Context Postmenopausal women have a greater risk than men of developing Alzheimer
disease, but studies of the effects of estrogen therapy on Alzheimer disease
have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin,
in the Women's Health Initiative (WHI) trial were discontinued because of
certain increased health risks in women receiving combined hormone therapy.
Objective To evaluate the effect of estrogen plus progestin on the incidence of
dementia and mild cognitive impairment compared with placebo.
Design, Setting, and Participants The Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind,
placebo-controlled clinical trial, began enrolling participants from the Women's
Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the
4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women
free of probable dementia, aged 65 years or older, and recruited from 39 of
40 WHI clinical centers were enrolled in the WHIMS.
Intervention Participants received either 1 daily tablet of 0.625 mg of conjugated
equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or
a matching placebo (n = 2303).
Main Outcome Measures Incidence of probable dementia (primary outcome) and mild cognitive
impairment (secondary outcome) were identified through a structured clinical
Results The mean (SD) time between the date of randomization into WHI and the
last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants
was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia,
40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the
placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence
interval [CI], 1.21-3.48; 45 vs 22 per 10 000 person-years; P = .01). This increased risk would result in an additional 23 cases
of dementia per 10 000 women per year. Alzheimer disease was the most
common classification of dementia in both study groups. Treatment effects
on mild cognitive impairment did not differ between groups (HR, 1.07; 95%
CI, 0.74-1.55; 63 vs 59 cases per 10 000 person-years; P = .72).
Conclusions Estrogen plus progestin therapy increased the risk for probable dementia
in postmenopausal women aged 65 years or older. In addition, estrogen plus
progestin therapy did not prevent mild cognitive impairment in these women.
These findings, coupled with previously reported WHI data, support the conclusion
that the risks of estrogen plus progestin outweigh the benefits.
Approximately 10% of persons older than 65 years and about 50% of those
older than 85 years have Alzheimer disease (AD).1 At
present, this represents approximately 4 million persons in the United States,
and that number is projected to increase to 14 million by the year 2040.2
Postmenopausal women may have a greater risk of developing AD than men,3 perhaps due to lower endogenous estrogen levels following
menopause.4,5 Estrogen's protective
effects on the brain may include promoting cholinergic activity, reducing
neuronal loss and stimulating axonal sprouting and dendritic spine formation,
reducing cerebral ischemia by improving blood flow and reducing cholesterol
levels, and modulating expression of the apolipoprotein E gene.6,7
Support for the estrogen deficiency hypothesis as one cause of dementia
comes from reported positive associations between exogenous estrogen and cognitive
performance in older women without dementia.8-14 In
addition, case-control,15,16 cross-sectional,17 and prospective studies11,18-22 have
reported a lower risk of dementia for women taking compared with those not
taking postmenopausal estrogen. Two recent meta-analyses of estrogen and dementia
reported risk reductions of 29%23 and 34%,24 yet several prospective observational studies found
no protective effect of estrogen on either cognition or the incidence of dementia.21,22,25,26 In
addition, clinical trials of unopposed estrogen in women with AD have shown
no beneficial effect on cognitive performance.27-29 Moreover,
recent reviews point to serious methodological problems in most studies.30,31 Thus, the mixed findings underscore
the need for a large, well-designed randomized controlled trial.
The Women's Health Initiative Memory Study (WHIMS),32 an
ancillary study to the 2 larger Women's Health Initiative (WHI) hormone therapy
trials, is examining whether postmenopausal estrogen supplementation (both
estrogen alone and estrogen plus progestin) reduces the risk of all-cause
dementia (primary outcome) and subclinical (mild) cognitive impairment (secondary
outcome) in healthy women aged 65 years or older. Study drug administration
in the planned 8.5-year trial for estrogen plus progestin was discontinued
after 5.6 years because women in the intervention group were at increased
risk for heart disease, stroke, pulmonary embolism, and breast cancer compared
with women receiving placebo, and these risks outweighed the beneficial effects
of estrogen plus progestin on colon cancer and osteoporotic fracture.33 The WHI estrogen-only hormone therapy trial, which
enrolled women with a prior hysterectomy, continues, as does the WHIMS component
of this trial. The data reported herein are from the estrogen plus progestin
and the placebo components of the WHIMS.
WHI Hormone Therapy Trials: Participant Enrollment
The WHIMS trial was started in June 1995. All participants who were
enrolled in the WHIMS trial first met enrollment criteria and then provided
written consent to participate in the WHI hormone therapy trials. The eligibility
criteria and recruitment procedures for the WHI hormone therapy trials34 and more specific information about the estrogen
plus progestin trial have been published.33 Briefly,
in the WHI estrogen plus progestin trial, women 50 through 79 years of age
at initial screening and with an intact uterus were potentially eligible.
A 3-month washout period was required before baseline evaluation of women
using postmenopausal hormones at initial screening. Major exclusions related
to competing risks (invasive cancer in the past 10 years; breast cancer at
any time or suspicion of breast cancer at baseline screening; acute myocardial
infarction, stroke, or transient ischemic attack in the previous 6 months;
or known chronic active hepatitis or severe cirrhosis), safety (blood cell
counts indicative of disease; severe hypertension; or current use of oral
corticosteroids), and adherence or retention concerns (unwillingness or inability
to complete baseline study requirements).
Participants had 3 screening visits before enrollment. At the third
screening visit, if the participants complied with taking study medication
during the 28-day run-in phase (participants could have up to 2 run-in phases
and still be eligible for the trial), met all inclusion and exclusion criteria,
remained interested in participating, and signed an informed consent for the
WHI estrogen plus progestin trial, they were randomly assigned to take either
1 daily tablet that contained conjugated equine estrogen, 0.625 mg, and medroxyprogesterone
acetate, 2.5 mg (PremPro, Wyeth Pharmaceuticals, Philadelphia, Pa), or a matching
placebo (also provided by Wyeth Pharmaceuticals). Randomization was determined
using a permuted block algorithm that was stratified according to age group
and clinical center site with implementation by the WHI Clinical Coordinating
Center (CCC) (Fred Hutchinson Cancer Research Center, Seattle, Wash). Participants
were given their next supply of study pills semiannually. They returned annually
for clinic visits and were contacted semiannually for safety and outcomes
WHIMS Participant Enrollment
Thirty-nine of the 40 WHI clinical centers elected to participate in
the WHIMS trial. Women were enrolled in the WHIMS trial between May 28, 1996,
and December 13, 1999. The trial was designed to evaluate the effects of the
combination of estrogen with and without progestin vs placebo on all-cause
dementia (primary outcome), mild cognitive impairment (MCI) (secondary outcome),
and global cognitive functioning (reported in Rapp et al35).
However, the early discontinuation of study drug administration of estrogen
plus progestin in the WHI trial resulted in the early, unplanned examination
of this same component within the WHIMS.
Participants were recruited during WHI hormone therapy trial enrollment
from participants in the estrogen plus progestin trial who were aged 65 years
or older and free of probable dementia, as determined by the WHIMS protocol
(described below). No other inclusion/exclusion criteria were required. In
addition, prospective WHIMS participants were asked to name a friend or family
member (ie, the designated informant) who could provide information regarding
the participant's cognitive and behavioral functioning. At a WHI screening
visit, prospective WHIMS participants were informed about the study objectives,
design, and requirements, and written informed consent was obtained. Ninety-nine
percent of the WHIMS participants were enrolled within less than 6 weeks of
WHI hormone therapy randomization, and 45 women (1.0%) were enrolled after
randomization (Figure 1).
Of the 4894 women eligible for the estrogen plus progestin component
of the WHIMS, 4532 (92.6%) had consented to participate. Study coordination
for the WHIMS was provided by the WHIMS CCC, the central administrative and
data site (Wake Forest University Health Sciences, Winston-Salem, NC). The
National Institutes of Health and the institutional review boards for all
participating institutions approved the WHI and WHIMS protocols and consent
WHIMS Detection of Probable Dementia and MCI
A detailed description of the WHIMS protocol has been published previously.32 Technicians who were centrally trained and certified
by the WHIMS CCC collected all WHIMS-specific data. In addition, some baseline
data collected in the WHI hormone therapy trials (eg, demographic characteristics)
were used in the WHIMS analyses. To maintain strict quality control in the
administration of WHIMS-related measures, all technicians were centrally recertified
The WHIMS dementia ascertainment protocol was divided into 4 phases.
In phase 1, all participants completed the Modified Mini-Mental State Examination
(3MSE)36 at baseline and annually thereafter.
The 3MSE was used to screen for global cognitive impairment and to track changes
in global cognitive function (reported in Rapp et al35).
Initially, participants with 3MSE scores of 72 or lower (for participants
with ≤8 years of education) or of 76 or lower (for participants with ≥9
years of education) were identified for an expanded neuropsychological battery
and clinical examination (phases 2 and 3), with an estimated sensitivity of
80% and specificity of 85% based on earlier studies.37,38 After
16 months, the protocol was altered to increase the sensitivity (at the expense
of specificity) of the 3MSE to ensure that we successfully detected any women
with MCI or dementia. New cut points of 80 or lower (for participants with
≤8 years of education) and 88 or lower (for participants with ≥9 years
of education) were implemented prospectively.37,39 Participants
scoring below these cut points on their yearly cognitive screening went on
to phases 2 and 3 of the WHIMS protocol.
In phase 2 of the WHIMS, certified technicians administered a modified
Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological
battery.40 The battery contains tests measuring
verbal fluency (animal category),41 naming
(15-item Boston Naming Test),42 verbal learning
and memory (10-item, 3-trial word list memory task with delayed recall, and
recognition tasks),43 constructional praxis
(4 line drawings are copied and later recalled),44 and
executive function (Trail-Making Test, parts A and B).45 Certified
technicians also administered standardized interviews to assess behavioral
symptoms, such as generalized anxiety, major depression, and alcohol abuse,46 and the 15-item Geriatric Depression Scale.47 Lastly, both the participant and her designated informant
were administered separately a standardized set of 36 items (yes/no) that
assessed observed cognitive and behavioral deficits (memory, language, orientation,
personality/behavior, basic and instrumental activities of daily living, social
and intellectual activities, and judgment and problem solving).32 All
participants in phase 2 also completed phase 3.
In phase 3 of the WHIMS, participants were evaluated by a physician
(ie, geriatrician, neurologist, or geriatric psychiatrist) who was identified
by the local WHIMS clinical center and approved by the WHIMS CCC as having
the experience required for diagnosing dementia. WHIMS clinicians were provided
with a detailed protocol for their portion of the assessment. The clinicians
reviewed all data collected on the WHIMS participant in phases 1 and 2 and
completed a structured medical history, which focused particularly on possible
causes of cognitive impairment, and a physical and neuropsychiatric examination.
The local expert then classified the WHIMS participant as having no dementia,
MCI, or probable dementia based on Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.48 Mild cognitive impairment
was operationally defined as poor performance (10th or lower percentile) on
modified CERAD tests in at least 1 area of cognitive function, a report of
some functional impairment reported by the designated informant but not in
a basic activity of daily living, no evidence of a psychiatric disorder or
medical condition that could account for the decline in cognitive function,
review of past 3MSE scores or phase 2 through 4 data that suggested a decline
from the woman's baseline functioning score, and an absence of dementia.49 If the clinician suspected probable dementia, the
participant went on to phase 4 of the WHIMS trial, in which she was referred
for a computed tomography scan of the brain (without contrast) and laboratory
blood tests to rule out possible reversible causes of cognitive decline and
dementia. If dementia was judged present, the clinician was required to specify
the most probable etiology based on all findings. In classifying the participants'
dementia, the clinician followed the WHIMS protocol, which was based on DSM-IV criteria and included detailed descriptions for
diagnosis of vascular dementia and AD, as well as other dementia-related classifications.
All clinical and test data were then transmitted to the WHIMS CCC for review
and central adjudication.
The central adjudication committee at the WHIMS CCC consists of 3 board
certified specialists (2 neurologists and 1 geriatric psychiatrist) with extensive
experience in diagnosing dementias. The adjudicators independently reviewed
all probable dementia cases identified by the local clinician, a random sample
of 50% of MCI cases, and a random sample of 10% of cases without dementia.
All information on a given participant's test scores, except the field clinician's
classification, was provided to 2 of the 3 adjudicators, who independently
evaluated the data and assigned a classification. The field clinician's diagnostic
assessment was then shared with each adjudicator, who independently made a
revised diagnosis. If all the adjudicators agreed, this was considered the
consensus diagnosis. If they disagreed, the adjudicators discussed the case
and attempted to make a consensus classification. The adjudication committee
and a geriatric psychologist, discussed all cases of disagreement until they
reached a consensus classification. The same process was followed to reach
consensus on the etiologic classification of the dementia. Regardless of the
participants' classification, all continued to be screened annually thereafter
with the 3MSE.
All WHIMS-certified technicians, local WHIMS physicians, and WHIMS adjudicators
were blinded to participants' treatment assignment. The certified technicians
and local physicians were held to the same rigorous blinding protocol that
is present throughout the WHI. That is, official unblinding (to address safety
issues) occurred through a designated unblinding officer at each site. The
unblinding officer was the only individual authorized to access unblinding
information in the WHI database and to provide this information to the clinic's
consulting gynecologist. This information was not recorded in the participants'
clinic files or provided to any individuals involved in outcomes ascertainment
or coding. The adjudicators were independent of the clinical center clinicians;
data provided to them were blinded.
Adherence data for hormone therapy were collected annually after randomization.
According to WHI criteria, a participant became nonadherent by stopping study
medication by her own decision or for protocol-based safety issues, by taking
less than 80% of her pills between dispensing and collection, or by starting
prescribed hormone therapy outside of the main WHI hormone therapy trials.
For these 3 criteria, the earliest nonadherence date was selected and follow-up
data were censored 6 months later for secondary analyses examining the effect
of nonadherence on hormone therapy.
The WHIMS trial was designed to provide more than 80% statistical power
to detect an observed 40% relative reduction in the incidence rate of clinically
diagnosed all-cause dementia associated with randomization to receive hormone
therapy either with or without progestin.27 Based
on a projected enrollment of 8300 women, approximately 165 incident cases
of all-cause dementia were expected over 5 years. When the estrogen plus progestin
component of the WHI trial was terminated, 61 cases of all-cause dementia
were identified. Post hoc calculations indicate that the WHIMS estrogen plus
progestin trial provided 80% statistical power to detect a hazard ratio (HR)
of 1.89 at the 5% significance level. Survival analyses were conducted on
intention-to-treat principles for all eligible WHI estrogen plus progestin
participants enrolled in the WHIMS (4532/4894, [92.6%]). One hundred fifty-one
participants in the WHIMS had only a baseline 3MSE score. Mean (SD) baseline
3MSE scores did not differ significantly between the 2 intervention groups
for these participants (estrogen plus progestin, 94.15 [4.1] and placebo,
95.18 [4.1], P = .28). A survival time equal to zero
was assigned to these 151 participants and they were included in the overall
We compared the effect of estrogen plus progestin and placebo on the
primary outcome of probable dementia. All events up to July 8, 2002, when
the study drug in the WHI estrogen plus progestin trial was discontinued,
were included in the analyses and were adjudicated as described in the section
"Adjudication Process." Hazard ratios and nominal 95% confidence intervals
(CIs) from unadjusted Cox proportional hazards models50 were
compared between the treatment and placebo groups. Given the wide range of
clinical and behavioral outcomes examined in the WHI estrogen plus progestin
trial, some nominal CIs may exclude 1 based on chance alone. The time to event
was defined as the number of days from randomization into the WHI estrogen
plus progestin trial to the date of the 3MSE that initiated the referral for
additional cognitive testing resulting in the first postrandomization diagnosis.
Participants without a diagnosis were censored at their last follow-up contact
before July 8, 2002. Cumulative hazards ratios are presented. A significance
level of less than .05 was used for all primary analyses. WHIMS analyses for
the effects of estrogen plus progestin on global cognitive function are reported
Secondary analyses were conducted for participants with a diagnosis
of MCI only and of probable dementia or MCI. Cox proportional hazards models
were fitted separately with treatment assignment and 1 of the following 10
baseline factors as independent variables: age; education; self-reported history
of stroke or diabetes; prior use of hormone therapy, unopposed estrogen, estrogen
plus progestin, statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors),
or aspirin; and baseline 3MSE scores. In each of the 10 models, the interaction
between treatment assignment and the factor was tested; HRs are presented
for subgroups defined by these factors and a Bonferroni adjustment was used
to control for type I error (.05/10 = .005). Additional secondary analyses
also were conducted censoring participants 6 months after they became nonadherent
and when they started using statins. We used SAS release 8.2 (SAS Institute
Inc, Cary, NC) for the statistical analyses.
The monitoring of the WHI hormone therapy trial was conducted semiannually
by an independent data and safety monitoring board. Trial-monitoring guidelines
for early stopping considerations have been published.51 Although
not part of the stopping rules, the WHIMS data were reviewed in conjunction
with the overall assessment of risk/benefit by the monitoring board.
Figure 1 depicts the enrollment
and referrals to additional cognitive testing (phases 2-4) for the WHIMS cohort.
Participants could be referred to phase 2 more than once if they did not meet
diagnostic criteria for probable dementia or MCI. The total number of referrals
for phases 2 through 4 in the estrogen plus progestin group were 213 in phase
2, 201 in phase 3, and 40 in phase 4. In the placebo group, the total number
of referrals were 165 in phase 2, 157 in phase 3, and 27 in phase 4. Of the
58 participants (62 referrals) who refused further testing at least once,
22 (38%) had subsequent visits at which a diagnosis was made. Furthermore,
of the 32 participants (34 referrals) with incomplete data, 13 (41%) also
had a diagnosis at a subsequent visit. The mean (SD) time between the last
3MSE and the date of randomization into the WHI for all WHIMS participants
was 4.05 (1.19) years.
Table 1 lists baseline characteristics
of WHIMS participants by treatment assignment at enrollment into the WHI trial.
Other demographic data are described elsewhere.35 Nearly
half of the participants were 65 to 70 years old. No significant differences
were found between study groups at baseline, including smoking, except for
the slightly lower prevalence of stroke (P = .01)
and the slightly higher percentage of participants using statins (P = .02) in the estrogen plus progestin group. Adherence rates were
lower each year for participants assigned to receive estrogen plus progestin
compared with participants assigned to receive placebo (P<.001).
Overall, 61 participants from 31 of the 39 clinical centers (range,
0-4 participants per clinical center) were diagnosed with probable dementia:
40 (66%) in the estrogen plus progestin group and 21 (34%) in the placebo
group (Table 2). The rate of women
experiencing probable dementia in the estrogen plus progestin group was twice
that of women in the placebo group (HR, 2.05; 95% CI, 1.21-3.48; 45 vs 22
per 10 000 person-years, P = .01) (Figure 2). Cumulative hazards ratios indicate
that the 2 groups began to diverge 1 year after randomization and that the
differences continued through 5 years of follow-up (Figure 2). Twenty-eight participants in the estrogen plus progestin
group and 13 in the placebo group were diagnosed with probable dementia after
the 3MSE cut point for referral to further cognitive screening was changed.
These data support the improved sensitivity in identifying probable dementia
cases achieved by implementing the revised cut points on the 3MSE. After excluding
265 participants at higher risk for developing dementia at baseline (ie, participants
with 3MSE scores at or below the screening cut point), the HR for probable
dementia was 2.64 (95% CI, 1.26-5.53), with 24 and 10 cases in the estrogen
plus progestin and the placebo groups, respectively.
Alzheimer disease was the most common classification in both the estrogen
plus progestin (20 [50.0%]) and the placebo (12 [57.1%]) groups (P = .79, Table 3). Seventy-five
participants had a stroke during follow-up (39 in the estrogen plus progestin
group and 36 in the placebo group), but only 1 participant diagnosed with
probable dementia (who was in the estrogen plus progestin group) had a stroke
during the trial before her diagnosis. Two other participants diagnosed with
probable dementia in the estrogen plus progestin group had a history of stroke.
Diagnoses from local clinicians were compared with those from central
adjudicators to determine the rate of agreement (Table 4). In the estrogen plus progestin group, 80% of the diagnoses
made by local clinicians agreed with the diagnoses of those made by the central
adjudicators, as did 76% in the placebo group (κ = 0.66, 95% CI, 0.59-0.74).
Of the 82 clinician diagnoses of no dementia in the estrogen plus progestin
group, 78 were adjudicated as no dementia and 4 as MCI. In the placebo group,
56 of the 61 clinician diagnoses of no dementia were adjudicated as no dementia
and 5 as MCI. Most disagreements resulted in a less serious classification
by the central adjudicators. Sixty-six cases were diagnosed with probable
dementia by local clinicians, 42 in the estrogen plus progestin group, and
24 in the placebo group, yielding an HR of 1.88 (95% CI, 1.14-3.10; P = .01).
At some point during the trial, 2534 participants were nonadherent.
When nonadherent participants were censored 6 months after first becoming
nonadherent, the number of probable dementia cases that occurred before censoring
was reduced to 21 in the estrogen plus progestin group and to 6 in the placebo
group. The risk of being diagnosed with probable dementia was 3.22 times greater
in the estrogen plus progestin group (95% CI, 1.25-8.29; P = .02) (data not shown in tables).
The percentage of participants using statins in the estrogen plus progestin
and placebo groups was 12.0% and 9.8%, respectively, at baseline (P = .02) (Table 1); 13.4%
and 14.1% at year 1 (P = .49); 16.6% and 19.7% at
year 3 (P = .01) and 24.3% and 23.1% at year 6 (P = .85) (data not shown in tables). After censoring at
the time participants started using statins during the trial, the estrogen
plus progestin group had 33 cases and the placebo group had 18 cases of probable
dementia. The risk of being diagnosed with probable dementia among participants
not starting statins was 1.93 times greater in the estrogen plus progestin
group (95% CI, 1.09-3.43; P = .03) (data not shown
Mild Cognitive Impairment
In the estrogen plus progestin group, 45 participants were diagnosed
with MCI who did not proceed to probable dementia during trial follow-up,
11 with MCI followed by probable dementia, and 29 with probable dementia not
preceded by an MCI diagnosis, compared with 45, 10, and 11, respectively,
in the placebo group. The risk of being diagnosed with MCI was not statistically
different between the women in the estrogen plus progestin group and those
in the placebo group (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10 000
person-years; P = .72) (Table 2, Figure 2). The
risk of being diagnosed with MCI or probable dementia was increased by 37%
for women taking estrogen plus progestin compared with placebo (HR, 1.37;
95% CI, 0.99-1.89; 95 vs 71 cases per 10 000 person-years, P = .06) (Table 2 and Figure 2). Figure 2 shows that these rates began to separate in the first year.
Dementia Risk by Subgroup
Table 5 shows the rates
per 10 000 person-years of probable dementia diagnoses for the 10 subgroups
defined at baseline by dementia-related variables and treatment assignment.
No interaction between treatment assignment and these factors reached statistical
significance (P>.05 for all). In separate models
including the main effects of treatment and a factor, the HR for treatment
remained similar to the unadjusted ratio (range, 1.95-2.14) (data not shown).
Effects of Age and Baseline 3MSE Scores
In their respective models, main effects for age and baseline 3MSE scores
alone were statistically significant (P<.001 for
both). Specifically, the risk of developing probable dementia was 3.54 times
(95% CI, 1.57-8.00) greater for women aged 70 to 74 years, and 12.22 times
(95% CI, 5.60-26.65) greater for women aged 75 to 80 years than for women
aged 65 to 69 years. The risk of developing probable dementia was 3.78 times
(95% CI, 1.91-7.50) greater for women with baseline 3MSE scores ranging from
above the screening cut point to 94, and 24.84 times (95% CI, 13.19-46.75)
greater for women with baseline 3MSE scores at or below the screening cut
point, than for women with baseline 3MSE scores ranging from 95 to 100.
To our knowledge, the WHIMS is the largest among randomized clinical
trials assessing the effects of estrogen plus progestin on dementia and MCI,
and it provides the most detailed characterization of a cohort at baseline
and follow-up, the longest follow-up time, an extensive and well-documented
battery of cognitive assessments, and rigorous quality control in ascertainment
of events. Of the 4532 participants in the estrogen plus progestin component
of the WHIMS trial, 61 were diagnosed with probable dementia; 40 (66%) in
the estrogen plus progestin group compared with 21 (34%) in the placebo group.
Overall, the risk of probable dementia for women in the estrogen plus progestin
group was twice that of women in the placebo group, and evidence of an increased
risk began to appear as early as 1 year after randomization, with differences
persisting over 5 years of follow-up. In additional analyses assessing the
influence of baseline risks associated with dementia, the higher risk of probable
dementia for women in the treatment group remained. Controlling for adherence
did not alter the findings. The pattern of results was similar for all-cause
probable dementia and for the specific classifications of probable dementia
(ie, AD, vascular dementia, and other etiologies). These results are unexpected
and in striking contrast to most of the earlier research on the effects of
hormone therapy on AD and dementia.
Most research on hormone therapy and cognition of postmenopausal women
evaluates cognitive function, not dementia.35 The
less extensive research on the possible role of hormone therapy for the prevention
of dementia is primarily observational and focuses on AD as opposed to all-cause
dementia. These studies vary substantially in terms of the participants' characteristics
and the study design (eg, sample size, years of follow-up), as well as in
the use of cognitive tests or test batteries for determination of dementia
status.30 In a meta-analysis of 14 epidemiologic
studies assessing the risk of AD, the overall odds ratio associated with estrogen
use was 0.56.30 Early and less rigorous epidemiologic
studies showed no "protective" effects of estrogen, unlike the later and larger
investigations. It is probable that a greater proportion of women used estrogen
alone in the earlier studies. However, for the most part, investigators did
not distinguish between estrogen alone vs estrogen plus progestin, and when
these distinctions were made, benefits regarding prevention of AD were found
for both treatments. In contrast, in one observational study, investigators
noted a slight improvement in cognitive function for those women taking estrogen
alone, but a decline among those women taking estrogen plus progestin therapy.52
In the estrogen plus progestin component of the WHIMS, cases of probable
dementia appeared in the first year of intervention in both the active hormone
and the placebo groups (Figure 2).
This observation suggests that some participants already had cognitive decline
at baseline. Thus, rather than slowing progression of the symptoms associated
with probable dementia, estrogen plus progestin increased progression to probable
dementia. An alternative possibility is that the distribution of pre-existing
cognitive decline favored the placebo group. However, this is unlikely because
when low baseline 3MSE scores were deleted from the analyses, an increased
risk for probable dementia in the estrogen plus progestin group remained (HR
for probable dementia, 2.64).
The short interval required to see an effect of estrogen plus progestin
on dementia may have implications for understanding the pathogenesis of dementia
related to hormonal therapy. One hypothesis relates to the increased risk
of stroke seen in the results of the WHI estrogen plus progestin trial. Although
the risk of probable dementia was increased even in WHIMS participants without
previous or incident strokes, we cannot determine from these data whether
small, undetected cerebrovascular events were more likely to occur in the
estrogen plus progestin participants or whether such events could have increased
risk for probable dementia. Recent studies suggest an overlap in pathophysiological
mechanisms and clinical symptoms between AD and vascular dementia. As noted
by Kalaria et al,53 standard clinical diagnostic
methods tend to favor a designation of AD over vascular dementia when both
may be present. Jellinger et al54 suggested
that in ischemic vascular dementia, cognitive decline is often associated
with small widespread lesions (microinfarcts or lacunae) that may both interact
with early AD and promote Parkinson disease. Furthermore, early AD and microinfarcts
may interact in promoting probable dementia.54 Silent
brain infarcts more than doubled the risk of dementia in 1015 participants
(52% women) in the Rotterdam Scan Study.55 Autopsy
data from the Nun Study56 support this hypothesis.
In addition, in the Cardiovascular Health Study (N = 3608), magnetic resonance
imaging brain scans, apolipoprotein E4 levels, and measures of cognitive function
were all strong predictors of AD and dementia.57
Few observational studies have distinguished between the effects of
estrogen alone and estrogen plus progestin on dementia. Basic science studies
have produced many insights regarding possibly beneficial roles of unopposed
estrogens in brain function. Although some studies suggest the effects of
unopposed estrogen may be transitory or even harmful,58,59 on
balance most studies support the protective effects of estrogen in both in
vitro and in vivo studies.60-66 However,
far less is understood regarding the effects of progesterone. In the few studies
that do exist—in cell culture systems,67 rat
models,68 and cynomolgus monkeys69—the
combination of estrogen plus progesterone appears to reverse the positive
effects of estrogen alone.
The risks for probable dementia associated with estrogen plus progestin
continued throughout the study, suggesting that mechanisms that require longer-term
exposure may also be in place. The manifold effects of exogenous and endogenous
hormones on brain function deserve greater scrutiny in unraveling possible
pathogenetic mechanisms, including identifying individuals at high risk of
hormone therapy–related consequences.
Studies support a prospective association between diabetes and cognitive
decline and dementia,70-72 although
findings are complex and data on this relationship in women are limited (see
Coker and Shumaker73 for a recent review).
In the current analyses, history of diabetes was self-reported. Few cases
of prior diabetes were reported and no relationship was identified between
diabetes and dementia. Similarly, there is a growing body of literature on
the potential protective effects of statins on cognitive decline and dementia.74-76 Controlling for prior
statin use and censoring for onset of statin use after randomization did not
alter the effects found in the current study. Data were not available on family
history of dementia or apolipoprotein E4 levels for the WHIMS participants.
Thus, we were unable to test for a possible interaction between these factors
and hormone treatment for dementia.
Despite the significant negative effect of estrogen plus progestin on
risk for developing probable dementia, our findings need to be kept in perspective.
Although participants assigned to active therapy were at twice the risk for
dementia, the absolute risk is relatively small. That is, for every 10 000
postmenopausal women aged 65 years or older with risk factor profiles similar
to those of WHIMS participants who took estrogen plus progestin for 1 year,
45 would be diagnosed with probable dementia vs 22 women taking placebo. This
increased risk would result in an additional 23 cases of dementia per 10 000
women per year. The total number of cases of dementia was small in the WHIMS
(n = 61). This is in keeping with both the age of the cohort and the expectation
that healthier, cognitively and behaviorally competent women were more likely
to have enrolled in this complex and rigorously conducted clinical trial.
This effect of enrolling healthy participants on clinical trial results has
been previously reported, at least in epidemiologic research.77
The WHIMS results are specific to the use of conjugated equine estrogen
plus medroxyprogesterone acetate, and may not apply to other estrogen/progestin
combinations, doses, or routes of administration. However, no current evidence
is available showing that other estrogen plus progestin therapies would lead
to substantially different outcomes. The WHIMS estrogen plus progestin trial
was restricted to women aged 65 years or older. Some investigators have suggested
that for hormone therapy to prevent probable dementia, women must initiate
its use around the menopause.78-80 This
alternative hypothesis cannot be tested in the WHIMS. However, within the
age distribution included in the WHIMS, probable dementia occurred at all
ages and almost 50% of the study participants were 65 to 70 years of age at
Petersen et al81 have stated that MCI
as defined by memory impairments (or what some now term the "amnestic" form
of MCI) often represents very early AD. However, the belief that persons with
isolated cognitive impairments in domains other than episodic memory are at
the same risk for a later diagnosis of AD or another form of dementia is more
controversial.82 Because consensus has not
been achieved on these competing points of view, we chose to analyze the MCI
outcomes alone and combined with probable dementia. When viewed independently
from probable dementia, the study groups showed no statistical differences
in the risk of developing MCI. The risk of developing either MCI or probable
dementia increases by 37% for women taking estrogen plus progestin compared
with women in the placebo group (P = .06). One possible
explanation for the lack of an effect of estrogen plus progestin on MCI alone
may relate to the greater variability in cognitive status and greater heterogeneity
in possible underlying diseases among the participants with MCI as opposed
to the participants with probable dementia. Both of these factors limit the
predictive power of MCI as well as its use as a classification in clinical
practice. The ongoing follow-up of the full WHIMS cohort, including those
participants identified as having MCI, and future studies in which consensus
has been achieved on a more precise MCI designation, may help to clarify this
Study drug administration in the WHI estrogen plus progestin trial was
stopped on July 8, 2002, after an average exposure to the hormones of 5.6
years33; however, monitoring of important clinical
(including cognitive) outcomes in these women continues in both the WHI and
the WHIMS trials. Of particular interest in the WHIMS estrogen plus progestin
cohort is the degree to which the negative effects of the hormone treatment
have on dementia are sustained over time. The WHI estrogen-alone trial continues,
as does the WHIMS estrogen-alone component with its assessments of global
cognitive functioning, MCI, and probable dementia. As with the estrogen plus
progestin component of the WHIMS, the WHIMS estrogen-alone study is the largest
of its kind with the same rigor in design and outcome ascertainment as the
WHIMS estrogen plus progestin trial. Given the current findings, the results
of the estrogen-alone component assume added significance because they may
elucidate the impact of estrogen alone on the cognitive status of postmenopausal
women. Furthermore, that either study component of WHIMS will be repeated
in the near future, if ever, is not likely.
The WHIMS results demonstrate that estrogen plus progestin therapy increases
older women's risk for probable dementia. Furthermore, estrogen plus progestin
does not protect against MCI. Thus, estrogen plus progestin should not be
prescribed with the expectation that it will enhance cognitive performance
in postmenopausal women. When considered in conjunction with the WHI results
reported earlier, the WHIMS estrogen plus progestin data reinforce the conclusion
that the risks of estrogen plus progestin outweigh the benefits.
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