There are many questions, doubts, and fears about the risks and benefits of hormone replacement therapy (HRT). From a wonderful interview of Peter Attia with Dr. JoAnn Manson, principal investigator of the Women's Health Initiative (WHI) study, Peter Attia writes this beautiful article to try to better clarify the salient and important points to understand.
The goal is to enable readers to gain a deeper understanding and greater confidence in their ability to make decisions related to their own health.
A brief update on the context
When women enter menopause, levels of the sex hormones estrogen and progesterone plummet, causing all the vasomotor symptoms (e.g., hot flashes and night sweats) that are classically associated with this period of female life. These hormonal changes also result in a loss of bone mineral density and muscle strength, mood changes, decreased libido and sexual function, and various other effects that affect quality of life and physical health. Hormone therapy aims to alleviate these unwanted symptoms of menopause by providing exogenous estrogen (with or without progesterone) to supplement low levels in the body.
Observational studies conducted in the 1980s and 1990s had indicated that hormone replacement therapy could also reduce the risk of cardiovascular disease (CVD) and cognitive decline, which motivated Dr. Manson and her fellow researchers to initiate the Women's Health Initiative, two randomized clinical trials (one testing estrogen alone and the other estrogen plus a synthetic form of progesterone) aimed at studying the effectiveness of hormone replacement therapy for the prevention of chronic diseases. However, when the WHI results were first published in 2002, the investigators reported no reduction in heart disease among women taking HRT, but a slight increase in the incidence of breast cancer. The media made a big deal about these results, and the use of HRT, which until then was the standard of care for menopausal symptoms, plummeted by 70-80%.
Since then, many have pointed out that the risks were greatly exaggerated, and Dr. Manson herself has expressed the belief that these results should not be extrapolated to the point of denying HRT to early menopausal women for symptom relief. However, debate continues to rage over the magnitude of risks and benefits and who should take HRT and for how long.
What do we all agree (and disagree) on?
I want to be very clear: HRT is unquestionably the most effective treatment available for relieving menopausal symptoms. Despite the WHI reports and subsequent alarmist media coverage, no one questions the effectiveness of HRT in relieving menopausal symptoms and thus improving quality of life. Rather, the debate centers on whether this relief comes at the cost of increasing the risk of certain diseases, particularly breast cancer, dementia, and cardiovascular disease.
This brings me to another point of broad consensus in the medical community: Hormone replacement therapy should be initiated only in the first 10 years after the onset of menopause. Starting hormone therapy more than 10 years after the onset of menopause means experiencing a prolonged period of estrogen deprivation, which likely diminishes the potential benefits of HRT and may increase its potential risks. For example, a 2004 meta-analysis of randomized trials reported that women enrolled in hormone therapy trials before age 60 had a significantly reduced risk of all-cause mortality compared with placebo (OR: 0.61, 95% CI: 0.39-0.95), but this apparent benefit was absent in women enrolled after age 60 (OR: 1.03, 95% CI: 0.90-1.18). The risk of dementia with HRT-as discussed in more detail below-may also be reduced in those who begin treatment during early menopause, but may increase in those who begin treatment late. However, this concern relates only to starting HRT more than 10 years after the onset of menopause, which should not be confused with continuing HRT beyond 10 years after the onset of menopause.
Whether or not HRT should be continued after menopause is another point of debate. Some believe that, regardless of the time of initiation, hormone therapy carries an increased risk of disease and is justified only in cases where menopausal symptoms are severe enough to warrant an increased risk. These people are therefore opposed to continuing hormone replacement therapy after menopausal symptoms have subsided, as any other possible benefit is insufficient to offset the risks. Others-including myself-argue that hormone therapy has a substantial positive impact beyond menopausal symptom relief and that the alleged risks associated with HRT are not supported by evidence, have no clinical significance, or otherwise do not outweigh the health and quality-of-life benefits.
In other words, the decision to start HRT or to continue it after menopause comes down to a risk-benefit analysis, and the best choice may vary from one individual to another based on factors such as the severity of menopausal symptoms, family history, and personal preferences. So while I cannot offer a generic, one-size-fits-all answer, I can share what we currently know about the benefits and risks of HRT so that you can make informed decisions for you or your patients.
What is the impact of HRT on breast cancer risk?
First, let's talk about the main concern raised by the WHI: breast cancer
The WHI reported an increased incidence of breast cancer in the group given conjugated equine estrogen (CEE) plus the progestin medroxyprogesterone acetate (MPA), the main form of HRT used in the 1990s, compared with placebo controls (HR: 1.24, 95% CI: 1.02-1.50). This difference, which caused alarm in the popular press, corresponded to about one additional case of breast cancer per 1,000 patients per year, and the discrepancy disappeared entirely if only women without hormone therapy before the study (most women) were considered. The latter analysis also revealed that the apparent increased risk was not due to an unusually high incidence in women taking CEE + MPA, but to an unusually low incidence in those taking placebo and who had previously used HRT (see Figure 1). The parallel study, which compared placebo with CEE alone, showed no increased risk of breast cancer with treatment, and indeed, the CEE alone group (without MPA) was found to have a nearly 20% lower risk than the placebo group.
Notably, even for women on CEE + MPA therapy, breast cancer deaths were not significantly increased compared with women on placebo, despite the very small increase in breast cancer incidence. The data showed a nonsignificant trend of increased mortality, although this is probably attributable to the increase in breast density with treatment, which makes lesions more difficult to detect. This is less of a concern today, as screening methods and recommendations have improved significantly over the past 20 years. In addition, the estrogen-only group experienced a 40% reduction in breast cancer mortality compared with placebo at 20-year follow-up, a difference that reached statistical significance.
I want you to read it again, because perhaps there is no bigger lie than this one that women are being told: based on the WHI we "know" that estrogen causes breast cancer. This is categorically false. But, as Mark Twain said, "a lie can travel halfway around the world before the truth gets its shoes on." It would be hard to find a better example of this phenomenon in modern medicine.
The contrasting results between estrogen alone and estrogen + MPA strongly suggest that MPA, not estrogen, is responsible for any elevated risk observed in WHI and that estrogen itself may actually be protective. Since MPA is no longer used in hormone replacement therapy (as a synthetic hormone it has fallen out of use and has been replaced by micronized bioidentical progesterone for women needing systemic progesterone or progestin-coated IUDs for those needing only endometrial protection), the WHI findings on breast cancer are effectively outdated. However, data from studies using newer formulations of HRT, particularly transdermal estradiol and micronized progesterone, do not yet exist, and probably never will, so we do not know if and how these formulations affect breast cancer risk.
What is the impact of HRT on bone health?
Estrogen is an essential hormone for maintaining bone density, as it inhibits bone resorption and is part of the signaling pathway through which mechanical stress (i.e., resistance exercise) triggers the formation of new bone tissue. Therefore, when estrogen levels decrease dramatically during menopause, the rate at which bone is consumed increases and, at the same time, resistance training becomes less effective in stimulating bone regrowth. This combination leads to significant loss of bone mineral density (BMD), often to the level of osteoporosis. Because hormone replacement therapy prevents estrogen levels from dropping too low, it prevents this loss and thus reduces the risk of potentially debilitating fractures, as shown by WHI itself.
As soon as hormone replacement therapy is discontinued, the protection provided against BMD loss disappears. But even though bone mass loss will occur after the cessation of hormone replacement therapy, simply delaying this loss means maintaining healthy bone mass for a longer period of time and delaying the time it takes for the bones to develop into a state of osteoporosis. If two women lose bone mass at the same rate, but woman A starts losing mass at age 50 and woman B at age 70, woman B will have much stronger bones at age 80 than the woman who had a 20-year head start on bone deterioration.
Importantly, osteoporosis drugs, such as bisphosphonates, can also slow bone loss. However, these drugs act by interfering with resorption mechanisms and, unlike HRT, do not address the underlying cause of altered signaling for bone remodeling: estrogen loss. Replacing estrogen levels can restore the ability of resistance training to stimulate bone formation, effectively giving a woman a longer window in which to maintain or improve BMD with weightlifting so that she can start from a better position when bone mass begins to decline.
What is the impact of HRT on dementia risk?
The WHI also reported higher rates of probable dementia with both estrogen alone (HR: 1.24, 95% CI: 0.83-2.66) and CEE + MPA (HR: 2.05, 95% CI: 1.21-3.48) compared with placebo groups, although this increase did not reach significance for estrogen-only treatment. However, as the authors themselves note, age of initiation of hormone replacement therapy may be a critical factor for this apparent risk.
This analysis of WHI data was limited to women aged 65-79 years at baseline, a range that we can safely assume is well after the onset of menopause. Slightly more than half (~55%) of the women in the estrogen-only group had never used hormone therapy before the study, meaning that their first experience with hormone replacement therapy would have followed several years of estrogen deprivation-as discussed earlier, physicians generally advise against it. Indeed, when the analysis was restricted to only those who had not previously used hormones, the hazard ratios with HRT were higher than for the entire cohort (HR: 1.95, 95% CI: 0.94-4.04). Similarly, when the analysis was restricted to those who had previously taken HRT, any apparent increase in risk disappeared completely (HR: 0.87, 95% CI: 0.32-2.39). Subanalyses of the estrogen + MPA data provided almost identical results.
These findings on age dependence agree with an observational study that stratified women into four groups based on HRT intake: (1) only in middle age (mean age: 48.7 years), (2) only in late age (mean age: 76 years), (3) both middle and late age, or (4) never. Similar to the WHI, the investigators found that HRT was associated with an elevated risk of dementia only when started in late life compared to those who had never used hormones (adjusted HR: 1.48, 95% CI: 1.10-1.98). For those who took HRT only during middle age, the therapy actually had a significant protective effect (adjusted HR: 0.74, 95% CI: 0.58-0.94), and no difference in risk was observed between those who never used HRT and those who started in middle age and continued until the end of life (adjusted HR: 1.02, 95% CI: 0.78-1.34). Overall, these results certainly reinforce the idea that hormone replacement therapy should not be started more than 10 years after the onset of menopause, but more importantly, for those who start early, hormone therapy does not increase the risk of dementia, even if treatment continues for many years after the disappearance of menopausal symptoms.
What is the impact of HRT on cardiovascular disease risk?
Menopause is associated with the development of a number of risk factors for cardiovascular disease, including increased visceral fat, decreased glucose tolerance, hypertension, and dyslipidemia. The decrease in estrogen that occurs during the menopausal transition causes a redistribution of adipose tissue from subcutaneous stores to the visceral space, which in turn can lead to insulin resistance, dyslipidemia, and other effects that increase the risk of cardiovascular disease (CVD).
By replacing estrogen deficiency, hormone therapy could theoretically ameliorate some of these risks. This concept has been supported by large-scale epidemiologic studies, particularly the Nurses' Health Study, in which it was found that women with no history of heart disease (n=48,470), at a 10-year follow-up, had a 44% reduction in risk of major coronary artery disease when taking estrogen (95% CI: 20-60%). The age-adjusted risk of cardiovascular mortality was 32% lower (95% CI: 10-48%) in women who had taken HRT.
Reviewing the WHI data, the evidence for HRT's potential to reduce the risk of MCV mortality seems less compelling. The study did not reveal a significant decrease (or increase) in CVM mortality for either formulation of HRT in either the initial dataset or the last follow-up point (data through 2016), suggesting that HRT may not be detrimental to cardiovascular health, but neither does it appear beneficial.
However, the age of initiation of hormone replacement therapy may again influence these results. A secondary analysis of pooled data from both WHI studies found that, among women who started the study within 10 years after the onset of menopause, HRT was associated with a reduction in coronary heart disease (HR: 0.76, 95% CI: 0.50-1.16) compared with placebo, although not statistically significantly. In contrast, for women who started hormone therapy more than 20 years after the onset of menopause, HRT was associated with a significantly increased risk of MCV (HR: 1.28, 95% CI: 1.03-1.58), while those with 10-19 years of postmenopause showed an intermediate and nonsignificant risk. This trend indicates that, with regard to HRT, starting early reduces potential cardiovascular risks and may even provide additional CV protection.
In addition, outdated formulations may again be an important factor. Both treatment groups in the WHI studies were taking CEE, an oral estrogen formulation. Such formulations are known to slightly increase blood viscosity, resulting in increased cardiovascular risk. However, oral estrogens can be largely replaced by topical formulations that do not have the same effects on blood viscosity.
What can we conclude?
A careful analysis of existing data reveals that the widespread panic about the risks of hormone therapy is not even remotely justified. Yet tragically, literally millions of women today have been and continue to be denied this therapy by physicians who simply do not study the results of the very studies they use to criticize hormones. The results of the WHI and other studies do not indicate that hormone replacement therapy poses a significant threat if started early in menopause; on the contrary, it is likely to protect against chronic diseases such as breast cancer, dementia, and heart disease, as well as offering clear benefits for bone health and prevention of frailty. While these data show that risks may increase significantly when HRT is initiated a decade or more after the onset of menopause, they do not demonstrate a similar risk if HRT continues after menopause.
Unfortunately, most of the available data (including those from WHI) have studied formulations of HRT that are now obsolete and have conducted studies in which the interventions lasted only a few years. No randomized trials have been published on newer formulations, such as transdermal estradiol and micronized progesterone, so we cannot be certain that the risks and benefits associated with older formulations apply to those more commonly used today. There is also a lack of clinical trial data on the long-term use of HRT, even for the formulations used in WHI, and such results will probably never exist because of the high costs and difficult logistics of decades-long studies.
Some see this uncertainty as a reason to avoid HRT altogether, but as I have expressed many times in the past, certainty is an unattainable goal in science and medicine, and the best we can do is to weigh the risks and benefits based on the available evidence and make a choice that has the highest probability of a positive outcome. The information obtained by studying previous formulations of HRT provides some of the best available clues about the effects of those in use today, and the cost of waiting for future studies to reach a somewhat higher level of confidence must be weighed against the number of patients whose lives and health might improve by starting or continuing HRT now. Similarly, we do not have data from long-term randomized trials on almost all chronic drugs used today, but should we deny patients life-saving drugs just because no one will ever conduct an exorbitantly expensive 30-year clinical trial? Absolutely not.
So again, when it comes to HRT or any other therapeutic intervention, there are always risks and benefits. How they are balanced may depend on the individual patient, but in my opinion the balance more often hangs in favor of HRT than against. Reports of health risks are dubious at best, while the benefits for menopausal symptom relief, bone health, psychological and sexual well-being, and possibly reduced risk of chronic disease all have the potential to increase the chances of living healthier, happier and longer.
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