Big study finds no rise in death risk among women who took hormone therapy

A new twist to menopausal hormone replacement dilemma
photo of doctor and female patient with pill bottle
The latest study from the Women's Health Initiative examined the risk of death associated with women's use of menopausal hormone replacement therapy. Photo by Andy Dean Photography

More than a decade after a massive study of hormone replacement therapy was halted due to higher rates of breast cancer, heart attack and stroke among women assigned to the drugs to treat menopausal symptoms, a new follow-up study has found those women had no higher risk of death as of 2014 than participants who took a placebo.

The latest findings are published today in JAMA by investigators in the Women’s Health Initiative, the same multi-institutional research program that conducted the original trial begun in 1993 and stopped in 2002 because of those adverse effects. The new study focuses on “all-cause mortality,” or deaths from any cause, up to 18 years after the start of therapy and 10 to 12 years after the therapy was stopped. It offers reassurance to postmenopausal women who took hormone replacement therapy during the trial that they have not increased their risk of dying.

“Mortality rates,” said lead author Dr. JoAnn Manson, chief of preventive medicine at Harvard’s Brigham and Women’s Hospital, in Boston, “are the ultimate ‘bottom line’ when assessing the net effect of a medication on serious and life-threatening health outcomes.”

Overall, the researchers found that the risk of dying from any cause through the end of the follow-up period in 2014 was the same for women who had taken hormone therapy as for women who had taken a placebo. To Manson, the study results give women and their doctors useful information when considering a complex treatment decision. They also offer comfort to younger women now contemplating hormone therapy to bring relief from hot flashes, night sweats and higher rates of bone loss or fractures due to menopause.

“We think the findings of no increase in mortality provide reassurance for women who are seeking hormone therapy for management of symptoms in early menopause,” she said.

photo of Dr. Garnet Anderson
Epidemiologist Dr. Garnet Anderson was a co-author of the study. Photo by Stefanie Felix for Fred Hutch

Dr. Garnet Anderson, a co-author of the new JAMA study and senior vice president and director of the Public Health Sciences Division at Fred Hutchinson Cancer Research Center, said these latest results are statistically sound, but she also issued a note of caution. “I do think these results will be somewhat reassuring to women,” she said, "but they aren’t the entire picture.”

“To me, the basic findings of the trials have not changed,” said Anderson, who is principal investigator of the Hutch-based WHI Clinical Coordinating Center and holds the Fred Hutch 40th Anniversary Endowed Chair. In those trials that were stopped, she said, “We never showed a significant effect on mortality. We showed an effect on women who were having heart attacks, blood clots, strokes and breast cancer diagnoses.”

The newest analysis, she noted, leaves untouched the fundamental findings from the original WHI hormone study report in 2002 showing that women taking a combination of estrogen and progestin to counter menopausal symptoms had a higher rate of those potentially life-altering side effects. Anderson said that for women taking combined hormones to prevent menopausal symptoms, this should still give them pause. For women with a hysterectomy considering taking estrogen alone for menopausal symptoms, the effects on chronic diseases were more balanced, and the benefits for symptom relief may be worth it

Original findings prompted big changes

The dramatic step of halting the trials led millions of women to abandon hormone replacement therapy. The U.S. Preventive Services Task Force subsequently recommended against the use of combined therapy for prevention of chronic conditions in postmenopausal women and against the use of estrogen alone for similar use in women who have had a hysterectomy. The task force never went so far as to recommend against its use for relief of menopausal symptoms.

In 2007, The New England Journal of Medicine reported that the rate of breast cancer diagnoses had dropped by more than 8 percent in 2003, a finding they attributed largely to women stopping their hormone replacement therapies.

In 2014, a team of scientists from the Hutchinson Institute for Cancer Outcomes Research, or HICOR, published a mathematical analysis of the impact of some 4.3 million women no longer taking combined hormone therapy. The modeling showed that decrease resulted in 126,000 fewer breast cancer cases and 76,000 fewer cardiovascular disease cases — but an increase in bone fractures of 263,000. The bottom line: a net savings in medical costs of $35.2 billion.

photo of Dr. Josh Roth
Dr. Josh Roth led a study modeling the impact of the WHI study on disease incidence and medical costs. Photo by Bo Jungmayer / Fred Hutch

Dr. Joshua Roth, lead author of the HICOR analysis, said he does not believe that the new WHI study would change his findings. “The biggest cost savings,” he said, “were related to reduced prescriptions for combined hormone therapy and reduced breast cancer incidence and treatment costs. These costs wouldn’t be greatly impacted by long-term mortality rates.”

Different therapies, different risks

The new JAMA paper shows that participants in the original studies who had hysterectomies and took estrogen alone had a 45 percent lower risk of death specifically from breast cancer.

The new study also showed that those who took combined hormone therapy of estrogen plus progestin had a 44 percent increase in breast cancer mortality, but that result failed to reach statistical significance.

Fred Hutch’s Anderson has stated in the past that women eligible for estrogen-only therapy may want to consider it for a year or two, despite an elevated risk of stroke, if their symptoms are severe. “A woman having a few moderate hot flashes may not want to take the risk of a stroke to relieve those,” she told Fred Hutch News Service in 2014. “But for a woman waking up nightly from hot flashes or night sweats, for a woman going for days without any quality sleep, that trade-off may seem much more reasonable.”

On the other hand, for women who have not had a hysterectomy, Anderson sees combined hormone replacement therapy as a much riskier tradeoff. “Estrogen plus progestin has all of these adverse effects — breast cancer, heart disease, stroke, blood clots, dementia,” she said previously. “It’s much more risky and the adverse effects were the same in younger women in their 50s as in women in their 60s and 70s. And breast cancer in some ways is the bigger concern.”

Anderson said the risks and benefits for hormone replacement therapies should always be considered; this newest study adds another layer of information about mortality risks that a woman and her doctor can use when considering treatment options. In weighing the risks, she said, a woman may want to consider that “a stroke in your 50s can be a horribly disabling event, even if it does not translate into mortality for another 10 to 15 years.”

Harvard’s Manson also stressed that the new study does not support the use of hormone replacement therapy for the prevention of cardiovascular disease. Uncovering the link between these drugs, heart attack and stroke remains a crowning achievement of the Women’s Health Initiative, because it disproved observational studies that had been used to promote hormone therapy as enhancing heart health.

WHI studies are conducted to give patients and their doctors grounds on which to make informed choices, Manson said. “In clinical decision making, these considerations must be weighed against the impact of untreated menopausal symptoms that women experience, including impaired quality of life, disrupted sleep, reduced work productivity and increased health care expenditures.”

The WHI is funded by the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.

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Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs. 

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