Menopause Hormone Therapy: Politics and Personal Agendas are Threatening Science

The WHI Steering Committee Responds to the FDA Panel on MHT

The word on the street is that the Food and Drug Administration (FDA) is going to announce changes to the package insert for menopause hormone therapy (MHT). Whether this will be changes to just the labeling for vaginal estrogen or just for systemic estrogen or both is not known.

I know many menopause influencers are extremely excited about the prospect of changes to the labeling, but I am not in that category as the entire process for changing the labeling has been subverted. Pre-Trump and RFK Jr. changes to drug labeling required an FDA advisory committee, where new data was reviewed by appropriate experts who themselves had a strict vetting of their conflicts of interest. Experts from several fields were included as well as a consumer representative. In addition, there would also be an open public hearing, so there was transparency.

Those days are over. Under RFK Jr. and Dr. Marty Makary, that crucial scientific process has been dismantled, and now it’s just so-called “expert panels,” as we saw with the panel on MHT and the one on antidepressants in pregnancy. Some participants were unqualified and many had either undisclosed or inappropriately disclosed biases. In my opinion, the MHT panel was a Trojan horse for disinformation, where good science was presented alongside grossly cherry-picked data.

This new process appears to only include public commentary on a website, which will be seen by very few people and is unlikely to get much attention from the press. Forgive my cynicism, but I am sure anything that dissents from Makary’s woefully incorrect views on MHT will be ignored (I have previously addressed Makary’s abuse of the science around MHT here). Now, instead of scientific rigor and public health, we have panels designed to rubber stamp pet projects.

This doesn’t just mean the wrong decisions could be made about MHT, it means that decisions about medications will be based on political motivation and back room financial deals. In short, our drug supply is going to get a lot less safe, and of course, drugs for medication abortion or even vaccines could be pulled from the market or be restricted.

I want to be clear, I don’t think that the current black box warning on vaginal estrogen is appropriate, but I also think it should be addressed correctly and not be subject the whims of the Commissioner of the FDA who seems woefully uneducated about the topic and doesn’t let that stop him from blathering on about it on Fox.

I want to focus on the online public commentary that the FDA opened up for MHT, specifically about systemic hormones (estrogen with or without a progestogen). I submitted something (you can read it here), but I want to discuss and share the response submitted by the WHI Steering Committee as their data has been abused and cherry picked by Makary and many others. You can read their full commentary here, but I will break down the key points, which, coincidentally are the same three key points that Makary messed up in his book, Blind Spots (irony is dead, I tell you).

The Preamble

Before we begin, I need to clarify that the WHI is not a terrible study.

I see this a lot on social media. I am also asked about “that terrible study” daily by patients. Despite what Makary and the menopause influencers who appear to profit from a scientifically flawed “hormones fix everything” perspective, the WHI was not a bad study. The investigators did not randomize people incorrectly, nor did they screw up the statistics, and there were not too many protocol violations (which are some of the ways that studies can be problematic). This matters because misinformation about the WHI is leading some practitioners to completely disregard the largest randomized clinical trial for women or to cherry-pick it to death because they don’t like or understand the results. Disavowing quality research harms women, because it misleads them about the data and, it sets the precedent that women’s don’t need science, the opinion of influencers is all tat matters.

For the record, the WHI was not designed to look at the risk/benefit ratio for managing symptoms of menopause with MHT. It was primarily designed to look at the potential cardiac benefits of MHT, as observational studies suggested a benefit. Premarin and medroxyprogesterone acetate was specifically chosen because this was the most common regimen at the time and people believed this specific combination protected the heart based on the observational studies.

Claims of Prevention of Heart Disease and Reduction in Mortality from MHT

Several speakers at the expert panel spoke as if the timing hypothesis regarding MHT was proven as fact. This is the idea that when MHT is given within a few years of the last period it can be protective for the heart and reduce mortality, but when given later, it is not, and may even be harmful. This hypotheses has been largely used to explain away the findings of the WHI. The problem is that the timing hypothesis is exactly that, a hypothesis, and it’s far from settled science.

It’s true that the WHI showed that younger women did have a lower risk of cardiovascular disease with MHT than older women but in their letter, the WHI Steering Committee highlight several key issues:

• Younger women have a lower risk of cardiovascular disease than older women by virtue of being younger. To actually support the timing hypothesis the results would need to hold up after 20 or so years of hormone and placebo use. We don’t have that data. Both the ELITE and KEEPS trials were deigned to test the timing hypothesis, and they were unsuccessful.

• During the expert panel, data was shown for the age group 50-59 years which did show a low absolute cardiac risk for women taking MHT, but, according to the WHI Steering Committee, “The data shown are correct, but somewhat misleading. For most health outcomes there was no statistical evidence that the MHT relative risks differed by age groups.” In addition, the information that was presented at the FDA panel was cherry picked, as data showing a reduction in risk (for fractures and diabetes) was shown, but similar data showing an increase in risk (for gallbladder disease and urinary incontinence) was conveniently not shared.

• A claim was made that 50,000 women died prematurely over 10 years because they were denied MHT, but that is not supported by the data. During the trial there was no significant effect on all-cause mortality for the combined hormone arm. After 18 years of follow-up there was no statistically significant difference in all-cause mortality. It’s hardly possible to project an excess of 50,000 additional deaths when there was no statistically significant difference in all-cause mortality.

• There is a Finnish study that Makary seems obsessed with and was brought up at the expert panel. I wrote about it here, and the claim is that 27% of women will die in their first year after stopping MHT, hence, stopping MHT kills women. The WHI Steering Committee rightly points out that is an observational study and the WHI, AN ACTUAL CLINICAL TRIAL (I am getting a little shouty here, my emphasis not the WHI Steering Committee) showed there was no increased risk of heart attacks upon stopping the hormones. Hmm, what do we accept, an observational study with a lot of limitations (like a lot, as in the dose or duration or type of hormones were all unknown) or a randomized controlled clinical trial? Le Sigh.

The Timing Hypothesis and Dementia

The expert panel was provided with data that claimed MHT is associated with a lower risk of dementia, but this was based on studies of brain metabolism and observational data, so once again, not clinical trials and evidence of cause and effect. The WHI Steering Committee wrote, “We do not have long term trials of MHT for dementia prevention started in early menopause, but in the WHI trial of women aged 50-55 studied ~7 years after trial ended there was no residual benefit for MHT regarding cognition. In women aged 65 and older, there was harm for probable dementia/mild cognitive impairment during the trials. We encourage the FDA to review WHI’s MHT trial results on cognitive function, mild cognitive impairment, and probable dementia.”

Once again, I remind people that all the data on MHT and dementia was reviewed at the 2024 Menopause Society Annual Meeting and we were explicitly told that science does not support starting MHT to prevent dementia

Misleading Information about Cancers, Especially Breast Cancer

The WHI Steering Committee wrote, “The presentations and discussions were potentially misleading, particularly regarding breast cancer, and incorrect for other cancers. Most importantly, it was repeatedly mentioned that the 2002 CEE+MPA paper only “suggested” an increase in breast cancer incidence and that there was no significant increase in breast cancer mortality. This statement distorts the appropriate statistical inference and ignores the totality of the evidence that has been presented over time.”

The combined MHT arm (Premarin plus progestin) was stopped on the advice of an independent data safety monitoring board when the risk of breast cancer crossed the “prespecified monitoring boundary for harm.” The risk of invasive breast cancer increased progressively over time and later became statistically significant. In addition, “a recent published update reported a statistically significant 28% increase at 20 years of cumulative followup, again with no variation by age group and in fact the age group younger than 60 years had a significantly increased cumulative risk (HR 1.36; 95%CI 1.09 - 1.69).”

There is a claim that only women who had previously been exposed to hormones developed breast cancer on the WHI, and those with no prior use did not. This is sometimes used in what I can only be described as incredible feat of mental gymnastics to explain away the increased risk of breast cancer. in the WHI. It is true that women who had taken combined MHT prior to the WHI were initially at higher risk of breast cancer than those who had never taken it. However, there was no difference at 20 years, showing both groups, those who had previously used hormone therapy and those who had not, had increased risks of breast cancer. What this does support is that it takes several years for that increased risk to emerge, which is encouraging. What I tell people is that you have a few years to see if this works for you before the risk starts to rise and then you can decide if that risk is then worth it to you.

The WHI Steering Committee took issue with the statement from the expert panel that combined MHT showed no increase in mortality related to breast cancer. Women with breast cancer undergo chemotherapy, radiation therapy, surgery and all the complications of those treatments in addition to the stress. I know many women who have had all those therapies, and to wave that off as if mortality is the only outcome is both bizarre and dismissive. Also the 11 year mark there was an increase in breast cancer mortality, but by year 20, that no longer held true.

And the following is too important for me to paraphrase:

During the panel discussion, a speaker claimed that the decline in U.S. breast cancer incidence that followed the stopping of the WHI CEE+MPA trial was “a statistical change in how the data was being analyzed by the group from the CDC.” The speaker’s claim is unsubstantiated and not consistent with SEER coding. The report by Ravdin et al. (2007) attributed the sharp decline in U.S. breast cancer incidence after 2002 primarily to the abrupt reduction in postmenopausal hormone therapy use, particularly combined estrogen plus progestin, following the early termination of the WHI CEE+MPA trial. The analysis was peer-reviewed and published in one of the most rigorous medical journals. There are no known technical flaws in the methodology, NEJM has never retracted, corrected, or revised these findings. We encourage the FDA to fully examine the U.S. breast cancer incidence following the stopping of the WHI trial, and temporal trends reported by Chlebowski et al.

Regarding other cancers, the WHI Steering Committee stated “The speaker’s statements regarding WHI portrayal of MHT’s association with lung cancer and ovarian cancer are inaccurate.”

Yeah, It’s a Lot

At this point you might think that I am anti-MHT. I am not. I appropriately prescribe it to patients on a regular basis. Absolute risks for most women under age 65 are low. For example, the risk of breast cancer attributed to Premarin and medroxyprogesterone acetate (the combined hormone arm) is about 6/10,000 women per year for a woman between the ages of 50-59. We think it is lower with progesterone, but it’s important to be honest that data comes from observational studies, so we can not be definitive. In addition, a different estrogen, for example estradiol which is used more commonly now, may also have a different impact. The risks are different as women age.

MHT is the gold standard for hot flashes and night sweats and can be very helpful in preventing osteoporosis for those at risk. I also prescribe MHT for symptoms that have emerged around menopause that we don’t know for sure if they are due to menopause or not, because the WHI reassures me it is a safe therapy and if the symptoms, for example burning mouth or muscle pain, don’t resolve with several months of therapy, then my patient has been exposed to a very low risk to see if MHT might help her or not. I also have a book with a lot of information on MHT (The Menopause Manifesto) and a large series of articles here on The Vajenda with the facts about MHT and how to take it in the most evidence-based way possible. Anyone who says that I am anti-MHT is cherry-picking, which says a lot about them.

What I despise is the misrepresentation of studies, because I believe that women deserve science from unbiased sources so they can make informed decisions. It’s wrong to tell women that MHT can prevent heart disease or dementia when we don’t have the data to back up that claim. Telling the truth is really a low bar, one that Marty Makary seems to have difficulty clearing and that’s pretty sad. I encourage you to read the entire letter from the WHI Steering Committtee and to share it.

Abusing the WHI and cherry picking studies about MHT almost feels like a competitive sport among some menoinfluencers. The irony is that I am sure everyone who has abused the WHI, the largest clinical trial for women, and cherry-picked what they want from its carcass has also likely complained about women’s health being understudied. Can’t quite find a superlative for that level of irony.

It seems like a foregone conclusion that FDA will alter MHT labeling, and if they do it will be in large part due to a complete rewriting of the WHI along with abandonment of the traditional scientific process and disregard for transparency. Makary seems to reward and revel in spectacle and propaganda, which does not advance science or health.

The truth is, the WHI is simply inconvenient for Makary and many influencers. As one person who was involved with the study once told me, the WHI is pretty great evidence that hormones aren’t going to kill you and that they are also not going to make you live forever. But where’s the profit in that?

Manson JE, Crandall CJ, Rossouw JE, Chlebowski RT, Anderson GL, Stefanick ML, Aragaki AK, Cauley JA, Wells GL, LaCroix AZ, Thomson CA, Neuhouser ML, Van Horn L, Kooperberg C, Howard BV, Tinker LF, Wactawski-Wende J, Shumaker SA, Prentice RL. The Women’s Health Initiative Randomized Trials and Clinical Practice: A Review. JAMA. 2024 May 28;331(20):1748-1760. doi: 10.1001/jama.2024.6542. PMID: 38691368.

Manson JE, Aragaki AK, Rossouw JE, et al; WHI Investigators. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials.  JAMA. 2017;318(10):927-938.

Anderson GL, Chlebowski RT, Rossouw JE, Rodabough RJ, McTiernan A, Margolis KL, Aggerwal A, David Curb J, Hendrix SL, Allan Hubbell F, Khandekar J, Lane DS, Lasser N, Lopez AM, Potter J, Ritenbaugh C. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006 Sep 20;55(2):103-15. doi: 10.1016/j.maturitas.2006.05.004. Epub 2006 Jul 11. PMID: 16815651.

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Longterm Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA. 2020;324(4):369-380.