Estrogen-Alone Hormone Therapy Could Increase Risk of Dementia in Older Women
Older women using estrogen-alone hormone therapy could be at a
slightly greater risk of developing dementia, including Alzheimer's
disease (AD), than women who do not use any menopausal hormone therapy,
according to a new report by scientists with the Women's Health
Initiative Memory Study (WHIMS). The scientists also found that
estrogen alone did not prevent cognitive decline in these older
women. These findings from WHIMS appear in the June 23/30, 2004, Journal of the American Medical Association*.
"These studies further support last year's recommendations
that menopausal hormone therapy should not be used to prevent cognitive
decline or dementia in older postmenopausal women," stated
Judith A. Salerno, MD, MS, Deputy Director of the National Institute
on Aging (NIA). "Women should follow the Food and Drug Administration's
recommendation that those who want to use menopausal hormone therapy
to control their menopausal symptoms should use it at the lowest
effective dose for the shortest time necessary."
The latest findings were reported by WHIMS Principal Investigator
Sally A. Shumaker, PhD, Wake Forest University School of Medicine,
and her colleagues at the 39 study sites. This research was funded
by Wyeth Pharmaceuticals, which manufactures Premarin, the
conjugated equine estrogens used in this trial, and Wake Forest
University Baptist Medical Center. WHIMS is a substudy of the Women's
Health Initiative (WHI) Hormone Trial, which is funded by the National
Institutes of Health (NIH) at the Department of Health and Human
Services (DHHS). The National Institute on Aging (NIA), a component
of NIH, has been involved in reviewing the current findings as the
lead NIH institute on age-related cognitive change and dementia.
The WHI Hormone Trial using estrogen plus progestin was stopped
early in July 2002 when researchers found an increased risk of breast
cancer, along with greater risks of heart disease, stroke, and blood
clots, and determined that these risks outweighed the benefits of
reduced risks of hip fracture and colorectal cancer. In May 2003,
WHIMS investigators reported the results of the estrogen plus progestin
part of their memory substudy**. They found that estrogen plus progestin
increased the risk of probable dementia in women 65 and older and
did not preserve cognitive function. This part of WHIMS was also
stopped in July 2002.
At the end of February 2004, the remaining parts of the WHI Hormone
Trial and WHIMS, the estrogen-alone components, were halted because
results were showing an increased risk of stroke and no reduction
in the risk of heart disease in the women using estrogen alone.
Scientists further believed that continuing the study until its
planned conclusion next year would probably not add new information.
In April 2004, the WHI investigators reported that they found an
increased risk of blood clots, but no significant effect on breast
or colorectal cancer and also a reduced risk of fractures in those
women using estrogen alone.
Now, the WHIMS scientists have evaluated the cognition and dementia
data from the estrogen-alone part of the trial. Some 2,947 women
age 65 to 79 at the beginning of the trial received estrogen alone
(a daily dose of 0.625 mg of Premarin) or a placebo. (The
women received estrogen alone because they had all had hysterectomies
at some time before beginning the study. A progestin is used with
estrogen in menopausal hormone therapy in any woman with a uterus
to prevent thickening and, sometimes, cancer of the lining of the
uterus, the endometrium. Because the uterus is removed in a hysterectomy,
there is no need for progestin when women who have had hysterectomies
use menopausal hormone therapy.)
Participants were determined to be dementia free before they were
enrolled in WHIMS. At the beginning and then annually for the more
than 5-year average duration of the trial, WHIMS participants were
evaluated to determine if they might have developed dementia or
mild cognitive impairment (MCI). All women received the Modified
Mini Mental State Exam (3MSE), and those suspected of having dementia
also received an extensive clinical evaluation by a specialist physician.
At the end of the study, the risk of dementia in the estrogen-alone
group was 49% higher than the risk in women using the placebo. That
is, among 10,000 women using conjugated equine estrogens, 37 could
be expected to develop dementia, compared to 25 in 10,000 women
using the placebo 12 extra cases of dementia in every 10,000 women
using estrogen alone each year. This increased risk was not statistically
significant.
Last year WHIMS scientists reported a 105% increase in the risk
of dementia in older women using estrogen plus progestin compared
to those using a placebo. That means, on average, each year in 10,000
women over age 65 using estrogen plus progestin there might be 45
cases of dementia compared to 22 cases in 10,000 older women on
placebo.
Almost half of the dementia cases in the estrogen-alone study 46%
in older women using estrogen alone and 47% of those in older women
using the placebo were Alzheimer's disease (AD). Similarly, in the
estrogen plus progestin study, 50% of the cases in older women using
estrogen plus progestin and 57% of those in older women using placebo
were classified as AD.
A second article on general cognitive function *** from Mark A. Espeland,
PhD, and other WHIMS investigators appears in the same issue of
JAMA. It reports that beginning estrogen-alone hormone therapy after
age 65 can have a small negative effect on overall cognitive abilities
and that this negative effect may be greater in women with existing
cognitive problems. The differences in scores on cognitive testing
for the estrogen-alone and placebo groups were statistically significant,
but the differences were so small that they are not considered clinically
relevant by the investigators.
As with the earlier WHI and WHIMS result reports, these increases
in risk must be viewed in perspective. Significant increases in
risk are important for public health officials who are concerned
with large groups in the population, where a small increase could
have health implications for millions of people. For an individual
woman, however, the increased risk is still quite small. (A detailed
discussion of risk is presented in the NIA Fact Sheet, Understanding
Risk: What Do Those Headlines Really Mean?, available online
at http://www.niapublications.org/engagepages/risk.asp.)
Further, these findings relate to women age 65 and older taking
this particular estrogen-alone hormone therapy. The cognitive risks
and benefits for younger women using Premarin or other estrogen
formulations are unknown. Any younger woman who is considering menopausal
hormone therapy because of her menopausal symptoms should talk to
her doctor about how the various Women's Health Initiative study
findings relate to her own medical history and treatment.
General information on menopause, menopausal hormone therapy, and
the Women's Health Initiative can be found on the NIH home page,
www.nih.gov, by clicking on the
link "Menopausal Hormone Therapy," or by going directly
to www.nih.gov/PHTindex.htm.
The NIA leads the Federal research effort on aging in general
and on aging and memory, including Alzheimer's disease. For more
information on these topics, the public and media are invited to
visit the NIA's websites. Information on memory and Alzheimer's
disease may be viewed at www.alzheimers.org,
the NIA's Alzheimer's Disease Education and Referral (ADEAR) Center
website. The general public also may call the ADEAR Center toll
free at 1-800-438-4380. General information on health and aging
may be viewed at www.nia.nih.gov.
Publications may be ordered online at www.niapublications.org
or by calling the NIA Information Center toll free at 1-800-222-2225.
*
Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit
H, Stefanick ML, Hendrix S, Lewis CE, Masaki K, Coker LH, Conjugated
Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive
Impairment in Postmenopausal Women: Women's Health Initiative Memory
Study. JAMA. 2004; 291: 2947-2958.
**
Shumaker SA, Legault C, Rapp SR. Estrogen plus progestin and the
incidence of dementia and mild cognitive impairment in postmenopausal
women. The Women's Health Initiative Memory Study: a randomized
controlled trial. JAMA. 2003; 289:2651-2662.
Rapp S, Espeland MA, Shumaker SA, et al. Effect of estrogen plus
progestin on global cognitive function in postmenopausal women:
Women's Health Initiative Memory Study; A Randomized Controlled
Trial. JAMA. 2003; 289: 2663-2672.
***
Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin
BB, Hsia J, Margolis KL, Hogen PE, Wallace R, Dailey M, Freeman
R, Hays J for the Women's Health Initiative Memory Study. Conjugated
Equine Estrogens and Global Cognitive Function in Postmenopausal
Women: Women's Health Initiative Memory Study. JAMA. 2004; 291:
2959-2968.
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