JoAnn Manson

"We need a more refined view of HRT’s effects," said Manson, whose primary appointment is as professor of medicine at Harvard Medical School and who is chief of the Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital. "The pendulum has swung from the view that estrogen is good for all women to the view that it is bad for all women. Both are oversimplifications, and the truth is likely in between."

Manson is in a unique position to judge the merits and risks of HRT. She was a researcher on two massive studies that came to famously different conclusions about the therapy and so is particularly well informed about the breadth of evidence.

For several years, data from the Nurses’ Health Study (NHS) and dozens of other observational studies had suggested that HRT lowered women’s risk of heart disease. Then, two years ago, the federal Women’s Health Initiative (WHI) found the exact opposite–that a common estrogen-progestin combination did not protect women from heart disease and, in fact, appeared to increase women’s risk of heart attacks, strokes, and breast cancer.

Experts, who included representatives of the Nurses’ Health Study and the Women’s Health Initiative, gathered last year at HSPH to debate the studies’ conflicting results. Some suggested that the discrepancies may in part be the result of the very different natures of the studies’ designs. The NHS is a prospective, observational study. The WHI study was a clinical trial.

Others wondered if differences between the groups of study subjects could account for the conflict. Women in the Nurses’ Health Study had begun taking hormone replacement therapy soon after menopause, whereas most women in the WHI study had begun many years after menopause. The NHS subjects were also younger and thinner than their WHI counterparts, whose extra weight and older age already put them at higher risk for heart disease. Also, many wondered if the form of estrogen and progestin that was used was a factor. Recent findings from the WHI in April 2004 suggested that estrogen alone did not increase the risk of heart disease and may have even lowered risk in the youngest age group, said Manson.

Those questions have motivated the new private study called KEEPS (Kronos Early Estrogen Prevention Study), which involves eight national study centers: Harvard Medical School/Brigham and Women’s Hospital; Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center; Columbia University College of Physicians and Surgeons; Mayo Clinic College of Medicine (Rochester, Minn. campus); University of California-San Francisco/Center for Reproductive Health; University of Utah School of Medicine; University of Washington School of Medicine; and Yale University College of Medicine.

The study is being funded with $15 million from the Kronos Longevity Research Institute in Phoenix. Manson is the principal investigator for the study at HMS/BWH.

At what age women start taking HRT may matter tremendously because it is now believed that estrogen can slow artery-clogging atherosclerosis in relatively young women if taken soon after menopause, said Manson. But estrogen given later appears to be harmful, precipitating heart attacks and strokes in women in their 60s or older who are well into menopause and already have narrowed blood vessels. These women may be more susceptible to the blood-clotting effects of HRT, said Manson.

KEEPS hopes to enroll a total of 720 women ages 40 to 55 and in early menopause (a maximum of three years since their last menstrual period.) One group will receive a placebo, another will get an estrogen pill, and a third will take natural estrogen (estradiol) through a skin patch. The women will also receive a natural progesterone (micronized progesterone) 12 days a month to protect against uterine cancer.

Because KEEPS is funded to run five years, the study cannot compare rates of heart attacks and strokes, but instead will use noninvasive imaging to measure the thickening of artery walls, a precursor to cardiac problems.

The entry of a private funder into the hormone replacement therapy question may be unusual, but Manson is glad that research in this area will continue. After the WHI findings, she had continued to sift through data, trying to see if an overlooked subgroup of women might benefit from estrogen. A few months ago, she learned that Dr. S. Mitchell Harman at the Kronos Institute and a handful of other researchers were puzzling over the WHI findings and thought a new trial could help.

"The WHI results didn’t answer what I considered the most important question: what about the women who started estrogen at menopause, as the women in the Nurses’ Health Study did," said Harman.

He and his colleagues decided to "get together and see what we could do to fill in the gaps," he said. Harman proposed the trial to John Sperling, the 83-year-old founder of Kronos, reportedly worth almost $3 billion, who has been financing research into extending good health and combating diseases of aging.

Manson and Harman agree that, because the WHI trial results have created a negative climate about hormone replacement therapy, recruiting volunteers for KEEPS will not be easy. "It will be a challenge, but I don’t think it will be impossible," Manson said.

The women must have an intact uterus, so that the KEEPS’ findings will apply to the largest group of women who are interested in hormone therapy for menopausal symptoms. Advertising and mailings will target women in health care, who may be especially interested in the issue, said Manson.

Recruiting may start as early as October–but not until the study’s protocol has been approved by an Institutional Review Board (IRB) at Kronos and by IRBs at each participating center, said Manson.

If the KEEPS volunteers on estrogen have healthier arteries at the end of five years, funding agencies may be inspired to support much larger studies to compare actual heart disease events, said Manson.

In any case, she believes the study is an important one. "Right now estrogen is the most effective treatment for hot flashes and other menopausal symptoms," she said. "It doesn’t look like it is going to become obsolete any time soon, and a lot of women will pressure their doctors to start HRT."

What’s become clear through the ups and downs of the research, Manson said, is that in terms of HRT, "one size doesn’t fit all."

--RS