Vintage Data, Modern Misinformation:

The FDA’s use of outdated studies and Makary’s inaccurate all-cause mortality claim, explained

Imagine you are coming to see me for a consultation about menopause, and I explain my recommendations, assure you that I practice evidence-based medicine, and then tell you I am relying on a 45-year-old study to guide your care. Not even a clinical trial, but a case-control study (which is an observational study).

You look shocked, so I follow up with, “Don’t worry, I am also going to use a 34-year-old review article of mostly observational studies that are 35-48 years old, as well as a 29-year-old retrospective case-control study.” I add, for extra reassurance, “I really love that up-to-date data!”

At this point, you might wonder to yourself, “Isn’t there any better quality data than that? Don’t you have studies that were started after I entered puberty?” And you would be correct: there are both higher-quality and more recent studies (I’ll get to those later). Regardless, imagine I continued in our conversation, either pretending or just plain ignorant of the fact that more recent data and better studies exist. You would not be faulted for thinking you had entered the Twilight Zone or a horror movie, or even wonder if you were seeing a real doctor.

Unfortunately, this is our reality, because I have just described the three publications that Dr. Makary and the FDA cited in both their press release and in a recent JAMA opinion piece as proof of the effectiveness of menopausal hormone therapy for heart, bone, and brain health.^1,2 This is from the press release (and the wording is not much different in the JAMA article:

Women may also reduce their risk of cardiovascular diseases by as much as 50%, Alzheimer’s disease by 35%, and bone fractures by 50 to 60%. Though the starting time of HRT and duration of use are decisions made between the prescriber and the individual patient, the FDA’s labeled recommendation will be to start HRT within 10 years of menopause onset or before 60 years of age for systemic HRT.

What are these stunning pieces of “evidence-based” medicine?

• The cardiovascular disease article is a 34-year-old narrative review on unopposed estrogen (no progestogen), so it is not even applicable to most women taking MHT. Only one clinical trial from 1979 is even included in this paper; all the other articles are observational.³ The authors conclude that a randomized clinical trial is needed so even they knew it should not be used for clinical guidance..

• The Alzheimer’s paper is a 29-year-old case-control study. Almost 9,000 women living in a Southern California retirement community were sent a survey in the early 1980s.⁴ Investigators then looked at death certificates between 1981 and 1995 and identified 246 women with dementia, and 1,193 matched controls for women who died for other reasons, and then they looked back to see who had reported using estrogen. Pharmacy records were not checked to ensure the women had accurate recall, and creams, which may have been vaginal, were lumped together with injections, and no information on progestins was available. This study controlled for only a few variables, is small, and should never be used as proof of anything. Also, there is no information on progestogens.

• The information on bone fractures comes from a 45-year-old case-control study where 327 women with fractures were compared with 567 women who did not, and then they were queried about estrogen use.⁵ Again, no cross-checking with the pharmacy and no data on many, many important variables. We also have no idea if the women only took estrogen or if they also took a progestogen.

Makes you wonder if the press release was dug up from the George Bush Senior’s Administration.

None of these papers are clinical trials, so we can’t infer causation. We know that women who have access to MHT typically have higher incomes, education levels, and better access to health care, so there is a strong healthy user bias, especially in the United States where there is no universal health care.

In short, these are not papers that truly evidence-based physicians (not just those who claim they are) would use to determine treatment. If a medical student used these papers for a presentation, I would fail them.

Now let’s walk through the modern data, meaning what the FDA should have been quoting:

Cardiovascular disease: The WHI, ELITE, and KEEPS are randomized, placebo controlled trials and they show no meaningful benefit for primary prevention of cardiovascular disease, and the WHI shows an increased risk for women ages 70 and older.^6-8 There is also a Cochrane Review from 2015, which only addresses oral estrogen, which suggests that when MHT is started within 10 years of the final period there is a reduction on cardiovascular disease by 50%. The absolute numbers sound much less impressive: 1.8% with placebo and 1.1% with MHT.⁹ And while it is statistically accurate that this represents a 50% decrease, the absolute risk reduction is 0.7%, which is not clinically meaningful. However, and this is a big however, when the Danish Osteoporosis Prevention Trial, an unblinded study that was not designed to evaluate cardiovascular disease, is removed from the analysis in the Cochrane review, the beneficial effect of MHT on cardiovascular disease for those within 10 years of menopause disappears completely.¹⁰ So I guess that answers why they used the 1994 paper.

Alzheimer’s Disease: Four clinical trials show no benefit on cognition in early menopause, and the WHI memory study showed an increase in dementia risk for those starting MHT at age 65 and older.^6,11-14 Long-term follow-up of the KEEPS study shows no benefit on brain health, and that is probably the best long-term data that we currently have.¹⁵

We can also look at newer, more robust observational data that has far more women and a more diverse sample than the 1,000 or so in a retirement community in Southern California. Four observational studies from countries with large databases actually show an increase in dementia with MHT. Here is a screen shot of a slide detailing those studies that was presented by Dr. Pauline Maki at the Menopause Society meeting:

These are observational studies with tens of thousands or hundreds of thousands of women. In addition, they are registry studies so they capture a representative sample from an entire country, not a single retirement community in one state.

Bone Health: While Makary et al. are right that MHT reduces fractures, ignoring the randomized controlled trials completed in the past twenty years that actually show benefit on bone health in favor of a 45-year-old retrospective case-control study is a…choice—and not a good one. Perhaps this is because the WHI and other studies don’t show as dramatic a reduction in fractures, and they were looking for big numbers (this is conjecture on my part). The WHI showed a reduction in fractures, and is probably the best evidence as it is the longest randomized trial. The only issue is that fractures are a secondary outcome, so women were not selected based on fracture risk or osteoporosis history. In the WHI, both arms (estrogen with and without a progestin) reduced the combined risk of vertebral fractures, hip fractures, and total fractures by 34% compared with placebo.⁶ During the active treatment, when women were taking the hormones, the reduction in hip fractures was 5/10,000 women per year. There are other randomized controlled trials, but the WHI is the largest and longest.

What About All Cause Mortality?

This is also a claim that was made in the press release and the JAMA editorial.

Randomized studies show that women who initiate HRT within 10 years of the onset of menopause (generally before age 60) have a reduction in all-cause mortality…

This claim is from the WHI, which is problematic as the WHI does not support a claim of reduced all-cause mortality with MHT.

In the WHI there was no statistically significant reduction in all cause mortality in the 50-59 year old group with estrogen plus a progestin versus placebo or the same age group with estrogen alone versus placebo.⁶ We would want to see a statistically significant difference between active drug (MHT) and placebo to make the claim of reduction in all cause mortality, and we don’t.

I suspect that they are confusing the analysis that compared the age groups with each other. In this analysis, the women ages 50-59 who took Premarin had a lower all-cause mortality than the groups ages 60-69 and ages 70-79 who took estrogen (this effect was not seen on the Premarin plus progestin group). These kinds of comparisons get trippy, statistically speaking. Think of the results here as looking through a cloudy window, we can’t be as sure of what we see. In fact, the authors say that for this kind of analysis the results should be “interpreted cautiously,” and they conclude that “current WHI findings do not support the use of either estrogen-progestin or estrogen alone for chronic disease prevention,” even for younger women. If the WHI concluded with confidence that MHT reduced all cause mortality, the authors would have stated that but they did not.

Irony is Dead

The press release, apparently unironically, states:

For more than two decades, bad science and bureaucratic inertia have resulted in women and physicians having an incomplete view of HRT. We are returning to evidence-based medicine and giving women control over their health again.

I guess, dear reader, these papers from 1980, 1991, and 1996, pried from the hands of the medical crypt-keeper, are the “evidence-based” medicine women need to control their health.

With one breath the same people who argue the WHI contributed to two decades of harm use their very next breath to use that same study (incorrectly) as proof of reducing all-cause mortality! It sure seems like the only expertise displayed by Makary and his team is Olympic-level cherry-picking.

Why The Disinformation?

I have several theories:

Incompetence. It’s not as if the correct references here are hard to find. It really seems as if they looked for papers with the most dramatic percentages. I mean, really, a 45-year-old case-control study on fractures? Really?!?

Makary’s ego. He used decades-old papers in his book chapter on menopause hormone therapy and was a cherry-picking champion and so got a lot wrong (read about my review of his chapter here). Most of what we’ve seen presented at the announcement, in the press release, and in JAMA is based on his book. Interestingly, his book was mentioned at the press release and he cites his book as a conflict of interest in the JAMA article. A lot of this smacks as one big ego trip for him to use the power of the government to prove his book was right, when in reality it was embarrassingly bad.

Drive business to telemedicine. Makary was previously an executive at the telehealth weight-loss company Sesame that sold compounded weight loss drugs, and the new Health Director for the Advanced Research Projects Agency is Alicia Jackson, Ph.D., the CEO of Evernow, a menopause telemedicine company. Note that as of Nov 13, 2025, two days after the press conference and about 20 days after her public start date at HHS, Jackson still lists herself on LinkedIn as CEO of Evernow.

It honestly would not surprise me if more people in the administration or those outsiders working behind the scene to make this happen, had financial entanglements with telemedicine companies. In using the weight of the government to push that every woman needs menopause hormone therapy, many of those women will filter over to telemedicine.

Why the benefit for telemedicine? First, not all telemedicine is bad. Like any medical practice, there is good and bad (I like Gennev because their Chief Medical Officer is evidence-based and they don’t sell supplements or estrogen face creams). However, a lot of telemedicine in menopause is becoming predatory. Some seem to dispense hormones based on little more than a questionnaire, and then there are companies with add-ons like inadequately studied supplements, unnecessary testing, and compounded face creams. My theory is the press conference and Makary’s press tour will send more women to telemedicine asking for this “longevity medication,” menopause hormone therapy, and the companies poised to make the big bucks are the ones that get as many women in the door as possible for hormone therapy and then upsell them with supplements, compounded estrogen creams, and other add-ons. I was not surprised to see that Evernow sells compounded estrogen face cream as well as supplements, such as Dr. Haver’s “Pause Life supplements.

Wasn’t This a Leap Forward for Women? Don’t the Ends Justify the Means?

Not in my opinion. I’ve just laid out in detail how the FDA cherry picked data and misled the public under the guide of improving health. This is not a good thing for an agency tasked with the health of the nation. It’s hard to see how using decades old low-quality data while ignoring modern, higher quality data to guide policy decisions for women is anything but regressive. Misleading women is misogyny. And of course, what data will they cherry-pick and abuse with the next drug that comes on their radar?

The right thing would have been to remove the black box warning on vaginal estrogen for which there was broad scientific support, and then start the formal process, with all of its transparency, to review the labeling on systemic estrogens and progestogens (the ones for menopause hormone therapy). There was no reason not to do this, time was not of the essence. The label was outdated, and we have new data, but this approach would not have satisfied egos at the FDA or over promoted hormone therapy as the fountain of youth. There was absolutely an agenda here, it just wasn’t using the evidence from the latest research to advance health care for women.

Makary has done exactly the same thing to women and menopause hormone therapy as he himself has previously accused the WHI researchers of doing: using a media blitz to spread misinformation to women about MHT.

References

1. Press Release FDA on MHT https://www.hhs.gov/press-room/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy.html

2. Makary MA, Nguyen CP, Høeg TB, Tidmarsh GF. Updated Labeling for Menopausal Hormone Therapy. JAMA. Published online November 10, 2025. doi:10.1001/jama.2025.22259

3. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA. 1991 Apr 10;265(14):1861-7. PMID: 2005736.

4. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med. 1996 Oct 28;156(19):2213-7. PMID: 8885820.

5. Weiss NS et al. New England Journal of Medicine Volume 303 • Number 21 • Novembe 20, 1980. Pages: 1195-1198

6. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040. PMID: 24084921; PMCID: PMC3963523

7. Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. doi: 10.1056/NEJMoa1505241.

8. KEEPS Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM, Neal-Perry G, Santoro N, Taylor HS, Vittinghoff E, Yan M, Hodis HN. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014 Aug 19;161(4):249-60. doi: 10.7326/M14-0353. PMID: 25069991.

9. Roberts H, Hickey M. Should hormone therapy be recommended for prevention of cardiovascular disease?. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: ED000097. DOI: 10.1002/14651858.ED000097.

10. Schierbeck L L, Rejnmark L, Tofteng C L, Stilgren L, Eiken P, Mosekilde L et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial BMJ 2012; 345 :e6409 doi:10.1136/bmj.e6409

11. Maki PM, Gast MJ, Vieweg AJ, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology. 2007 Sep 25;69(13):1322-30. doi: 10.1212/01.wnl.0000277275.42504.93. PMID: 17893293.

12. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G, Santoro NF, Taylor HS, Black DM, Budoff MJ, Hodis HN, Naftolin F, Harman SM, Asthana S. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015 Jun 2;12(6):e1001833; discussion e1001833. doi: 10.1371/journal.pmed.1001833. PMID: 26035291; PMCID: PMC4452757

13. Espeland MA et al. JAMA Intern Med August 12/26, 2013 2013;173;(15):1429-1436. doi:10.1001/jamainternmed.2013.7727

14. Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016 Aug 16;87(7):699-708. doi: 10.1212/WNL.0000000000002980. Epub 2016 Jul 15. PMID: 27421538; PMCID: PMC4999165.

15. Gleason CE, Dowling NM, Kara F, et al. Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLOS Medicine, November 21, 2024. https://doi.org/10.1371/journal.pmed.1004435