Not too long ago, long-term use of hormone replacement therapy (HRT) seemed like a great idea to many women. Taking estrogen after menopause, usually in combination with the hormone progestin, was purported to help maintain sexual vitality, supple skin, and energy. In addition, the hormones combated osteoporosis and preliminary research suggested that HRT might protect the heart, reduce the risk for dementia, and perhaps maintain memory and other mental skills.

By 1999, approximately 90 million American women were on HRT. But now the party is over for hormone replacement. According to a study in the January 7, 2004, Journal of the American Medical Association (JAMA), HRT prescriptions plummeted to 57 million in 2003. The reason? The Women’s Health Initiative (WHI), the first large-scale clinical trial of HRT in older women. Released in July 2002, the study found that the potential benefits of HRT were significantly outweighed by increased risk of heart attacks, blood clots, and breast cancer. Two additional studies based on the WHI research data showed no improvement in mental function in older women taking HRT and, more disturbing, a twofold increase in risk of dementia. This left a lot of women wondering: How could the preliminary research have been so wrong?

The WHI bombshell
The portion of the WHI trial halted prematurely in July 2002 involved 16,608 healthy women between the ages of 50 and 70. Half took an inactive placebo pill; the others took Prempro, a widely prescribed brand of HRT combining estrogen and progestin. Researchers stopped the trial after just over five years when they determined that the risks of HRT in this group of women exceeded the benefits. As part of the WHI, researchers also looked at the effect of long-term HRT on risk for dementia and whether it would prevent age-related decline in memory and other cognitive skills. In short, would estrogen protect the brain?

There was reason to believe it might. Studies with laboratory animals and cultured brain cells suggested that HRT boosts levels of acetylcholine, a chemical important to memory that declines in people with Alzheimer's disease. Estrogen also appears to reduce the formation of an abnormal protein, beta amyloid, that damages the brains of people with Alzheimer's. Estrogen increases the number of dendritic spines, the tree-like branches that allow brain cells to form connections. Estrogen also promotes the growth of brain cells and may enhance their blood supply.

Estrogen and rat brains
One of the pioneers in animal research on estrogen and the brain is Tracey J. Shors, Ph.D., an associate professor in the department of psychology and the Center for Collaborative Neuroscience at Rutgers University in Piscataway, New Jersey. Her experiments have shown that in female rats with their ovaries removed, large doses of estrogen improve learning and memory. Also, natural increases in estrogen that accompany ovulation have noticeable effects on mating behavior. “When estrogen levels go up, they become very different animals,” Shors explains. “They become more exploratory. They don’t eat as much, they don’t drink as much. They basically go out and find a mate. They go out and get pregnant.”

Enhanced learning and memory may be part of this generally heightened brain function. Estrogen-fueled mental sharpness could help the female rats get the job of reproduction done. “It’s an important time to be paying attention, to know what’s going on,” Shors says.

Estrogen and the aging brain
This rat research is fascinating, but what about humans? Anecdotally, some women going into menopause say they have memory lapses and impaired concentration. This raised the question of whether the decline in estrogen levels that comes with menopause contributes to memory impairment. And if so, would HRT counteract it? Also, would giving HRT to women with dementia help? Before the WHI, studies failed to establish that estrogen benefits women already diagnosed with Alzheimer’s disease. However, the question was still open whether it might prevent dementia in healthy older women. A study based on the WHI data, published in the May 23, 2003, JAMA, has laid that question to rest.

The dementia portion of the WHI study involved 4,532 women. All were 65 and older and were free of dementia at the start. After an average of four years, 40 women in the estrogen-plus- progestin group were diagnosed with dementia, compared to 21 taking an inactive placebo pill. This represented a doubling of risk. In absolute terms, this meant that out of every 10,000 women on HRT, an additional 23 would develop dementia compared to women not taking HRT.

An additional study based on the WHI data addressed the question of whether HRT would prevent age-related decline in memory and other mental skills. The study showed that it didn’t help. In fact, the trend was just the opposite: Women on HRT showed a slight decline in function as measured by a standard test called the Modified Mini-Mental State Exam (3MSE). However, it should be noted that the 3MSE is not considered a precise measure of mental function.

Where are we now?
The WHI is not the final word on estrogen and the brain, but it offers some important lessons. The risks of long-term HRT now appear to outweigh the benefits. While many women still use HRT temporarily to relieve hot flashes and other symptoms of menopause, doctors are advising them to taper off the therapy as soon as they can.

Another lesson concerns the standards of scientific evidence that were used to justify prescribing HRT to tens of millions of women, partly based on the expectation of health benefits not yet proven in a large, carefully designed scientific study. All that we knew before the WHI was that women who took HRT seemed to have a lower risk for Alzheimer’s and heart disease. Nobody could be sure, however, whether these women were simply in better health for reasons unrelated to HRT, or whether the HRT was having a positive effect. Only the “gold standard” of medical research—a randomized, placebo-controlled, double-blind clinical trial—can decide such questions.

Further Reading

“Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women,” by Sally A. Shumaker, PhD, and others. (Journal of the American Medical Association, May 28, 2003, Volume 289, Number 20, pp. 2651-2662).

“Effect of estrogen plus progestin on global cognitive function in postmenopausal women,” by Stephen R. Rapp, PhD, and others. (Journal of the American Medical Association, May 28, 2003, Volume 289, Number 20, pp. 2663-2672.)

Tracey J. Shors web site: www.rci.rutgers.edu/~shors/