Estrogen Benefits Still in Question

Medically Reviewed by Craig H. Kliger, MD
From the WebMD Archives

March 20, 2001 -- Does taking hormone replacement therapy after menopause help prevent dementia and possibly Alzheimer's disease? Can the hormones increase a woman's risk for ovarian cancer? When it comes to the potential benefits, or risks, associated with hormone replacement therapy, it's hard to get a straight answer.

Three new studies in the March 21 issue of The Journal of the American Medical Association may help clear up some of the confusion, although not completely.

One complicated question: Does hormone replacement therapy, or HRT, actually protect women from mental decline as they age? Some studies have suggested it may. But numerous studies have tried to answer that question, and the results have still been mixed. Some studies have shown benefits on certain thinking and memory abilities, while others have shown no effect and some a harmful effect.

After evaluating dozens of studies identified in the medical literature from 1966-2000, Erin S. LeBlanc, MD, MPH, and colleagues found that only women with postmenopausal symptoms experienced improvements in thinking or memory while taking HRT. But the reasons for this are unclear and could be related to having fewer hot flashes and better sleep, compared with women not taking hormones.

LeBlanc and colleagues of Oregon Health Sciences University in Portland say the problem of the mixed messages is that most of the previous studies are flawed and conflicting, making it hard for women and their doctors to draw much conclusion from them about the value of hormones to protect against mental decline.

"Unfortunately, the message that has gotten out is that estrogen is of no value," says C. Dominique Toran-Allerand, MD, DSc, professor of neurobiology and behavior at Columbia University's College of Physicians and Surgeons in New York. "You can't say that on the basis of [the studies performed over the years], because those studies have been done incorrectly."

Toran-Allerand says that's because the estrogen in a woman's body is released on a carefully timed cycle, and no studies have tried to mimic that cycle after menopause to see if it protects women's brains.

Doctors are now making more of an effort to give women HRT that replicates that normal cycle, but many still receive estrogen on a continuous basis, which Toran-Allerand says can overload the estrogen receptors in the brain and make them less functional or kill them off. The receptors also become reduced in number or disappear when estrogen is stopped, such as in women who choose not to take hormones after menopause, she says.

Another study in the journal calls into question a fairly widely held belief that the natural estrogen to which a woman is exposed to before menopause plays an important role in protecting her from mental decline as she ages.

In a study of more than 3,600 women aged 55 years and older, researchers found that women who retain their reproductive capabilities longer -- and who are therefore exposed longer to natural estrogen -- had a higher risk of dementia than those with shorter reproductive periods.

"Insofar as reproductive period is a [sign] of long-term exposure to [naturally produced] estrogen, these findings do not support the hypothesis that high estrogen levels reduce the risk of dementia," write Mirjam I. Geerlings, PhD, and colleagues.

Geerlings, of Erasmus University Medical Center in Rotterdam, the Netherlands, says the study supports other research showing that high levels of natural estrogen are associated with poorer performance on some mental tasks.

Although the findings are reasonable, the study does not disprove the theory that estrogen might be playing an important role in the development of dementia as women age, says Zaven Khachaturian, PhD, director of the Alzheimer's Association's Ronald and Nancy Reagan Research Institute.

"Estrogen does more than just regulate a woman's reproductive cycle," he tells WebMD. "From an evolutionary point of view, it's a very old substance and it plays an important role in cell division, cell repair, and in protecting against toxins. So the idea of giving estrogen to preserve [mental ability] is probably more based on those mechanisms because it interacts with other substances such as nerve growth factor, which plays an important role in repair mechanisms."

But Khatchaturian says the definitive word is not yet in on what role estrogen plays in preventing or delaying dementia, which makes it hard for women and their doctors to make informed decisions about whether or not to take it for that reason.

Another study in the same issue of the journal finds that estrogen can significantly increase the risk of ovarian cancer when given for long periods of time.

"If this association is real ... women who have intact ovaries and are taking postmenopausal estrogen for 10 or more years may have twice the risk of dying from ovarian cancer than a woman who has never taken it," says Carmen Rodriguez, MD, MPH, of the American Cancer Society.

But Rodriguez, author of the study of more than 200,000 postmenopausal women, says women should not be frightened by the findings.

For one thing, the study was [largely] done before doctors started adding progestin to estrogen to protect the ovaries.

"We don't know what the effect of progestin is on ovarian cancer risk, and most women are taking combination therapy now," she says. In addition, the doses of estrogen in the study were higher than those given today.

Rodriguez says although ovarian cancer is relatively rare, women and their doctors should be mindful of the additional risk if estrogen alone was given for 10 years or more. Unfortunately, no screening tests or other preventive measure are available to accurately detect ovarian cancer in these women at this time, but a government research group is working on such a test, and Rodriguez says women who took estrogen long term likely will benefit most from it when it becomes available.