Hormone Therapy to Help the Heart?

Yes? No? Maybe So?- What's behind the controversy

Chances are you have heard at least one expert say that systemic hormone therapy will prevent heart disease. But you also may have heard other experts say, “No- if you don’t have hot flashes or low bone mass, it is not recommended to take hormone therapy just to prevent heart disease down the road”. So, who is right? Why is there any controversy about this? Isn’t the data, the data?

Setting the Stage

Estrogen receptors are not just in the reproductive tract. They are everywhere including the brain, mouth, throat, bones, joints, muscles, skin, and the vascular system. So, it makes sense that estrogen deprivation will impact organs and tissue throughout the body, including the heart and all your blood vessels. And it is a fact that heart disease increases dramatically post-menopause. So, if a lack of estrogen is associated with an increase in heart disease, intuitively it seems that if you take estrogen, you can decrease the risk of cardiovascular disease. Right?

Then why is it that so many smart academic menopause experts say that we do not have the data to support taking estrogen for anything other than hot flashes, bone health, and sexual function?

To explain why experts are not all on the same page when it comes to the long-term cardiovascular benefits of hormone therapy, first I need to walk you through the types of studies that are used to determine if estrogen is beneficial beyond fixing your flashes.

Randomized Controlled Trials

Randomized controlled trials are the gold standard to prove that a drug will do what it claims to do. In a randomized controlled trial, also known as an RCT, you enroll a large group of people who share a common condition or concern. You then divide that group into at least two subgroups to compare treatments. One group will get the drug that you're testing. The other group will get a fake version of the drug, the placebo group.

Neither group knows if they are getting the real deal or the fake. The investigators don’t even know who is getting what until the trial ends. You then study those people over time to see what impact the drug has compared to the group that is not getting the drug. Randomized controlled trials minimize bias, and prove a cause-and-effect relationship.

For example, take 1000 people with insomnia and randomly divide them into two groups. Group 1 is educated on sleep hygiene and gets a new sleeping pill. Group 2 gets the same instructions regarding sleep hygiene but is given a placebo pill. Six months later you analyze the data and find that 90% of the people who got the sleeping pill slept through the night 80% of the time. Only 10% of the people who got the placebo pill slept through the night 80% of the time. The conclusion is straightforward- the sleeping pill worked.

Observational Studies

Observational studies, on the other hand, tend to be real-world situations. You are not assigning people to different groups. You are just making observations about different groups which then allows you to tell if something is associated. But, observational studies do not necessarily determine cause and effect. These are legitimate scientific studies, but they don’t provide the same proof as a randomized controlled study.

For example. Of a hundred men who committed mass murder, 100% of them ate bread the day before they committed murder. Therefore, you can legitimately conclude that eating bread is associated with committing mass murder. But you cannot conclude that eating bread caused them to go on a killing spree.

Another example. Many observational studies show an association between sexual activity and a longer life span. Magazines love this fact, cite it regularly, and encourage readers to have lots of sex to ensure longevity. But that’s misleading. More sex won’t cause you to live longer. If you are healthy, you are more likely to have sex. And healthier people live longer. Association is not the same as cause and effect.

So, while observational trials are valuable, they are generally only going to tell you if an outcome is associated with a certain behavior or characteristic, which means, you can’t always make definitive conclusions.

So, let’s get to the relevant studies researchers rely on to determine if post-menopause hormone therapy will prevent cardiovascular disease.

The Women's Health Initiative -revisited

The 1991 Women's Health Initiative (WHI )is an example of a randomized controlled trial designed to answer that very question.

The purpose of the WHI was not to determine if hormone therapy helped with symptoms such as hot flashes. That wasn't in question. The purpose of the WHI was to determine if long-term hormone therapy could prevent cardiovascular and other life-threatening and chronic diseases.

There were 60,000 women enrolled.

• Group 1 received an oral estrogen (Premarin™) and a synthetic progestogen ( Provera™ )

• Group 2 included women who'd had a hysterectomy and therefore received only estrogen

• Group 3 was the placebo group -they received no hormone therapy

They then observed those groups over time to determine how the different groups did and, as you've heard many times, there was a small increase in heart attack, stroke, and blood clots, in the group that was taking estrogen and the synthetic progestogen. It was not cardioprotective.

The WHI was a classic randomized controlled trial. Women were arbitrarily assigned to different treatment groups. No one, including the researchers, knew who was getting estrogen, and who was getting a placebo drug. It was a perfect design except for one major flaw.

WHY the WHI was Problematic

Only women who were not having hot flashes were eligible to participate because if they enrolled women with hot flashes, and their hot flashes went away, they would know they were getting estrogen. So, all of the women in the study were either post-menopause women who had never had hot flashes or post-menopause women who were done with having hot flashes.

As a result of this restriction, 70% of the women who enrolled were over age 60.

This was problematic for many reasons. First, older women are more likely to have heart disease in general, but it is now known, that women who have endured years of hot flashes are more likely to have vascular damage as a result of those hot flashes, The damage had already been done.

Giving women estrogen who are in their 70s or 80s with damaged blood vessels is not the same as giving estrogen to a 50-year-old with pristine blood vessels. The idea of the WHI was to see if estrogen was protective, not to see if estrogen would reverse established cardiovascular damage. And the results were much more reassuring in the 50–60 year-old group.

There were other issues as well, such as the type of progestogen and the use of oral estrogen, but the main problem was the age of the women in the study group.

We often hear that the WHI was a bad study, or that the WHI has been debunked. The truth is, the WHI was an excellent study. It was an excellent study if you wanted to understand what the outcome would be if you give older women who no longer have hot flashes, or never had hot flashes an oral estrogen and a synthetic progestogen.

The WHI was not a bad study.

It just asked the wrong question.

Data from the WHI has informed clinical care and subsequent studies. For example, we now know that it is safer to start hormone therapy within ten years of the menopause transition and that many women are better off using transdermal estrogen. We know that while there was an increase in heart attack, stroke, and blood clots, we also know from WHI that 98% of the women in that study, even in this older high-risk group, did just fine.

Again, the problem wasn’t that it was a bad study. The real problem is that most doctors didn’t, and still don’t understand the real lessons of the WHI. The real problem is that the FDA and many doctors extrapolate the data from the WHI to younger women who are using a different combination of hormone therapy, such as transdermal estrogen and micronized progesterone.

Moving on.

The Study of Women’s Health Across the Nation

The SWAN Study

Most published studies in the menopause world are observational studies. People are not assigned to different groups. It is simply a real-life survey and documentation of different groups to determine if a specific characteristic, drug, or activity is associated with a specific outcome.

The largest observational study regarding menopause is The Study of Women’s Health Across the Nation, the SWAN study.

The Study of Women’s Health Across the Nation is an ongoing research of more than 3,000 midlife women. Starting in 1994, women between the ages of 40 and 55 from all over the United States were enrolled to evaluate multiple parameters of midlife health and the impacts of menopause with and without hormone therapy. One of the major strengths of the SWAN study is that younger women (pre-menopause) were specifically included to evaluate the impact of menopause.

The other strength is the diversity of the participants. This is important since most older studies were limited to white women. In SWAN 46% of the women were Caucasian, 28% were Black, 9% were Hispanic, and 17% were Asian. This culturally diverse group continues to be seen annually to study the physical, biological, and psychological aspects of aging, including bone health, depression, stress, sleep, sexual health, and vaginal health, to name a few.

The data continues to roll in, and more than any other research, it has increased our knowledge about the effect of aging and menopause on health. SWAN has changed the way menopause experts advise and treat midlife women.

In addition to studying natural hormonal changes, SWAN data also includes the impact of smoking, diet, medications, hormone therapy, and multiple psychosocial variables on a woman’s health. As of March 2024, 662 scientific studies have been published. All are publicly available on the SWAN website, www.swanstudy.org.

*At the bottom of this post, are additional findings from the SWAN study

Unlike the WHI, which randomly assigned women to a treatment group and a control group to test the effect of a specific intervention, in SWAN, data was collected on participants without manipulating any of the variables. It was observational.

That doesn’t mean that the data is not accurate or meaningful. It just studied things that do not require randomization. As an example, because of SWAN, we know how long hot flashes last. Before SWAN, most doctors would tell their patients they should tough out their hot flashes since they would only last a few years. Because of SWAN, we know that hot flashes last on average for seven years but can last up to 14 years. Up to 9% of women continue to have hot flashes for 20 years. And because SWAN included a diverse study population, we know that independent of what kind of food someone eats or their diet and exercise patterns, ethnicity is a major determinant of the length of time someone is destined to flash.

SWAN, more than any other study, has helped us understand the impact of MHT and mid-life aging on health and well-being.

As far as cardiovascular health, we know from SWAN that menopause is associated with adverse cardiovascular risk factors, such as higher LDL (“bad”)-cholesterol, higher blood pressure, metabolic syndrome, and higher blood sugar levels.

SWAN also informed us that persistent frequent or severe hot flashes are associated with changes in the blood vessels such as a thickening of vessel walls or accumulation of plaque on the vessel walls, which increase future risk for heart disease. Hot flashes are also associated with insomnia, which in turn, are associated with cardiovascular disease.

SWAN has shown us that a loss of estrogen in and of itself is associated with an increased risk of cardiovascular disease and hot flashes are red flags that are associated with an even higher risk for heart attacks, strokes, and other cardiovascular disease events as they age.

So, it seems like a no-brainer to give women estrogen before the damage is done to decrease risk.

OK, what does SWAN tell us about women who take hormone therapy?

In an excellent 2021 review written by Dr. Chrisandra Shufelt and Dr. JoAnn Manson, they summarize that “Available evidence indicates that oral unopposed estrogens have a favorable effect on lipoprotein levels, glycemia, insulin, and CVD risk: …. Transdermal estrogens have less effect on coagulation, inflammation, and lipids than oral estrogens and observational studies suggest they pose a lower risk of venous thromboembolism and stroke than oral estrogens”

So, it sounds biologically plausible that estrogen, if given early on, would decrease the risk of heart disease down the road.

Most clinicians who promote the long-term preventive cardiovascular benefits of HT often quote SWAN data.

So, you’re thinking- OK, what’s wrong with that? What’s the problem?

The problem is, that SWAN is observational. The women in SWAN were not randomized to different groups They just enrolled and said, “Yes I’m taking hormone therapy”, or “No I’m not”. It was not blinded. And there may have been bias that determined which group women were in. Maybe the women taking hormone therapy were healthier. Maybe the women in the estrogen group ate a heart-healthy diet.

Here's the other problem, again quoting from the SWAN site,

“In an analysis of 40,000 women, overall, the results showed no evidence that hormone therapy provides any protective effects against death from any cause, and specifically death from cardiovascular disease, non-fatal heart attacks or angina, either in healthy women or women with pre-existing heart disease. “

Well, that bursts that happy bubble and certainly doesn’t help team “estrogen for all. ” It does support the academics who say that even though hormone therapy is associated with a decrease in cardiovascular risk factors, there are no studies that definitively prove that taking estrogen will prevent heart disease. And until we have that study, we should not prescribe it for primary prevention.

Team “estrogen for all”. says: “Are you kidding? I don’t buy your ivory tower analysis. We have plenty of evidence that hormone therapy is associated with better heart health, and just because we don’t have a randomized controlled study to prove it, doesn’t mean that it should be denied to women who are more likely to die from cardiovascular disease than anything else”.

A Solution to the Controversy?

The obvious solution is to definitively settle the question by doing a new randomized controlled trial and enrolling young women both with hot flashes and without hot flashes, give them either a placebo, a transdermal or oral estrogen and see who develops heart disease.

That would be an excellent idea! And would answer the question.

But it’s not going to happen.

The WHI cost 625 million dollars in 1991. A similar study today would probably cost double that and take at least 10 years from inception to results. In other words, if it were to happen, it would be long after the current population of 50–60-year-olds would benefit. But the other problem is that it would be impossible to have a true randomized controlled blinded study since, just like in the WHI women with hot flashes would know if they were getting estrogen.

Those opposed to the party line say: “We can’t wait for the results of a study which would be impossible to do and will never happen. It’s time to be less strict about only recommending evidence-based treatments based on randomized controlled trials.”

My Position-straddling both sides

So, where do I stand on this? I’ve thought a lot about this. I completely understand why my academic colleagues tell their patients and teach that estrogen should not be prescribed for primary prevention of cardiovascular disease. Before the existence of the modern FDA, clinical trials did not exist. New drugs were released to the public based on the idea that they might work. Today, to get a prescription drug to market, pharmaceutical companies must submit specific types of clinical trials to the FDA which prove not only safety, but also that the drug will treat a specific symptom or disease.

The reason the FDA has always insisted on randomized controlled trials is to protect people from using drugs that don’t work. When that doesn’t happen, products get out there that are later proven to be ineffective, and possibly even harmful.

Ivermectin- a drug that wasn’t adequately vetted

Ivermectin is a recent example of what can go wrong when there is inadequate testing. During Covid-19, there was this huge push to approve Ivermectin without appropriate trials. Subsequent RCT proved Ivermectin to not work, and to have some pretty scary side effects. You have also heard me rant countless times about the long list of over-the-counter drugs that do not require FDA approval and therefore have no obligation to do any testing to prove that their combination of herbs and spices decrease hot flashes or any other menopause symptoms. So, it is critically important to properly test drugs before they are released to the public, or claiming specific benefits.

But I also see the other side.

The observational data is compelling and realistically, it is all we are going to have for the foreseeable future. My opinion is that with shared decision-making, it’s not unreasonable to prescribe hormone therapy to protect the heart. But, I also have an obligation to tell my patients that we don’t yet, and will not, anytime soon, have the kinds of studies we would all like to see to prove that it will prevent heart disease. I would not present it as a definitive benefit. I would say, we have observational data that suggests it might be beneficial. And then let the patient decide.

The reason I am comfortable with my approach is because I know that if prescribed correctly, hormone therapy is safe and has many other benefits. Unlike Ivermectin which has no known benefits and is not safe.

Confusing? Yes. Nuanced? Absolutely.

The bigger issue is women should not put in the middle.

A few months ago, Tamsen Fadal, a menopause advocate, and I discussed the dilemma of the woman who is left trying to figure out what to do when your personal doctor who you trust, tells you that the social media expert, who you also trust, is wrong. We had a good discussion, but when I posed the above question to Tamsen, her response was, “Women will have to figure out who to trust, and who to believe”. I wasn’t satisfied with that response.

I trust women. They are smart, and if they are given good information, they will make the right choices. But it’s asking too much for someone to not only read the medical literature but also understand the nuances. It is not realistic, it can be overwhelming, and confusing.

We live in a world where women are barraged with information when it comes to how best to manage menopause and it’s hard to know what’s fact and what’s hype.

There are 80 million women over the age of 40. Only 5% of women know anything about menopause. Only 2-4% take HT.

As menopause experts, we have an obligation to get accurate information out there. In a perfect world, the people with the large megaphones (the social media folks) would collaborate with the academic researchers (who have no megaphones) to give clear, scientifically accurate messages to the millions of menopausal women who want to know their options.

Selected Additional Findings of Interest from SWAN

• · There is a clear connection between the age when women experience menopause, the severity of symptoms, and their risk of cardiovascular disease

• During the menopause transition, women see increases in LDL-C (the “bad” cholesterol), increases in metabolic syndrome risk, and adverse changes in the structure of blood vessels, likely due to the menopause transition’s effects rather than just age.

• Changes in body composition during the transition include more belly fat and less muscle mass, which can also elevate heart disease risk.

• There appears to be a link between midlife cardiovascular risk factors and the rate of adverse changes in cognitive function during midlife.

• Greater declines in cognitive function during midlife may increase the risk of developing Alzheimer’s disease and related dementias later in life.

• Vasomotor symptoms (hot flashes) often start before a woman’s periods stop; almost 30% of women will have hot flashes in their 30s when still getting regular menstrual periods.

• Hot flashes may last longer if they start early or if a woman is also experiencing anxiety, stress, or depressive symptoms.

Vasomotor symptoms (hot flashes) are associated with:

• · Diabetes

• · Insomnia

• · Brain fog

• · Mood alteration

• · Fatigue

• · Future cardiovascular disease (heart attack and stroke)

• · Adverse cardiovascular risk factor profiles

• higher LDL (“bad”)-cholesterol

• higher blood pressure

• higher blood sugar levels

• adverse changes in the underlying vasculature, such as a thickening of vessel walls or accumulation of plaque on the vessel walls

• Women who have their ovaries removed are 2-3 times as likely to develop vaginal dryness as women who go through natural menopause.

• Women who have less frequent sexual intercourse over time, or have breaks from sexual intercourse, are NOT more likely to develop sexual pain than women who have consistent or more frequent sexual intercourse during midlife and beyond.

• Being over- or under-weight is NOT associated with changes in sexual function across the menopausal transition.

• About two-thirds of women reported memory complaints such as forgetfulness during the menopause transition

• After menopause (which occurs on average at age 52) cognitive processing speed fell, but declines in verbal and working memory scores did not typically start until later, after ages 58 and 61 years, respectively

• Nearly 1 in 5 women ages 40-55 years reported limitations in physical functioning. Difficulties in physical functioning increase with age such that by 56-66 years of age, nearly 50% of women had physical functioning limitations

• During the menopausal transition, women tend to gain fat mass and lose lean mass.

• Women with more lean mass and less fat mass have better physical functioning including faster walking speed, more leg strength, and faster stair climbing speed.