The FDA recently made headlines when it announced that it was removing the black box warning on hormonal replacement therapy (HRT) for perimenopausal and postmenopausal women. We previously covered this change in depth at Natural Womanhood, but the gist of it is that the FDA removed a warning on HRT products that originally came from a two decades-old study on HRT for postmenopausal women. The FDA has since labeled this warning as “misleading,” as there were multiple missteps made by the study in concluding that HRT was dangerous for women.
The original study, which was a part of the Women’s Health Initiative (WHI) and ran from the 1990s to the early 2000s, was a randomized controlled trial which tested the risks and benefits of synthetic estrogen plus progestin in healthy postmenopausal women. In its conclusions, published in 2002, the WHI study did indeed say that the “overall health risks exceeded benefits” from the use of combined HRT. But what else did the study say? In this article, we’ll explore what the now-infamous 2002 WHI study actually said about HRT for postmenopausal women, including the missteps that led the FDA to originally cite it as reasoning for a black box warning on HRT.
What did the Women’s Health Initiative study on HRT look like?
The Women’s Health Initiative was a long-term national health study which was funded by the National Heart, Lung, and Blood Institute (NHBLI) and originally ran from the early 1990s and officially ended in 2005. There has since been a second set of extension studies which began in 2010 and are still active. The original studies focused on a number of topics, including HRT, the effects of a low-fat diet on cardiovascular disease, and supplementation of vitamin D.
The study, which led to the original black box warning on postmenopausal HRT, was published in 2002 after running for a little over 5 years (3 years fewer than the original intended run time, which we’ll discuss later) [1]. It included 16,608 postmenopausal women aged 50-79 years (with an average age of 63) who had intact uteruses. Because these women had not received hysterectomies, it was protocol for these women to receive a mixture of synthetic estrogen and synthetic progesterone (which is called progestin).
Mainly, researchers wanted to discover whether or not receiving HRT after menopause was able to decrease risk of coronary heart disease (CHD), though they also tracked other health issues such as cancer and bone fractures. To achieve this, half of the women in the study were given HRT and the other half received a placebo. They had biannual follow up appointments where they were screened for disease with tests such as mammograms and blood draws.
What were the results?
As stated earlier, while the test was originally supposed to run for a little over 8 years, it had to be prematurely stopped at the five year mark. This was due to the fact that the Data Safety Monitoring Board (DSMB) found that the risks of breast cancer, stroke, and blood clots began to outweigh the benefits of HRT. The DSMB found that these were statistically significant risks, so the trial was halted as a means of protecting the trial participants. In the conclusions section of the study, researchers agree with this decision on behalf of the DSMB, stating that the risks outweighed the benefits and HRT should not be used as a means to prevent CHD in postmenopausal women.
What exactly did the Women’s Health Initiative data say about HRT?
For coronary heart disease, researchers found a hazard ratio of 1.29, which means that there was a 29% increase in CHD among women who received HRT. There was a 41% increase in strokes, and a 211% in blood clots, including deep vein thrombosis and pulmonary embolism.
Cancer rates were more mixed, with the HRT group having a 26% higher rate of breast cancer but a 17% lower rate of endometrial cancer and a 37% lower rate of colorectal cancer. Bone fractures were also improved in the HRT group, with 34% fewer hip fractures and 24% fewer fractures overall.
As you can see, these results were quite varied, with the biggest negative effects being on cardiovascular events like CHD, blood clots, and strokes. As the researchers stated in the overall risks and benefits section of the paper: “Over 1 year, 10 000 women taking estrogen plus progestin compared with placebo might experience 7 more CHD events, 8 more strokes, 8 more PEs, 8 more invasive breast cancers, 6 fewer colorectal cancers, and 5 fewer hip fractures.”
So, what was wrong with the study?
There are a couple of reasons why the FDA and HHS have since labeled this study as “misleading.” First is because of the study’s design: it used women who were all postmenopausal, but with a large age range—between 50 and 79. The average age of study participants was 63, which is over a decade older than the average women experiencing menopause.
The problem with this is that researchers now know there is generally a “window of opportunity” in which to use HRT in order to reduce the risk of CHD during menopause. We have since learned that the ideal time to use HRT to reduce CHD risk (and other risks such as bone fractures and Alzheimer’s) is within 6 years of menopause and/or before 60 years of age. With half of study participants being over 63, clearly this window of opportunity was not met in the 2002 WHI study. The FDA’s new labeled recommendation is that while women need to work with their doctor to determine the right time to begin HRT, the ideal is to begin within 10 years of menopause onset or before 60 years of age.
The second issue with the 2002 WHI study is that it used a formulation of HRT that is no longer in common use and has generally been found to be risky. Experts now believe that this older formulation of synthetic hormones was what largely contributed to the small increase in breast cancer risk that came about in the WHI trial.
In fact, the particular progestin used for the 2002 WHI study’s HRT formulation was the drug medroxyprogesterone, which is actually the same form of progestin found in the Depo-Provera birth control shot. Depo-Provera has a host of risks associated with it, including an increase in breast cancer rates and bone density loss. There are also over a thousand lawsuits filed against the Depo shot claiming that it has caused brain tumors in women—clearly, medroxyprogesterone is a compound fraught with risks, whether it is used for menopausal HRT or as birth control.
In fact, the particular progestin used for the 2002 WHI study’s HRT formulation was the drug medroxyprogesterone, which is actually the same form of progestin found in the Depo-Provera birth control shot.
The bottom line on the 2025 HRT labeling changes
The FDA and HHS are justified in claiming that the conclusions of the 2002 WHI study are misleading and not an accurate picture of the risks and benefits to women who use HRT to manage the symptoms of perimenopause. The average age of the 2002 WHI study participants and the formulation of HRT used are two of the biggest limitations of the study, as well as the fact that the study was stopped early, which made it impossible to understand the long-term effects of these drugs. With the removal of the black box warning on HRT, hopefully we will be able to see more research into women’s health during perimenopause and menopause, and continue to improve health outcomes for women during this phase of their lives.
