Can hormone therapy improve heart health in menopausal women?

HERSHEY, Pa. — Deciding whether to start hormone therapy during the menopause transition, the life phase that’s the bookend to puberty and when a woman’s menstrual cycle stops, is a hotly debated topic. While hormone therapy, or replacing the hormones that were previously produced by the body with synthetic medication, is recommended to manage bothersome symptoms like hot flashes and night sweats, Matthew Nudy, assistant professor of medicine at the Penn State College of Medicine, said there’s confusion about the long-term effects of hormone therapy, especially on cardiovascular health.

However, long-term use of estrogen-based hormone therapies may have beneficial effects on heart health, according to a new study, led by Nudy. A multi-institutional team analyzed data from hormone therapy clinical trials that were part of the Women’s Health Initiative (WHI) — a long-term national study focused on menopausal women — and found that estrogen-based hormone therapy improved biomarkers associated with cardiovascular health over time. In particular, the study suggests that hormone therapy may lower levels of lipoprotein(a), a genetic risk factor associated with a higher risk of heart attack and stroke.

Their findings were published in the journal Obstetrics & Gynecology. The study adds to the understanding of the complex interaction between hormone therapy and heart health, providing additional guidance to patients and doctors, according to Nudy.

“The pendulum has been swinging back and forth as to whether hormone therapy is safe for menopausal women, especially from a cardiovascular disease perspective,” Nudy said. “More recently, we’re recognizing that hormone therapy is safe in younger menopausal women within 10 years of menopause onset, who are generally healthy and who have no known cardiovascular disease.”

Hot flashes and night sweats are symptoms commonly associated with menopause but the hormonal changes that accompany this phase of life usher in another major shift — an increased risk of cardiovascular disease. The decline in the hormone estrogen can lead to changes in cholesterol, blood pressure and plaque buildup in blood vessels, which increase the risk of heart attack and stroke.

The research team was interested in understanding the long-term effect of hormone therapy on cardiovascular biomarkers, which hasn’t been evaluated over an extended period of time. Prior research in the field primarily looked at short-term effects.

Here, the team analyzed biomarkers associated with cardiovascular health over a six-year period from a subset of women who had participated in an oral hormone therapy clinical trial that was part of the WHI. Participants were randomly assigned to one of two groups — an estrogen-only group and an estrogen plus progesterone group — were between the ages of 50 and 79 when they were assigned to a group and were post-menopausal. They provided blood samples at baseline and at one-, three- and six-years. In total, they analyzed samples from 2,696 women, approximately 10% of the total trial participants.

The research team found that hormone therapy had a beneficial effect on most biomarkers in both the estrogen-only and the estrogen-plus-progesterone groups over time. Levels of LDL cholesterol, the so-called “bad” cholesterol, were reduced by approximately 11% while total cholesterol and insulin resistance decreased in both groups. HDL cholesterol, the so-called “good” cholesterol, increased by 13% and 7% for the estrogen-only and estrogen-and-progesterone groups, respectively.

However, triglycerides and coagulation factors, proteins in the blood that help form blood clots, increased.

More surprising to the research team, they said, levels of lipoprotein(a), a type of cholesterol molecule, decreased 15% and 20% in the estrogen-only and the estrogen-plus-progesterone groups, respectively. Unlike other types of cholesterol, which can be influenced by lifestyle and health factors such as diet and smoking, concentrations of lipoprotein(a) are thought to be determined primarily by genetics, Nudy explained. Patients with a high lipoprotein(a) concentration have an increased risk of heart attack and stroke, especially at a younger age. There’s also an increased risk of aortic stenosis, where calcium builds up on a heart valve.

“As a cardiologist, this finding is the most interesting aspect of this research,” Nudy said. “Currently, there are no medications approved by the Food and Drug Administration (FDA) to lower lipoprotein(a). Here, we essentially found that oral hormone therapy significantly reduced lipoprotein(a) concentrations over the long-term.”

When the research team examined the findings by self-reported racial and ethnic group, they found that the decrease in lipoprotein(a) concentration was more pronounced among participants with American Indian or Alaska Native ancestry or Asian or Pacific Islander ancestry — by 41% and 38%, respectively. Nudy said it isn’t clear why the reductions were steeper among these groups, but the team said they hope to investigate it further in future research studies.

Nudy noted that the estrogen therapy the women received in the clinical trial was conjugated equine estrogens, a commonly prescribed form of oral estrogen therapy. Before being absorbed by the body, oral hormone therapy is processed in the liver, through a process called first pass metabolism. That process could increase inflammatory markers, which may explain the rise in triglycerides and coagulation factors.

“There are now other common formulations of estrogen hormone therapy like transdermal estrogen, which is administered through the skin,” Nudy said. “Newer studies have found that transdermal estrogen doesn’t increase triglycerides, coagulation factors or inflammatory markers.”

For those considering menopause hormone therapy, Nudy recommended undergoing a cardiovascular disease risk assessment, even if the person hasn’t had a previous heart attack or stroke or hasn’t been diagnosed with cardiovascular disease. It will give health care providers more information when considering the best option to treat menopause symptoms.

“Currently, hormone therapy is not FDA-approved to reduce the risk of coronary artery disease or stroke,” Nudy said. 

Other authors on the paper include: Aaron Aragaki, Fred Hutchinson Cancer Center; Peter Schnatz and Xuezhi Jiang, Drexel University College of Medicine; JoAnn Manson, Brigham and Women’s Hospital, Harvard Medical School and Harvard T.H. Chan School of Public Health; Aladdin Shadyab, University of California San Diego; Su Yong Jung, University of California Los Angeles; Lisa Martin, The George Washington University; Robert Wild, University of Oklahoma Health Sciences Center; Catherine Womack, University of Tennessee Health Science Center; Charles Mouton, University of Texas Medical Branch; and Jacques Rossouw, formerly of the National Heart, Lung, and Blood Institute at the National Institutes of Health.

Funding from the National Center for Advancing Translational Sciences supported this work.