| National Institutes of Health |
National Institute on Aging
Rates of Dementia Increase Among Older Women on Combination Hormone Therapy
Older women taking combination hormone therapy had twice the rate
of dementia, including Alzheimer’s disease (AD), compared with women
who did not take the medication, according to new findings from a
memory substudy of the Women’s Health Initiative (WHI). The
research, part of the Women’s Health Initiative Memory Study (WHIMS)
and reported in the May 28, 2003, Journal of the American Medical
Association (JAMA), found the heightened risk of
developing dementia in a study of women 65 and older taking
PremproTM, a particular form of
estrogen plus progestin hormone therapy.
The study also found that the combination therapy did not protect
against the development of Mild Cognitive Impairment, or MCI, a form
of cognitive decline less severe than dementia.
“Because of possible harm in some areas and lack of a
demonstrated benefit in others, we have concluded that combination
hormone therapy should not be prescribed at this time for older,
postmenopausal women to maintain or improve cognitive function,”
says Judith A. Salerno, M.D., M.S., Deputy Director of the National
Institute on Aging (NIA) at the National Institutes of Health (NIH),
U.S. Department of Health and Human Services.
The findings were reported by WHIMS Principal Investigator Sally
A. Shumaker, Ph.D., Wake Forest University School of Medicine,
Winston-Salem, NC, and colleagues at the 39 sites involved in the
study.
The memory substudy WHIMS was funded by Wyeth Pharmaceuticals,
which manufactures PremproTM, which
it provided for use in the WHI trials. The larger WHI trials are
supported by the National Heart, Lung, and Blood Institute (NHLBI)
of the NIH. The NIA has been involved in reviewing the current
findings as the NIH’s lead institute on age-related memory change
and dementia.
Importantly, the women in the combined estrogen plus progestin
arm of the WHI and substudies such as WHIMS are no longer taking the
combination therapy as part of the research trials. In July 2002,
all combination therapy components of the WHI were halted when it
was found that increased risk of breast cancer, heart disease,
stroke, and blood clots among participating women on combined
estrogen plus progestin therapy outweighed benefits for hip
fractures and colorectal cancer.
As they did in the July 2002 report on increased risk of breast
cancer, heart disease, and stroke, researchers stress with today’s
announcement that the data should be viewed in perspective. While
the increased risk of dementia is significant when calculated over a
large population of women, the risk to any individual older woman is
actually relatively small.
The current findings address combined estrogen plus progestin
therapy, specifically PremproTM,
among women 65 years of age and older. For younger women, the
cognitive risks and benefits of this combination therapy are
unknown. Short-term hormone therapy in younger women for some
symptoms of menopause has been approved by the U.S. Food and Drug
Administration and the new findings do not directly address
decisions about such treatment. Researchers and officials at the NIH
suggest that women of any age consult with a physician about their
individual risks and benefits.
The memory study findings on women 65 and older showed that over
a 5-year period:
- The risk for dementia among women taking estrogen and
progestin was twice that of women taking placebo pills. This
represents an increase per year from 22 women per 10,000 at risk
of dementia in the placebo group to 45 women per 10,000 in the
combination therapy group, an additional 23 cases per 10,000 per
year among women taking combination therapy. Sixty-one cases of
dementia were diagnosed among the 4,500 women participating in the
study; 66 percent of those cases occurred among women on
combination therapy while 34 percent occurred in women taking
placebo.
- Most of the dementia found among women participating in the
study was classified as probable Alzheimer’s disease, with
vascular dementia ranking second. There were 20 cases of
Alzheimer’s disease among the 40 dementia cases in women in the
combination therapy group (50 percent of the cases); in women on
placebo, 12 of the 21 cases (57 percent) of dementia were deemed
Alzheimer’s disease.
- There was no significant difference in the risk of being
diagnosed with MCI alone when the placebo and combination therapy
groups were compared.
About 4,500 women participated in the WHIMS substudy of women 65
and older. Once the women met the criteria for participation,
including screening tests to make sure they did not have dementia at
the study’s start, they were randomly assigned to take estrogen plus
progestin therapy (one pill per day of conjugated equine estrogen
(CEE), 0.625 mg, plus medroxyprogesterone acetate (MPA), 2.5 mg -
brand name PremproTM) or a
look-alike placebo. Cognitive status was evaluated annually, and
women who showed signs of decline were examined in greater depth to
further characterize their cognitive status.
The researchers looked at several other factors that might
influence cognitive status, including socioeconomic status,
educational attainment, prior estrogen or progestin use history, and
use of cholesterol lowering medications or aspirin or other
non-steroidal anti-inflammatory drugs. These factors were not
significantly different between the therapy group and the placebo
group and did not account for the differences in rates of cognitive
decline, the researchers said.
A second report in the same issue of JAMA showed general
cognitive status to be adversely affected by the combination therapy
in older women. WHIMS investigator Stephen Rapp, Ph.D., Wake Forest
University School of Medicine, and colleagues at the other sites
examined the participants’ performance on an often-used test, the
Modified Mini-Mental State Exam (3MS). All participants’ average
performance on the cognitive tests actually improved over time,
which researchers suggest may be due to a “practice effect” as a
result of taking the same tests every year. However, the rate of
increase in the performance of women on the 3MS was somewhat lower
for women in the combination therapy group when compared with women
receiving the placebo.
About 3,000 women are continuing to participate in a second arm
of the WHIMS research, a study of the effects on cognition of
estrogen-only therapy in women who have had a hysterectomy. A Data
Safety Monitoring Board will continue to monitor the risks and
benefits for that part of the study.
The NIH is considering implications of the dementia findings for
other clinical studies involving estrogen and progestin.
The text in this news release was prepared by the National Institute on Aging, National Institutes of Health.