The US Food and Drug Administration (FDA) exists for the purpose of protecting the public by ensuring any products on the market are safe and efficacious. This, of course, is an extraordinarily worthwhile cause, but even the noblest of missions can occasionally lead to a few missteps, and on certain rare occasions, the FDA issues warnings and restrictions where they aren’t sufficiently justified by research. Such was the case in early 2003 when, in the wake of the Women’s Health Initiative (WHI) on hormone replacement therapy (HRT), the FDA issued a black box warning on estrogen products. The label warns that such products can increase risk of stroke, blood clots, and breast cancer, and the inclusion of this warning on estrogen products contributed substantially to the subsequent trend toward fear and avoidance of HRT among many providers and postmenopausal women.
Now, more than two decades later, we have new hope that the 2003 decision might finally be reversed. Last week, in a panel discussion organized by FDA commissioner Dr. Marty Makary, experts emphatically called for the removal of the warnings from HRT products. If the agency acts on the panel’s recommendation, the decision would constitute an enormous victory for women’s health. But what prompted the addition of the warning in the first place, and why has it now been re-opened for debate?
The cause of the alarm
When women experience menopause, levels of the sex hormones estrogen and progesterone plummet, giving rise not only to classical vasomotor symptoms (e.g., hot flashes and night sweats) but also to many other negative effects on quality of life and physical health, such as losses in bone mineral density and muscle strength, changes in mood, and a decline in libido. Hormone replacement therapy, which involves supplementing the body’s low post-menopause levels with exogenous estrogen (and, for women with an intact uterus, exogenous progesterone), offers an effective means of attenuating these symptoms, and as a result, this approach steadily grew in popularity throughout the latter half of the the 20th century.
But the trend came to an abrupt halt following the 2002 publication of results from a series of two landmark randomized trials — collectively known as the Women’s Health Initiative, or WHI — on the health effects of estrogen alone and of estrogen plus a synthetic form of progesterone.1 Prompted by earlier observational data suggesting that HRT might be cardioprotective, the two trials examined the relationship between the use of menopausal HRT and risks for various chronic diseases. Yet results from these studies failed to substantiate the alleged reduction in risk of cardiovascular disease with HRT. Even worse, the WHI investigators reported that the use of estrogen plus progesterone increased the incidence of breast cancer by 26% (95% CI: 0-59%) relative to placebo, as well as increasing risk of stroke by 41% (95% CI: 7-85%).
The findings were widely publicized and ultimately led the FDA to require warning labels on any estrogen products regarding potential health risks. The impact was profound: within three years, the use of HRT had dropped by over 70% and has remained low ever since.2,3
But both the WHI results and the about-face reaction that they inspired have been mired in controversy from the very beginning — and rightly so. A closer look at the design and results of the WHI trials reveals several holes in the broad interpretation that HRT increases health risks.
Flaws in the conclusions on breast cancer risk
The greatest fear to arise from the WHI concerned the 26% higher breast cancer incidence in the HRT group relative to controls, yet the absolute numbers remained very low — this difference corresponded to about one additional case of breast cancer per 1,000 patient-years. Further, the two groups did not differ in the number of breast cancer deaths. So although women on HRT were slightly more likely to receive a breast cancer diagnosis over the average follow-up of 5.2 years, this didn’t equate to a higher risk of dying from breast cancer.
Of course, cancer is a terrible disease that can cause great suffering even when it doesn’t result in death, so the increase in incidence itself would be a significant cause for concern — if it weren’t for the fact that even this finding is riddled with flaws. The discrepancy in risk disappeared altogether when considering only women with no HRT prior to the study (roughly 75% of the women in the study), and the apparent increase in risk in the full cohort (including women with and without prior HRT) wasn’t due to an unusually high incidence in those on HRT, but to an unusually low incidence in those on placebo who had previously used HRT.
These problems alone would raise plenty of doubts about the WHI’s conclusions, but we also have compelling evidence that the increase in risk was specific to the outdated progestogen used by the WHI. The estrogen used in these trials was conjugated equine estrogen (CEE), and the progestogen (used only in the trial among women with intact uteruses) was medroxyprogesterone acetate (MPA) — the dominant forms of HRT at the time that the research began in the 1990s. Yet the apparent increase in breast cancer risk was only seen in the trial involving CEE plus MPA. Indeed, a subsequent analysis of WHI data on CEE alone versus placebo revealed that the CEE group had nearly a 20% lower risk of breast cancer incidence than the placebo group, as well as 40% reduction in breast cancer mortality relative to placebo by 20 years of follow-up.4 These results strongly suggest that MPA, and not estrogen, is responsible for any elevated risk observed in the WHI and that estrogen itself may even be protective.
MPA is no longer used in HRT, having been replaced primarily by micronized progesterone. Thus, the WHI’s results are effectively irrelevant for modern medical practice, yet the FDA’s label nevertheless continues to flag all HRT products with this outdated (at best) warning about breast cancer.
Flaws in the conclusions on cardiovascular risk
A major motivation for the WHI trials was the observation from large-scale epidemiology studies that the use of HRT was associated with lower risk of cardiovascular disease (CVD). The correlation makes some mechanistic sense, as the drop in estrogen that takes place during menopause tends to cause an increase in visceral fat accumulation, which can lead to other risk factors for CVD, such as insulin resistance, inflammation, hypertension, and dyslipidemia. Yet the WHI’s reports indicated that HRT may do more harm than good from a cardiovascular perspective — the researchers observed increases in risk of stroke both in women on estrogen alone (HR: 1.41; 95% CI: 1.07-1.85) and on estrogen plus progesterone (HR: 1.39; 95% CI: 1.10-1.77).
However, these numbers are a bit misleading from a statistical point of view. Each of the WHI trials involved assessment of several different outcomes, essentially constituting many unique tests within the same trial. While this may create a richer dataset, it also creates what’s known as a “multiple comparisons problem”: the more tests you run, the greater the probability of finding a result that’s statistically “significant” but does not actually represent a true association. This issue can be circumvented by statistical adjustments that effectively narrow the range over which a given result would be considered significant, and indeed, when the WHI researchers applied such a correction to their results, stroke risk was statistically equivalent between HRT and placebo groups.
Even if we take the hazard ratios at face value, the observed discrepancy in risk again has questionable relevance for modern HRT usage. The oral CEE formulation used in the WHI does increase blood viscosity by a small degree, which might conceivably lead to more blood clots and strokes, but in modern practice, oral estrogens have largely been replaced by transdermal formulations, which do not raise blood viscosity and have accordingly been shown to have no negative impacts on risk of blood clots.5,6
Finally, when we expand our view to other metrics of cardiovascular health, HRT appears to have a net positive effect. While the WHI identified no significant benefits in this area, a 2015 Cochrane meta-analysis of 19 RCTs (including over 40,000 women) found that HRT reduced risk of CV events by 48% (RR: 0.52; 95% CI: 0.29-0.96) when initiated within 10 years of menopause (though this analysis showed no benefit for CVD when HRT was initiated >10 years postmenopause).7
The cost to quality of life
In breaking down the specific numbers and subgroups from WHI data to expose the multitude of faults, it can perhaps be easy to lose sight of the true cost of those flawed conclusions. The fear (and FDA warning) that they inspired led an entire generation of women and their healthcare providers to eschew HRT, a treatment that has demonstrated the potential to drastically improve quality of life and physical health following menopause.
The main reason women start HRT is to manage vasomotor symptoms, which, apart from being unpleasant on their own, can also negatively impact sleep, mood, and ability to engage in everyday activities. Numerous large trials and meta-analyses have consistently established HRT as the single most effective known treatment for these symptoms, with most women experiencing a symptom reduction of 60-90%.8
But the known benefits of HRT extend even beyond the realm of these classical menopausal symptoms. Estrogen also serves as an important inhibitor of bone resorption, which is why so many women experience substantial losses in bone mineral density after estrogen levels fall during menopause, which in turn increases risk of debilitating fractures. Replacing estrogen with HRT has been shown in many studies (including the WHI) to improve bone mineral density and reduce fracture risk,9,10 allowing women to maintain higher levels of physical function well beyond the menopausal transition.
In the aftermath of the WHI publications, millions of women have been deprived of these positive effects. The faulty belief that potential risks with HRT outweigh potential benefits persists to this day, in large part due to the continued requirement for warning labels on HRT products. Thus, the true message of the recent FDA panel becomes clear: remove the black box label to stem the growing list of women who have suffered needlessly.
Time for a change
The FDA panel’s recommendation is no guarantee that the warning label will soon be abandoned. Many remain skeptical about HRT and have criticized the panel as trivializing potential health risks, yet those on this side of the debate tend to point to a lack of large-scale randomized trials using newer formulations rather than addressing the holes in the WHI data or pointing to any other evidence of cancer or stroke risk. In other words, this argument has no basis in evidence at all — they’re saying that, in the absence of rigorous evidence that HRT doesn’t raise breast cancer risk (despite general safety data), we have to assume that it does. Just like how there have never been any randomized trials investigating whether wearing blue jeans increases risk of colon cancer relative to wearing slacks, so we shouldn’t trivialize the risks of blue jeans and should avoid them as a general rule. See how little sense this makes?
I encourage readers to listen to the panel’s arguments for yourselves, as the whole discussion is currently available on the FDA’s YouTube feed. To echo the words of recent podcast guest Dr. Rachel Rubin in her presentation as part of the FDA panel: “[the] box label that was blanketly placed on all products in 2003 has no data to support its existence … 22 years later (and consensus guidelines later), this deserves another look.” Indeed, between shaky evidence of risk and the emergence of newer and safer HRT formulations, it’s time we finally break down the barriers and fears that keep women from living healthy and full lives long after menopause.
For a list of all previous weekly emails, click here.
References
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. doi:10.1001/jama.288.3.321
- Parente L, Uyehara C, Larsen W, Whitcomb B, Farley J. Long-term impact of the women’s health initiative on HRT. Arch Gynecol Obstet. 2008;277(3):219-224. doi:10.1007/s00404-007-0442-1
- Iyer TK, Manson JE. Recent trends in menopausal hormone therapy use in the US: Insights, disparities, and implications for practice. JAMA Health Forum. 2024;5(9):e243135. doi:10.1001/jamahealthforum.2024.3135
- Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324(4):369-380. doi:10.1001/jama.2020.9482
- Persico N, Mancini F, Artini PG, et al. Transdermal HRT and Doppler findings in normotensive and hypertensive postmenopausal patients. Ultrasound Obstet Gynecol. 2005;26(5):546-551. doi:10.1002/uog.2585
- Weller SC, Davis JW, Porterfield L, Chen L, Wilkinson G. Hormone exposure and venous thromboembolism in commercially insured women aged 50 to 64 years. Res Pract Thromb Haemost. 2023;7(3):100135. doi:10.1016/j.rpth.2023.100135
- Boardman HMP, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2015;2015(3):CD002229. doi:10.1002/14651858.CD002229.pub4
- Zhou T. Estimation of placebo effect in randomized placebo-controlled trials for moderate or severe vasomotor symptoms: a meta-analysis. Menopause. 2023;30(1):5-10. doi:10.1097/GME.0000000000002094
- Villareal DT, Binder EF, Williams DB, Schechtman KB, Yarasheski KE, Kohrt WM. Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial. JAMA. 2001;286(7):815-820. doi:10.1001/jama.286.7.815
- Cartwright B, Robinson J, Seed PT, Fogelman I, Rymer J. Hormone replacement therapy versus the combined oral contraceptive pill in premature ovarian failure: A randomized controlled trial of the effects on bone mineral density. J Clin Endocrinol Metab. 2016;101(9):3497-3505. doi:10.1210/jc.2015-4063
