It's Complicated: The Relationship Between Your Heart and Hormones

Estrogen is protective in some circumstances, while testosterone may increase your risk

With Samar El Khoudary PhD, MPH and Virginia Miller PhD

Hormones and the heartYou heart and your hormones are more entwined than you might think.

Sex-based differences in heart health are still not fully understood. According to the American Heart Association, there are seven core indicators for cardiovascular health: physical activity, diet, cholesterol, blood pressure, fasting glucose, weight, and smoking. Socioeconomic and lifestyle factors also play significant roles. So where do hormones fit in? 

The fact that we’re even talking about how sex hormones affect cardiovascular health may seem surprising. We often tend to talk about different systems of the body as if they all exist independent of one another. In reality, all of your body’s systems are intertwined, working together in complex ways. Hormones, as the body's chemical messengers, are part of every process.

For example, heart disease is the leading cause of death overall for people in the US at 42% of all deaths, according to the CDC. But take a closer look at the statistics around cardiovascular disease (CVD) and significant differences between men and women emerge.

To begin with, 54% of males over 20 have some form of CVD, while only 44% of women do. The average age for a first heart attack among men is 65 years, while for women it's 72. Interestingly, women are at a lower risk for CVD until menopause, when their risk grows. The incidence of CVD among people aged 60 to 70 is 77.2% for men, 78.2% for women, while for people over 80 it’s 89.3% for males and 91.8% for females. 

Women also take longer to recover from heart attacks and are less likely to be prescribed blood-clot preventing medications after a heart attack, which makes them more likely than males to suffer a second heart attack within one year. A 2019 study of 1,700 patients found that women are also more likely to have poorer outcomes following aortic surgery. Even when controlling for age, weight, pre-operative health, and comorbidities, women were nearly twice as likely to experience a stroke or death following surgery.

Hormones affect everything that happens in your body, including your heart

For example, the human body, for both sexes, produces a few different kinds of estrogen. The type produced by the ovaries is called 17 beta-estradiol. This is the hormone best known for regulating the female reproductive system. Your body converts some testosterone into estradiol through an enzyme called aromatase, so it’s present in male bodies as well, just at lower levels (the testicles also produce small amounts of estradiol).

Estradiol performs numerous functions that have seemingly nothing to do with reproduction. In fact, we have estrogen receptors in systems throughout our entire bodies: in our brains, digestive systems, in skin and bones, and even in our hearts. Those estrogen receptors are picky, though. Certain receptors have a natural affinity for 17 beta-estradiol, and they’re more sensitive to that form of estrogen than other forms of estrogen.

Estrogen can be heart protective

Estrogen’s role in cardiovascular health is one piece in a very complex system of factors that researchers are still just beginning to understand. What we know so far suggests that the estradiol produced by the ovaries appears to be heart protective in a number of ways.

  • It helps tissues throughout the body stay supple and flexible, and that includes blood vessels. This helps to increase blood flow.
  • It helps keep blood pressure low.
  • It helps keep blood triglycerides low, increases HDL cholesterol (the helpful kind) and lowers LDL cholesterol levels.
  • It promotes blood clotting.
  • It absorbs free radicals, particles that cause damage

Until recently, it wasn’t uncommon for women to have their uterus and/or their ovaries removed (elective surgery) after having their last child in order to reduce the risk for various diseases or conditions, such as ovarian or uterine cancer. But studies have shown that when women get elective hysterectomies and ovariectomies before natural menopause, incidents of heart disease along with many other chronic conditions associated with aging become accelerated. However, researchers see a decline in heart and other disease when they are given estrogen up until the age of menopause. This changes if they are given it after menopause, which is why understanding the connection between estrogen and the heart is more complicated than initially thought.

Testosterone’s role in cardiovascular health is still coming into focus

If estrogen (specifically estradiol) is heart protective in a number of ways, at least until menopause, and we know that males suffer cardiovascular disease sooner and in greater numbers than females, does testosterone play a role? The verdict is still out. We know that cardiac cells have receptors that bind to androgenic hormones like testosterone. But based on the research so far, there is not yet a direct link between normal levels of testosterone in males and heart disease.

On the other hand, extremes either in low testosterone levels or high doses of testosterone supplementation do seem to be linked with CVD, though more research is needed to confirm why.

  • Athletes who take large amounts of performance-enhancing testosterone and androgenic steroids have an increased risk of blood pressure, heart attack and stroke.
  • Large doses of testosterone supplements can lower HDL (the good kind) cholesterol levels and raise LDL levels.
  • Testosterone-lowering therapy as part of prostate cancer treatment also adversely affects cholesterol levels.
  • Supplemental testosterone in animals leads to enlarged hearts.
  • Even among men with healthy levels of testosterone, those with levels on the low side tend to have worse cholesterol numbers.

How does progesterone affect cardiovascular health?

We know even less about progesterone’s effect on the heart. This is mainly because there isn’t enough research on progesterone-only therapy independent of estrogen, and the studies that have been conducted are mostly on animals. “We do know that if given at high enough doses, progesterone can counteract the effects of estrogen,” says Virginia Miller PhD, a professor emerita of surgery and physiology at the Mayo Clinic who has done extensive research on hormones and cardiovascular health. There is evidence that natural progesterone is more heart healthy than synthetic progesterone, she adds. Synthetic tends to bind to other receptors other than progesterone receptors, which makes it detrimental to health.

How does menopause affect your risk of CVD and heart attack?

Women seem to have a lower risk for CVD, and are less likely to die from it, up until menopause. From that point on, the risk for CVD and heart attack rises dramatically.

Large scale studies like the Study of Women’s Health Across the Nation (SWAN) show that during the menopause transition there are significant changes to cardiovascular health, says Samar El Khoudary PhD, MPH, an Associate Professor of Epidemiology at the University of Pittsburgh Graduate School of Public Health. These include:

  • HDL cholesterol decreases and LDL cholesterol rises.
  • Blood lipids increase.
  • Blood vessels change, making it more likely for plaque and blood clots to form.
  • A protein found in blood plasma called fibrinogen, which is linked with heart disease and stroke, increases.

“We additionally showed that as women transition through menopause, they become higher risk for metabolic syndrome, where women experience changes in important cardiovascular risk factors including obesity, blood pressure and diabetes, as well as cholesterol,” says El Khoudary, “and that women experienced changes in the distribution of body fat as they transition.” During reproductive years, females who gain weight tend to collect fat around the hips and thighs, which is neutral to heart health. But post-menopause, more fat is distributed in the abdomen, around the heart, and this visceral fat is linked with CVD.

The earlier you reach menopause, the higher your risk for CVD. This goes for people who experience early (before 45) and premature (before 40) menopause because of ovarian failure. But the risk rises yet more for people who have their ovaries removed, especially before the age of 45. There is also some evidence suggesting that having severe vasomotor symptoms (hot flashes and night sweats) and/or experiencing these at an earlier age is linked with a higher risk for CVD.

For these reasons, the American Heart Association recently issued an update to its guidance for menopausal patients. Describing menopause as a “physiological process that severely affects cardiovascular health and CVD outcomes in half of the human population,” the AHA acknowledged that, along with racial and ethnic disparities, this transition had long been overlooked in previous versions of its clinical guidance (the last addressing gender was in 2011). According to the AHA update, the sooner we recognize the menopause transition as a critical period in women’s life that should be specifically addressed to improve the wellbeing and health outcomes of this population, the better. The guidance also recommends early prevention interventions that could save lives.

Why estrogen is not the only cause of increased CVD after menopause

Of course, it is at menopause that the ovaries also stop producing progesterone and estradiol. (This can be a gradual process over the span of years or a shorter, more abrupt change.) Other tissues throughout the body still produce other kinds of estrogen (as they do in male bodies), and we continue converting testosterone into estradiol, though never at the same levels that the ovaries were producing. And other types of estrogen don’t serve the exact same functions that estradiol does. So it’s not just the amount of estrogen that matters, but the type of estrogen as well.

That said, “It’s not just about estrogen,” cautions Dr. El Khoudary, one of the authors of the AHA’s recent update. Through clinical trials examining the effects of estrogen on cardiovascular health after menopause, “we are learning that the process is quite complex,” she says.

“Women do become more vulnerable to cardiovascular disease because there are multiple changes that accompany the menopause transition. Estrogen likely contributes to some of it, but it’s really a multifactorial process that works together to reduce the protective nature for cardiovascular disease.”

Menopause is one significant event specific to the female experience that can influence cardiovascular health, but it’s not the only one. Pregnancy issues such as preeclampsia and gestational diabetes also raise the risk of accelerated cardiovascular disease as women age, whether or not they have a natural menopause, says Miller.

Does hormone therapy help prevent CVD in menopause?

In trying to understand why and how estrogen affects cardiovascular health, researchers have been looking at how hormone therapy, or administering supplemental estrogen postmenopause, could improve health outcomes. It seems intuitive that it would lower the risk of CVD, and animal studies seem to support that notion. When it comes to human studies, the answer is less clear.

In the late 1990s, the Heart and Estrogen-Progestin Replacement Study (HERS) tested 2,700 women with existing coronary heart to disease to see if a combination treatment of conjugated equine estrogen, or o-CEE, with synthetic progestin could prevent a heart attack. (Estrogen therapy can put you at risk for cervical cancer, and progesterone minimizes that risk.) After two years, there were fewer heart attacks and strokes. Researchers still had questions, however, and a follow-up three years later found no decrease in heart attacks and strokes among those receiving hormone therapy. In fact, that group showed an increased risk for blood clots.

A much larger study, the Women’s Health Initiative (WHI), sought to find out if hormone therapy could prevent a heart attack (among several other interventions). The 160,000 women were, on average, about 10 years past menopause. Those with an intact uterus were given o-CEE with a synthetic progesterone called progesterone acetate, or MPA. Those who’d had a hysterectomy were given o-CEE alone, without the progesterone.

Early in the study (2002), participants taking the combination o-CEE and MPA showed a significantly higher risk of heart attack, stroke, and blood clots. They also showed a higher risk for breast cancer. The National Institutes of Health (NIH) halted that part of the study. And when the estrogen-only group also showed an increase in the risk of blood clots and stroke in 2004, that part of the study was shut down as well. The hormone treatment did not seem to have reduced the risk of heart attack.

Miller points out that many of the WHI participants already had cardiovascular disease that had progressed beyond the point where intervention like hormone therapy could help. “What estrogen does to the blood vessels may have actually precipitated some of those heart attacks because estrogen was doing what it was supposed to do, in terms of affecting the immune system and the vascular remodeling that the cells are programmed to do,” says Miller.

Those earlier studies were limited to specific formulations of hormone therapy, says Dr. El Khoudary. Now we have many more formulations to learn about, from oral to transdermal patches to vaginal creams, as well as varying dosages (the lowest dose for the shortest possible time is the current medical recommendation) and that has complicated the question. She would like to see more studies looking at these various formulations.

Perhaps most significantly, the early studies used conjugated equine estrogen (or o-CEE) which is not the same thing as the 17 beta-estradiol humans produce naturally. Conjugated equine estrogen is made from mare urine, which means the estrogen has been metabolized through the liver. It’s a formulation that contains compounds found in the human body, like estrone and estrone sulfate, but in different ratios than those found in premenopausal females. As we said earlier, different forms of estrogen serve different functions.

As for the progesterone, the synthetic formulation has since been linked to an increased risk of breast cancer compared with natural progesterone.

Why the current recommendation for hormone therapy (HT) is the lowest dose for the shortest possible time

Another aspect first overlooked in response to the early WHI data was the age of the participants. Most were over 60 and a decade past the menopause transition. Researchers have since developed what’s called the menopausal hormone therapy timing hypothesis, where hormone therapy may be protective for women who are younger than 60 years old and within 10 years of the menopause transition. After that point, hormone therapy may do more harm than good.

The 2001 Estradiol Prevention Atherosclerosis Trial (EPAT) and the 2003 Women’s Estrogen-progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) were the first trials to test the menopausal hormone therapy timing hypothesis. This was followed by the Early versus Later Intervention Trial with Estradiol (ELITE), which showed that hormone therapy could reduce the progression of atherosclerosis in women less than 6 years since menopause. This study used oral 17 beta-estradiol instead of o-CEE.

The data from WHI has since been reconsidered and researchers have been investigating earlier timing of hormone therapy with different formulations. One of those studies, the Kronos Early Estrogen Prevention Study (KEEPS), departed from the WHI in several key ways, says Miller, who was a lead author of the study.

  • It tested younger postmenopausal women who were an average of a year and a half from the transition.
  • The participants had cholesterol levels within normal (healthy) ranges.
  • It compared the effects of an oral o-CEE (lower concentration than used for WHI) with transdermal (patch) 17 beta-estradiol.
  • It used an oral micronized natural progesterone rather than a synthetic formulation.
  • This progesterone was taken the first 12 days of each month rather than daily.
  • Rather than trying to prevent a heart attack, it sought to slow the progression of atherosclerosis, the clogging of arteries and the accumulation of fat in the arteries.

The transdermal patch sends estradiol directly into the bloodstream, while the oral estrogen goes through the digestive system and is metabolized by the liver before circulating through the bloodstream. So the first group had higher concentrations of t-E2 in their bloodstream and the second group had higher concentrations of estrone and estrone-sulfates in their bloodstream. This matters, remember, because certain estrogen receptors are more sensitive to t-E2 than other estrogens. Different kinds of estrogen are not interchangeable.

Four years later, it appears that neither formulation affected the progress of atherosclerosis, except that the o-CEE formulation reduced the accumulation of coronary artery calcium. There were no severe adverse reactions to either formulation, underscoring the safety of well-timed hormone therapy for relatively healthy people. 

“If you look at all these studies in total, in spite of their flaws and in spite of their different formulations, they all come up to the same conclusions,” says Dr. Miller. Timing matters: starting estrogen treatment early after menopause slows progression of disease. Natural progesterone is safer than synthetic. And people with healthy cholesterol levels to begin with seem to have better outcomes from estrogen therapy.

“Any studies that go forward to investigate women's health, with any kind of intervention, really need to pay attention to their hormonal medical history,” says Dr. Miller. This would include when a person goes through menopause, to whether or not they have pregnancy complications, especially related to preeclampsia or hypertension. “All those factors enter into a woman's overall risk for cardiovascular disease as she ages.”

Personalization is important for Dr. El Khoudary. “The big message is that we really still have to personalize the way we are prescribing these hormones based on the evidence that we have.” She wants to see more studies looking at different formulations in the future.

Hormone therapy is now considered safe for most people in menopause, depending on the timing

In 2017 the North American Menopause Association issued a position statement stating that “for women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS (vasomotor symptoms) and for those at elevated risk for bone loss or fracture.” The statement cautioned against HT for people more than 10 to 20 years from menopause or older than 60 because of the greater risk of coronary heart disease, stroke, venous thromboembolism, and dementia.

On the other hand, the American Heart Association “recommends against using postmenopausal hormone therapy to reduce the risk of coronary heart disease or stroke because some studies have shown it appears to not reduce the risk.” They aren’t disputing its safety and efficacy for addressing other menopausal conditions; they’re simply questioning its use specifically for addressing cardiovascular health. Perhaps they also want to urge people to rely more on the numerous lifestyle interventions that have proven to save lives.

Regardless, Miller would like to see people taking a more integrative approach to their health. “I would encourage women to think holistically about their bodies and their general cardiovascular health and how it can really affect their cognition and the link between the two.”

And that thinking needs to happen well before menopause, before conditions become serious. Doctors should take in their patients’ entire hormonal and reproductive history, including pregnancy issues like gestational diabetes and preeclampsia. Those with a history of those conditions during pregnancy need to continue monitoring their cardiovascular health after they give birth. “The sooner you get that hypertension treated, the better it's going to be for long term cardiovascular health and to reduce the risk of stroke and cognitive decline,” Miller says. They also need to be monitored for insulin resistance and type 2 diabetes, which also affect cardiovascular health.

When making a decision about hormone therapy, pay attention to the formulation, the delivery, the dosage, the timing, and your own personal medical history

For people considering an elective ovariectomy before natural menopause in order to prevent ovarian cancer, Dr. Miller cautions that for most women, the risk of cancer is small compared with the risk for cognitive decline, cardiovascular disease, and colon cancer following that removal. Fortunately, this practice is in decline. But those who decide to go through with it anyway should have estrogen therapy because it prevents the accumulation of calcium in the coronary arteries.

When it comes to cardiovascular health, hormones play a significant role within an entire constellation of intertwined factors. Declining estrogen levels are not going to doom you to cardiovascular disease. We have more agency than that. When it comes to the heart, hormones alone are not destiny, and your best course of action is to work with your endocrinologist to arrive at the treatment plan that is best personalized to your condition and medical history.

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