Timing and Type of Hormone Therapy Impacts Its Effectiveness in Preventing Heart Disease

  In the years leading up to menopause, women go through hormonal changes that can increase their risk of heart disease, including increased body fat and high levels of “bad” LDL cholesterol. Recent research shows that the type of hormone replacement therapy (HRT or HT) and the timing of when it’s given can impact a woman’s future risk for heart disease.

Hormone Therapies Differ; Women’s Needs Differ

“The main takeaway is that all hormone therapies are not the same, and it’s not that one is good and another is bad,” says Stephanie Faubion, MD, MBA, the director of the center for women’s health at the Mayo Clinic in Rochester, Minnesota. Dr. Faubion was not involved in the new research. “We need to take these differences into account when we look at each individual woman, to determine what therapy is best according to her needs and what her risk factors are,” she says.

Women Face Greater Risk of Heart Disease in Midlife

Cardiovascular disease is the leading cause of death in women, and the risk increases after age 50, when many women officially reach menopause, a status that is diagnosed in retrospect, after a woman has not had her period for 12 consecutive months.

The Role of Estrogen in Heart Health

Estrogen is a hormone produced by a woman’s ovaries. It has heart-protective effects, but as women age and approach menopause, their ovaries produce less estrogen.

In the first study, published in the March 2020 issue of the journal Menopause, data suggested that hormone replacement therapy with oral conjugated equine estrogens may have had a protective effect on heart health when compared with transdermal estradiol HT or no hormone therapy at all.

Investigators examined data gathered from 467 menopausal women who had participated in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, placebo-controlled trial. To be included in the trial, women had to have an intact uterus, be between 42 and 58 years old, and have had their most recent menstrual period 6 to 36 months before (so that it had been less than three years since menopause).  

It's important to note that the amount of estrogen used in this study was a lower dose than that used in the Women’s Health Initiative research (the 2002 study that connected combined hormone therapy — estrogen and progestin — with a higher risk of heart disease, breast cancer, and other health issues).

Fat Accumulates in Midlife

It’s known that as women progress through the menopause transition, they are likely to accumulate abdominal visceral fat and fat around the heart, according to Samar R. El Khoudary, PhD, MPH, an associate professor of epidemiology at the University of Pittsburgh Graduate School of Public Health in Pennsylvania and the lead author of the study. Deposits of heart fat have been linked to atherosclerosis progression.

To find out if estrogen affects heart fat accumulation and atherosclerosis progression, researchers measured carotid intima-media thickness (CIMT), as well as the accumulation of heart fat over a 48-month period.

Researchers divided women into three groups to see the potential effect on the progression of CIMT and heart-fat accumulation. One group was given 0.45 milligram (mg) per day of oral conjugated equine estrogens (CEE), and one group was given 50 micrograms per day of transdermal 17 beta-estradiol; a third group was given a placebo.

Researchers used CAT scans to measure epicardial adipose tissue, paracardial adipose tissue, and CIMT at baseline and 48 months. CEE and 17 beta-estradiol are commonly used (sometimes along with a progestin) to manage menopausal symptoms such as hot flashes, vaginitis, or insomnia.

Gauging Heart Health in Midlife Women

Carotid intima-media thickness is a measure used to diagnose the severity of carotid atherosclerotic vascular disease, which is typically caused by atherosclerosis. Atherosclerosis is a condition in which plaque builds inside the arteries, and it’s the underlying cause of most cardiovascular disease or events such as heart attack, stroke or even death, according to the National Heart, Lung, and Blood Institute.

Tests of CIMT measure the thickness of the inner two layers of the carotid artery, which can reveal thickening even if a person doesn’t have any symptoms yet. The carotid arteries are two large blood vessels in your neck that supply your brain with blood.

Investigators found that compared with estrogen patches or placebo, oral CEE slowed the negative effects of increasing pericardial fat accumulation around the heart in atherosclerosis (it did not find a difference in how another kind of fat, epicardial fat, affected atherosclerosis). Other research has shown a link between the amount of pericardial fat and the risk of coronary heart disease.

The finding is consistent with what we’ve seen in previous work in the SWAN study, says Dr. El Khoudary. In the Study of Women’s Health Across the Nation (SWAN), published in September 2015 in the Journal of Clinical Endocrinology & Metabolism, El Khoudary's team found that as concentrations of the sex hormone estradiol (the most potent estrogen) declined during the transition from perimenopause to post-menopause, there were greater amounts of cardiovascular fat, even after they controlled for body mass index (BMI) and physical activity.

“Our new findings in KEEPS support the role of estrogen in how this fat could hurt or impact the functionality of the heart,” says El Khoudary. The use of hormone therapy may modify the association, depending on the formulation of the hormone therapy and the route of administration, she adds.

The Hormone Treatment Versus How the Hormone Is Delivered

What isn’t clear is whether the superior protective effect shown by oral CEE was due to the type of estrogen or the fact that it was delivered orally; the less-effective estradiol was delivered through the skin, via patch, according to El Khoudary. This also contradicts the results of previous research, which showed transdermal estrogen (delivered through a patch on the skin) may have more heart health benefits than oral treatment.

“This is because these studies were originally designed before there was strong evidence that showed that hormone therapies differed from each other,” she says. Further research should be designed to clarify whether it is the type of estrogen or the way it’s administered that slows the progression of carotid intima-media thickness, El Khoudary says.

Hormone Therapy Around Menopause: Women Need to Demand More From Doctors

“The study emphasizes that we should not keep using the term ‘hormone therapy’ for every single formula or route of administration, as there are many in the market,” says El Khoudary. “As we do more research, we realize that they are not all the same, and they are not all the same in how they impact cardiovascular health or risk. This study proves that,” she says. The impact of hormone use really depends on the specificity of the formulation and the route of delivery, she adds.

Earlier Intervention With Hormone Therapy Provides Greater Benefit

Another piece of recent research suggests that the start time of hormone therapy makes a difference in slowing the progression of atherosclerosis (a buildup of plaque in the arteries that can lead to a form of heart disease).

The ELITE trial, published in 2016 in the New England Journal of Medicine, compared the impact of hormone therapy on IMT thickness (a measure of how much plaque is accumulating in arteries) in women less than 6 years past the onset of menopause to those who were more distant from menopause, at least 10 years. The women closer to menopause had an overall slower progression of atherosclerosis measured by IMT thickness, but the older women did not.

Those findings support the timing hypotheses on when to initiate hormone therapy that were originally proposed about a decade ago, says Roksana Karim, MD, an associate professor of clinical preventive medicine at the Keck School of Medicine at the University of Southern California in Los Angeles and the lead author of the research.

“It shows that women who are closer to menopause respond better to hormone therapy compared with those who are further away from menopause,” says Dr. Karim.

To try to uncover what caused this difference, researchers used data from the ELITE trial to measure the circulating concentrations of 12 different inflammatory markers. Their results were presented during the 2020 Virtual Annual Meeting of the North American Menopause Society (NAMS), which opened on September 28.

Investigators found that 4 of the 12 markers of inflammation (E-selectin, ICAM-1, IFNγ, and IL-8) were significantly lower in the women on HT who were 6 years or less from the onset of menopause compared with the placebo group. In the group 10 years or more away from menopause, only one marker, E-selectin, was significantly lower than in the placebo group.

“These results further support the finding of the primary ELITE results, and show that hormone therapy reduces the level of inflammation,” says Karim.

The anti-inflammatory effect of hormone therapy could be a potential mechanism behind the improvements in atherosclerosis from hormone therapy that were seen in the ELITE trial, she says.

There Are Many Different Types of HT, and the Differences Matter

The risks and benefits of hormone therapy are altered significantly by all these factors, Faubion agrees. “So, when people say hormone therapy is ‘good’ or ‘bad’ and make it a black or white thing, it completely misses the point,” she says.

“We’re just beginning to be able to really individualize therapy for each woman, which is a huge, huge step forward for us. It’s important to find a healthcare provider who understands the risks and benefits of all the different types of hormone therapy,” says Faubion, who is the medical director of the North American Menopause Society.

One way to do that is to visit the North American Menopause Society at Menopause.org, says Faubion. The site offers a doctor locator to help you find a provider who has completed the North American Menopause Practitioner certification.

Advocate for Personalized Treatment That Addresses Your Individual Risks

Women need to demand more from their providers, says Faubion. “We need to empower women to say, 'If you’re not individualizing hormone therapy for me and taking into account my cardiovascular risk and my breast cancer risk, then I need to find another provider,’” she says.

Faubion cautions that women shouldn’t change the hormone therapy they are currently on because of the new research. “This research identifies that there are important differences that need to be further fleshed out, but I wouldn’t recommend that anyone jump off what they’re taking or switch to anything else based on these findings,” says Faubion.

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