Getting on the Same Page About the WHI

Yes, THAT study and why it matters

A new paper was published summarizing the key findings of the Women’s Health Initiative (WHI). This isn’t a new analysis; rather, it’s a review by some of the experts who have brought us much of the data about menopause hormone therapy (MHT) over the years from the WHI.

You might be thinking, ugh, more about that study. 

Yes, I get that. You may know it as the study that “stopped” hormone therapy, and you might question its relevance today. But a lot of what you think you know about the WHI may well be wrong. Interestingly, I have been spending more time explaining what the WHI was and wasn’t in interviews, which suggests perhaps there is a rise in WHI-related misinformation, so perhaps this review is as timely as it is important.

While it’s true we rarely prescribe the most common hormone regimen used in the WHI research, this study has provided a lot of information that helped guide other studies, so it’s vital background information. It’s also a massive randomized clinical trial with a wealth of data, so it looms large even today in our guidelines. It’s also tragically misunderstood. It has been used and is still being used, to scare women with symptoms away from therapies that can help them. But the converse is also true. The results have also been cherry-picked and mischaracterized to promote MHT for disease prevention. I’ve even heard some people refer to the WHI with phrases like the greatest harm science has ever done to women, but then see that same person unironically select what they want from the study to promote MHT for longevity. It can’t be both! 

I’ve also heard claims the WHI was “debunked” or that the researchers “walked back” their findings, but this new review doesn’t support those claims. After the study ended, many of the participants were still followed, but collecting new information isn’t a debunking or disavowing; it’s an extension of the study. It’s the literal path of science. Words matter because debunking, disavowing, and walking back sounds like the original data was faulty, and it is not. 

The Purpose of the WHI: Disease Prevention

The primary goal of the WHI was to evaluate strategies for post-menopausal women to reduce their risk of:

• Heart disease

• Breast and colon cancer

• Hip fractures

This was not a study to determine the value of MHT for bothersome menopause symptoms; it was a study to determine whether MHT should be recommended to prevent disease for all menopausal women. 

This was a massive clinical trial, possibly one of the largest randomized placebo control trials ever conducted. Over 160,000 women aged 50-79 were enrolled in one of the four arms. There were two hormone arms: Premarin (combine equine estrogens or CEE) for those without a uterus, and Premarin and medroxyprogesterone acetate (MPA, which is a progestin, a synthetic drug similar in many ways to progesterone) for those with a uterus. There was also a calcium plus vitamin D arm and a low-fat diet arm. Here, we will discuss the hormone arms. 

The primary goal of the two hormone arms of the WHI was to determine if Premarin or Premarin plus MPA could reduce the risk of heart disease without significantly increasing the risk of breast cancer. The study also looked at other outcomes, such as hip fracture, stroke, pulmonary embolism, endometrial cancer, and colorectal cancer. While there was some data about symptoms, this study was primarily about disease prevention. For MHT to be helpful for disease prevention, we needed to ensure that A) it could prevent diseases and B) it didn’t achieve that goal by creating another, more significant, health concern. 

What Happened?

Over 27,000 women were included in the two hormone arms (16,608 took Premarin plus MPA, and 10,739 took Premarin). Like all clinical trials with a drug, there was a safety review board that periodically evaluated the results. This happens because investigators and participants don’t want to find out at year eight or whatever years into the future when the study closes that during the study, the treatment was actually causing net harm or even killing people. The other reason for monitoring is to ensure the placebo group isn’t being harmed by withholding therapy. If, during interim analysis, the study medication is far outperforming the placebo, it may become unethical to continue giving the placebo. 

The Premarin and MPA arm was stopped when people had been taking the hormone therapy or placebo for an average of about 5.6 years, which was 3.3 years before the study was supposed to end. This was because of an increased risk of breast cancer, coronary heart disease, stroke, and pulmonary embolism. According to the safety review board, given the remaining time left in the study, it was highly unlikely that enough benefits could accrue to offset these accumulating risks. 

The Initial Results

The initial WHI paper was published July 17, 2002 (see image above), but the press had the information in print on July 9, which allowed the words breast cancer, heart disease, and hormones to go viral before going viral was a thing. The subheading for the New York Times article was “Hormone replacement is called into doubt,” but an accurate subheading would have been “Hormone replacement for disease prevention is called into doubt.” It changes the messaging a lot, don’t you think? 

And so the message somehow became no one should ever take hormones, as opposed to Premarin plus MPA isn’t effective for disease prevention. The point of releasing the results was to put the breaks on prescribing combination MHT for the prevention of heart disease, not to put the breaks on the treatment of hot flashes and night sweats. All medications have risks, and adults get to decide if those risks are worth it to them. People with joint pain may take non-steroidal anti-inflammatories regularly, and while there are risks with those medications, they may be worth it given the alternative of suffering from joint pain or taking medications or having procedures with even greater risks. If it’s valid to treat suffering from joint pain, it’s valid to treat suffering from hot flashes. However, scaring women makes copy. Case in point, in 2002, over 130 major news stories were dedicated to the WHI, most emphasizing risk.

Let’s look some more at the key findings from Premarin and MPA arm of the original study, which I have compiled into the chart below. This chart includes all age groups, so this is the information that would have been initially available at the time (risks in red are higher and in green lower):

Experts often talk about relative risk, which means how much risk has increased compared to placebo, which is typically explained as a percentage. However, when the baseline risk of something happening is low, relative risk sounds much worse than absolute risk, which is the actual chance this bad thing will happen to you (which is what most people care about). A 37% increased risk of stroke (relative risk) sounds devastating, but 9 additional strokes per 10,000 women per year, meaning 0.09% percent of women taking hormones for a year, sounds a lot less alarming. (Note: This isn’t meant to downplay the significance of stroke). 

The absolute risk can also look different when applied to the entire population. If the hypothesis is that everyone in menopause should be on hormones for disease prevention (the point of the study), there are 55 million or so women in the United States who are menopausal, so the absolute numbers begin to add up. For example, if 20 million women took Premarin and MPA, that would result in 18,000 extra strokes a year. If these same women took Premarin and MPA for 30 years, based on the initial data in 2002, it would mean 540,000 additional strokes or 2.7% of people would eventually have a hormone-related stroke in their life due to hormone therapy. 

The WHI investigators used a global index to help sort out risks because it’s true that while some risks might be raised, others could be lowered, and that would be important to weigh in the final disease prevention hypothesis. The global index looked at coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death. I think this is valuable because death isn’t the only negative outcome. Getting cancer that leads to chemotherapy, a hip fracture that causes you to lose independence, or a stroke that affects memory are all life-changing, devastating diagnoses. I think of the global index as a net good or bad.

When the study was halted, the global index for the Premarin and MPA arm was an additional negative outcome for 20/10,000 women/year (or 0.2% of women per year). If a group of women took this hormone combination for 5 years, that would mean 1% of them would have a significant negative hormone-related event. A medication to prevent disease can’t really be recommended if it results in net harm for 1% of those people over five years if they have no existing symptoms that need to be treated by that medication. I think it’s pretty clear why the Premarin and MPA arm was stopped at the time. 

The Premarin-only trial was stopped in 2004, which is about 1 year early when women had been taking hormones for an average of 7.2 years. This was due to an increased risk of stroke and a trend towards an increased risk of pulmonary embolism. There was no benefit for heart disease (the primary reason for the study) or benefit looking at the global index, which is that net positive or negative (the global index didn’t include endometrial cancer as these women had hysterectomies), and so with one year left to go, these trends indicated that continuing the study couldn’t possibly change the results and achieve the primary goal of protecting the heart. 

Okay, now we are all clear on why the two arms of the study were stopped early. 

Looking Back More than 20 Years Later

The data from the WHI was massaged long after the people in the study stopped taking the hormones. In addition, follow-up analyses have been conducted with the participants to understand the long-term benefits and consequences. Although some participants have been lost to follow-up, and as those who remain are now unblinded, it is possible that some have made lifestyle and health choices based on their arm of the hormone trial. 

One key analysis not present in the initial publication is the risk by age. The average age in the WHI was 63, but most women start hormones earlier than that to treat symptoms. However, we did not understand the impact of age before the WHI. Remember, before the WHI, some people were recommending hormone therapy to prevent disease, even for women with no apparent symptoms, to 75-year-olds!

This new review highlights the risk by age group, as it should, as this group is most likely to have symptoms. Let’s look at the data, remembering that while we can get some general ideas, we can’t translate these results directly to other hormone regimens. For example, Premarin is a very different estrogen than estradiol, and we now believe there are different risks with oral versus transdermal therapy.

Premarin and MPA

Most women who take hormone therapy take a combination regimen, meaning an estrogen plus a progestogen. If anyone is using the WHI to advance a general position on hormones, they should be emphasizing this arm. Let’s look at some of the key results for women ages 50-59.

While there was an increase in the risk of heart disease (coronary heart disease and heart attacks) for those ages 50-59 compared with placebo, it wasn’t statistically significant. (This analysis by subgroup was not available in the original study). In addition, women with a lower risk of cardiovascular disease tended to have better outcomes, although it’s important to point out that the study wasn’t designed to tease out those differences. After thirteen years of follow-up, there was no difference between the groups, meaning that five years or so of the hormones did not set anyone on a course to cardiac badness. The takeaway is that there is no net negative for the heart for those ages 50-59. This is good information!

The increased risk of breast cancer was a little lower for women ages 50-59, 6 per 10,000 women/year for women, and this remained relatively steady over the course of the long-term follow-up. The hormones also increased the density of mammograms and the need for breast biopsies. The risk of dying from breast cancer increased up to 11 years of follow-up, but by 20 years, there was no increased risk. The takeaway here is that while Premarin plus MPA increased the risk of breast cancer, these odds still make this a rare risk (rare is between 1 in 10,000 and 1 in 1,000).

Although Premarin plus MPA was initially associated with a reduced incidence of colon cancer, it seemed that this was not likely a true effect, and at the long-term follow-up, there was no significant difference between groups. 

The Premarin plus MPA group had a 33% lower rate of hip fractures, which was 6 fewer fractures per 10,000 people. Interestingly, some benefits of fracture prevention were maintained at long-term follow-up. 

Regarding dementia, the risk was increased for those aged 65 and older but not for women ages 50-59. 

Overall, compared with placebo, CEE plus MPA for women ages 50-59 resulted in a global index (remember, that score that is our net positive or negative) of 12 per 10,000 women per year at the time the study was halted, but after stopping the hormones by 13-year follow-up, there was no significant effect on the global index outcome compared with placebo, meaning any net negatives that were incurred eventually dissipated. 

Summary: The authors of the new review state that the WHI does not support the use of Premarin and MPA for disease prevention. 

Premarin Only Trial

When the trial was stopped, the only statistically significant negative outcome was an increased risk of stroke; the only positive outcome was a reduced risk of hip fractures. However, on further analysis, more heart benefits were seen for those ages 50-59; the global index for this age group also favored Premarin, with 19 fewer global index events per 10,000 person-years.

During long-term follow-up, a decrease in the rate of breast cancer was detected for those who took Premarin, and that has persisted through 20 years of follow-up, and a decrease in breast cancer mortality also emerged. There was also a reduction in coronary heart disease and total mortality without any safety signals from the other conditions included in the global index.

There was no significant reduction in colon cancer in the short or long term. There was an increased rate of dementia at long-term follow-up for those over age 65, but this wasn’t statistically significant. Premarin reduced hip fracture rates by 33%, but this was no longer seen at 13 years. There was a net beneficial effect on the global health index only for those ages 50-59 in the long-term follow-up. 

Summary: The authors of the new review state that WHI does not support the use of Premarin for disease prevention. 

But I thought the Findings of the WHI Regarding Breast Cancer Had been “Walked Back”?

Another article from some of the experts associated with the WHI specifically addresses this claim, and their summary is as follows: 

none of the originally stated WHI conclusions regarding estrogen plus progestin or estrogen therapy and breast cancer have been “walked back.”

The Summary of the WHI Findings 

The WHI gave us a lot of data we didn’t have before. For example, it set in motion the efforts to determine if transdermal estradiol was safer from a blood clot perspective, and it helped us understand that starting hormones after age 65 came with more risks. While we now know that some of the risks associated with hormone therapy are age-related, that information wasn’t available at the time because we know it courtesy of the WHI. 

It’s important to point out that the WHI isn’t a bad study, a travesty, or something to ignore. However, it has been misinterpreted in a lot of different ways. The original paper from 2002 detailing the first results concluded:

The WHI trial results provide the first definitive data on which to base treatment recommendations for healthy postmenopausal women with an intact uterus. This trial did not address the short-term risks and benefits of hormones given for the treatment of menopausal symptoms.

And a big 2013 review on long-term follow-up from the WHI concluded:

…although hormone therapy remains a reasonable option for the management of moderate-to severe menopausal symptoms among generally healthy women in early menopause, current WHI findings do not support the use of either estrogen-progestin or estrogen alone for chronic disease prevention. 

And a key message from the 2024 review just published:

Results from the WHI do not support either CEE plus MPA or CEE alone for preventing CHD, stroke, dementia, or other chronic diseases in postmenopausal women.Younger menopausal  women typically have low absolute risks of most of these chronic diseases, with low hormone therapy–related attributable risks in early menopause (generally less than 1 additional adverse event per 1000 women per year), and younger menopausal women may derive significant quality-of-life benefits from symptom relief. Differences in breast cancer outcomes with combination estrogen plus progestin vs estrogen alone have clinical implications, with risk increasing with longer duration of use of combination therapy.

None of these statements say that all menopausal women should take hormones, nor do they say that no menopausal women should ever take hormones. But nuanced and reasonable conclusions like the ones above don’t make for sensational headlines or produce clickbait that drives traffic or the opportunity for fearmongering that can be used to build reputations.  

The issue with the WHI was how these results were translated to women, which is a whole different story that includes medical malpractice claims (the lawyers looking to sue hormone prescribers was a very real phenomenon), a failure to appropriately communicate the results to both medical professionals and the public, and the rise of predatory so-called “natural” hormones that entered into the communication gap aided by people like Suzanne Somers, Dr. Christiane Northrup, and Oprah.

The authors of the new review conclude that the long-term follow-up data of the WHI don’t support using menopause hormone therapy, either Premarin alone or Premarin with medroxyprogesterone acetate, for the prevention of heart attack, stroke, or dementia. So, one can hardly conclude, based on this data, that MHT matters for every woman. 

What Does This Mean for Me?

It might make you angry that fears about the study were over-hyped (and still are), and consequently, many women suffered from symptoms. And your anger is justified. It also might make you angry that some people cherry-pick data from the WHI to make claims about longevity. And it should make you angry that a rogue’s gallery of hormone grifters has capitalized on this confusion and continues to do so. 

We now believe that transdermal estradiol is preferable to oral hormones regarding the risk of heart disease, blood clots, pulmonary embolism, and some strokes. Thus, a transdermal estradiol regimen is likely safer than the regimens in the WHI.

We still believe there is an increased risk of breast cancer associated with any estrogen plus progestogen regimen. I am working on a post to help explain those risks in more detail. But if the hormones are helping you, then this small risk is likely worth it to you. 

We also believe that transdermal estrogen may (emphasis on may) have a protective effect on the heart for those starting it within 10 years of their final period/younger than 60, but the data is not certain. The best way to consider the potential benefit for the heart is that it likely offsets the increased risk of breast cancer for those who need to take a progestogen, which is most women. Regarding heart disease, the 2002 Menopause Society Hormone Therapy Guidelines state: 

Observational data and meta-analyses show reduced risk of CHD in women who initiate hormone therapy when aged younger than 60 years or within 10 years of menopause onset. Meta-analyses show a null effect of hormone therapy on CHD after excluding open-label trials. 

Meaning, take away the lower quality data and the results don’t look as positive

Final Take Away

In simpler terms, while MHT should be used to treat appropriate symptoms, the WHI does not support using MHT for disease prevention, and the WHI should not be misinterpreted as saying that it does.

References

Manson JE, Crandall CJ, Rossouw JE, et al. The Women’s Health Initiative Randomized Trials and Clinical Practice: A Review. JAMA. Published online May 01, 2024. doi:10.1001/jama.2024.6542

Manson JE, Chlebowski RT, Stefanick ML, et al.  Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040. PMID: 24084921; PMCID: PMC3963523

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials. JAMA. 2020 Jul 28;324(4):369-380. doi: 10.1001/jama.2020.9482. PMID: 32721007; PMCID: PMC7388026.

Chlebowski R, Aragaki AK. The Women's Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context. Menopause 30(4):p 454-461, April 2023. | DOI: 10.1097/GME.0000000000002154

Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321

Prentice RL, Aragaki AK, Chlebowski RT, et al. Randomized Trial Evaluation of the Benefits and Risks of Menopausal Hormone Therapy Among Women 50-59 Years of Age. Am J Epidemiol. 2021 Feb 1;190(3):365-375. doi: 10.1093/aje/kwaa210. PMID: 33025002; PMCID: PMC8086238.