Women’s Health Initiative (1991–)

In 1991, the US National Institutes of Health, or NIH, launched the Women’s Health Initiative, or WHI, which is one of the largest and one of the first long-term, nationwide studies of health conditions affecting postmenopausal females in the United States. Menopause is defined as the point in time twelve months after a female has had her last menstrual period. After menopause, females face higher risks of certain conditions, such as cardiovascular diseases. In 1991, Bernadine Healy, a physician who studied cardiology, became the first female director of the NIH and founded the WHI because she observed that research into female health was lacking. The WHI initiated several clinical trials to study whether changing diet, taking supplements, or undergoing hormone therapy could alleviate menopause symptoms. The trial of hormone therapy identified risks associated with that treatment and generated controversy. Despite the controversy, the WHI was one of the first organizations to produce comprehensive research into treatments and preventative methods for menopause symptoms, thereby improving healthcare options for postmenopausal females. 

1. Background and Context
2. Early Clinical Trials
3. Hormone Therapy Controversy
4. Extension and Ancillary Studies
5. Legacy and Impact

Background and Context

Prior to becoming director of the NIH and founding the WHI, Healy had worked as a researcher and professor of cardiology and acted in multiple leadership roles in cardiovascular research organizations. In 1970, Healy received her medical degree from Harvard Medical School in Boston, Massachusetts, and soon after completed her residency in internal medicine and cardiology at the Johns Hopkins University School of Medicine, in Baltimore, Maryland. She was a professor at Johns Hopkins University School of Medicine from 1976 to 1984, where she focused on cardiovascular research. In February of 1984, Healy became deputy director of the Office of Science and Technology Policy at the White House in Washington, DC, which allowed her to be a part of various government advising boards and groups, including the National Heart, Lung, and Blood Institute, or NHLBI, which is one of the institutes that make up the NIH. Throughout the rest of the 1980s, Healy held high-ranking positions, such as serving as chairman of the Research Institute of the Cleveland Clinic Foundation and president of the American Heart Association, a nonprofit organization that funds cardiovascular research and educates consumers about heart-healthy living. In 1991, former US President George Herbert Walker Bush appointed Healy as the thirteenth director of the NIH.

According to the New York Times, when Healy worked as director of the NIH, she pushed for research in female health, particularly heart disease in females, and started the WHI in 1991 to address that need. For many years prior to 1991, groups advocating for female health and congresspeople had requested that the NIH conduct more research on female health issues such as heart disease, cancer, and hormone changes in postmenopausal females. In the US, as in most countries, researchers have historically performed more clinical trials on men, according to Lea Merone and colleagues, a group of researchers working at James Cook University in Queensland, Australia. In their 2022 article “Sex Inequalities in Medical Research: A Systematic Scoping Review of the Literature,” Merone and colleagues argue that the overrepresentation of men in clinical trials reflects researcher bias, as most researchers have historically been men. It also reflects a perception among those researchers that males are representative of all humans. It was not until Healy became director that the NIH addressed the lack of research on female health by requiring the inclusion of females in NIH research trials whenever appropriate. Healy further addressed the previously ignored health issues in females by creating the WHI study, which focused on the prevention and treatment of heart disease, cancer, and osteoporosis in postmenopausal females. The NHLBI awarded a $625 million research grant to support the project.

Among the topics the specific topics the WHI studied was hormone therapy. Hormone therapy is a treatment method for menopausal symptoms that started in the 1960s and grew in popularity in the 1990s. Physicians prescribed hormone therapy to women as a way to balance their estrogen levels. Estrogen typically helps direct the menstrual cycle and maintain the female reproductive system as well as other systems such as the cardiovascular system, skeletal system, and nervous system. Prior to menopause, estrogen declines. With lower estrogen levels, females experience numerous symptoms, such as hot flashes, headaches, and weak or brittle bones. Some females experience menopausal symptoms at a higher intensity and seek treatment methods. Almost eighty-five percent of postmenopausal females report experiencing symptoms related to menopause. The common use of hormone therapy for menopausal symptoms led the WHI to investigate its effects on health conditions associated with menopause. 

Early Clinical Trials

Work on the WHI study officially began in 1992, when researchers set up the Clinical Coordinating Center, or CCC. The CCC was responsible for coordinating the WHI trials in the forty clinical centers across the nation. The CCC also compiled summaries of study information from those centers. For the first set of clinical trials, the WHI started recruiting subjects in 1993 and finished in 1998, enrolling a total of 161,808 postmenopausal female between the ages of fifty and seventy-nine. According to Jennifer Hays and colleagues, a group of researchers and physicians affiliated with a WHI clinical center in Baylor, Texas, recruiting subjects was one of the most difficult parts of the study. In a 2003 article, Hays and colleagues explain how in addition to the lack of research about postmenopausal females, there was also a lack of inclusion of racial and ethnic minorities in clinical trials, so the WHI also made an increased effort to recruit those populations. The WHI recruited postmenopausal females, minority groups representative of the general population, and females who were willing to be a part of a study that would last eight to twelve years. The researchers randomly placed over 68,000 subjects of the original 161,808 into one of three clinical trials that the WHI created. Those were the Hormone Therapy Trial, the Diet Modification Trial, and the Calcium and Vitamin D trial. The remaining 93,676 of subjects were placed into the Observation Study, which did not expose participants to any novel treatments, and instead recorded the participants’ health conditions over time to look for other possible risk factors and to serve as a comparative group for the other trials.

The Hormone Therapy Trial began in 1993 and explored whether hormone therapy could help lower the risk of heart disease in postmenopausal females while also considering the possible risk of breast cancer. The Diet Modification Trial started in 1993 and aimed to examine whether low-fat diets could help prevent heart disease, stroke, breast cancer, and colorectal cancer in postmenopausal females. Finally, in the early 1990s, the Calcium and Vitamin D Trial examined whether calcium and vitamin D supplements can prevent fractures, as well as breast and colorectal cancer in postmenopausal females.

The WHI researchers set up the Hormone Therapy Trial to observe the efficacy of two forms of hormone therapy in preventing coronary heart disease as well as other symptoms such as fracture prevention in postmenopausal females. Prior to the Hormone Therapy Trial, the FDA had approved hormone therapy to treat certain symptoms of menopause, such as hot flashes, and then in 1988, osteoporosis. The two treatment methods researchers used in the Hormone Therapy Trial were estrogen by itself and estrogen combined with progestin. Progestin is the synthetic form of another female sex hormone called progesterone, which maintains the menstrual cycle as well as the beginning of pregnancy. In addition to the two treatment groups, the researchers also included a group of women who received a placebo, which is a fake treatment with no actual drugs, as a way to compare to the treatment group. The Hormone Therapy Trial studied the treatments in 27,347 people from 1993 until the early 2000s, when concern began to arise around the risks of the hormone treatments.

Hormone Therapy Controversy

In 2002, WHI researchers stopped the combined estrogen and progestin portion of the trial earlier than they had planned when it became clear that the risks associated with the treatment outweighed the benefits. The WHI planned a big news conference at the National Press Club, located in Washington, DC, on 9 July 2002 to announce their reasons for stopping the combined treatment portion of the study. Jacques Rossouw, who was the director of the WHI at that time, explained at the conference how instead of helping to reduce the risk of coronary heart disease, WHI researchers observed an increase in coronary heart disease among participants undergoing combined estrogen and progesterone treatment.

Along with that, researchers found higher risks of stroke, pulmonary embolism, which is when a blood clot forms in the arteries of the lungs, and a small increased risk of breast cancer—findings that alarmed the public. According to Susan Dominus, a reporter for the New York Times, over the next several weeks, news anchors and researchers presented the results of the study in a way that caused widespread panic among a lay audience. For example, on the Today Show, anchor Ann Curry interviewed one of the chief investigators of the WHI. Curry cited many statistics from the WHI study that a non-expert audience could misinterpret. More specifically, Curry mentioned that the risk of breast cancer for participants in the Hormone Therapy Trial increased by twenty-six percent. However, females’ risk of having breast cancer during their fifties is 2.33 percent, and a twenty-six percent increase would mean a 2.94 percent risk, which is a much smaller risk than what audiences might expect after hearing Curry’s report. Another example of the panic caused by the publication of the 2002 study was when, after the Today Show broadcast, Mary Jane Minkin, a physician in obstetrics and gynecology and clinical professor at Yale School of Medicine in New Haven, Connecticut, failed to reassure her patients about hormone therapy and many immediately quit using hormone therapy after reading new of the 2002 study. Thus, although the WHI accurately described the increased risks from the combined progesterone trials, those risks became misrepresented in the media.

Then in 2004, the WHI also stopped the estrogen-only portion of the Hormone Therapy Trial due to an increased risk of stroke and virtually no observed prevention of heart disease. Initially, there was debate amongst the NIH’s Data and Safety Monitoring Board on whether the trial should be stopped. The Data and Safety Monitoring Board advises researchers and monitors the safety and effectiveness of a study. Research ethics guidelines dictate that researchers must end a trial if it is causing harm or if there is no demonstrated advantage over existing treatments. In the case of the estrogen-only portion of the trial, it had many of the same risks as the combined estrogen and progestin trial, further adding to the researchers’ argument for stopping the study. However, the estrogen-only treatment showed some benefits in reducing the risk of breast cancer, but these benefits did not provide sufficient evidence to prolong the study. After the Hormone Therapy Trial ended, the Diet Modification and Calcium and Vitamin D Trials also ended soon after, in 2005.

According to the WHI, the Diet Modification Trial and the Calcium and Vitamin D Trial ended with no significant results in the reduction of various postmenopausal conditions. The set-up of the Diet Modification Trial had subjects eat more servings of fruits, vegetables, and grains daily along with a low-fat diet. The set up for the Calcium and Vitamin D Trial had a placebo group, and subjects who took 1000 mg of calcium and 400 IU of vitamin D every day, due to previous research suggesting that calcium supplements can slow bone loss and that vitamin D could help recipients absorb the calcium. Researchers also relied on previous research revealing possible fracture prevention from taking the supplements. Neither trial showed a statistically significant decrease in the risks of heart disease, stroke, breast, or colorectal cancer, but there was some indication of increased hip bone density in the subjects, implying such treatments may help fracture prevention.

Extension and Ancillary Studies

After the completion of the three clinical trials in the mid-2000s, the WHI researchers continued gathering long-term data through extension studies and pursuing other research questions through ancillary studies. An extension study is where researchers continue collecting new data from participants of the original or first study, while ancillary studies are separate research projects where researchers use data collected from a parent study to explore other aspects of the research topic. From 2005 to 2010, the WHI ran its first extension study that continued to gather yearly health updates from the participants of the original studies and outcomes of the study treatments many years after initiation. There were 115,400 subjects enrolled in the first extension, and researchers invited participants from the original three trials to join again. Then from 2010 to 2015, the WHI had their second extension study with 93,500 subjects and collected the same information as in the previous extension. As a part of the second extension study, from 2012 to 2013, 7,875 subjects participated in the Long-Life Study, which collected various biological samples such as blood samples to establish an extensive collection of new biospecimens as well as provide resources to other researchers to explore aging and health. As of 2024, researchers conducting approved ancillary studies through the WHI continue to have access to the biospecimens collected. By 2014, the WHI had approved its 500th ancillary study. In 2015, the WHI gained funding for its Second Extension Study until 2020, and then in 2021, the same extension study was approved until 2026.   

As of 2024, research on health risks in postmenopausal females continues to grow, as other researchers use the data provided by the WHI. For example, Nancy E. Ringel and colleagues, a group of US-based researchers and physicians, conducted an ancillary study on whether artificially sweetened beverages correlate with cancer of the urinary tract in postmenopausal females. The researchers analyzed the data of subjects enrolled in the WHI study from 1993 to 1998, who answered questions on how frequently they drink artificially sweetened beverages. Then, using data from follow-up visits of the subjects until 2020, the researchers concluded that consuming artificially sweetened beverages could be associated with higher risk of kidney cancer.

Legacy and Impact

The controversy surrounding the WHI’s estrogen and progesterone therapy study, and the backlash it received from other researchers and physicians, has left a lasting impact on how women view hormone therapy. Several observers have criticized how the WHI communicated its results. According to Dominus of the New York Times, the WHI director in 2002, Jacques Rossouw, implied that their study could apply to a broad range of age groups, which was misleading, as the WHI primarily recruited females over age sixty for the study. Heart attacks, cancer, and strokes are health problems that do not commonly show up in females until their seventies or eighties. Because the original WHI study recruited an older population, its results did not necessarily apply to females in their fifties who had fewer risks for those diseases and are typically the ones experiencing the greatest number of menopausal symptoms. Nonetheless, many researchers interpreted the results of the Hormone Therapy Trial as applying to menopausal females at large. Due to that interpretation, use of hormone therapy decreased sharply. According to the WHI, their research has resulted in 4.3 million fewer combined hormone therapy users in the US since 2002.

Researchers and physicians have also criticized the 2002 study specifically because of the fear of hormone therapy it spurred, causing a decrease in the number of users of hormone therapy. According to Angelo Cagnacci and Martina Venir, physicians who work in the area of female health, the 2002 study damaged the image of hormone therapy and failed to offer alternative treatment methods for females experiencing menopausal symptoms. Furthermore, considering that the publicity of the 2002 study caused panic among hormone therapy users, Avrum Bluming, physician and co-author of the 2018 book Estrogen Matters, explains how important it is for researchers to properly contextualize the risks they report. Bluming explains that there is a risk of pulmonary embolism in those taking estrogen treatments like the ones used in the Hormone Therapy Trial, but the risk is similar to that of people using oral contraceptives or even to pregnant females. Since the 2002 WHI article, researchers and physicians have conducted further research on how to properly use hormone therapy to treat symptoms of menopause.

As of 2024, many researchers recognize that the hormone therapies the WHI studied have some benefits for some postmenopausal females that may outweigh the risks. Because the WHI found more risks in hormone therapy for older females, later researchers reassessed the optimum time for females experiencing menopause to take hormone therapy. As of 2024, according to the Harvard T.H. Chan School of Public Health, the benefits of hormone therapy may outweigh the risks of hormone therapy, especially in younger menopausal females. Researchers have found that the risks associated with hormone therapy, such as stroke, are much lower in recently postmenopausal females who are younger than sixty. Furthermore, various researchers have confirmed that certain forms of hormone therapy are better for certain situations. In the 1970s, researchers explored the risks of estrogen by itself  and in 1975, one team of researchers confirmed that estrogen-only hormone therapy commonly showed an increase in cancer in the uterine lining. As of 2024 physicians typically prescribe estrogen-only hormone therapy to females who have had their uterus surgically removed. The risk of cancer goes down when the patient is no longer on the hormone therapy. Using the knowledge that has accumulated on hormone therapy, physicians and researchers recognize that treatment is not always detrimental for every patient and take careful consideration when prescribing it.

As of 2024, the WHI continues to conduct extension and ancillary studies to gather information on the health risks and treatments for postmenopausal females. Since 2020, the project officer heading the WHI is Jared Reis, a researcher who studies cardiovascular epidemiology. Researchers analyzing the WHI’s data continue to find connections between postmenopausal females and possible health risks. In 2023, using data from the participants in the WHI studies, researchers from Columbia University’s Mailman School of Public Health in New York City, New York, found that exposure to high levels of air pollution may cause a loss of bone density in postmenopausal females.

The WHI has acquired various awards for its work on postmenopausal females. In 2015, the Association for Clinical and Translational Science, which is an association that promotes clinical and translational research, awarded the WHI study the Team Science Award, for the collaborative structure of the investigators involved as well as for the scientific advancements the team made. In 2016, the WHI earned the Team Science Award from American Association for Cancer Research, for innovative work on advancing knowledge of cancer research.

The WHI propelled research in female health issues, and more specifically in postmenopausal risks and methods to prevent or treat their symptoms. Even with the criticism some of their work has faced, it brought awareness to identifying which individuals need and can use hormone therapy safely to ease menopausal symptoms. The WHI continues its long-term studies as of 2024, and influences other researchers to use their data to further research in that field.