After Near Miss, What's Next for Women's Health Initiative?

Medscape

08-05-2025

Dolores Verdona was in her 50s in 1974 when she responded to an ad seeking women to join a study on osteoporosis. Now 104, she is one of the oldest of more than 161,000 volunteers to have signed up for the Women's Health Initiative (WHI).
Dolores Verdona
Every year she fills out a battery of questions related to her health. She has worn devices that track her every movement, taken tests related to smells, and had more scans of her legs than she can recall.
'I'm proud to belong to it,' Veronda said in a recent interview. 'I hope that my little bit of help helped.'
Narrow Escape
Last month, that past tense construction appeared to apply to the WHI in general. For a brief moment, the US Department of Health and Human Services threatened to cut off funding for the more than 3 dozen WHI study centers, before quickly reversing course.
The narrow escape has highlighted the continued need to fund research that follows cohorts of women like Veronda throughout their lifetimes.
The women enrolled in the WHI when the study launched in 1992 are now between 75 and 109 years old. Among them are 574 centenarians, including Veronda, and 12,646 women in their 90s.
The original focus of the project was to conduct the research needed to create strategies for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women. Researchers involved with the initiative say the remaining group of some 42,000 women is now an irreplaceable resource that helps clinicians better understand how women age. Their closely followed lives continue to answer new research questions that no other cohort can — but what this single group can do is limited.
For this reason, some experts say now is the time to look ahead. While continuing to fund the WHI to its end, which would be in January 2026 at the earliest, they say the US government should also be building a new cohort of women who can inform what clinicians know about younger generations who have been exposed to risk factors, medicines, hormone therapies, and lifestyles that the participants in the original study were not.
'The reality is this is true that no cohort can answer the questions of the next as well as they can because everything is always changing,' said Marcia Stefanick, PhD, a professor of medicine and obstetrics and gynecology at Stanford Medicine, in Stanford, California, and the principal investigator of the WHI Extension Study.
But 'to cut this study short before we have even been able to fully analyze the data we have would be a complete waste,' Stefanick added. 'We definitely have not run our course, and there is no way you can replicate this cohort.'
Room for Both
You can't get 20 years of follow-up without 20 years of data.
Many of the new papers coming out of the WHI are ancillary studies that expand on previously published findings. These reassess research questions as the women in the cohort age or combine the findings of multiple trials and observational studies to get a clearer picture of how diet, exercise, hormone therapy, birth weight, and menopause affect cardiovascular disease, diabetes, and the risk for complications of COVID-19 in older women. But the centers are still collecting new blood samples, scans, and cognitive assessments from the women as well.
'We are still following what happened when women were randomly assigned to hormones or not. You can't get 20 years of follow-up without 20 years of data,' Stefanick said.
The initiative has ongoing ancillary studies on topics ranging from cognitive function to supplements to physical fitness in old age. However, its long-term research on how temporary use of hormone therapy affects women for decades is typically considered the initiative's most notable contribution to physicians' understanding of women's long-term health.
That research continues to inform clinical practice, said Rebecca Thurston, PhD, assistant dean for Women's Health Research at the University of Pittsburgh, Pittsburgh, who is not involved with the WHI.
In a 2024 review published in JAMA , researchers from across the country laid out how clinical trials conducted at WHI centers support uses for hormone therapy in a way clinicians help inform how they care for patients — for example, while hormone therapy can be a good treatment for menopause symptoms, it should not be used to protect heart health.
'That really helped provide a balanced and nuanced view about the use of hormone therapy for multiple indications but specifically for menopausal symptoms. I found it to be quite helpful from a clinical perspective,' Thurston said.
The guidance came at an important time, she said. When researchers enrolled 160,000 women in the trial in the early 1990s, hormone therapy was seen as a panacea, with the potential to prevent heart disease, Thurston said.
'One of the things about hormone therapy specifically is that the pendulum has continued to swing in different directions as time has gone on,' she said.
The notion that hormone therapy was a miracle remedy shifted after the WHI published the results of their randomized clinical trial.
'The WHI provided a really important counter to that enthusiasm that was really based on observational studies,' Thurston said. 'When they set up a clinical trial, it didn't show the benefits for heart disease.'
In fact, the data hinted at an increased risk for heart disease and stroke for women randomly assigned to receive hormone therapy. Other research linked hormone therapy to an increased risk for breast cancer.
'Hormone therapy then came to be regarded as poison, so the pendulum swung maybe too far in the other direction,' Thurston said.
What is occurring now is something of an evening out, she added. As the researchers explain, the clinical trials support using hormone therapy to treat symptoms of menopause but not as a prevention for heart disease.
The WHI study used a specific type of progesterone, medroxyprogesterone acetate. Although still used to treat symptoms of menopause, it is not the only option. New studies will need to determine whether these long-term findings hold up for younger generations, who are taking formulations of hormone therapy that differ from those used in the 1990s.
'We need to set up a new cohort,' Thurston said. 'The Millennials are coming into menopause age now, and this is such a different time with access to information, access to misinformation, the health profiles of people entering the menopause transition are different today.'
The WHI 'cannot do all things,' she said. 'It's set in a current era, in a certain cohort.'
Although the WHI 'cannot do all things' for all women, Thurston said, it can still continue to provide information on women in the final decades of their lives. What makes the WHI irreplicable is not only that researchers continue to study these women into old age but also that they have a deep archive of biosamples, scans, and medical history collected from these women over the past 30 years. 'I'm seeing that a case needs to be made for why we need to do women's health research,' she said. 'Women are not small men; women are not men with estrogen. Women have unique and specific needs and physiologic factors that merits research.'
The JAMA review also discussed what vitamin D and calcium supplementation can and cannot do, based on decades of data collected from the same women over time. Supplements can fill nutrient gaps for women who do not get enough vitamin D or calcium from their diets but do not appear to lower the risk for a postmenopausal woman, who does not have osteoporosis, fracturing her hip. Decades of follow-up showed eating a low-fat diet rich in vegetables does not seem to prevent breast cancer, but it does appear to reduce a person's chance of dying from the disease.
Some of the 40 WHI centers are set up to answer novel research questions, such as how visceral fat affects people in old age, said Andrea LaCroix, MD, a distinguished professor of public health at the University of California, San Diego, and senior investigator for San Diego's WHI site. The focus of research in this phase is determining what factors allow women not just to live longer but to maintain good physical, cognitive, and mental health during the last chapter of their lives.
'Many other cohorts are now too small, but we started out with so many women that we are able to have a substantial number of women to study how we can help women live longer with their health intact,' LaCroix said.
The answers to these questions can inform how clinicians treat and counsel patients not just on their habits in old age but in the decades that precede that phase of life.
'There aren't really studies of women — or men — in their 90s related to cardiovascular disease. The question is, how do we make our hearts last a long time?' LaCroix said.
Time for a 'Modern Cohort'
Despite their value, the clinical recommendations born from the WHI cannot serve as the last word for female health, Thurston said. Fewer women are having children. Cancer trends among young women are shifting. The foods they eat, the jobs they work, and the environments in which they live are different from those for women born in the 1920s, '30s, and '40s.
To build on what the WHI has established, the United States should invest in what LaCroix calls 'the modern cohort of the future.' Ideally, this database would look something like a combination of the UK Biobank, which continuously updates the data it collects on participants as new technology comes out, and the UK's ONS Longitudinal Study, a birth cohort study that has been recruiting new participants since the 1970s.
Rather than defunding the WHI, LaCroix said the strategy should be to study the current cohort in the last phase of their lives while building up a new one that can replace these women in the scientific literature when they are gone. Including men in the cohort would allow researchers to better understand sex differences in health. She envisions a 'study of everybody that renews itself over time.'
As people die, newborns replace them in the study, ensuring a representative sample of Americans — and their biospecimens and health histories — through time.
'I have been passionate about the need for that for a long time,' LaCroix said, noting that a study like that would ensure health researchers are able to study a representative sample of Americans as the nation evolves. 'If we had this, there would be much less need to fund individual studies of each demographic subgroup in the future.'
And Veronda offers another reason to fund other, large-scale longitudinal studies: Being followed for so long by people who wanted data about her health encouraged her to live a healthier life. 'Whenever they asked me if I wanted to be in something, I never said no.'