known as WHI (Women's Health Initiative Study).

WHI study revealed estrogen therapy causes disease instead of preventing it

The Women's Health Initiative is a group focused on defining the risks and benefits of potential treatments to reduce the incidence of heart disease, breast and colorectal cancer and fractures in post-menopausal women. Between 1993 and 1998, the WHI enrolled 161,809 post-menopausal women from 50 to 79 years old in a set of clinical trials and an observational study at 40 clinical centers in the United States. One arm of the study was done by the National Heart, Lung and Blood Institute (NHLBI), which was a sub-organization of the prestigious National Insititutes of Health (NIH).

The NHLBI arm of the WHI study consisted of 16,608 women ages 50 to 79 with a uterus. They were randomly assigned to a dose of either placebo or the combination of estrogen plus progestin (i.e., combination HT) in the form of Wyeth's drug Prempro. The study's objective was to look at the effect of HT on the prevention of heart disease and hip fractures, as well as any change in risk for breast and colon cancer over the 5-year study period.

On May 31, 2002, the study's Data Safety and Monitoring Board - which met regularly to review results and patient safety - determined that the number of cases of invasive breast cancer in the Prempro group had risen to the point of showing an increased risk. The DSMB recommended stopping the trial based on the finding a heightened breast cancer risk, supported by the evidence that overall health risks exceeded any benefits. In July, patients were notified of the results and told to discontinue the medications.

The results of the WHI study were published in JAMA in July, 2002. The results showed not only an increased risk of breast cancer, but an elevated risk of cardiovascular disease and heart attacks, the very conditions Wyeth claimed its HT drugs would prevent. Compared to placebo, HT was associated with the following:

• 41% increase in strokes.
• 29% increase in heart attacks
• 100% increase -- a doubling of risk -- of venous thromboembolism (blood clots)
• 22% increase in total cardiovascular disease
• 26% increase in breast cancer
• 37% reduction in cases of colorectal cancer
• 33% reduction in hip fractures

The study concluded that over the long-term, combination HT should not be used or continued for the primary prevention of coronary heart disease. The authors stated that the risk was too high a price to pay for any benefits such as reduction of the risk of hip fractures. Dr. Roussow, the lead author, pointed out that "even small individual risks over time, and on a population-side basis, add up to tens of thousands of these serious adverse health events."

Never before had hormone therapy created so much attention until the results of the WHI and NCI became public. The two studies received enormous media coverage. Front-page newspaper headlines, magazine covers and broadcast news programs urgently reported the alarming findings. For the first time, physicians and researchers were forced to confront the risks versus benefits of hormone therapy for patients.

The publicity that the WHI and NCI studies received also generated new research on the risks and benefits of hormone therapy. As the next section explains, later studies confirmed the findings of WHI and NCI.

Study after study shows that the risks of HT outweigh its benefits

Beginning in 2002, additional research yielded more evidence that long-term hormone therapy has dangerous side effects and no meaningful upside. Specifically, these studies found that HT increases the risk of breast cancer, heart attacks, bone loss and other conditions. And more studies are currently underway. Below is a summary of the key research:

• WISDOM. The United Kingdom's Medical Research Council began a prospective study entitled Women's International Study of Long Duration Oestrogen after Menopause (WISDOM). The study was to follow 22,000 women. Following the WHI study, the Council canceled WISDOM on October 22, 2002, concluding that "[t]here is strong evidence that taking hormone therapy long term increases the risks of some diseases such as breast cancer and decreases the risks of others such as osteoporosis."
• Li Study (University of Washington). January 2003. J. Clin. Oncol. Dr. Li and colleagues conducted a case/control study of a nationwide comprehensive breast cancer registry from 1992 to 1998. The data from the registry have long been available to the public. They found that among older women, hormone receptor negative breast cancers did not increase. But the rate of hormone receptor positive breast tumors did increase in older women. The study concluded that HT is probably responsible for all of the increase in breast cancer in the U.S. since at least 1992.
• Quality of Life Study: NEJM, March 17, 2003. This was the same study pool of 16,000 women as the 2002 WHI study. In its follow-up, researchers found that HT drugs fail to do the very thing women took them for in the first place: to make them feel happier and healthier after menopause. In other words, HT did not improve the quality of life for menopausal women. In addition, the authors concluded that HT plays no meaningful role for HT in treating women without menopausal symptoms. If women do continue with HT, they should take the lowest possible dose for the shortest possible time.
• Bone Loss Study: JAMA, May 21, 2003. This study examined the efficacy of estrogen + progestin therapy (e.g., Prempro) for prevention of bone loss in elderly women. It included 373 women ages 65 to 90 who had either thinning bones or full-blown osteoporosis. The study compared the effectiveness of HT to Fosamax (alendronate, a bone-building drug), the combination of Fosamax and HT, and placebo. The authors concluded that Fosamax alone was more effective than both Fosamax/HT and placebo.
• Mammography Study: JAMA, June 25, 2003. This study analyzed additional data from the WHI. It found that besides stimulating the growth of breast cancer combination estrogen-progestin therapy makes breast tumors harder to detect, leading to dangerous delays in diagnosis. The report found that breast abnormalities can develop even after short-term use. In the same issue, JAMA published an editorial by Dr. Peter Gann, a cancer epidemiologist, who stated that the study represents "further compelling evidence against the use of combination estrogen plus progestin hormone therapy."
• Million Women Study: Lancet, August 9, 2003. This is an ongoing study of over 1 million women between ages 50 and 64, which will continue to yield valuable research over time. This particular report looked at the data between 1996 and 2001, following women to look for cancer incidence and death. It is the largest study of women to date. Results showed that post-menopausal women using combination estrogen/progestin therapy were twice as likely to develop breast cancer as non-users - a 100% increased risk. The risk went up with the duration of use. The study confirms the findings of WHI.
• Swiss Breast Cancer Study: Int. J. Cancer, May 10, 2003. Researchers analyzed the histology of 6,647 breast cancers in the Geneva breast cancer registry to see if there was an increasing trend of breast cancers. The study found a significant 7-fold increas

  Wyeth changed its HT label and reversed "long-term use" marketing strategy

  After the WHI, NCI and other studies became public, it was clear that the labeling information Wyeth provided to consumers was inaccurate and misleading. Wyeth changed its warning label on Premarin and Prempro during the last week of August, 2002 to reflect the results of the July, 2002 WHI and NCI studies.

  Before August 2002, the Prempro warning labels were also inadequate and misleading. For example, the label stated a risk of breast cancer with conjugated estrogens (i.e., the Premarin component of Prempro), but then indicated that combining the progestin component did not raise the risk of breast cancer: "The overall incidence of breast cancer does not exceed that expected in the general population." The WHI study plainly reveals that this warning is false and was known or should have been known by Wyeth for decades.

  The Prempro warnings also understated the risk of two thromboembolic disorders: pulmonary embolisms and blood clots. Wyeth also downplayed the risks of cardiovascular disease and strokes. The "precautions" sections stated, "The effects of estrogen replacement therapy on the risk of cardiovascular disease have not been adequately studied." Nevertheless, Wyeth has long promoted the supposed benefits of long-term hormone therapy for cardiovascular disease.

  On January 6, 2003, Wyeth finally abandoned its long-standing marketing strategy of promoting long-term use of Premarin and Prempro. Wyeth issued a "Dear Doctor" letter to healthcare professionals, explaining that it would adopt new labeling for its HT drugs as a result of the WHI findings. According to the letter, Wyeth's new HT labels would contain a "black box" warning:

  "... [E]strogens and estrogens plus progestin therapies should not be used for prevention of cardiovascular disease ... The boxed warning also includes information [stating that because of the WHI study] ... estrogens and estrogens plus progestin should be prescribed for the shortest duration consistent with treatment goals."