Five years ago, the mammoth Women's Health Initiative startled millions of women and their doctors with the finding that women who take menopausal hormone supplements have a higher risk of heart disease.
Now, researchers from the same study say hormone therapy actually lowers the risk of heart disease for some women, at least while they're taking the drugs. Women in their 50s taking estrogen pills had 40 percent to 60 percent fewer calcium deposits in their coronary arteries — a reliable marker of heart disease.
Study leader JoAnn Manson says the absence of a heart disease risk changes the equation for hormone replacement therapy among women just entering the menopause years.
"The findings are reassuring to younger women close to the onset of menopause who are considering hormone therapy for the treatment of moderate to severe hot flashes or night sweats," Manson says.
She says the risk of breast cancer and blood clots is not elevated among women who take hormones for fewer than five years.
Women in the study took estrogen alone because they'd had hysterectomies. Women who still have a uterus need to add a second hormone, progestin, to protect against uterine cancer. But Manson says the message is now the same for both groups.
"Whether they would need estrogen alone or estrogen together with progestin, there's really no substantial evidence that younger women would have an increased risk of heart disease."
The news is the kind of thing that exasperates many people about medical research.
"The pendulum has swung from one extreme to the other," Manson says. "Originally, hormone therapy was considered good for all women — and that was clearly not the case. Many more women were taking hormone therapy than actually needed it or should have been taking it."
In 2002, the Women's Health Initiative gave the pendulum a big push in the opposite direction with its conclusion that hormone therapy increases heart disease. As a result, the number of menopausal women taking hormones plummeted from 15 million to around 5 million.
Manson says the new findings don't justify a return to the old days.
Fewer than one in five women would be considered appropriate candidates for hormone therapy, Manson says. These are women in their 50s who have persistent, moderate-to-severe hot flashes and night sweats that interfere with sleep.
Perhaps 1 million to 2 million additional women might fit that definition and might safely take hormones. But only early in menopause, and only for a few years, to avoid the risk of breast cancer and blood clots.
The new findings, published in the New England Journal of Medicine, raise a question: How could research results be so contradictory?
Dr. Michael Mendelsohn of New England Medical Center says it's because estrogen has a dual effect. It works in opposite ways in the coronary blood vessels of younger and older women.
"We believe that the response to (the) hormone in a younger vessel leads to differences in which genes are turned on and off, compared to genes that are turned on and turned off in an older blood vessel," Mendelsohn says.
In a younger woman, estrogen delays blood vessel disease. But in a woman with established coronary disease, estrogen can cause the built-up deposits in arteries to rupture and cause clots to form.
That new insight explains the previously contradictory research, experts say. The protective effect had been observed years ago in studies that observed the rates of heart attacks and heart disease in younger women on hormone therapy.
But the Women's Health Initiative, which enrolled more than 27,000 women randomly assigned to hormone therapy or placebo, largely enrolled older women who continued taking hormones into their 60s. That led to a higher rate of heart problems and the premature termination of the hormone replacement trial.
Experts considered the Women's Health Initiative more believable because it was a so-called randomized placebo-controlled trial – the gold standard of medical research.
Only recently, when researchers looked specifically at hormone therapy in younger versus older women and those who had been on hormone therapy for shorter or longer periods of time, did they discover estrogen's dual effect.
In retrospect, Manson says, the lesson is that researchers should pay attention to "the totality of the evidence," including both randomized trials and so-called observational studies.
But, she adds, if the Women's Health Initiative had not enrolled and randomized many older women, the link between hormone therapy and increased risk of heart disease in that group would have been missed.
Manson says it will take awhile before many women suffering from menopause symptoms choose hormone therapy.
"There was a lot of alarm five years ago, and many women who would otherwise be considered good candidates tossed their hormone pills and decided that the risk very likely outweighed the benefits," Manson says.
She says she hopes younger women with troublesome menopausal symptoms will consider the new evidence carefully — and try to understand why it took years of research to resolve the frustrating contradictions.