Hormone Therapy Could Increase Risk of
Dementia in Older Women
article syndicated from NIH
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
" 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
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 or by going directly to www.nih.gov/PHTindex.htm.
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
article syndicated from National Institutes of
EMBARGOED FOR RELEASE - Tuesday, June 22, 2004 - 4:00 p.m. ET