"This is another level of evidence for younger women that estrogen does not harm the heart and may have a heart benefit," study researcher JoAnn E. Manson, MD, PhD, chief of preventive medicine at Harvard's Brigham and Women's Hospital, tells WebMD.
During menopause, a woman's ovaries stop making estrogen. Many women develop life-disrupting symptoms such as hot flashes and night sweats. Estrogen replacement is the most effective treatment for these symptoms. Women with an intact uterus risk uterine cancer from this treatment unless estrogen is balanced with another hormone, progestin.
The new findings come from a WHI substudy of women who had had a hysterectomy and thus received estrogen-only hormone treatment (Premarin, in the WHI study). But Michelle Warren, MD, says that women taking combination hormone therapy do not need to worry about increased risk of heart disease -- provided they start treatment soon after menopause.
"I don't think that women with or without a uterus need to worry about this issue [of heart disease risk]," Warren said at a news conference.
Warren, medical director of the Columbia University Center for Menopause, Hormonal Disorders, and Women's Health, has studied the timing of menopausal hormone therapy but was not involved in the WHI. The news conference was sponsored by Wyeth, which makes Premarin and Prempro (combined estrogen and progesterone), the two drugs studied in the WHI.
Despite the findings, Manson stresses the fact that hormone therapy is intended only for the short-term relief of menopausal symptoms and not as a long-term treatment to prevent heart disease. An editorial accompanying her report in the June 21 issue of the Journal of the American Medical Association agrees.
"It remains important ... to continue to emphasize that hormone replacement therapy should not be considered as a strategy to prevent cardiovascular disease in women," write Michael E. Mendelsohn, MD, and Richard H. Karas, MD, PhD, of Tufts University in Boston.
But Mendelsohn and Karas also agree with Warren, who says that the initial reports from the WHI unduly frightened younger menopausal women.
"Unfortunately, the initial WHI results were unfairly generalized, creating widespread concern that hormone replacement therapy is neutral or even harmful, with respect to cardiovascular disease, in all women," Mendelsohn and Karas write. "[The current study] and other recent studies support the hypothesis that estrogen can reduce the risk of coronary heart disease in women 50 to 59 years old, which should help clarify this confusion."
Hormone Therapy: Timing Key to Benefit
The WHI trial was designed to see whether long-term treatment with combined estrogen plus progestin (Prempro) (or, for women who have had hysterectomies, estrogen alone (Premarin)) offered health benefits after menopause. The study enrolled women up to age 79.
The estrogen-plus-progesterone arm of the study was halted early, after five years, when it became clear that, overall, women taking Prempro had an increased risk of breast cancer, dangerous blood clots, stroke, and heart disease. However, there was no increased risk of death -- and a significant benefit in reducing hip fracture due to bone loss.
The estrogen-only arm of the trial continued. These results, plus new analyses of the earlier data, strongly suggested that hormone therapy was far less risky and far more beneficial when begun soon after menopause.
That's why Manson and colleagues took a closer look at 50- to 59-year-old women in the estrogen-only arm of the study. They used CT scans to measure calcium deposits in the women's coronary arteries -- an excellent predictor of hardening of the arteries and future heart disease.
They found that about 7.5 years after starting hormone therapy -- and more than a year after the trial ended -- women taking estrogen were 30% less likely to have serious hardening of the coronary arteries.
Women who took their estrogen pills every day did even better. They had more than a 60% lower risk of serious hardening of the arteries.
"This suggests that estrogen was slowing the different stages of plaque buildup in the arteries," Manson says. "These findings, together with earlier findings that women taking estrogen have lower rates of heart attack and coronary artery bypass and balloon angioplasty, provide reassurance that for recently menopausal women, estrogen will not have an adverse effect on their heart and may even have some benefit."
Howard Hodis, MD, director of atherosclerosis research at the University of Southern California, is far more convinced of the heart benefits of hormone therapy. Hodis, who spoke at the Wyeth news conference, is a paid consultant to Wyeth (and other pharmaceutical companies) but says his opinions are not those of the company.
"The timing issue is absolutely crucial -- below the age of 60, probably right at the time of menopause, is when women want to start hormone therapy," Hodis says. "Early initiation of hormone therapy ... is quite efficient at reducing coronary artery disease. Taken together with previous reports ... we see that with estrogen-only hormone therapy, we have not only seen a reduction in coronary heart disease and overall mortality but also no risk of breast cancer, stroke, and other adverse outcomes."
"My patients are more worried about hormone therapy causing breast cancer than about heart disease," Warren says. "But there is no increased risk of breast cancer with estrogen alone, only with estrogen plus progesterone, and the risk is tiny."
Statements from leading menopause societies largely support the opinions expressed by Warren and Hodis.
"We are clearly learning that the benefits of estrogen in young, healthy, postmenopausal women outweigh the risks," says Robert W. Rebar, MD, executive director of the American Society for Reproductive Medicine.
"Since most, if not all, women do not start hormone therapy at an old age, safety concerns on its possible adverse cardiac effects are actually invalid for the vast majority of hormone users," reads a statement from the International Menopause Society. "In fact, treatment seems to be associated with reduction of risk for coronary artery disease if initiated early."
Hormone Therapy: How Long?
Hormone therapy with any of the several available estrogen/progesterone or estrogen-only products is currently intended only for relief of moderate to severe menopausal symptoms. Current recommendations call for the products to be used at the lowest effective dose, for the shortest possible time.
"There are some risks of hormone therapy, and that is why it is important for women not use these hormones expressly for reduction of heart disease risk," Manson says. "There is increased risk of blood clots in the legs, and of breast cancer. Now we are treating women only for moderate to severe menopausal symptoms, and only for three years. In that scenario -- recently menopausal woman in good cardiologic health with severe menopausal symptoms -- for them it is much more likely the benefits will outweigh the risks."
Manson now recommends that women use hormone therapy for no more than five years. Hodis and Warren disagree, noting that the long-term benefits of hormone therapy disappear when treatment stops.
"In clinical trials, the longer the women took hormones, the greater the benefit. And other data show that when women stop hormones, the heart disease benefit goes away," Hodis says. "Personally, I think that if there is going to be protection, this is something that has to be continued. ... I think you can have even greater adverse effects from stopping estrogen than from taking it."
"The question is, when should we stop hormones? We will never know for sure," Warren says. "But the bulk of the evidence is it does protect the heart. ... I feel reassured. I can tell patients, 'Look, if you are worried about your heart and have been on this since menopause, I am not worried any more.' I feel if you don't need a drug, you shouldn't be on it. But there is a downside to stopping estrogen, and what this study implies is the heart disease will accelerate, and we know from other studies you will lose bone."
But Stanford University professor Marcia Stefanick, PhD, chairwoman of the national steering committee for the WHI, warns that the effect of estrogen on just one risk factor for heart disease does not prove hormone therapy protects women's hearts. And estrogen carries other risks, too, she says.
"We have to keep in mind that heart disease is only one potential health risk of hormone therapy," Stefanick says in a news release. "When women are thinking about taking estrogen, they should consider the overall risk-benefit balance, which includes an increased risk of stroke and blood clots, regardless of age."
More Hormone Therapy Answers to Come
Manson says many of the questions Warren and Hodis raise will be answered by the Kronos Early Estrogen Prevention Study (KEEPS). The study -- which is now recruiting patients -- is looking specifically at the question of whether hormone therapy can prevent plaque buildup in the arteries.
The study will compare oral estrogen pills to transdermal estrogen patches. Women receiving estrogen will also take bioidentical human progestin, which is considered safer than previous progesterone products.
Women can learn more about the study -- and volunteer to participate -- via the KEEPS web site, keepstudy.org.
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