Early Menopause: Precursor to Coronary Heart Disease?

R. Scott Wright, MD; Sharon L. Mulvagh, MD


January 12, 2015

Editorial Collaboration

Medscape &

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What Is Early Menopause?

R. Scott Wright, MD: Hello, and welcome to a Mayo Clinic broadcast on at Medscape. I am Dr Scott Wright, Professor of Medicine in Cardiology at the Mayo Clinic. I am joined by Dr Sharon Mulvagh.

Dr Mulvagh has had an incredible career at Mayo. Before coming to Mayo, she worked in Houston and did some consulting work at the National Aeronautics and Space Administration (NASA), and she is a very accomplished physician and researcher.

Today, Sharon holds the title of director of the Women's Heart Clinic, and she is a well-known and respected imaging cardiologist as well as preventive cardiologist. She is here today to discuss early menopause as a precursor to coronary artery disease and stroke.

Thanks for tackling a very important and tough topic. Help us understand, what is early menopause?

Sharon L. Mulvagh, MD: First of all, what is the average age of menopause in women in North America?

Dr Wright: I would say approximately age 50 years.

Dr Mulvagh: It's 51, with a range of 50-54 years. Early menopause is considered to occur in women who have menopause between the ages of 40 and 45 years (< 46 years). The term "premature menopause" is used for onset of menopause before age 40 years.

Dr Wright: Does the onset of menstruation predict when menopause might happen?

Dr Mulvagh: It's predicted more by the family history.

Cardiovascular Risk and Early Menopause

Dr Wright: So the age when a woman's mother and grandmother went through menopause. Is there a difference, in terms of cardiovascular risk, for surgical menopause, which happens in some women, vs "natural menopause," if we may call it that?

Dr Mulvagh: You are bringing up an important point. There is an increased cardiovascular risk with early menopause and premature menopause. Several smaller studies have looked at whether there is a difference between natural and surgical menopause. There doesn't seem to be a difference. It's when menopause starts (early or premature) that increases the risk for cardiovascular disease, on the order of at least two times.

Dr Wright: That is comparable to the increased risk associated with diabetes and heterozygous familial hypercholesterolemia. It's a significant risk factor. Is this appreciated by the medical community?

Dr Mulvagh: No, not at all—in part because of the hysteria that almost developed about hormone replacement therapy after the earlier trials.

Dr Wright: Could you summarize for our audience your take on the estrogen replacement therapy studies? Do hormones raise cardiovascular risks? Do they alter them at all? Do they improve risks?

Dr Mulvagh: We are going to talk about early menopause and premature menopause. Repleting hormones in those situations provides nothing but benefit as far as the cardiovascular system goes, unless there is a contraindication to hormone therapy, such as a breast cancer history or a history of a stroke or thromboembolic event.

Dr Wright: Would pulmonary embolism would be a contraindication?

Dr Mulvagh: It would be a relative contraindication.

Hormone Therapy and Proximity to Menopause

Dr Mulvagh: The largest study—and we are talking about the Women's Health Initiative (WHI) Study[1]— unfortunately was not a study of what happens physiologically in women. The average age of women enrolled in the WHI was 62 years. That is a decade beyond the average age of menopause in North American women.

Dr Wright: So if there is a risk to mitigate, you started late in the process.

Dr Mulvagh: Exactly. From the WHI, we learned that you don't give hormone therapy to women who are a decade after the onset of natural menopause. Less than one fourth of the women in the WHI were in the age group of 50-60 years. There were no women younger than 50 years. It is not readily known, but it has been published, that that tertile of women had a lower cardiovascular risk, and fewer events (heart attacks and strokes), than women who were not on hormone therapy. It's very thought-provoking.

There have been subsequent studies to the WHI, including one that we participated in at Mayo, the KEEPS (Kronos Early Estrogen Prevention Study).[2]

The objective of that study was to look at women at the time of natural menopause; there were no hysterectomies in this particular group.

All women were administered hormone therapy—an estrogen (either oral or transdermal) and a progestogen—and they were tracked with respect to the surrogate endpoints of coronary artery calcification and carotid intima-media thickness.

Dr Wright: Those are good predictors of subsequent cardiovascular and neurologic risks.

Individualizing Hormone Therapy Decisions

Dr Mulvagh: The data were very reassuring. The women were followed for 5 years, and there was no increased risk for increased carotid intima-media thickness or coronary artery calcification, and there was a trend toward less coronary artery calcification in women who were treated with hormones. It probably was a time factor and a number factor as to why we couldn't detect significance. But it's reassuring that there were no untoward cardiovascular effects when hormone therapy was taken physiologically, within 3 years of menopause.

Most of us who see patients every day who are going through menopause and having significant, uncomfortable vasomotor symptoms can feel very confident in saying that it is okay to use hormone therapy as long as you don't have any specific contraindications.

Dr Wright: Do you feel that the Kronos study was powered adequately? If you were given a budget by the National Heart, Lung, and Blood Institute that was sufficient, would you redo it with higher numbers?

Dr Mulvagh: We are never going to be able to repeat that. The WHI was a $650 million study with 16,000 women in each arm. Unfortunately, the KEEP study included 700-800 patients and a much lower budget. The findings are not as powerful because of that, but a trend was suggested that gives us confidence to say that in women who are confused about using hormones for their vasomotor symptoms, thinking that they might be hurting their hearts, we can say, "No; indeed, you may be actually benefiting your heart." The data are not strong enough to make that statement; hormone therapy is not recommended for the prevention of cardiovascular disease.

Dr Wright: So in a guideline document, it might be a 2B indication rather than a 3, or a 1, or a 2A.

Dr Mulvagh: It's better than moving from a 3, in which hormones are completely contraindicated, which is what was in the document for the prevention of cardiovascular disease in women. We have to temper with our judgment and our common sense, recognizing that the WHI was a study of older women a decade past their menopause. We need to individualize treatment for the patient who is sitting in front of us.

Dr Wright: That is well said. It is true for all clinical trials. Generally trials, although they answer great questions, sometimes create more issues and questions that we had not contemplated before we did the trial. We learn with each study where we have designed it less than adequately, or where other issues pop up.

Cardiovascular Prevention and the Menopausal Woman

Dr Wright: What preventive advice do you give the female patients who come through our Women's Heart Clinic? What can a woman do to lower her cardiovascular risk when she is either in menopause naturally, or in early menopause, or feels that she is approaching it? What can she do to prevent heart disease?

Dr Mulvagh: The onset of menopause is an extraordinarily good time to take stock. For most women, it's mid-lifetime. We have been very busy, perhaps neglecting the optimization of our cardiovascular risk factors.

It is a very good opportunity for the physician to discuss, with the patient, getting things in line—knowing your numbers, your lipid profile, and your weight. Natural hormones, and estrogen in particular, have very positive physiologic cardiovascular benefits. The lipid profile is improved. High-density lipoprotein is augmented, and low-density lipoprotein is reduced. When we transition into the menopause, we lose that protection, so to speak.

Women have a tendency to gain a little weight, and the distribution of that weight may be different, with central adiposity increasing; it is an unfavorable spot for extra weight with respect to cardiovascular risk. So it's extremely important to take those things into consideration. The closer a woman can be to an ideal body weight, the better. How do we achieve that—adequate physical activity, excellent nutritional choices, restricting calories, and portion control?

Another good choice is not smoking. Among some of the studies that have been looked at more recently, the MESA study[3] looked in detail at women and their age at menopause, and their risk of developing atherosclerosis. It found that women who were smokers had an even higher risk, if they had an early menopause, of developing early atherosclerosis.[3]

Another very recent Swedish study[4] looked at the onset of heart failure in women who had early or premature menopause. In those women, the risk was increased 40% if they had early menopause and not been treated with hormone therapy; if they were smokers, it was even higher.

Dr Wright: These are observational data, but are still the best we have to apply to the patients we see, supporting use of hormone replacement therapy at physiologic doses. Is that fair to say?

No Prophylactic Oophorectomy

Dr Mulvagh: I would say so, particularly in women with premature or early menopause.

Another important point is for women who are undergoing hysterectomy. The Mayo data showed that 40% of women who had a hysterectomy (and it was about 10% of women aged 35-45 years) were getting prophylactic oophorectomies.[5] Maybe the thought was to prevent ovarian cancer.

In 2008, the American College of Obstetricians and Gynecologists (ACOG) determined that it's not appropriate to do prophylactic oophorectomy at the time of hysterectomy.[6] That is very important. Women aged 45 years or less who are undergoing hysterectomy, if someone recommends that they have their ovaries removed, should question that recommendation. They should have a discussion with their provider, because that will put them at increased risk for subsequent cardiovascular disease unless they are repleted with hormones.

Dr Wright: That is an important change in the practice recommendation, which will hopefully benefit the long-term cardiovascular health of women. Correct me if my impressions are incorrect, but the risk for ovarian cancer is substantially lower than the lifetime risk for cardiovascular disease.

Dr Mulvagh: One in 3 women dies of heart disease—the same number as men.

Dr Wright: Heart disease spares no gender, financial issues, or ethnic issues. We all have the same risks. It's an equal-opportunity killer.

This has been very enlightening, and I know the audience appreciates your expertise today. You live what you preach. I live not too far from Sharon, and I see her running nearly every day during the temperate season. I don't know whether you run in the winter.

Dr Mulvagh: You are not out in the winter, but I'm there.

Dr Wright: If our viewers have questions, they can contact you at Mayo Clinic. And they're certainly happy, in the Women's Heart Center, to see any patients with particular challenges and to provide cardiovascular counseling.

Dr Mulvagh: Absolutely.

Dr Wright: Thank you for joining us today for this discussion about menopause, early menopause, and premature menopause. I want to thank Dr Sharon Mulvagh for her great insights for all of us who have joined this conversation. We hope that you will continue to check out future content on the Mayo Clinic page at at Medscape.


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