Not too long ago, long-term use of hormone
replacement therapy (HRT) seemed like a great idea to
many women. Taking estrogen
usually in combination with the hormone
progestin, was purported to help maintain sexual vitality,
supple skin, and energy. In addition, the hormones combated
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
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
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,
decide such questions.
“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,
Tracey J. Shors web site: www.rci.rutgers.edu/~shors/