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New paper on hormone therapy represents a shattering of long-held dogma regarding women’s health

October 4, 2013

By Andy Koopmans

A paper published this week in the Journal of the American Medical Association details the integrated findings of the Women’s Health Initiative Postmenopausal Hormone Therapy Trials, two long-term, federally funded, randomized clinical studies of hormone therapy use in postmenopausal women.

Dr. Garnet Anderson

Dr. Garnet Anderson is Director of Public Health Sciences at Fred Hutch and principal investigator of the Hutch-based WHI Clinical Coordinating Center.

The trials, which ran from the early 1990s to the early 2000s and were run by the WHI Clinical Coordinating Center based at Fred Hutchinson Cancer Research Center, studied hormone therapies that had been prescribed and in use among older women for decades with the hope the drugs might improve health outcomes for a number of issues. However, both trials stopped early due to an unanticipated increased incidence of negative health effects among women who took hormones as compared to those who received a placebo. Such negative consequences included heart disease, stroke and breast cancer.

Results from the trials have been extensively cited in more than 100 different publications over the years, but the JAMA article, authored by 30-plus scientists, including Fred Hutch scientists Drs. Garnet Anderson, Ross Prentice, Andrea LaCroix, Shirley Beresford and Charles Kooperberg, is the first publication of an integrated, side-by-side overview of findings of both trials with extended postintervention follow-up.

The WHI Postmenopausal Hormone Therapy Trials were based on substantial evidence available at the time that estrogen, with or without progestin, might prevent disease in older women, including heart disease, hip fracture, colorectal cancer and other conditions. More than 27,000 women aged 50-79 years at the time of entry were enrolled in the hormone studies between 1993 and 1998 at 40 centers across the U.S., including Fred Hutch.

Approximately 11,000 of the women had undergone a hysterectomy at some point prior to the trials and were entered into the estrogen-alone trial group while about 16,000 who had not undergone hysterectomy were entered into a trial that evaluated the effects of estrogen plus progestin. This separate treatment was based on evidence from earlier research that estrogen alone was associated with endometrial cancer, a malignancy in the lining of the uterus, and that progestin protected the uterine lining against the disease.

Participants were followed during active treatment for 5.6 years in the estrogen-plus-progestin trial and 7.2 years in the estrogen-alone trial, and for an extended period without intervention, for a total follow-up of 13 years. The original intent was to follow women from both groups for nine years, but both of the hormone therapy trials were stopped early due to the aforementioned higher incidence of several adverse health effects observed among women who took hormones versus placebo. The estrogen-plus-progestin trial was stopped in 2002 because of an increased risk of breast cancer, heart disease, stroke, blood clots and overall harm; the estrogen-only trial was stopped in 2004 due to increased incidence of stroke.

The WHI is a large, federally funded national research project, planned and launched by the U.S. National Institutes of Health in 1991. It consisted of three clinical trials and one observational trial conducted to address major health issues in postmenopausal women—particularly cancer, cardiovascular disease and osteoporosis—which are the leading causes of morbidity, mortality and impairment of quality of life among older women. The WHI enrolled more than 160,000 women aged 50-79 over 15 years, making it the largest prevention study of its kind to date.

Announced by Dr. Bernadine Healy in April 1991 upon her appointment as director of the NIH—the first and to-date only woman to hold the position—the WHI was intended as a “makeup” to rectify the fact that biomedical research had disproportionately addressed issues of white males while women and minority health issues were neglected. The WHI requested and received funding directly from Congress in a line item in the federal budget with a projected budget of $625 million over the life of the study.

“Unpopular at every stage”

Anderson, who is director of the Public Health Sciences Division at Fred Hutch and principal investigator of the WHI Clinical Coordinating Center, said that the WHI research has been controversial from its inception due to the fact that it threatened what had become ingrained knowledge and beliefs about hormone therapy, which started in the 1940s.

“WHI was unpopular at every stage. When we started some people thought it was unethical to deprive women of hormone therapy. Even randomizing the control group to a placebo was considered unethical by some of our critics. Beyond that, in the scientific-review process, we had to face individual physicians who didn’t want their patients to be part of the trial. Hormones in the early 1990s had been approved by the FDA for osteoporosis and they didn’t want to deprive their patients of those benefits, so it was a real challenge to get 27,000 women into the studies,” she said.

Anderson said that OB-GYNs have been some of the most ardent critics of the WHI study results in large part because they changed their businesses drastically. “If you’ve got a woman on hormone therapy, she has to come in once a year for an office visit to renew her prescription, and some women on the estrogen-plus-progestin pill will experience bleeding, which as a postmenopausal woman is a concern, and that sends her back to the doctor as well,” she said. “Certainly the doctors don’t want any sort of harm to come to their patients, but it’s a fact that hormone therapy is a business generator for doctors and the WHI results changed many doctors’ practices overnight. Some have been slower to open their minds to this data.”

Additionally, many investigators who hoped the results of the trials would support the studies’ original hypothesis that hormone therapy would guard against chronic health conditions were consequently upset when the trials shut down early due to increases in the very health issues they were hoping to mitigate.

The collective hormone findings also threatened profits for drug companies.  When the first estrogen-plus-progestin study was stopped in 2002, there were 8 million women in the U.S. using Prempro, the market name for the drug, manufactured by Wyeth. “I went online and the cheapest price on the drug I could find was $1.11 per pill. Taken once a day for 365 days a year by 8 million women, that’s a lot of money at stake,” Anderson said. Indeed: Between 2004 and 2006, Wyeth saw its profits from the drug decline by about a billion dollars as women stopped taking it following the release of the first WHI results.

Few alternatives

Although the results of the trials were unpopular and have changed the way hormone therapy is prescribed in the U.S., its use continues for management of menopausal symptoms while researchers look for alternatives. Anderson and her co-author and fellow Fred Hutch colleagues La Croix and Dr. Katherine Guthrie are coordinators for MSFLASH (Menopause Strategies Finding Lasting Answers for Symptoms & Heath), an NIH-funded network of five clinical research centers across the country to test non-hormonal treatments for menopausal symptoms in randomized clinical trials. So far, the alternatives they’ve found have been few. Lexapro, a selective serotonin-reuptake inhibitor, has shown modest benefits in reducing hot flashes, while yoga and exercise have been found to help with insomnia symptoms, but no alternatives to hormone therapy provide similar relief for vasomotor symptoms.

Because of the lack of alternatives, Anderson said that estrogen-only hormone therapy is still the best treatment available for symptom management, despite the associated risks. “For women having significant problems, estrogen-alone is still the safest way, but the dosage should be much lower than it was in the past. Since 2002 the recommendation has been to take the lowest dose for the shortest time necessary to alleviate symptoms,” she said.

Meanwhile, other modalities of hormone therapies using estrogen and progestin are being produced and prescribed, such as patches, and intrauterine-device delivery systems. “They’re experimenting,” Anderson said. “But these methods have not been well-studied. You have to do a big randomized study to really test these modes and that’s not likely to happen, particularly these days with funding under threat.”

Dr. Elizabeth Nabel, president of Boston’s Brigham and Women’s Hospital and professor of Medicine at Harvard Medical School, wrote an editorial accompanying the JAMA article echoing this sentiment, pointing out how crucial public funding is to such research and how sequestration and other federal funding cuts pose a real threat to public health. “The WHI underscores the decisive importance of taxpayer-funded research conducted by the NIH. Further reductions in the NIH budget virtually ensure that vital important studies like the WHI will not be conducted, and hence U.S. society will be poorly served.”

A new gospel

Nabel also applauded the WHI studies as important reparation for years of neglect of women’s health in biomedical research as well as a shattering of outmoded beliefs. “The WHI has overturned medical dogma regarding the use of menopausal hormone therapy,” she wrote. Anderson agreed, indicating that while critics will likely attack the researchers for the paper, it is an important landmark in research. “In the long run I think this is going to be the paper that everyone refers to when you want to know the effects of hormone therapy. This is going to be the gospel according to WHI,” she said.

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