There has been a dramatic change when it comes to hormone therapy. In the U.S., the FDA essentially admitted it had taken the wrong approach for decades, potentially keeping millions of women from an effective treatment. That shift could help with bone strength, heart health, and other symptoms related to menopause.
This change also highlights an important pattern in medicine—where excessive caution can backfire, causing a beneficial treatment to be wrongly withheld. Here is how it happened.
Table of Contents
The Story
By 2002, there was a pretty settled story about hormone therapy for women. Not only did it help with symptoms like hot flashes. More significantly, observational studies found as much as a 50% reduction in risk for heart attacks and related heart problems in postmenopausal women [1].
It was like a fountain of youth that helped keep women's arteries working as they should. On the strength of this picture, prescriptions soared. In 2000 in the U.S., 46 million were written for Premarin, a common hormone replacement. It was the second most frequently prescribed medication in the country [2].
But in the background, researchers were in the midst of a study that would flip this picture of benefit on its head.
We had observational evidence that hormone therapy cut heart disease risks. But there was a worry. With observational studies, it is impossible to be certain about causal connections. Some speculated that what the data showed might simply be healthy user bias—perhaps women who chose hormone therapy were healthier for other reasons than those who did not. Randomized clinical trials were needed to be confident about what was really going on [3].
The Women's Health Initiative (WHI) was launched in the early 1990s to provide that kind of trial data.
One arm of the study included over 16,000 women with an intact uterus. They were randomized to receive a combination of estrogen and progesterone or a placebo [4].
In 2002, after an average follow-up of about five years, the data was sending a clear message—and it was not a positive one. The trial was stopped early [5].
The primary outcome being tracked was the impact of treatment on heart attacks and heart-related deaths. The actual outcome was precisely the opposite of what everyone had expected. The overall risk was 29% higher for those taking hormones. Stroke risk was 41% higher, and the risk of blood clots in the lungs more than doubled [6].
Estimated hazard ratios were:
- CHD: 1.29 (95% CI: 1.02–1.63)
- Stroke: 1.41 (95% CI: 1.07–1.85)
- Pulmonary embolism: 2.13 (95% CI: 1.39–3.25)
And there was another problem unrelated to the heart. The risk of breast cancer increased with treatment, rising 26%—with a hazard ratio of 1.26 (95% CI: 1.00–1.59) [7].
There were two bright spots. Risk of colorectal cancer was 37% lower (HR 0.63, 95% CI: 0.43–0.92), and hip fracture risk was 34% lower (HR 0.66, 95% CI: 0.45–0.98) [8].
But the good news was drowned out by the bad. The FDA responded with dramatic warning labels on hormone medications. Prescriptions for hormone therapy to treat menopause symptoms plummeted. In the U.S., usage went from as high as a quarter of women over 40 to 5% or less [9].
But the story does not end there. While patients and doctors quickly moved away from hormone therapy, the Women's Health Initiative trial pressed ahead. Even though active hormone treatment stopped, researchers continued to collect follow-up data. And when they looked at that data years later, they uncovered a surprise.
A study published in JAMA in 2017 reported on 18 years of follow-up from WHI participants. The finding: there was no difference in all-cause mortality between the two groups [10].
It was an important clue that the earlier worries may have been exaggerated. Despite what looked like elevated risks in the short term, those risks did not translate into a meaningful mortality difference over time.
But there was more. Those who designed the WHI study made a consequential decision about whom to include. Since they were primarily interested in outcomes related to heart health, they gravitated toward an older demographic. Recruiting women in their 40s would have meant waiting many years to see the impact on heart disease, since it tends to develop later in life. So they narrowed their focus to women aged 50 to 79. The average age in the study ended up being 63 [11].
Here is why this matters. The typical woman seeking hormone therapy to manage menopause symptoms is not 63. Most women seeking menopausal hormone therapy are in their late 40s or early 50s—consistent with the average age of menopause at 51 [12].
So the Women's Health Initiative was not studying the same population that typically seeks hormone therapy. And researchers have come to understand that timing may be everything.
Though research is ongoing, a central reason appears to involve the arteries. When women are younger, any arterial plaque that is building up is at an early, unstable stage. At this point, estrogen appears to be protective. In older women with established plaques, however, estrogen may have the opposite effect and appears to elevate cardiovascular risks [13].
This early protective effect of estrogen is likely why women tend to develop heart disease later than men—and why risks become elevated following menopause [14].
With this understanding, researchers went back to the WHI data and did something the original analysis had not done: they sorted outcomes by age cohort. The question was straightforward—what would the risk profile look like if the focus were restricted to the younger women in the study?
What they found underlined the importance of age. In younger women, aged 50–59, hormone therapy looked protective. All-cause mortality was 31% lower than in the placebo group. That advantage disappeared when looking at women between 60 and 69. Then the trend reversed for those between 70 and 79, though the actual impact was not statistically significant [10].
Hazard ratios by age group:
- 50–59: HR 0.69 (95% CI: 0.51–0.94)
- 60–69: HR 1.04 (95% CI: 0.87–1.25)
- 70–79: HR 1.13 (95% CI: 0.94–1.36)
P-value for trend by age = 0.01
Another study, published in JAMA Internal Medicine, took a careful look at the WHI research with a focus on heart health. Its findings add further weight to the conclusion that age is crucial: hormone therapy did not increase heart disease risks for younger women, while risks were elevated for those over 70 [15].
A Cochrane review reached a similar conclusion. For women who started hormone treatment within 10 years of menopause (or before the age of 60), there were benefits in terms of overall mortality and heart disease risk [16].
The picture now emerging is this: the initial response to the Women's Health Initiative findings was too simplistic. Partly, that was a consequence of a study design that focused on older women and did not account for age at the time of treatment initiation. It now appears clear that timing is crucial. Given at the right time, hormone therapy can be beneficial. Initiated too late, the risks may outweigh the benefits.
FDA Changes and Where We Are Now
This brings us to the FDA's recent change. Various medical groups had been urging the agency to take a different public stance when it came to hormone therapy.
Here are the key changes.
First, the FDA removed warnings on hormone medications about heart disease, strokes, breast cancer, and dementia. The exception is for estrogen-only products taken by women who have not had a hysterectomy—in this case, there remains an increased risk of endometrial cancer [17].
Second, the FDA removed the recommendation to prescribe hormone therapy at the lowest effective dose for the shortest possible duration. The agency now recommends that treatment decisions be made on an individual basis [17].
Finally, the FDA formally recognized the importance of timing. Current guidance recommends starting hormone therapy in women younger than 60, or within 10 years of menopause, to optimise the risk/benefit ratio [17].
This brings the FDA into alignment with the latest clinical guidelines, which have already emphasized the timing element for the reasons covered above.
Given how prominently FDA warnings had appeared on hormone prescriptions, this shift carries significant implications. According to a statement from the American College of Obstetricians & Gynecologists (ACOG), the label change helps remove a barrier that has stood in the way of more women getting relief from menopause symptoms—and it shifts more decision-making power to women engaging in shared discussions with their physicians about their health [18].
Those discussions should rest on a candid consideration of both the benefits and the risks. For many women, the benefits of managing menopausal symptoms—including hot flashes, sleep disruption, and bone density loss—may substantially outweigh the risks when therapy is started at the right time and tailored to the individual. Hormone therapy is not recommended for those with breast or endometrial cancer, certain heart-related conditions, or liver disease [19].
References
1. https://pubmed.ncbi.nlm.nih.gov/2005736/
2. https://jamanetwork.com/journals/jama/article-abstract/195112
3. https://www.sciencedirect.com/science/article/pii/S0015028208011370
4. https://jamanetwork.com/journals/jama/fullarticle/195120
5. https://jamanetwork.com/journals/jama/fullarticle/195120
6. https://jamanetwork.com/journals/jama/fullarticle/195120
7. https://jamanetwork.com/journals/jama/fullarticle/195120
8. https://jamanetwork.com/journals/jama/fullarticle/195120
9. https://pmc.ncbi.nlm.nih.gov/articles/PMC3607288
10. https://jamanetwork.com/journals/jama/fullarticle/2653735
11. https://jamanetwork.com/journals/jama/fullarticle/2653735
12. https://www.acog.org/womens-health/faqs/the-menopause-years
13. https://pmc.ncbi.nlm.nih.gov/articles/PMC9178928/
14. https://pmc.ncbi.nlm.nih.gov/articles/PMC10074318/
15. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2838720
16. https://pmc.ncbi.nlm.nih.gov/articles/PMC10183715/
17. https://jamanetwork.com/journals/jama/fullarticle/2841321
19. https://www.acog.org/womens-health/faqs/hormone-therapy-for-menopause
