A decade ago, researchers shocked women around the world when they abruptly halted a landmark clinical trial on hormone therapy, a drug regimen widely used to relieve hot flashes, night sweats, and other unpleasant symptoms of menopause.
Just five years in, the study results suggested that hormone therapy increased the risk of several serious health conditions, including breast cancer, heart disease, and stroke. A follow-up study soon added Alzheimer's disease to the list, after finding that women taking hormones had higher rates of dementia than women taking placebo.
Since then, however, doctors have begun to reexamine hormone therapy and the conclusions of the trial, known as the Women's Health Initiative. In the latest such study, published today in the journal Neurology, researchers report that taking hormones may actually lower, not raise, the risk of developing Alzheimer's disease.
But there's a catch: The timing of therapy appears to be key. The study participants who initiated therapy within five years of starting menopause were 30% less likely than women who never took hormones to develop Alzheimer's later in life. Outside that timeframe, by contrast, hormone therapy increased Alzheimer's risk by a statistically insignificant 3%.
"Among women who started to take hormone therapy around this critical window around menopause, we observed a subsequent reduction in Alzheimer's disease 20 to 30 years later," says senior author Peter P. Zandi, Ph.D., an epidemiologist at the Johns Hopkins Bloomberg School of Public Health, in Baltimore. "But among women who initiated hormone therapy for the first time later in life, we started to see a trend towards increased risk."
The new evidence shouldn't be seen as an endorsement of hormone therapy, as the risks associated with the drugs continue to outweigh the benefits for many women.
On Monday, in fact, the United States Preventive Services Task Force, an independent panel of experts that advises the federal government on preventive care, restated its recommendation that hormone therapy not be used to prevent chronic conditions, most notably osteoporosis. The panel was silent on the use of hormones for hot flashes and other so-called vasomotor symptoms.
The new study isn't "a green light to use hormone therapy for Alzheimer's or dementia prevention," says Dr. Victor W. Henderson, M.D., an epidemiologist and professor of neurology at the Stanford University School of Medicine, in Stanford, California. "It does provide some reassurance that if a woman is considering hormone therapy for moderate to severe vasomotor symptoms, concerns about Alzheimer's disease should not impact [her] decision."
The study followed 1,768 women in Utah for 11 years, during which time they were screened for dementia on three separate occasions. All of the participants, who were at least 65 years old when the study began, had already passed through menopause but provided detailed information about their hormone use and age at menopause.
The idea of a critical timeframe in which hormone therapy may help, rather than hurt, is emerging as a leading hypothesis to explain the seemingly contradictory results of past studies on hormone use.
If the sudden depletion of estrogen associated with menopause weakens the aging brain, potentially paving the way for dementia,taking hormone drugs "may have some softening effect on that transition and…the pathologic chain of events leading to Alzheimer's," Zandi says.
But later in life, as Alzheimer's starts to set in, the brain may be a vastly different landscape that responds negatively to hormone therapy, Zandi adds.
The timing hypothesis has also been used to explain a similar pattern in the study results on hormone use and heart disease, a condition that appears to share some risk factors and mechanisms with Alzheimer's. Evidence suggests that the effect of estrogen on the cardiovascular system may depend on the system's underlying health, says Henderson, who coauthored an editorial accompanying the new study.
Timing probably isn't the only factor involved, however. The duration of therapy and the type of hormones used also may play an important role.
In this study, the risk of developing Alzheimer's was lowest in women who started hormone therapy early and also continued it for a decade or more. On the other end of the spectrum, the Alzheimer's risk associated with starting therapy later in life seemed to be highest among women who took estrogen plus progestin (common practice for women who still have a uterus), rather than estrogen alone.
Finally, hormone therapy in any form may reflect a healthier overall lifestyle, which could have shaped the study results. Although the authors controlled for an array of health measures and behaviors, this type of study, known as an observational study, can't entirely rule out extenuating factors unrelated to hormone therapy.
"Women taking hormone therapy were more health conscious in ways we didn't measure and account for," Zandi posits. "That could be a very reasonable explanation."