Cardiovascular effects

Schiff: We’ve been focusing on short-term effects of HRT and continuance because those are the immediate concerns of those of us who see menopausal women every day. But I’d like to briefly consider long-term effects as well—specifically, those impacting cardiovascular health, since the thinking about that has changed in the past several years. In fact, the thinking about estrogens and heart disease has changed back and forth several times over the past half century.

About 40 years ago, we recognized that women had fewer heart attacks than men before the age of 50. After age 50, it seemed women were in a race to catch up with men in heart attack numbers. These facts were interpreted as showing that when women lost ovarian estrogen, they lost the protection of estrogen against heart disease.

Since the concept was that estrogens protect against heart disease and men have more heart attacks, the first major study of estrogen and heart disease was done with men. This study, the Coronary Drug Project, was initiated in the late 1960s in 53 separate medical centers across the country. The men received high doses of 2.5 or 5 mg of CEE per day. After 18 months, the study had to be stopped because these high doses, given to men who had had coronary insults, increased the rate of myocardial infarction and pulmonary embolism.³⁷

The next major study of estrogens and heart disease was also done in men. In this case, they were men who suffered from prostate cancer and who were being given high doses of diethylstilbestrol [DES] to treat their prostate cancer.³⁸ In this study, the men who got DES died of heart disease and the men who got placebo died of prostate cancer. So the first two major studies of estrogens and heart disease established that estrogen, at least in high doses, was bad for men.

Now we come to the mid 1970s, and we start to see heart attacks in younger women. These turned out to be women who smoked and were taking estrogen-containing OCs. It took us about 10 years to tease out that information, but the perception again was bad for estrogen. So if this discussion were taking place 25 years ago, we’d be saying estrogen causes heart disease because of the birth control pill studies and the studies in men.

In the late 1970s and early 1980s, the tide turned as a number of retrospective studies provided data showing that estrogens prevented heart disease in women.^39,40 By the early 1990s, the thinking had come full circle, with estrogen considered not only as preventive care but potentially as first-line therapy for heart disease in women. The HERS trial was begun in February 1993 to test the assumption that a standard continuous combined HRT regimen [0.625 mg of CEE + 2.5 mg of MPA] would protect women who already had some form of heart disease from further coronary events.⁴¹ Instead, the HERS trial produced a null result after 5 years, with an increase in coronary events in the first year.

Since it was thought that the HERS results might have been caused by MPA attenuating the effects of CEE, a subsequent secondary prevention study, the ERA [Estrogen Replacement and Atherosclerosis] trial, included an estrogen-only arm as well as continuous CEE + MPA and placebo arms.⁴² The endpoint was atherosclerotic buildup in the coronary arteries as demonstrated by angiography. No protective effect was observed with either CEE alone or CEE plus MPA. Lack of secondary protection by estrogen was also apparent in a transdermal study in Europe and early reports from the Women’s Health Initiative [WHI], the largest trial of hormone effects thus far but not scheduled to conclude until 2005. In WHI, as in HERS, risk of coronary events was increased in the first and second years among hormone users, though the association did not reach statistical significance. Of course that negative news was well covered by the popular media.

So estrogen, albeit at different doses, has had an interesting trip over the past 40 years with respect to heart disease. It went from probably beneficial to probably harmful, after the male and OC studies, back to beneficial in the 1980s and early 1990s, to ineffective for secondary prevention as we come to the present. The pendulum has swung back and forth on its benefits versus its risks for heart disease and is still swinging today.

If I had to sum up my views now, I’d say that I hope estrogen prevents heart disease, because heart disease is the number one killer of women. We have a lot of reasons to think it does because of its positive effects on the lipid profile and the coronary arteries. But probably there is a subset of women who have an increased risk for heart disease in the first year or two of hormone use. We need to find ways to identify those women. For most women, I think and hope that the WHI will show that estrogen eventually does protect against heart disease. In the meantime, we have the evidence of many observational studies suggesting that it reduces the risk of heart disease overall in postmenopausal women by 40% to 50%.^39,40

That’s how I see things today on the issue of heart disease. Dr. Nachtigall, what’s your view?

Nachtigall: I agree with your summary, and I think estrogen does prevent heart disease, but I think we need to recognize that we now have other drugs that prevent heart disease as well or better than estrogen does. In fact, the use of those drugs may have influenced the results of the HERS trial. We know that many of the HERS women were on multiple medications, including aspirin and lipid-lowering agents such as the statins. That could have made the results for the placebo group better than expected. We also know that when you combine estrogen with a statin the combination does better than estrogen alone or statins alone.

So it’s not so simple as “Yes, it does prevent heart disease,” or “No, it doesn’t.” Estrogen’s effects on clotting factors are also very significant, and that’s probably what caused the increase in coronary events in the first year of HERS and WHI. Remember that in the HERS trial the subjects were women who had heart disease, and they weren’t screened for any of the clotting disorders. We need a way to study these factors, especially those such as the factor V Leiden mutation that have come to light only recently. Then maybe we can select out women who should not go on estrogen.

Schiff: Dr. Berga, do you have something to add on estrogens and heart risk?

Berga: Dr. Tom Clarkson and Dr. Jay Kaplan at the Bowman Gray School of Medicine have done some very interesting work showing that premenopausal heart disease factors predict postmenopausal heart disease and that the early postmenopausal heart disease detected in HERS and other studies cannot be prevented with postmenopausal hormone use. According to their thinking, primary prevention for those events has to be done premenopausally by such measures as weight control, exercise, smoking cessation, stress reduction, and lipid therapy. If you’ve done what you need to do premenopausally, it looks as if you can take estrogens postmenopausally and not be at risk. However, if you’ve done all the wrong things premenopausally, then you’re not going to get much protection from estrogen postmenopausally. That’s a different strategy than the primary prevention concept that’s been advanced recently by cardiologists—widespread use of statins even in asymptomatic women. In either case, no one expects short-term HRT to provide much secondary prevention for heart disease patients, and the risks might be greater than the benefits of HRT for these women in the short term.

Schiff: The reason we’ve talked about heart disease is that we’re interested in continuance, and one of the motivating factors for continuance is protection against heart disease. But, now, as Dr. Nachtigall pointed out, the patient is liable to say, “I just read in the newspaper that hormones don’t prevent heart disease—that in fact they might increase my risk of it. I don’t want to get a heart attack. Why are you prescribing hormones for me?” How do we respond to that?

Nachtigall: Hormone replacement may not be necessary for women who’ve had heart attacks, because we have drugs that are better than estrogen for secondary prevention. But I think estrogen is still important for primary prevention—protection against cardiovascular events in women with no history of heart disease.

Sarrel: It may still have a role in secondary prevention as well. My own belief is that if estrogen is taken properly and if serum levels are maintained and fluctuations are avoided, then in fact you can demonstrate ongoing long-term protective vascular effects.

Berga: I agree completely.