Dr. Garnet Anderson, PhD, is Senior Vice President and Director, Public Health Sciences Division at Fred Hutch and the Fred Hutch 40th Anniversary Endowed Chair. She is also a renowned biostatistician and perhaps best known as the principal investigator on the Women’s Health Initiative, one of the longest and largest studies ever undertaken into women’s health.
The study made big news in 2002 when it reported a correlation between women who had used hormone replacement therapy (HRT) and an increased incidence of breast cancer, heart disease and stroke. Almost overnight, American women stopped taking estrogen, even though subsequent studies have shown that those risks decrease depending on the kind and combination of hormones used and the timing of when a woman begins to take them, but the use of HRT remains debated even today. One thing that isn’t, is the vision that went into developing this study and the treasure trove of data still being provided. Of the original 161,000 women recruited, over 60,000 are still being followed–with Dr. Anderson right alongside them keeping track of lessons learned. She shared some of them with WAM. Learn more about Dr. Anderson.
Read the Q&A with Dr. Garnet Anderson below.
WAM: The Women’s Health Initiative was one of the most visionary medical studies ever conceived—the idea of following a group of American women post menopause and over the long term. Why was a group of older women chosen for the study? Had they not been studied before, and if not, why not?
Garnet Anderson: Many reasons, some reasonable and some unreasonable, were given for excluding women from prior research. In some cases, there was an interest in protecting women from the risks inherent in research. This rationale was primarily applicable to women in their reproductive years since some research could potentially harm a developing fetus. In the case of older women, however, the justification is much more tenuous and is partially rooted in the fact that women already live longer than men. For heart disease, since the risk of heart disease was both higher and started to rise 10 years earlier for men than women, the thinking was that women did not need the research as much as men. Indeed, the understanding that women were at lower risk was part of the foundation for the hypothesis that estrogen protects against heart disease. Ironically, the first big trial to test this hypothesis was done by giving men big doses of estrogen—with a terrible outcome.
WAM: One of the reasons this study is famous is because it made a connection between the use of hormone replacement therapy and an increased risk for various other medical problems, including a higher risk for developing breast cancer. What were some of the issues raised by HRT in the study—and why did they cause tens of thousands of women to stop taking HRT to treat their menopausal symptoms?
Garnet Anderson: The WHI hormone therapy trial was testing the estrogen hypothesis for heart disease in post-menopausal women. There was quite strong observational data, supported by some animal studies and intermediate outcome data that indicated that, despite the result in men, postmenopausal women might benefit from using estrogen with regard to their cardiovascular risk as well as their bone health. Because estrogen alone given to women who still have a uterus increases the risk of endometrial cancer dramatically, this trial was really two trials. Women who had not had a hysterectomy were randomized to either combined hormones (estrogen plus progestin) or placebo. Women with a prior hysterectomy were randomized to estrogen alone or placebo.
It was the combined hormones (estrogen plus progestin) that had such strong negative effects. Indeed we found increased risks of heart disease, strokes, blood clots and breast cancer. And in a subset of the older women in whom we assessed cognitive function, we also saw greater cognitive decline and risk of dementia. There were clear benefits for fractures and possibly colorectal cancer risk but these were small compared to all of the risks detected. This was a dramatic result that got lots of media attention in 2002 and upended so much of clinical practice and also how we think about some of the research we do.
The effects of estrogen alone on chronic disease risk in women with prior hysterectomy were more subtle. We did find an increased risk of stroke and a smaller increased risk of blood clots but no clear effects on heart disease. Estrogen alone gave the same protection for fractures as combined hormones, and did not appear to have adverse effects on cognitive function or dementia risk we saw with the combined hormones. The most puzzling part of this study was that we did not see an increase in breast cancer rates. In fact, in these older women, longer term follow-up has revealed a lower breast cancer risk among women taking estrogen alone.
WAM: The number one question we get asked at WAM is from women who want to know how and whether to balance the benefits to their brain health that estrogen therapy might provide against their risk for developing cancer. What do you advise women to do?
Garnet Anderson: The WHI provides no evidence that estrogen therapy improves brain health—at least in the dimensions of cognitive function and dementia. More broadly speaking, however, estrogen therapy is the most effective treatment of menopausal symptoms—in particular, hot flashes and night sweats, which when severe, can have a detrimental effect on mental health, sleep, and overall quality of life. Women suffering from severe symptoms should talk to their doctors about estrogen alone therapy or other combined hormone regimens that reduce the risks associated with progestin. Absent these menopause-associated problems, though, there are few women for whom hormone therapy would be recommended.
(Editors Note: We reached out to members of our Scientific Advisory Council (SAC) whose work on estrogen– contrary to the WHI data– have shown it to have measurable benefits on cognition and brain health in women. Their response was that women today who see benefits to cognition and brain health are typically advised to take estrogen early, starting in perimenopause, while the women tracked in the WHI were already older and post-menopausal when they were recruited into the study and may not have benefitted from early use of the hormone. The SAC members we consulted reiterated that the timing and type of hormones prescribed to women in 1991 when women were recruited into the study, may account for why the women in the study did not see benefits from HRT that women today may experience. And they reminded us that despite positive indications that estrogen may prolong or promote brain health, every woman should discuss her unique circumstances, biology and risk factors with her doctor before deciding on HRT.)
WAM: What are some of the other things we’ve learned about post-menopausal women’s health as a result of the WHI?
Garnet Anderson: With regard to hormones, we have learned that most of the effects, both positive and negative, disappear within a few years after stopping the pills. The exception is for breast cancer, where the increased risk for combined hormones and the decreased risk for estrogen alone seems to persist for at least a decade after the pills are stopped.
We have also been learning an amazing amount about diet and nutrition, including some strong support for the health benefits of a low-fat diet. Diet is a much more challenging topic to study because it is so hard to measure. But it is relevant to all of us and likely has many health consequences. Our low-fat diet trial suggested that a modest change in dietary fat intake may reduce breast cancer risk and even breast cancer mortality and provide possible benefits for heart disease as well. WHI is also producing some exciting information on physical activity and health. Many of our analyses indicate that modest levels of physical activity are associated with many health benefits. One doesn’t have to be a marathon runner or even join a gym to achieve many benefits of physical activity—most of our active women are just good walkers.
WAM: How many women are still in the study, and what are the health issues of interest to researchers today?
Garnet Anderson: We still have nearly 60,000 women actively participating in WHI. These women are phenomenal. They range in age from 73-103! They provide annual updates on their health status where we continue to focus on cardiovascular disease, cancers—all types, and fractures. We have recently added COVID-19 outcomes since the impact of the pandemic has disproportionately affected many of our older women. WHI is also supporting innovative studies on the impact of sleep quality on health and chronic disease risk. Additionally, WHI is part of another randomized trial looking at the effects of multivitamins and cocoa flavanol supplements and chronic disease. Stay tuned as these results should be coming out over the next year.
But increasingly our attention is turning to healthy aging—so many of our women provide excellent examples of how to live both long and well. We are hoping to understand their secrets to successful aging.