Ties that bind: Women's health, heart disease and hormone therapy

Volume 8, Issue 2
Summary illustration - Ties that bind: Women's health, heart disease and hormone therapy


Women's health is approached collaboratively at Mayo Clinic, including coordination of a national study that is raising new questions about hormone therapy and possible benefits to women's hearts.

Virginia Miller, Ph.D.

Virginia Miller, Ph.D.

  • Cross-section comparison of post-menopausal blood vessel obstruction, with and without treatment.

    Cross-section comparison of post-menopausal blood vessel obstruction, with and without treatment.

    Source: Journal of Applied Physics. 2005;99:381.

After studying estrogen's effects on blood vessels in the lab for 20 years, Mayo Clinic physiologist Virginia M. Miller, Ph.D., will soon see her work help millions of women concerned about the effects of hormone therapy.

Dr. Miller is part of the national network of experts leading the Kronos Early Estrogen Prevention Study, usually referred to as KEEPS. KEEPS is a multicenter clinical trial designed to answer whether hormone therapy protects against heart disease and stroke when administered within three years of the onset of menopause. Heart disease is the single biggest killer of adult women, greater than all cancers combined. Stroke is third on the list.

The KEEPS trial drew together for the first time colleagues from across Mayo Clinic to focus on women's health research.

"Investigators in a variety of fields saw that women's health was not defined by reproduction and that there are many things to be learned from each other," Dr. Miller says.

"We are now working together through multiple other joint research efforts as a result of what Dr. Miller started with the KEEPS trial," agrees Lynne T. Shuster, M.D., director of the Women's Health Clinic at Mayo Clinic and a trial collaborator. "We have made huge strides in a relatively short time in bringing together our doctors and researchers who are committed to women's health. I think as a result Mayo is becoming recognized as a leader in women's health and as a leader in women's health research."

A different approach

The impetus for the Kronos Early Estrogen Prevention Study began 10 years ago as a result of findings from a large clinical trial called the Women's Health Initiative. The initiative suggested that menopausal hormone therapy raised the risk of heart disease and stroke. But women in the trial had an average age of 63 when the study began — a full decade older than when menopause usually starts. Because of the age gap, many experts felt the trial results unnecessarily scared younger women away from hormone therapy.

"Women were terrified of hormones after that trial," says Sharon L. Mulvagh, M.D., director of the Women's Heart Clinic at Mayo Clinic.

Concerned with how the Women's Health Initiative study results impacted women, the Aurora Foundation, a charitable foundation based in Phoenix, Ariz., provided a grant to the Kronos Longevity Research Institute to privately fund the KEEPS trial.

Dr. Miller was director of Mayo Clinic's Office of Women's Health when the KEEPS trial was starting. The trial was the perfect opportunity to coordinate research in women's health throughout Mayo Clinic's medical disciplines, she says. The national network of collaborators leading KEEPS also meant Mayo Clinic was now linked with investigators with strong traditions in women's health research, Dr. Miller says.

Beginning in 2005, the study enrolled 728 women ages 42 to 58 within six months to three years of menopause. Some women took placebos, some took estrogen and progesterone pills, and some applied estradiol skin patches.

Dr. Mulvagh notes that the different estrogen delivery methods are one way the KEEPS trial was specifically designed for women.

"High triglycerides are a unique risk factor for the development of atherosclerosis in women," Dr. Mulvagh says. Estrogen delivered through a skin patch does not increase triglycerides, she explains, while estrogen delivered orally may have a different effect.

Menopause is a crucial time for preventing future cardiovascular disease. Thanks to researchers such as Dr. Miller, physicians now know that before menopause, estrogen plays a protective role. The hormone keeps blood vessels relaxed and dilated and maintains a healthy balance of good and bad cholesterol. But once the ovaries stop producing estrogen, cholesterol starts accumulating in artery walls. As menopause progresses, plaque builds up and arteries thicken and calcify.

KEEPS will show whether estrogen therapy can halt this postmenopausal disease progression.

"There's the old saying that an ounce of prevention is worth a pound of cure," Dr. Miller says. "If you can retard the disease process, maybe you're going to have heart attacks in women who are 80 instead of in women who are 60. Women will have another 20 years of quality of life."

The four-year trial isn't long enough to gauge heart attack risk, because women rarely have heart attacks in their 40s and 50s. Instead, KEEPS tracked two early disease indicators for cardiovascular disease: the amount of calcium in the coronary arteries and the thickness of the carotid artery wall in the neck.

Researchers also measured mental health, cognitive function, blood vessel lining (endothelial) health, bone loss, fat distribution, and breast pain and density.

"These women are right at the cusp of when they come into menopause," Dr. Miller says. "We're capturing all kinds of changes. I think we'll really understand some of the mechanisms of how estrogen affects a woman's body as she ages."

Translating basic science

Growing up in Pittsburgh, Virginia Miller didn't plan on a career delving into the inner workings of the blood vessels.

"I came from a blue-collar family, and I went to Slippery Rock State College with the goal of becoming a biology teacher," she explains.

Unable to find a job after graduation, she enrolled in graduate school instead. After earning a Ph.D. in comparative physiology, she landed in the Mayo Clinic lab of physiologist Paul Vanhoutte, M.D., in 1983.

In Dr. Vanhoutte's lab, Dr. Miller first worked on endothelium-derived relaxing factors, then an exploding research area. The endothelium is a layer of specialized cells lining the inside of blood vessels. These cells contain receptors that respond to different compounds carried in the blood, including estrogen.

Dr. Miller found her calling when Dr. Vanhoutte returned from a meeting with news that estrogen reduced cardiovascular disease in women. "He said, 'What does estrogen do to the endothelium?' and that launched my career in the hormone realm," she recalls. "My career was not planned by me, but I look back and I know that God has planned for my life by presenting me opportunities."

Dr. Miller's lab focuses on understanding the role endothelial cells and platelets play in hardening of the arteries (atherosclerosis) and formation of blood clots that lead to heart attack and stroke.

After working with animals for many years, she is now repeating her studies in women participating in the KEEPS trial.

"We've made the translation from basic science to a clinical trial, and that's what Mayo is all about," Dr. Miller says. "This is the first study that's looked at human platelets over a four-year period on estrogen treatment. We're very excited about what we're going to find. It's never been done before, and when combined with outcomes of KEEPS, we will learn even more about how platelets influence progression of arterial disease."

The next steps

The years spent studying estrogen's effects made Dr. Miller a strong advocate for understanding the role that sex and gender play in health.

"That's where my passion comes from," explains Dr. Miller, who is immediate past president of the Organization for the Study of Sex Differences, an international society for basic and clinical scientists. "It boggles my mind that whether the experimental material, animals or cells carry an X or Y chromosome is ignored in basic science studies."

Mayo Clinic has come a long way since Dr. Miller helped establish the Office of Women's Health in 2001. For example, one of the office's charges was to improve collaborations among different departments, a goal crystallized through the KEEPS trial.

"KEEPS brought people interested in women's health together in a new way, and it gained momentum to the point that some of the former boundaries that were limiting an integrative approach were broken down," Dr. Miller says.

The long-term vision of the Office of Women's Health was to have a multidisciplinary women's health research center. That goal was achieved in early 2012, when the Women's Health Research Center was formally approved, with endocrinologist Rebecca S. Bahn, M.D., as director.

The mission of the Women's Health Research Center is to understand and improve women's health across their life span and to be nationally recognized for translational research for improving the health and care of women.

Despite such advances, Dr. Shuster says she finds that people still wonder what women's health means.

"People think it's women doctors caring for women patients, but women's health is far beyond that," she says. "There are conditions that are unique to women, but there are also conditions that show up differently in women and conditions that are more frequent in women."

Or, as Dr. Mulvagh succinctly puts it, "Women are not small men."

Dr. Shuster, the director of the Office of Women's Health, says the next step is to open a multidisciplinary women's health center that geographically unites women's health care.

"One of the things women value most highly is integration for their care," Dr. Shuster says. "I think that's one of the reasons why we're becoming a destination for women's health. But I know how much more we could be doing."