Part 4 of The Menopause Files
19 May 2025
As discussed in Part 1 of The Menopause Files, the use of hormone replacement therapy (HRT) by peri- and postmenopausal women plummetted after the publication of results from the Women’s Health Initiative hormone therapy trials in 2002. To recap those findings, women taking combination HRT (equine, or horse-derived estrogen plus a synthetic progesterone called a progestin) for an average of just over five years (and a maximum of 8.5 years), had a slightly increased risk of coronary heart disease (CHD), stroke, pulmonary embolism and invasive breast cancer, along with a slightly reduced risk of colorectal cancer and hip fracture.
But in recent years, there has been a significant resurgence in the promotion of HRT – now rebranded ‘menopausal hormone therapy’ or MHT – by professional societies and individual doctors, many of whom have close ties to the pharmaceutical industry. This renewed enthusiasm for hormone prescription during the menopause transition is buttressed by claims that the Women’s Health Initiative (WHI) trial was flawed because most participants were started on HRT well past menopause and therefore had missed a critical window in which it may have had benefits; that the increase in risk of breast cancer was not statistically significant; and that the premature stopping of the trial was improper and was opposed by many members of the research team, whose concerns were overridden by the principal investigator.
One doctor who has been a vociferous critic of the WHI, and an enthusiastic proponent of broader use of MHT, is current Commissioner of the US Food and Drug Administration (FDA), Dr Martin (Marty) Makary. In his 2024 book Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health, Makary makes a series of claims about the benefits of MHT, and the hazards to women of avoiding it, that are – to put it mildly – highly questionable. Makary’s publicity blitz for the book resulted in many reviews and interviews, almost all of which were completely uncritical of his assertions about the “medical miracle” of menopausal hormone therapy. Even medically-trained interviewers and reviewers, on the whole, failed to push back on Makary’s cavalier approach to the use of scientific evidence, instead accepting his bold claims at face value.
A particularly grating example of this credulousness was an interview conducted by self-anointed ‘menopause expert’, Dr Louise Newson, whose British Menopause Society accreditation as a menopause specialist was yanked late last year due to her chain of private menopause clinics’ habitual practice of prescribing doses of transdermal oestradiol far above those tested in randomised controlled trials. Not only did Newson fail to challenge Makary’s baseless claim that MHT makes women live longer, or his hyperbolic accusation that “the dogma that taking hormone replacement therapy at the time of menopause causes breast cancer is probably the biggest screw-up in modern medicine”; she threw in some completely evidence-free assertions of her own, including that MHT reduces heart disease and dementia.
Makary and his fellow MHT enthusiasts’ dubious assertions are not only emblematic of the revived sales pitch for MHT; they also eerily echo a pharmaceutical industry-orchestrated, decades-long campaign of attack on the WHI that commenced almost immediately after its initial findings were published, and a parallel campaign of promotion of unproven benefits of hormonal therapy. These activities were unveiled through the examination of 1500 documents unsealed in litigation against the pharmaceutical company Wyeth, manufacturer of some of the most widely-used HRT drugs at the time. Wyeth was acquired by Pfizer in 2009.
In a nutshell, Wyeth hired multiple medical education and communication companies (MECCs) to produce ghostwritten articles, commentaries, reviews, scientific posters and slide kits, which played down the harms of MHT and laid claim to benefits that were unsupported by evidence.
For those unfamiliar with the term, ghostwriting is the production of books, articles and the like for another person to publish under their own name, without acknowledging the true author of the work. Jon Jureidini and Leemon McHenry lay bare the corrosive influence of medical ghostwriting in their brilliant book, The Illusion of Evidence-Based Medicine, citing example after example of how ghostwritten articles have corrupted the peer review process and hence degraded the scientific integrity of medical journals, polluted the evidence base of medicine, misled doctors and influenced their prescribing behaviour and ultimately, harmed patients.
The content developed by Wyeth’s hired guns was published in influential medical journals, and presented at conferences and symposia, as if it were the original output of leading researchers and clinicians, rather than the bought-and-paid-for promotional material of the company that stood to benefit financially from wider use of its hormone products – including so-called ‘off-label’ use, for conditions for which the drugs did not have FDA approval. The full, sordid story is told in ‘The Haunting of Medical Journals: How Ghostwriting Sold “HRT”‘, which is a must-read for anyone who wants to understand exactly how pharmaceutical companies shape the narratives on conditions and their treatments that are presented to health professionals and through them, to the wider public.
It’s both noteworthy and disconcerting that Marty Makary places the blame for the litany of medical errors (or claimed errors) that he profiles in his book solely on the phenomenon of “groupthink” among doctors, professional societies, researchers and research funding bodies… and not on the pharmaceutical companies and medical device makers which hire agencies to develop publication plans for the express purpose of sculpting that groupthink to their own commercial benefit. How ironic that a book titled Blind Spots has such a blind spot for drug and device industry malfeasance!
Following is a dissection of five of the claims made by Makary in the chapter of Blind Spots devoted to hormone replacement therapy, along with examination of the evidence that he cites for these claims, and the evidence against them that he ignores.
Claim #1: The premature termination of the WHI was improper and motivated by bias
Makary’s discussion of the premature termination of the WHI is selective and confused. Makary speculates that the lead investigator, Dr Jacques Rossouw “had made up his mind before the study began” that HRT was harmful to women. His only justification for this accusation is that Rossouw had written, six years before the publication of the initial WHI results, that “It is time to put the brakes on the hormone bandwagon”. Well, that’s an example of highly selective quotation, if I’ve ever seen one! The complete sentence from which Makary cherry-picked this incriminating quote, in its full context of an article that meticulously lays out the evidence for all the benefits and risks of supplemental estrogen known at the time of writing, is as follows:
“The status of estrogen as a potential preventive treatment may appear superficially similar to that of antioxidants. Expectations of benefit for antioxidants based on observational studies have not yet been borne out by clinical trials. Nevertheless, many physicians recommend and continue to take antioxidants themselves because they believe the risk of harm to be small. But estrogens are very different from antioxidants. The risk of harm may turn out to be very real. It is time to put the brakes on the hormone bandwagon while pushing ahead with the randomized trials that will provide definitive data on benefit and risk.” [My emphasis]
Estrogens for Prevention of Coronary Heart Disease: Putting the Brakes on the Bandwagon
Hmmm, that puts a different spin on Makary’s arch-villain, Rossouw, does it not? Sounds more like the words of a cautious man who has learned from previous medical mistakes, and is eager to avoid unnecessary harm inflicted on women by enthusiastic doctors touting a treatment for its unproven benefits.
But even more importantly, neither Rossouw nor any of the other investigators had the power to stop the trial regardless of any biases they may have had. That power rests with the Data Safety Monitoring Board, which Makary references briefly and obliquely, neglecting to mention that, as clearly explained in the paper which presented the initial findings, this fully independent board – not Rossouw, nor any of the other investigators – had recommended terminating only the combined estrogen + progestin arm of the WHI because of consistent and steadily-accumulating evidence that the net harms (not just the risk of breast cancer, which is the only outcome that Makary refers to) outweighed net benefits:
“Trial Monitoring and Early Stopping Formal monitoring began in the fall of 1997 with the expectation of final analysis in 2005 after an average of approximately 8.5 years of follow-up. Late in 1999, with 5 interim analyses completed, the DSMB observed small but consistent early adverse effects in cardiovascular outcomes and in the global index. None of the disease-specific boundaries had been crossed. In the spring of 2000 and again in the spring of 2001, at the direction of the DSMB, hormone trial participants were given information indicating that increases in MI, stroke, and PE/DVT had been observed and that the trial continued because the balance of risks and benefits remained uncertain.
In reviewing the data for the 10th interim analyses on May 31, 2002, the DSMB found that the adverse effects in cardiovascular diseases persisted, although these results were still within the monitoring boundaries. However, the design-specified weighted log-rank test statistic for breast cancer (z = −3.19) crossed the designated boundary (z = −2.32) and the global index was supportive of a finding of overall harm (z = −1.62). Updated analyses including 2 months of additional data, available by the time of the meeting, did not appreciably change the overall results. On the basis of these data, the DSMB concluded that the evidence for breast cancer harm, along with evidence for some increase in CHD, stroke, and PE, outweighed the evidence of benefit for fractures and possible benefit for colon cancer over the average 5.2-year follow-up period. Therefore, the DSMB recommended early stopping of the estrogen plus progestin component of the trial. Because the balance of risks and benefits in the unopposed-estrogen component remains uncertain, the DSMB recommended continuation of that component of the WHI.”
Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women
Claim #2: The WHI did not demonstrate increased breast cancer risk in women taking HRT
Makary makes much of the fact that the increased risk of invasive breast cancer in women taking combined HRT (equine estrogen plus progestin) reported in the initial publication of results from the Women’s Health Initiative trial did not reach statistical significance, meaning that there was no difference in risk between those taking hormones, and those taking placebo. He reproduces a small snippet of one of the tables from the paper to illustrate his point, explaining that when the confidence interval for an odds ratio includes the number 1, the results are nonsignificant:
While this is perfectly true, Makary neglects to show Figure 3 from the same study, the Kaplan-Meier curves which plot the estimated occurrence of outcomes over time. These curves clearly show that the difference in risk of invasive breast cancer between those taking combined HRT and placebo was widening as the study progressed, suggesting that the longer that women stayed on hormones, the greater their excess risk of breast cancer would become:
And indeed, when the longer-term follow-up results of the WHI were published in 2013, there was a statistically significant increase in risk of invasive breast cancer in women who had taken combined HRT, amounting to a 32 per cent higher relative risk, or an additional 10 cases of invasive breast cancer per 10,000 person–years:
In addition, breast cancers in women on combined HRT were diagnosed at more advanced stages (i.e. they were more aggressive), and the more time elapsed since women stopped taking hormones, the more their risk was attenuated, which strongly suggests a causal relationship between combined HRT use and breast cancer.
Claim #3: The WHI harmed women taking estrogen-only HRT, by taking away their protection against breast cancer death
Makary writes that
“A cruel irony came to light in follow-up studies. They found that participants who took estrogen alone had lowered their risk of breast cancer by 23% and lowered their risk of breast cancer death by 40%. That benefit diminished over time after women discontinued HRT.”
From Chapter 2 of Blind Spots, ‘OMG HRT: The untold story of hormone replacement therapy’
There is no reference provided to support this claim, but these are the exact same percentages stated by Makary’s preferred narrator of the WHI story, Robert Langer, in his 2023 paper ‘Tis but a scratch: a critical review of the Women’s Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer.’ Langer et al assert in this paper that “CEE [conjugated equine estrogen] alone reduces the risk of breast cancer by 23% and reduces the risk of breast cancer death by 40%”, but they too do not provide any reference for the claim. Where did these numbers come from? I can’t tell, and Makary seems not to care, as long as he finds a citation that supports his beliefs. It’s an astonishing omission; any first-year student knows that when writing an academic paper, every single statement of fact that one makes must be referenced. I’m surprised that the paper passed peer review given the failure to reference its most important and controversial claim.
Notably, Langer et al‘s assertions contradict the findings of the WHI investigators, who reported a 21 per cent reduction in invasive breast cancer incidence in the estrogen-only group during the follow-up period – that is, after they had discontinued the use of estrogen, and no statistically significant difference in breast cancer mortality either during the trial or after 18 years of follow-up, in either the women taking estrogen-only or combined HRT.
In fact, there was no overall mortality benefit of taking either estrogen-only or combined HRT, and the benefit that was seen in younger women (those aged 50-59 at the time of beginning treatment in the trial) disappeared after 18 years of follow-up, contradicting the ‘sensitive window’ hypothesis that administering HRT close to the time of menopause is helpful while delaying it until years after the final menstrual period is harmful.
It should be noted that whereas the combined estrogen + progestin arm of the WHI was halted in 2002, the estrogen-only arm of the trial was terminated prematurely in 2004, because of an increased incidence of stroke which was not offset by lower risk of coronary heart disease.
Claim #4: HRT reduces the risk of Alzheimer’s disease
Makary boldly asserts that “Women taking estrogen have a 35% lower incidence of Alzheimer’s.” Extraordinary claims require extraordinary evidence, so what is Makary’s evidence? He cites a 1996 case-control study in which 8877 women living in a retirement community were sent a questionnaire in 1981 which asked them, among other things, about their use of estrogen around or after menopause. Then, after 3760 of these women died, the researchers compared the number for whom “Alzheimer disease, senile dementia, dementia, or senility” was indicated as a cause of death on their death certificates, in those who had self-reported that they used estrogen, to those who had not.
To describe this as a weak study design is the understatement of the year. Case-control studies are retrospective and observational, meaning that they compare exposures of interest in people who develop a particular condition to those who don’t, after the diagnosis. The problem with this study design, as Makary’s nemesis, Dr Rossouw explained back in 1996, is that
“All these observational studies share a fatal flaw: women who take estrogens are different from women who do not. Some of the differences have been measured, others have not. As reviewed elsewhere, women who take estrogens are on average better educated, healthier, have higher incomes, and have better access to healthcare.21 It is important to note that women who eventually take estrogens appear to be healthier even before starting therapy.” [My emphasis]
Estrogens for Prevention of Coronary Heart Disease: Putting the Brakes on the Bandwagon
The whole point of a randomised controlled trial is to reduce differences between the treatment and placebo groups as much as possible, so that we can ascertain the true treatment effect rather than being misled by the systematic biases that plague observational study designs like case-control, including recall bias and selection bias.
In the WHI, women taking combined HRT had a statistically significant doubling of the risk of developing probable dementia during the intervention phase, which dissipated after they stopped treatment. Women closer to the age of menopause (50–55) at the time of entering the trial had “no overall sustained benefit or risk to cognitive function” when followed up seven years after the WHI trials ceased.
Claim #5: HRT reduces the risk of heart disease
According to Makary, HRT reduces the risk of heart disease “by about 50%”. Astonishingly, the citation for this grandiose claim is a 1991 paper that reviewed the results of observational trials in women who were taking unopposed estrogen, which of course is only possible in those who have had a hysterectomy. Observational trials were all that existed at that stage because no randomised controlled trials had yet been conducted. All the limitations of observational trials described by Rossouw above, apply to this situation as well. In fact, the authors of the 1991 paper stress that
“These important observations need to be confirmed in a double-blind, randomized clinical trial, since the protection is biologically plausible and the magnitude of the benefit would be quite large if selection factors can be excluded.” [My emphasis]
Estrogen and coronary heart disease in women
Well, the WHI addressed those selection factors, and found that women taking combined HRT had a statistically significant increased risk of coronary heart disease in the first year, with risk in subsequent years of the trial becoming less elevated or neutral. Women taking estrogen-only HRT had no change in coronary heart disease risk. During the follow-up phase (i.e. after women had stopped taking hormones), risk was neutral in both groups.
Risk of stroke was also increased by a statistically significant 37 per cent in the combined HRT group and 35 per cent in the estrogen-only group, while women taking combined HRT had a near-doubling of the risk of pulmonary embolism. No mention of these cardiovascular hazards of hormone therapy by Dr Makary, oddly enough.
The WHI is not the only study which has found an increased risk of cardiovascular disease in women taking MHT. In 2015, Cochrane – which Makary acknowleges as “a highly respected group of experts who conduct extensive scientific reviews” conducted a meta-analysis of 19 randomised controlled trials, which included 40,410 post‐menopausal women. Their conclusion was sobering:
“Our review findings provide strong evidence that treatment with hormone therapy in post‐menopausal women overall, for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events.”
Hormone therapy for preventing cardiovascular disease in post‐menopausal women
HRT – WTF?
Makary titled the chapter of Blind Spots that he devoted to attacking the Women’s Health Initiative and singing the praises of menopausal hormone therapy ‘OMG HRT’. After chasing down the references for just five of his litany of claimed benefits, my response is WTF????? His analysis is sloppy, to put it kindly. It’s clear that book publishers either no longer employ fact-checkers, or they don’t know how to do their jobs.
What the heck is Makary’s game? I do not have any special insights into what drives him, but recalling the point that I made previously – that he blames “groupthink” among doctors for inappropriate, unhelpful and harmful medical treatments, while ignoring the outsized role that pharmaceutical and medical device companies play in sculpting that groupthink, I’m left wondering: Is Dr Makary, by ignoring the culpability of drug and device makers for generating false narratives, paving his own pathway through the notorious revolving door to a lucrative post-government job in this sector? As the redoubtable Peter Doshi noted in a BMJ investigation last year,
“Since 2000 every FDA commissioner, the agency’s highest position, has gone on to work for industry.”
Revolving door: You are free to influence us “behind the scenes,” FDA tells staff leaving for industry jobs
And then there’s this:
Yes, it turns out that the current FDA commissioner is a co-founder of a company that makes money by, among other activities, onselling apps that harvest biometric data and charge users a fee for access to their own data, and that also reserves the right to further monetise its customers’ sensitive health data by onselling them to third parties. Once again, WTF?????
Is there a moral to this story?
Broadening the aperture back out from this focus on Marty Makary’s lopsided critique of the WHI and his poorly-grounded advocacy for widespread use of HRT, what conclusions can be drawn from the rise, fall, resuscitation, spectacular demise, and attempted resurrection of menopausal hormone therapy? Two things spring to my mind: cui bono and there’s no such thing as a free lunch.
Cui bono – who benefits? Never forget that the pharmaceutical industry’s business model is to redefine as many human experiences as diseases as it possibly can, in order to turn as many human beings into customers – preferably lifelong customers – as it possibly can. Every woman who lives long enough will go through the menopausal transition, and since women are generally more health-conscious and more inclined to seek medical help for their symptoms than men, they’re a prime market segment for Big Pharma. No wonder Big Pharma invests so heavily in shaping the narrative on menopause and the potential treatments for its symptoms. And doctors who – like Dr Makary – pride themselves on being contrarians, and deride others as victims of groupthink, may paradoxically be more susceptible to the pharma-crafted narrative on MHT precisely because it has been rejected by a large majority of their profession (on the basis of high-quality studies that were not funded by drug companies). You don’t have to be on the take from Big Pharma to be seduced by their storytelling.
There’s no such thing as a free lunch. As discussed in Part 2 of The Menopause Files, MHT is very effective at relieving bothersome vasomotor symptoms (hot flushes/flashes and night sweats). It also reduces the risk of osteoporotic bone fractures, and may reduce the incidence of – but not mortality from – invasive breast cancer in hysterectomised women taking estrogen-only preparations. But it also causes blood clots and strokes, and increases breast cancer risk in women on combination therapy.
Women considering MHT have a complex decision to make, in which they must weigh the risks and benefits, and decide whether they’re willing to put up with the potential costs in order to get relief from their suffering.
Of course, for women who decide against MHT, there are drug-free treatments for perimenopausal symptoms that are not only free of the drawbacks of hormonal therapy; they actually decrease the risk of coronary heart disease, dementia and breast cancer. So maybe you can get that free lunch, after all!
