There’s been a dramatic change when it comes to hormone therapy. In the U.S., the FDA essentially just admitted they’ve taken the wrong approach for decades, potentially keeping millions of women from an effective treatment. So make sure that your wife or partner knows what’s just happened—because it could help with their bone strength, heart health, and other symptoms.
And this change highlights an issue where too much caution can backfire—where a great treatment option is wrongly withheld. Here’s 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.
As already mentioned, we had observational evidence that hormone therapy cut heart disease risks. But there was a worry. With observational studies, we can’t be sure about the causal connections. Some speculated that we might just be seeing healthy user bias. Perhaps women who chose to take hormone therapy were healthier for other reasons than those who did not. So we needed randomized clinical trials to be confident we knew what was going on [3].
The Women’s Health Initiative was launched in the early 90s to give us 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 5 years, the data was sending a clear message. And it wasn’t a positive one. They stopped the trial early [5].
The primary thing they were looking for 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 not related to the heart at all. The risk of breast cancer jumped with treatment, too. It rose 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 in 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 doesn’t end there. While patients and doctors quickly moved away from hormone therapy, the Women’s Health Initiative trial pressed ahead. Even though they stopped treatment with hormones, they continued to collect data. And when researchers looked at that data years later, they uncovered a surprise.
A study was published in JAMA in 2017. After collecting data on study participants during 18 years of follow-up, they found there was no difference in all-cause mortality between the two groups [10].
It was an interesting clue that perhaps the earlier worries were exaggerated. Despite what looked like elevated risks earlier on, over time, this didn’t show up in the mortality figures.
But there was more. Those who designed the WHI study made a fateful decision about whom they included. Since they were primarily interested in outcomes related to heart health, they gravitated towards an older demographic. If they recruited women in their 40s, they’d have to wait a very long time to see the impact on heart health, since heart problems tend to develop when we’re older. So they narrowed their focus to women from 50 to 79. The average age of women in the study ended up being 63 [11].
Here’s why this matters. The typical woman seeking hormone therapy to manage menopause symptoms isn’t 63. Typically, I see patients in their late 40s or early 50s who are seeking menopausal hormone therapy, with the average age for menopause being 51 [12].
So the Women’s Health Initiative study wasn’t focused on the same population that’s generally seeking hormone therapy. And we’ve come to understand that timing may be everything.
Though research is ongoing, it looks like a central reason why has to do with our arteries. When women are younger, any plaque that is building up in their arteries is at an early stage. At this point, estrogen seems to be protective. In older women with established plaques, however, estrogen may have the opposite effect and appears to elevate risks [13].
This early protective effect of estrogen is probably why women tend to develop heart disease later than men. Their risks become elevated after menopause [14].
So researchers looked again at the WHI study data and did something the original analysis didn’t do. They sorted the outcomes by age cohort. They wondered: What would the risk profile look like if we focused our attention on just 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 with those between 70 and 79, though the actual impact wasn’t 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 just this fall took a careful look at the WHI research with a focus on heart health. What they found adds more weight to the thought that age is crucial. For the younger women, hormone therapy didn’t increase heart disease risks. On the other hand, risks were elevated for those over 70 [15].
A Cochrane review reached a similar conclusion. For those who started hormone treatment within 10 years after menopause (or before the age of 60), there were benefits when it comes to overall mortality and heart disease [16].
So the picture emerging now is this: The initial response to the Women’s Health Initiative study was too simplistic. Partly, that was a fault of the study design that focused on older women and didn’t take age into account. But it now seems clear that the age at which therapy begins is crucial. Given at the right time, hormone therapy can be beneficial. At the wrong time, the risks may outweigh the benefits.
FDA Changes and Where We Are Now
This brings us to the FDA’s recent change. Various groups have been urging them to take a different public stance when it comes to hormone therapy.
Here are the key changes.
First, they removed warnings on hormone medications about heart disease, strokes, breast cancer, and dementia. The exception is for estrogen-only products taken by women who haven’t had a hysterectomy. In this case, there’s an increased risk of endometrial cancer [17].
Second, they removed the recommendation to prescribe hormone therapy at the lowest effective dose for the shortest duration. They now recommend that the decision about treatment be made on an individual level [17].
Finally, they recognized the importance of timing. They recommend starting hormone therapy in women younger than 60 or within 10 years of menopause to optimize the risk/benefit ratio [17].
This recommendation brings the FDA into alignment with the latest clinical guidelines, which also emphasize this timing element for reasons we’ve covered.
Given the visibility of the FDA’s warnings on hormone prescriptions, this shift has huge implications. According to a statement from the American College of Obstetricians & Gynecologists, it helps remove a barrier that has stood in the way of more women getting relief from symptoms related to menopause. And it shifts more power to women to engage in shared decision-making about their health with their physicians [18].
And these discussions should rest on a candid consideration of the benefits and risks.
Hormone therapy isn’t recommended for those who have breast or endometrial cancer, certain heart-related problems, 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
