Timing and Type of Hormone Therapy Impacts Its Effectiveness in Preventing 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.