Context Observational studies have suggested that postmenopausal hormone treatment
may improve cognitive function, but data from randomized clinical trials have
been sparse and inconclusive. The Women's Health Initiative Memory Study (WHIMS)
is an ancillary study of the Women's Health Initiative (WHI) hormone therapy
trials. On July 8, 2002, the estrogen plus progestin therapy in the WHI trial
was discontinued because of certain increased health risks for women.
Objective To determine whether estrogen plus progestin therapy protects global
cognitive function in older postmenopausal women.
Design, Setting, and Participants A randomized, double-blind, placebo-controlled clinical trial, WHIMS
is an ancillary study of geographically diverse, community-dwelling women
aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen
plus progestin trial that started in June 1995. Of 4894 eligible postmenopausal
women aged 65 years or older and free of probable dementia at baseline, 4532
(92.6%) were enrolled in the estrogen plus progestin component of WHIMS. A
total of 4381 participants (96.7%) provided at least 1 valid cognitive function
score between June 1995 and July 8, 2002.
Interventions Participants received either 1 daily tablet containing 0.625 mg of conjugated
equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching
placebo (n = 2236).
Main Outcome Measure Global cognitive function measured annually with the Modified Mini-Mental
State Examination.
Results The Modified Mini-Mental State Examination mean total scores in both
groups increased slightly over time (mean follow-up of 4.2 years). Women in
the estrogen plus progestin group had smaller average increases in total scores
compared with women receiving placebo (P = .03),
but these differences were not clinically important. Removing women by censoring
them after adjudicated dementia, mild cognitive impairment, or stroke, and
nonadherence to study protocol, did not alter the findings. Prior hormone
therapy use and duration of prior use did not affect the interpretation of
the results, nor did timing of prior hormone therapy initiation with respect
to the final menstrual period. More women in the estrogen plus progestin group
had a substantial and clinically important decline (≥2 SDs) in Modified
Mini-Mental State Examination total score (6.7%) compared with the placebo
group (4.8%) (P = .008).
Conclusions Among postmenopausal women aged 65 years or older, estrogen plus progestin
did not improve cognitive function when compared with placebo. While most
women receiving estrogen plus progestin did not experience clinically relevant
adverse effects on cognition compared with placebo, a small increased risk
of clinically meaningful cognitive decline occurred in the estrogen plus progestin
group.
Declining cognitive function is a growing public health concern for
older adults, given the well-documented pattern of age-associated decrements
in many areas of cognitive performance1 and
the increasing proportion of elderly individuals in the US population. The
prevalence of age-associated memory impairment in the general older population
is estimated to be between 17% and 34%.2-4 In
postmenopausal women, the effect of reduced sex hormones, especially estrogen
and progesterone, on cognitive decline is of particular interest because of
their modulating effects on neurotransmitters,5 neuroconnectivity,6,7 and neuroprotection.8 Estrogen
receptors are widely distributed throughout the brain, but particularly in
the hippocampus,9 which has suggested a role
of estrogen in episodic memory function.10 Less
is known about the effects of progesterone on the brain11,12 although
progesterone could theoretically amplify, modulate, or antagonize the effect
of estrogen.13,14
The hypothesis that estrogen-containing hormone therapy improves cognition
has mixed support. Both a positive association between use of estrogen and
cognitive performance in postmenopausal women without dementia15-19 and
a failure to find improvement have been reported.20-24 Recent
systematic reviews12,25,26 conclude
that studies of the effects of estrogen are inconsistent, highlighting the
need for large, carefully controlled randomized trials of hormone treatment.
The Women's Health Initiative Memory Study (WHIMS)27 is
an ancillary study of the Women's Health Initiative (WHI) randomized trials
of hormone therapy, specifically estrogen alone and estrogen plus progestin.28 Both studies are described in an earlier article28 and in a related article,29 which
analyzes dementia-related events. Because of the increased risk of dementia,29 the results of longitudinal Modified Mini-Mental
State Examinations (3MSEs) were evaluated to determine whether estrogen plus
progestin modulates global cognition over time.
Participants and Enrollment
The study design, eligibility criteria, and recruitment procedures of
the WHI estrogen plus progestin trial have been described elsewhere.28,29 Participants in the WHIMS estrogen
plus progestin trial were recruited from women who were enrolled in the WHI
estrogen plus progestin trial and who were aged 65 years or older and free
of probable dementia as ascertained by the WHIMS protocol.27 Prospective
participants were informed about WHIMS and written informed consent was obtained.
Thirty-nine of the 40 WHI clinical centers participated in WHIMS. Of the 4894
women in the WHI estrogen plus progestin trial who were approached for WHIMS
participation, 92.6% (N = 4532) consented. Study coordination for WHIMS was
provided by the WHIMS clinical coordinating center located at Wake Forest
University School of Medicine, 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 forms. The sample analyzed
herein differs slightly from the sample described in the companion article29 because it excludes 151 (3.3%) participants without
at least 1 valid postenrollment 3MSE score (see "Results").
The main outcome in this analysis is global cognitive function measured
with the 3MSE.30 The 3MSE's 15 parts comprise
46 items that contribute to a total score that can range from 0 to 100, with
a higher score reflecting better cognitive functioning. The test items measure
temporal and spatial orientation, immediate and delayed recall, executive
function (mental reversal, 3-stage command), naming, verbal fluency, abstract
reasoning (similarities), praxis (obeying command, sentence writing), writing,
and visuoconstructional abilities (copying). The 3MSE has demonstrated good
internal consistency and temporal reliability,31,32 sensitivity,
and specificity for detecting cognitive impairment and dementia.31,33-38 The α
coefficient of the 3MSE was .55 at baseline.
The 3MSE was administered at a screening visit and annually thereafter
by a WHIMS technician trained and certified in its administration27 and who was blinded to randomization assignment and
symptom reports. Administration time averaged 10 to 12 minutes. The 3MSE was
scored immediately by clinic staff and later by optical scanning. These 2
approaches were compared routinely throughout the trial to identify scoring
discrepancies, which were resolved by clinic staff. Enrolled participants
were scheduled for their annual 3MSE assessments regardless of adjudicated
dementia status.29
Demographic, health, and behavioral information was collected at baseline.28,29 Women completed an inventory of 34
menopausal symptoms that they might have experienced during the prior 4-week
period. Vasomotor symptoms (hot flashes and night sweats) were assessed with
none, mild, moderate, or severe as response categories.
The primary outcome measure for WHIMS is probable dementia. The trial
was designed to evaluate hormone therapy with respect to this reported outcome.27,29 The analyses we report herein were
conducted to provide explanatory context to the primary results of WHIMS,
although the 3MSE scores were not formally planned secondary end points and
the trial was not specifically powered to detect treatment differences with
respect to these measures. As a result, for the main comparisons of 3MSE score
changes by treatment assignment, we have not adjusted P values and have used a 2-tailed significance level of .05.
The comparison of changes in 3MSE scores between estrogen plus progestin
and placebo is based on a random coefficient mixed model analysis39 in which the rates of change over time (ie, slopes
and intercepts) for women were fitted as random effects.39,40 The
decision to use rates as the basis for inference was supported by the observed
longitudinal patterns of scores. Analyses based on such rates show greater
statistical power via computer simulation than those based on more complicated
models, even if overall patterns are moderately nonlinear. We chose to report
analyses on untransformed scores as they allow rates of change to be more
easily interpreted and yielded inferences similar to analyses of transformed
scores. Random (rather than fixed) effects models were expected to provide
a more sensitive (and appropriately conservative) accounting of error.41 The underlying distributions for random intercepts
and slopes were assumed to be Gaussian; similar results were obtained from
parallel analyses in which data were transformed to permit asymmetrical distributions.
Our main analyses followed the intent-to-treat approach with supporting
analyses limited to women adherent to treatment assignment. Subgroup analyses
were planned and based on known risk factors for impaired cognition and/or
possible confounders of estrogen plus progestin therapy. The consistency of
treatment effects across these subgroups was assessed with formal tests for
interactions. Included among the subgroup comparisons was an analysis limited
to cognitive examinations at times during which women were adherent to their
study medications. Because of the relatively large number (n = 17) of subgroups
that were considered, we adopted a Bonferroni adjustment to control for type
I error and use 0.05/17 = .003 as the critical value for declaring significance
for the subgroup analyses.
Figure 1 depicts the enrollment
and follow-up status of the entire WHIMS cohort. Early in recruitment, 45
women (1.0%) were enrolled after their WHI randomization. Slightly fewer women
assigned to estrogen plus progestin (n = 16; 0.7%) were enrolled postrandomization
than those assigned to placebo (n = 29; 1.3%)(P =
.07).
To assess our primary outcome measure—rates of change in 3MSE
scores—analyses were restricted to 4381 women (96.7%) with at least
1 valid postenrollment 3MSE. The 151 women excluded from these analyses for
this reason were slightly, but not significantly, more likely to have been
assigned to receive estrogen plus progestin therapy (3.8% vs 2.9%; P = .11). These women had lower mean (SD) baseline 3MSE scores than
women who were not excluded (94.62 [4.1] vs 95.57 [4.0]; P = .005). Among all the characteristics considered in this analysis,
these women were significantly more likely to be current smokers (17.6% vs
6.5%; P<.001) and have lower family incomes (P = .02).
Table 1a lists characteristics
at WHI enrollment of those WHIMS participants who had at least 1 follow-up
3MSE. Nearly half were younger than 70 years and most had at least a high
school education. The 3MSE scores at baseline were comparable (P = .28). Most (70%) women scored 95 or above in each group and 6%
scored below the preset WHIMS cut point that triggered the work-up to determine
the presence of dementia.29 The average span
of measurement (times between first and last 3MSE) was 4.2 years (range, 0.9-7.0
years) and was similar in both groups (P = .99).
The only significant group differences were lower prevalence of stroke (P = .03) and a higher percentage of participants using
statins (P = .02) in the estrogen plus progestin
group. The 3MSE scores tended to increase in both groups over the first 4
years (Table 2). However, the
placebo group had a pattern of slightly higher scores and a steadier increase
compared with the estrogen plus progestin group. Differences were statistically
significant (unadjusted P value) at years 3 and 4.
Figure 2 portrays 3MSE mean
scores from random effects models, which use intrasubject longitudinal correlations
to control for varying patterns of examination times among women. The relatively
few data from visit 7 have been assigned to visit 6 in these plots for a more
concise portrayal of patterns. Treatment group 3MSE mean scores tended to
diverge only after 2 years (Table 2).
Overall (first row of Table 3),
mean (SD) 3MSE total scores increased 0.149 (0.021) units per year among women
assigned to estrogen plus progestin and 0.213 (0.020) units per year among
women assigned to placebo, providing a small statistically significant difference
(P = .03).
Adherence to assigned study medication was significantly higher among
women in the placebo group for each year (P<.01).
Adherence rates for the estrogen plus progestin group were 71.2% for year
1 compared with 83.3% for the placebo group; 60.5% vs 73.2% for year 2; 54.2%
vs 66.3% for year 3; 49.0% vs 60.6% for year 4; 45.1% vs 58.1% for year 5;
and 35.8% vs 55.0% for years 6 or more, respectively. Analyses of differences
between rates of 3MSE changes between the estrogen plus progestin and placebo
groups were repeated with all data censored after the first occurrence of
nonadherence. For this subset of visits, the fitted increase in scores was
still marginally more favorable for women in the placebo group (P = .008; Table 3).
At baseline, 64 women reported a history of stroke: 21 (32.8%) were
assigned to estrogen plus progestin and 43 (67.2%) were assigned to placebo
(P = .009). During follow-up, 39 (1.8%) women in
the estrogen plus progestin group and 36 (1.6%) in the placebo group were
adjudicated to have strokes (P = .62). To examine
the extent to which the lower 3MSE scores in estrogen plus progestin participants
could be explained by cognitive effects associated with preexisting or incident
strokes (the latter being increased by estrogen plus progestin),42 we
performed an analysis excluding women with prior stroke and censoring the
3MSE data in the remaining participants at the time of an incident stroke
event. In these data, differences between the estrogen plus progestin and
placebo cohorts remained significant (P = .03). The
estimated mean slopes were 0.149 (0.021) for estrogen plus progestin and 0.213
(0.021) for placebo (Table 3).
Among the women included in our analyses, 61 were diagnosed as having
probable dementia during our study: 40 were assigned to estrogen plus progestin
and 21 were assigned to placebo (P = .01).29 The mean (SD) 3MSE score triggering the more detailed
neuropsychological and neuropsychiatric assessment and adjudication leading
to these diagnoses was 78.1 (8.9) (range, 52-88). By protocol, these women
were given the 3MSE annually. Thirty-eight women provided data 1 year after
their diagnosis of probable dementia, 19 after 2 years, and 9 after 3 years.
Sixty-one women provided data 1 year prior to their diagnosis, 51 in 2 years
prior, and 35 in 3 years prior. Figure 3 illustrates
the 3MSE mean scores before, at the triggering visit, and after diagnoses
of probable dementia for these women. Average 3MSE scores decreased during
these years and were similar for both treatment groups. To determine whether
the lower 3MSE scores of women diagnosed as having dementia explain the group
differences, the primary 3MSE analyses were repeated after removing all scores
from the triggering test forward. The difference between average rates of
3MSE changes between the treatment groups remained statistically significant
(P = .04) in these analyses (Table 3). Additional analyses in which women were censored at the
first diagnosis of either probable dementia or mild cognitive impairment yielded
similar results, however the P value increased (P = .07). Finally, analyses censoring these observations
and those obtained after strokes, and removing both nonadherent women and
those enrolled following randomization yielded fitted mean (SD) rates of change
of 0.188 (0.018) for estrogen plus progestin and 0.246 (0.017) for placebo
(P = .02).
To determine whether the effect of estrogen plus progestin on cognitive
performance was the same or different according to several baseline participant
characteristics, we conducted a series of subgroup analyses. Table 4 lists fitted mean rates of change for women grouped by treatment
assignment for selected subgroups with tests for interactions. The impact
of treatment assignment on 3MSE scores was fairly consistent (based on tests
of interaction) among all subgroups, and none of these tests reached the adjusted
statistical significance level (P<.003).
Lastly, women assigned to estrogen plus progestin therapy were more
likely to have large decreases in 3MSE scores. For example, declines of 2
SDs or more (ie, ≥8 units) occurred in 6.7% of women assigned to estrogen
plus progestin compared with 4.8% of women assigned to placebo (P = .008) for at least 1 follow-up visit compared with baseline scores.
Increases of this magnitude occurred with similar frequency in the 2 groups
(8.0% among women assigned to estrogen plus progestin and 7.0% for women assigned
to placebo). Increases and decreases ranged from 2 to 10 units (Figure 4). The relative odds of 3MSE scores declining in estrogen
plus progestin women increased with the magnitude of this loss. The 95% confidence
intervals for odds ratios excluded 1.0 for losses of 8 units or more. The
odds of increases in 3MSE scores were similar between treatment groups, regardless
of the level of increase. The residual variances from linear models fitted
to women's scores over time were nearly identical for the 2 treatment groups.
When women with declines of at least 2 SDs and/or diagnoses of either dementia
or mild cognitive impairment were removed from analyses, the mean (SD) rates
of change were increased by 0.207 (0.016) for estrogen plus progestin and
0.247 (0.016) for placebo (P = .07).
Investigators recently concluded from the WHI that the combined postmenopausal
hormone treatment of estrogen plus progestin increased risks for coronary
heart disease, invasive breast cancer, stroke, and pulmonary embolism and
that these increased risks outweigh benefits from reduced rates of colorectal
cancer and hip fracture.42 Potential effects
of postmenopausal hormone treatment on cognition and dementia are a public
health concern, and WHIMS was specifically designed to address this issue
within the setting of the WHI hormone therapy trials.27
Plausible hypotheses have been offered for how hormone therapy might
influence cognitive function,5-8,10,43-46 but
prior evidence regarding postmenopausal hormone therapy and cognition is limited
and inconsistent. Some studies indicate protection17,18,47,48 and
others indicate little or no benefit from hormone therapy.21 Also,
in some studies, past but not current hormone use was associated with reduced
cognitive decline.49 Other studies have shown
cognitive decline occurred in current users of combined estrogen plus progestin
therapy,50 but not among current users of unopposed
estrogen.
Conclusions from previous randomized controlled trials of cognition
in postmenopausal women have been hampered by generally small samples of women
treated for relatively short periods.25,26,51 Somewhat
larger trials showed no treatment effects on a variety of tasks regarding
attention22 or memory.23 In
the Heart and Estrogen/progestin Replacement Study (HERS), 1063 older women
(mean age, 67 years) with coronary disease were assessed once after a mean
treatment interval of 4.2 years. The estrogen plus progestin and placebo groups
differed on only 1 of 6 cognitive tasks (verbal fluency)—a difference
that favored the placebo group.24 In the analysis
of 3MSE scores in the entire cohort of women aged 65 years or older in the
WHI estrogen plus progestin trial, score changes did not differ significantly
over 1 or 3 years.20
In the current WHIMS cohort, 4381 women provided baseline and at least
1 follow-up score on the 3MSE. Most women scored high at their initial testing
and yet mean scores in both the estrogen plus progestin and placebo groups
continued to improve through year 4, a finding that we attribute to a positive
practice (learning) effect known to result from repeated administrations of
cognitive tests.52-54 In
the present study, the mean rate of change in 3MSE scores over time was slightly
less favorable in the estrogen plus progestin group than the placebo group
(Figure 3) over an average follow-up
of 4.2 years. This difference, while nominally statistically significant,
is not clinically significant. Thus, estrogen plus progestin offers no benefit
for global cognitive function and the small differences in mean change scores
suggest that no clinically significant negative effect on cognition occurred
either. However, we also found that significantly more women taking estrogen
plus progestin registered substantial declines (≥2 SDs) in 3MSE scores,
suggesting that some women experienced a clear detrimental effect. The greater
frequency of large declines among women assigned to estrogen plus progestin
did not appear to result from increased variability in examination scores,
which could happen if they were driven by short-term reversible changes in
cognition. Removing these women from the analysis increased the mean rates
of change and reduced the group differences to statistically nonsignificant
levels.
The identification of subgroups of women who might be particularly vulnerable
to adverse effects of estrogen plus progestin on cognition is an important
area of future research. Our subgroup analyses, which were based on 17 different
baseline characteristics, failed to identify any women as having an especially
high or low risk of cognitive changes. Thus, future studies will be needed
to determine if any vulnerable subgroup can be identified.
The mechanisms by which estrogen plus progestin decreased 3MSE scores
in some women are unknown, although effects of estrogen plus progestin on
procoagulant55 and proinflammatory56 markers have been shown previously. Silent brain
infarcts increase the risk of dementia and global cognitive decline.57 Results from WHI42 and
HERS24 indicate that estrogen plus progestin
affects some clot-related events adversely. In WHIMS, the presence at baseline
of cardiovascular disease or hypertension did not confound study analyses,
and post-hoc exclusion of women with stroke did not substantially alter the
conclusions.
The 2 WHIMS reports thus fail to support the hypothesis that estrogen
plus progestin protects cognitive function in relatively healthy older postmenopausal
women and are consistent with other data on cognitive function from the larger
WHI estrogen plus progestin trial. Unlike the WHI data that showed no changes
in 3MSE scores over 1 and 3 years,20 WHIMS
data revealed a small but important number of women in the estrogen plus progestin
group who experienced an adverse effect on global cognitive function compared
with placebo. This effect is not entirely explained by the presence of dementia
or mild cognitive impairment.29
Several methodological features of this study should be considered.
Women in the WHIMS cohort were generally well educated, predominantly white,
and in good health. However, there is no reason to believe that these results
are not generally applicable to other women in this age group. Active treatment
in this component of WHIMS was with estrogen plus progestin. The conclusions
here, like those of the earlier WHI study,20,42 pertain
to this specific formulation of hormone therapy and not to estrogen alone
or to different formulations or routes of administration. The ongoing WHIMS
trial of estrogen alone vs placebo will provide valuable information on this
issue.
In WHIMS, menopause occurred some years before study enrollment. Therefore,
our results pertain only to estrogen plus progestin initiated during the late
postmenopausal period. Memory skills do not differ substantially between women
during menopause and women in the early postmenopausal period.58 Whether
the present findings on global cognitive function apply equally to estrogen
plus progestin initiated before the age of 65 years cannot be addressed by
these data directly.
Nonadherence was higher in the estrogen plus progestin group than in
the placebo group. However, a strict criterion for nonadherence (any assessment
point at which the woman reported taking fewer than 80% of her pills) and
excluding those who are not adherent from analyses did not change the overall
results.
Lastly, the 3MSE is a screening measure for global cognitive function
and it may be less sensitive to cognitive changes than a larger, more comprehensive
neuropsychological battery. The Women's Health Initiative Study of Cognitive
Aging (WHISCA) is an ancillary study to WHIMS designed to assess the efficacy
of postmenopausal hormone therapy on age-associated cognitive decline. WHISCA
includes 14 of the 39 WHIMS clinical sites and enrolled participants a mean
(SD) of 3 (0.69) years after randomization into WHI. Approximately 61% of
the WHISCA participants (n = 1414) are in the estrogen plus progestin group.
WHISCA participants undergo a detailed neuropsychological assessment annually,
which involves a battery of measures that differs from those used in WHIMS.
WHISCA was specifically designed to provide more specific and complementary
data on the role of hormone therapy on cognitive functioning in postmenopausal
women than that afforded by WHI and WHIMS. Thus, a kind of telescoping effect
is created by studies within studies, each providing more detailed assessments
in fewer women with different but complementary outcomes.
In conclusion, this study adds important new information to the discussion
regarding the effect of estrogen plus progestin on cognitive function in older
postmenopausal women. Results from this analysis within a large, randomized
trial do not support the use of combined estrogen plus progestin treatment
to protect cognition in older women. Moreover, while most women did not experience
a negative treatment effect on cognition, a small increased risk of clinically
meaningful cognitive decline occurred in the estrogen plus progestin group.
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