Study Links Hormones, Dementia

Times Staff Writer

In another blow against long-term use of hormone replacement therapy, a national study has found that women who take estrogen and progestin after menopause do not protect themselves against mental decline, but instead appear to double their risk for dementia.

The study, part of a large federally funded research project known as the Women’s Health Initiative, is the most comprehensive examination yet of the effects of hormones on cognitive decline. Its disappointing findings further limit the reasons for taking estrogen with progestin for anything other than short-term relief of symptoms at the time of menopause.

“The bottom line is there is really no reason for an older woman to take combination hormone therapy,” said Sally A. Shumaker, principle investigator of the memory study and a professor of public health sciences at Wake Forest University School of Medicine in Winston-Salem, N.C.

Doctors expressed dismay at the findings. Many had hoped, based on other evidence, that the therapy -- a long-established treatment used by millions of women -- would reduce, not increase, the risk of Alzheimer’s disease and other forms of dementia. Many women with a family history of Alzheimer’s disease -- the most common form of dementia, which currently afflicts an estimated 4 million people in the U.S. -- have opted to use hormones to try to avoid the same fate, said Dr. Jeffrey Cummings, director of UCLA’s Alzheimer’s Disease Center.


“Unequivocally, we’ll now recommend that estrogen plus progestin does not offer a benefit and may be a risk factor,” Cummings said.

The report is one more piece of bad news from the Women’s Health Initiative, which has delivered a series of disappointments about the effects of hormones on women’s health. In July, a segment of the study looking at women taking estrogen and progestin was abruptly terminated, three years early. A safety monitoring board concluded that an increased risk for breast cancer, heart attacks, blood clots and strokes uncovered by the study outweighed the therapy’s protective effects against osteoporosis and colorectal cancer.

Then, in March, another report from the initiative showed that the combination of estrogen and progestin did not improve the quality of life for post-menopausal women in such areas as emotional stability, sleep and sexual satisfaction.

Authors of the current study, published today in the Journal of the American Medical Assn., noted that although the risk of dementia was doubled, the number of new cases was still small. Each year, the hormone combination would be expected to result in 23 extra cases of dementia per 10,000 women.


The study consisted of 4,532 post-menopausal women ages 65 or older who were taking estrogen and progestin. Younger women were not included because dementia is very rare in women under age 65.

All women in the trial were declared free of dementia at the study’s outset. Half the women took a daily tablet of estrogen and progestin while the other half took an identical-appearing placebo.

At the start of the study and each year thereafter, participants took a mental test, known as the Modified Mini-Mental State examination, that is capable of identifying cognitive impairment.

Women with low scores were then referred for a more in-depth exam, including further mental tests, evaluation by a doctor and brain scans.


After five years, when the study was ended, 61 women had been diagnosed with probable dementia. Of these, 40 had been taking estrogen plus progestin and 21 had been taking a placebo.

The study found no difference in rates of mild cognitive impairment, such as memory loss, between the two groups of women.

The National Institute on Aging, a branch of the National Institutes of Health, issued a recommendation Tuesday that doctors should stop prescribing to older women a combination of estrogen and progestin for maintaining or improving cognitive function.

The authors of the study cautioned that their findings have limitations. For example, the study focused on women who were at least 65, and it is possible that effects on younger women might differ.


The study also comes to no conclusions about taking estrogen alone, which is an option available to women who do not have a uterus. The combination of progestin and estrogen is prescribed for women with a uterus to protect against uterine cancer.

The estrogen-only part of the study has not been terminated and is scheduled to run until March 2005. The study’s continuation suggests that estrogen alone is less harmful than estrogen combined with progestin, experts say, and might impart benefits that were blunted by adding the second hormone.

Scientists are uncertain why the combination of estrogen and progestin increases the dementia risk. They suspect it is tied to the heightened risk of blood clots and strokes uncovered in the study last year. Tiny blockages in the brain could kill brain tissue, said co-author Jennifer Hays, an associate professor of medicine at the Baylor College of Medicine in Houston.

In contrast, earlier studies had suggested that hormones would protect brain function, scientists said. In animal studies, estrogen appeared to protect nerve cells involved in memory from damage and death.


In addition, many epidemiological studies comparing women who chose to take hormones with those who did not had concluded that estrogen protects against Alzheimer’s.

But those studies had shortcomings, said Dr. Diana Petitti, director of research at Kaiser Permanente California in Pasadena. Often, they did not have accurate measures of hormone use in the two groups, relying on the memory of a spouse or that of a woman who already had mild cognitive impairment.

There were also differences between the women who decided to take hormones and those who did not. Women who take hormones tend to be healthier, less likely to smoke and more educated -- all of which could influence rates of dementia.

Also, many of the population studies were of women who took estrogen alone and not estrogen combined with progestin -- a possible key difference with the current study.