The impact of hormone replacement therapy (HRT) on cardiovascular disease (CVD) in menopausal women is one of the most fascinating questions in all of medicine. It’s an important question, because CVD is the number one cause of death for women in the U.S. And it’s a complicated question. It’s complicated for many reasons, not least of which is because the pendulum keeps swinging back and forth on what the medical community thinks about it.
Let’s spend a minute setting the stage. Women secrete three primary hormones from their ovaries during their reproductive years: estrogen, progesterone, and testosterone. As women approach mid-life, the production of these hormones begins to decline. This is a normal, physiologic process, and the decrease in estrogen and progesterone eventually culminates in menopause, which is formally defined as the cessation of menstrual cycles for at least 12 months. The average age of menopause is 51 years old, but it can occur a few years earlier or later and still be considered in the normal range.
Regulation of normal menstrual cycles is one of the primary roles of estrogen and progesterone, but both hormones have numerous other functions as well. The cessation of periods is the hallmark of menopause, but there are a whole host of other symptoms that can be caused by the decline in hormones. Hot flashes and night sweats are termed vasomotor symptoms, and are the first that come to mind for most people, but numerous other symptoms can also occur, including fatigue, sleeping problems, brain fog, heart palpitations, joint pain, weight gain, and more.
Premarin vs. Bioidentical Estrogen
Giving estrogen (and progesterone) as HRT is very effective for the treatment of these symptoms. This has been known for many decades, as treatment of menopausal symptoms with estrogen has been a common practice since the mid 1900’s. In previous generations the most common way to give estrogen was with a medicine called Premarin. Premarin is estrogen derived from female horses, specifically from the urine of pregnant mares (thus the name Premarin – pregnant mares’ urine). The U.S. Food and Drug Administration (FDA) approved Premarin in 1942. The chemical structure of horse estrogen is similar, but definitely not the same as human estrogen.
Today there are many different types of estrogen that can be given as HRT, and many different methods of administering them. Over the last two decades it has become common for doctors to use bioidentical estrogen. A bioidentical hormone is a hormone that has the same chemical structure as the human version of the hormone. Another term for this is isomolecular, which again just means that it is identical to the human version of the hormone, but I will use the term bioidentical in this article. 17-beta-estradiol is the most potent human form of estrogen, and “estradiol” and “bioidentical estrogen” are often used interchangeably.
We have learned that bioidentical estrogen causes less side effects than Premarin. For example, Premarin, despite its positive benefits, increases the risk for blood clots, thus increasing the risk for stroke. This is an adverse effect that fortunately we do not see with bioidentical estrogen. However, many medical reviews on the topic lump data from studies of Premarin together with data from bioidentical estrogen, which leads to never-ending confusion about the potential benefits and adverse effects.
In the 1980’s several large epidemiological studies were published that showed that HRT in menopausal women was associated with a substantial reduction in CVD. The largest of these studies, the Nurses’ Health Study, involved over 48,000 postmenopausal women and showed that women taking estrogen had a relative risk of major coronary disease of 0.56 compared to those who were not taking estrogen. A relative risk of 0.5 means that the risk is cut in half. So a relative risk of 0.56, if it is true, is a massive reduction, far more impactful than any of the more common medications that doctors use to reduce risk for heart disease (e.g. statins, blood pressure meds, and aspirin). But the problem with epidemiological studies is that they can only show correlation, not causation. There are lots of reasons why a true causative relationship may not exist even if a strong correlation is present.
The Women’s Health Initiative
A randomized, controlled trial is the best way to get to the bottom of the question of causation. And for this reason, in the 1990’s the National Institute of Health (NIH) designed a large randomized, controlled trial to answer this very question. The study was called the Women’s Health Initiative (WHI). It was a massive undertaking, enrolling 160,000 women at a budget of more than $600 million.
The WHI was actually two parallel studies. One study tested whether Premarin in combination with Progestin (synthetic progesterone) would reduce cardiovascular events in postmenopausal women. I will refer to the combination of Premarin and Progestin as “Prem/Pro” going forward. The second study tested whether Premarin alone would reduce cardiovascular events in postmenopausal women without a uterus (i.e. those who had had a hysterectomy). The reason Progestin was used in the first study is because when giving estrogen to women with a uterus, a form of progesterone must be added to protect against proliferation and cancer of the endometrium.
Both studies were designed to last for 8 years, but because of unexpected negative findings both studies were terminated early. The Prem/Pro study was stopped in 2002. At the time it was terminated, coronary heart disease, breast cancer, stroke, and blood clots were all increased in women who were assigned to receive treatment with Prem/Pro.
The Premarin alone study was stopped in 2004 due to a high rate of stroke and blood clots in women assigned to receive treatment with Premarin. Interestingly, the rate of breast cancer was decreased in the women taking Premarin. With the initial findings the rate of decrease was not statistically significant, however longer-term studies did eventually show a statistically significant reduction in breast cancer in women taking Premarin.
The impact of the WHI results cannot be overstated. The medical community’s viewpoint of HRT swung from “pro” to “anti” essentially overnight. In the 1990’s about 40% of postmenopausal women in the US were taking HRT and that number dropped to about 4% to 6% a decade later. It looked like the issue was settled: “hormones” were bad for you.
Evolving Interpretation of the Women’s Health Initiative
As you can probably guess, this was not the end of the story. Over the last two decades a number of important factors have affected how we view the WHI and have led to the HRT pendulum swinging back in the other direction.
The single most important critique of the WHI is that they used methods of HRT that, by and large, are not in use today. Premarin and Progestin are no longer the predominant medications of choice for management of menopausal symptoms, having been overtaken by bioidentical estradiol and progesterone. Today if the researchers had a “do over” they would take it in a heartbeat and there would be no need for discussion. They would conduct the study with bioidentical estradiol and progesterone. We now know that Premarin increases the risk of blood clots, which lead to the increase in strokes, whereas bioidentical estradiol does not. And we now know that synthetic forms of progesterone (like Progestin) increase inflammation, are cancer causing, and increase the risk of blood clots, whereas natural bioidentical progesterone does not.
A study as large as the WHI has not been done again, and there are no plans for one. But we do have data on bioidentical estradiol from trials performed in European countries, and smaller studies have been conducted in the US. They are highly favorable for bioidentical estradiol. We will review these further below.
A second factor that has shed new light on the WHI results is that a new idea has sprung up called the “timing hypothesis”. The timing hypothesis states that the effects of hormone therapy on atherosclerosis and CVD depend on the timing of the initiation of HRT relative to age. The results of the WHI have been re-analyzed, after the fact, by re-categorizing the participants into sub-groups by age. Those who started the study when they were between the ages of 50-59 years old had impressively good long-term outcomes. Their results were better than women who were between 60-69 years old, and it was even more striking compared to those who were between 70-79 years old. I want to emphasize that this finding is specific to Premarin, not bioidentical estradiol. It may still be true that outcomes can be expected to be better the earlier one starts bioidentical estradiol, but I am not aware of a study showing harm from starting bioidentical estradiol at a later age.
Along these lines, two meta-analyses published in 2004 and 2006 evaluated the effect of HRT on CVD and all-cause mortality. They categorized RCTs by whether the average age at baseline was less than or greater than 60 years old. For the younger age group, HRT reduced CVD events by 32% across 23 RCTs and all-cause mortality by 39% across 30 RCTs, both of which were statistically significant. On the other hand, there were no significant effects, good or bad, on either outcome in the older group. To put this in perspective, meta-analyses that evaluate the effects of statins on CVD and all-cause mortality for primary prevention in women routinely show that statins are far less effective than HRT. For example, a 2009 meta-analysis published in the British Medical Journal analyzed 10 RCTs with over 70,000 participants. In women (23,681 participants) statins reduced CVD events by 21% and all-cause mortality by 9%, and neither result was statistically significant.
Oral Bioidentical Estradiol
I would now like to turn our attention to studies examining HRT using bio-identical estradiol. We will briefly review four, one of which is a population study and the latter three are RCTs.
The Finnish Registry Study, published in 2015, examined data from nearly 500,000 women using estradiol-based (that is, bioidentical) HRT regimens compared to non-HRT users. Users were categorized by how long they had used HRT, and benefits were consistently better for those with longer HRT use. For those who used HRT for > 10 years, the risk of death from CVD was reduced by 54%, the risk of death from stroke was reduced by 39%, and all-cause mortality was reduced by 38%. This was just an observational study, not an RCT, but still those are very impressive numbers.
The EPAT (2001) and the ELITE (2016) studies were two smaller RCTs that tested the effect of oral bioidentical estradiol on two different markers of atherosclerosis. Both studies showed that the rate of progression of atherosclerosis was lower in the group of women taking oral estradiol vs. placebo. In fact, in the EPAT study the atherosclerosis actually decreased in the estradiol group. Note, however, that in the ELITE study this improvement was only seen in women who were within 6 years of menopause, it was not seen in the group of women who were > 10 years from menopause.
The fourth study, and the grand finale, is the Danish Osteoporosis Prevention Study (DOPS), published in 2012. This was an RCT of 1006 women who were randomized to receive HRT with bio-identical estradiol vs. a control group with no treatment. The primary endpoint was a composite of death, myocardial infarction, or admission to the hospital for heart failure. The average age of women at the start of the study was 50 years old, and the average duration of the study was 10 years.
Women in the estradiol treatment group had a risk of 0.48 vs. the control group for the composite endpoint. As mentioned earlier, a risk of 0.5 means the risk is cut in half. Therefore, the estradiol group had a greater than 50% reduction in experiencing the composite endpoint. This is a massive reduction and is far greater than the reduction seen with any statin or other drug traditionally used to treat cardiovascular disease. In addition, all-cause mortality was reduced by 43%, breast cancer by 42%, and stroke by 23%, however neither of these numbers reached statistical significance due to a low rate of occurrence of these conditions in both groups.
Why aren’t these impressive data from the DOPS more widely known? The study has two main criticisms. The first criticism is that the study was open label, which is to say that it was not blinded. The participants were assigned to take HRT or nothing at all. There was no placebo. This means that they knew which arm of the study they were assigned to, and that can introduce bias. Presumably the researchers did not design it as a blinded study because of the long duration of the study – 10 years. It is almost unheard of to run an RCT for that long. If you think about it, would you like to participate in an RCT in which for 10 years you did not know if you were taking the study drug or a placebo? Neither would I. So there was a trade-off between the long study duration (which is good), and the non-blinding (which is a drawback).
The second criticism of the DOPS is that the primary endpoint (composite of death, myocardial infarction, or heart failure) was not included in the original hypothesis. The original purpose of the study, as the name suggests, was to test how well HRT prevents osteoporosis. This does not mean that the data is any less true, it just means technically speaking it should be considered “hypothesis-generating.”
Let’s summarize this section on studies testing the effect of bioidentical estradiol on CVD. We have the Finnish Registry Study, a very large population study showing that long-term use of HRT reduced the risk of death from CVD by 54% and all-cause mortality by 38%. We have the EPAT and ELITE studies, two smaller RCTs that were designed to test an underlying mechanism, but were not large enough or long enough to be powered to detect CVD events or all-cause mortality. Both studies showed a decrease in the progression of atherosclerosis relative to placebo, providing a very plausible mechanism for why HRT decreases CVD. And we have a large, 10-year RCT, the DOPS trial, which showed a greater than 50% reduction in the composite endpoint of death, myocardial infarction, and heart failure.
One more note before I conclude. The four studies reviewed above all tested bioidentical estrogen given via the oral route. Bioidentical estrogen can be given through different routes, including oral (a daily pill) and transdermal (patches, creams, and pellets). While the transdermal route provides the same benefits as the oral route in terms of treating vasomotor symptoms and improving bone health, it has not been shown to provide the same benefit in terms of cardiovascular health. It is popular in hormone replacement clinics to give estrogen transdermally due to a belief that this route is associated with a lower risk of blood clots. This thinking is the result of the days of estrogen being given as Premarin, which was given orally, and unquestionably caused an increase in blood clots. As I dove into the medical literature on bioidentical estrogen, I was challenged to find a study that showed an increased risk of blood clots with oral bioidentical estrogen. So far I have not been able to find one.
Conclusion
In conclusion, the impact of HRT on cardiovascular disease remains controversial. Many mainstream medical organizations continue to recommend against the use of hormone replacement therapy for the prevention of chronic disorders such as CVD. In their analyses they focus on older studies such as the WHI in which the type of estrogen used was Premarin, and they ignore the DOPS study which used bioidentical estrogen due to the criticisms I mentioned above. However, I would argue that a thorough review of the literature supports that oral bioidentical estrogen, in addition to its many other benefits, causes a marked decrease in the incidence of cardiovascular disease in menopausal women.
References
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