Menopause Mondays: Estrogen & Heart Disease - Ellen Dolgen
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Menopause Mondays: Estrogen & Heart Disease

We are so excited and grateful that Dr. Harman has taken the time to talk to us about heart disease and HRT. Most women do not know that ten times as many women die from heart disease than from breast cancer. The 2002 WHI trials showed a link between women who took estrogen and higher heart disease risk. Unfortunately, many key factors were not considered before these results were published, suggesting that the study needs further interpretation. Researchers are currently revisiting the conclusions made in the WHI trials (see the Menopause News Flash for the latest information on this). Dr. Mitch Harman, MD, PhD, Director and President of the Kronos Longevity Research Institute, is nearly finished with a study called KEEPS, which aims to accurately show the effects of long-term estrogen use on key factors influencing the likelihood of heart disease.


Q: What is the Kronos Early Estrogen Prevention Study (KEEPS)?
A: The KEEPS is a clinical trial of the effects of estrogen and progesterone given to women early (within 3 years of the menopause) to examine the effects of 4 years of treatment on the progression of atherosclerosis, the arterial disease that causes most heart attacks and strokes. It is a randomized controlled trial, which means that women were assigned to be treated with active hormones or inactive placebos by a random process (like flipping a coin). The study is blinded in that neither the investigators nor the research subjects know which kind of treatment they are getting. To assess progression of atherosclerosis, we are measuring thickness of the wall of the carotid artery using ultrasound at the beginning of the study and annually, and also the amount of calcium in the coronary arteries (arteries that supply the heart) by high-resolution CAT scans at the beginning and end of the study. We have randomized 727 women at nine academic centers around the U.S. The study is nearly complete. The last subject visit will take place in February 2012 and we will unblind the study and begin analyzing the data in March.

Q: Why is the KEEPS necessary?
Before the Women’s’ Health Initiative (WHI) hormone trials were published in 2002, we had accumulated considerable and fairly consistent evidence that menopausal women who used estrogen treatment received significant protection (about a 40% reduction in rates) from heart attacks and cardiac death. If this is real, it is very important, because 10 times as many women die of heart disease than die of breast cancer. However, even though estrogens are known to have a number of effects that should help protect against heart disease (for example raising the “good” HDL cholesterol and helping arteries to open up and increase blood flow) we could not be sure that this was correct. This is because women who decided to take estrogen on their own might have been healthier in the first place or received better medical care than women who did not. The WHI trials were randomized; controlled, blinded studies (one of estrogen plus progestin and one of estrogen alone) designed to clarify this issue. To the surprise of many, these trials did not show cardiovascular protection, but trends in the opposite direction, with women taking estrogen having slightly more cardiac events. One problem with the WHI studies, though, was that the women starting hormone treatment were, on average, 63 years old, but women undergo menopause, at an average age of 51 (i.e. 12 years earlier). The women in the previous observational studies that showed benefit from hormones actually did start taking hormones at around 51 years of age. Another problem was that the WHI studies were stopped when most women had been treated for less than 5 years. However, there are several studies that show that protection from heart disease does not become apparent until women have taken hormones for more than 5 years. Finally, when the WHI data were analyzed by age or time since menopause, all the harm appeared to occur in the older groups, whereas the treated women under 60, or more recently menopausal women, showed trends toward lower rates of heart attacks than the placebo group. Thus, a serious question was raised whether there is a “window of opportunity” during which estrogen must be started to protect against heart disease, and that starting it after this window closes may be less useful or even harmful. This is called the “timing hypothesis.” The KEEPS is one effort to address this important question.

Q: How will the KEEPS work? What will it aim to show?
Women in the KEEPS took either conjugated oral estrogen tablets (Premarin®) or used an estrogen skin patch (Climara®) or placebo (blank) tablet and patches every day and either an active progesterone capsule (if on active estrogens) or a placebo capsule 12 days each month for 4 years. Measurements of carotid intimal medial thickness (CIMT) and coronary artery calcium (CAC) were made at baseline and CIMT was repeated every year and CAC at the end of the study. We also drew blood at 4 points during the study to look for estrogen effects on factors known to influence or predict risk of heart disease and clotting-related diseases. We hope to find that women taking active estrogen have significantly less increase in CIMT and CAC than women on placebo. We will also ask whether one kind of estrogen is better than another in this regard. Finally, we will examine the risk factor measurements to explore whether baseline values or changes during treatment predict the response of our arterial imaging end points.

Q: I am so glad that you are studying both bioidentical and non-bioidentical HRT. This will address another important question we all have, which is: Do different estrogens have different risks and benefits? On a more general note, how do you know if you’re at risk for heart disease?
Risk factors for heart disease have been investigated thoroughly in men, but we have less information as to what may be important in women. High blood pressure, smoking, obesity, and diabetes, as well as lack of exercise are all important risk factors. It is less clear what role cholesterol and triglyceride (fatty substances in the blood) play in women compared with men. Also, chronic inflammation, which can be estimated from levels of plasma markers like C – reactive protein (CRP) and interleukin-6 (IL-6), may be more important in women than in men. Family history also plays an important role. If you have a first degree relative (mother, father, sister brother) who had a heart attack at an early age (for men less than 40, for women less than 50) you may be at high risk yourself. Finally, it is clear that women who undergo premature menopause (under age 40), either spontaneously or after surgery to remove the ovaries, are at high risk.

Q: The American Cancer Society report contains a lot of information on the effects of HRT on breast cancer. Can you give women any advice on how to best evaluate their risks vs. benefits of HRT?
In general, women seem more afraid of breast cancer than heart disease, although the odds of dying of heart disease are much higher. HRT appears to increase the risk of breast cancer by 20 to 30% after 5 years of treatment. If it also reduces the risk of heart disease by 40%, then the odds would still be in favor of using it. Women with a strong family history of breast cancer would probably be better off to avoid HRT, especially if they are not at high risk for heart disease. This is a decision that each woman needs to make individually with help from an enlightened physician who appreciates the nuances of the available scientific data as well as the personal preferences and feelings of the woman herself.

Q: What measures can women take to reduce their risks of heart disease?
Obviously, you cannot change your family history. The best methods we have to avoid heart disease are to stay lean (body mass index – which is your weight in kilograms divided by the square of your height in meters- of less than 28), exercise regularly and vigorously (swimming, running, fast-walking, tennis, etc.), and DON’T SMOKE. Have your blood pressure and blood sugar checked regularly and treat high blood pressure to American Heart Association goals for your age and condition. Avoid salty food. We take in far too much salt in this country and recent studies have shown that salt intake is associated with greater risk of heart disease and stroke even when it does not raise blood pressure. We cannot say with high confidence that HRT is protective for menopausal women at this point in time, but if I had to bet, I would predict that it is.

The WHI scared women so much that they stopped taking their HRT cold turkey! Some of these women are still suffering today with serious menopausal symptoms. Other women just beginning their perimenopausal journeys are still not clear about the risks and benefits of HRT. The more factual and defensible data we have, the better decisions we can all make for our health and quality of life. Knowledge empowers us. DO NOT BE AFRAID TO GET THE HELP YOU DESERVE! I am going to jump on my bike more often and anxiously await the results of the KEEPS.


Thank you, Dr. Harman, for championing this critical research. On behalf of the sisterhood, we all LOVE YOU!


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