Did the FDA just remove class warnings from estrogen with no new evidence? Yes and here’s why.
Did RFK just make some stuff up? Are we ignoring the risks of drug because it’s suddenly popular? Have we thrown the rules out window? The answer to all of these things is no.
Since 2003 all estrogen containing products have carried a warning label saying that they might increase the risk of breast cancer, stroke and dementia. Where did this come from? Let’s go back in time a bit to that great era of the past - the 1990s. At the time, there were many longitudinal and observational studies that showed that there may be benefits from taking HRT that go beyond treatment of menopausal symptoms including heart disease prevention. Heart disease is the leading killer of women, so something with a 20% reduction in heart disease risk certainly deserved a closer look. Observational trials leave room for other explanations, so the NIH sponsored the Women’s Health Initiative starting in the late 90s. This was a randomized, placebo controlled trial that had thousands of women enrolled. While this was a valiant effort, there were a few decisions that in hindsight, don’t make alot of sense.
The WHI stats. The average age in the trial was 63 (the average age of menopause is 51) and they intentionally recruited older women because they are more likely to have cardiac events and they only had 7 years to run the trial. Of the women, 70% were overweight or obese and 40% were smokers. They also specifically excluded women who had bad hot flashes - they might have been tipped off too easily about whether they were getting drug or placebo. They gave women with a uterus oral premarin (estrogens derived from pregnant mares urine) and medroxyprogesterone acetate (MPA - a synthetic progestogin) at a single dose or placebo and if they didn’t have a uterus, they got oral premarin alone. They watched for a few years and then dropped a bombshell on the world of women’s health.
In May of 2002, there was a press conference where the head of the trial announced that they were canceling the premarin/MPA arm of the trial due to an increased risk of breast cancer. They also started counseling about the risk of blood clots and dementia. The other arm of the trial continued on, but the FDA was already writing the black box warning, which came out in 2003.
What happened in the other arm of the trial? Well, there was an inital bump in cardiovascular risk in the first year, it evened in the second and was 20% lower by the third year, which was consistent with the longitudinal trials. It also found an approximate 20% reduction in breast cancer, but this was not statistically significant. They did find a statistically significant decrease in osteoporosis and colon cancer and a trend towards lower rates of Alzheimers. These benefits were more profound in women who started HRT within 5 years of menopause. So, why the difference?
The most important thing to know about the premarin/MPA arm of the trial is that the increase in breast cancer wasn’t statistically significant, didn’t show an increase in breast cancer mortality, was mostly related to an unsually low risk of breast cancer in the portion of the placebo group that had previously taken HRT and the risk was really isolated to those women who where greater than 10 years post menopause. It’s also important to know that oral premarin is about 10x more likely to cause a blood clot than the same estrogen we make naturally, the most active form of which is estradiol. Oral estradiol does have some clot risk, but this can be avoided by using a topical preparation like an estrogen patch or an estrogen cream.
Anyway, this is where the black box warning came from. So, did the FDA make a warning that says oral premarin initiated by women more than 10 years after menopause have an increased risk of heart disease, blood clot and breast cancer? No. They put the warning on every estrogen containing product. Vaginal estrogen - might cause a stroke. Topical estrogen for 51 year olds - might casue breast cancer. Was any of this true? Nope.
What happened in the aftermath of this disasterous decision? We went from a country where 1 in 4 women were taking HRT to today when only about 1 in 25 women in menopause are on HRT. The genie was let out of the bottle and even though we’ve known for at least 10 years that the HRT/breast cancer thing wasn’t real, but many doctors still refuse to prescribe HRT or worse, are trying to scare good candidates off of prescribing HRT. We also now live in a world where I’m trying to help women in their 70s avoid utis and have less painful sex, but they are terffiried to use low dose vaginal estrogen because it carries this black box label. Vaginal estrogen doesn’t increase blood levels of estradiol and it doens’t spread systemically. There is no possible mechanism by which it could cause breast cancer and yet, that warning is there.
There is an excellent podcast where Dr. Peter Attia interviews Dr. Rachel Rubin, a board certified urologist who treats peri/post-menopausal women and they have a great discussion about how the 2003 problem persisted out of bureucratic sloth rather than good medicine. She, and a group of other doctors, went to the FDA to discuss removing the label just from vaginal estrogen. They said, well, you haven’t done a study showing that vaginal estrogen doesn’t cause these things. When it was pointed out that there was no study indicating that it does cause these things, that was not considered important. They demanded a randomized controlled trial to prove the black box warning could be removed safely. Guess what? There is no motivation to do a study of a generic drug from the pharmaceutical industry and I personally would prefer NIH dollars not go to study things with no plausible mechanism of action, so that study is never going to happen.
What changed? Was it the broken hip of the current FDA director’s mother that caused a top down change? Maybe. In Dr. Makary’s book Blind Spots, he discusses his mother’s broken hip, subsequent surgery and recovery and how that might have been prevented if his mom hadn’t been scared off of HRT. I think he did really take the lead in initiating this change. How does the medical community feel about this change? Excellent. I honestly have lookes and can’t find a single dissenting voice - other than whoever Dr. Rubin spoke to last year. Watching the expert panel the FDA convened, I can safely say they didn’t just assemble a panel of yes men - or yes women as the case mostly was.
What’s next? I’m really hoping for WHI 2. What should it look like? A randomized, placebo-controlled trial of women aged 50-55 using estradiol patches and prometrium planned to last 10 years. Ideally, we would do an extension for women who wanted to continue longer. We know that for women without a contraindication, HRT initiated in the early menopausal period is life extending and improved quality of life. What we don’t know is if there is a clock on how long that improvement continues for and is there a date when it tips towards no longer being beneficial. My personal take - because someone will ask - is that I have alot of patients who we wean down and they come off and they feel well. I have alot of patients who wean down, but can’t come off because they don’t feel as good. Turns out, I listen to my patients and we work it out together using a shared decision making framework. (See how I worked in one of those medical buzzwords that we love, but throw out as soon as a patient disagrees with us.)
For more information, please see the FDA panel discussion available in full on YouTube. It was a truly great discussion panel.