Context The Women's Health Initiative Memory Study (WHIMS) previously reported
that estrogen plus progestin therapy does not protect cognition among women
aged 65 years or older. The effect of estrogen-alone therapy, also evaluated
in WHIMS, on cognition has not been established for this population.
Objectives To determine whether conjugated equine estrogen (CEE) alters global
cognitive function in older women and to compare its effect with CEE plus
medroxyprogesterone acetate (CEE plus MPA).
Design, Setting, and Participants A randomized, double-blind, placebo-controlled ancillary study of the
Women's Health Initiative (WHI), WHIMS evaluated the effect of CEE on incidence
of probable dementia among community-dwelling women aged 65 to 79 years with
prior hysterectomy from 39 US academic centers that started in June 1995.
Of 3200 eligible women free of probable dementia enrolled in the WHI, 2947
(92.1%) were enrolled in WHIMS. Analyses were conducted on the 2808 women
(95.3%) with a baseline and at least 1 follow-up measure of global cognitive
function before the trial's termination on February 29, 2004.
Interventions Participants received 1 daily tablet containing either 0.625 mg of CEE
(n = 1387) or matching placebo (n = 1421).
Main Outcome Measure Global cognitive function measured annually with the Modified Mini-Mental
State Examination (3MSE).
Results During a mean follow-up of 5.4 years, mean (SE) 3MSE scores were 0.26
(0.13) units lower than among women assigned to CEE compared with placebo
(P = .04). For pooled hormone therapy (CEE combined
with CEE plus MPA), the mean (SE) decrease was 0.21 (0.08; P = .006). Removing women with dementia, mild cognitive impairment,
or stroke from the analyses lessened these differences. The adverse effect
of hormone therapy was more pronounced among women with lower cognitive function
at baseline (all P<.01). For women assigned to
CEE compared with placebo, the relative risk of having a 10-unit decrease
in 3MSE scores (>2 SDs) was estimated to be 1.47 (95% confidence interval,
1.04-2.07).
Conclusion For women aged 65 years or older, hormone therapy had an adverse effect
on cognition, which was greater among women with lower cognitive function
at initiation of treatment.
Age-associated memory impairment affects an estimated one fifth to one
third of older individuals and has important individual, family, and societal
costs.1,2 In older postmenopausal
women, the potential impact of declining levels of sex hormones on cognitive
functioning has received particular attention because of estrogen's presumptive
beneficial effects on neurotransmitters,3 neuroconnectivity,4,5 and neuroprotection.6 Observational
studies have suggested that long-term hormone therapy may attenuate cognitive
aging in postmenopausal women, although randomized clinical trial results
are inconsistent.7-12
The Women's Health Initiative (WHI) includes 2 randomized trials of
postmenopausal hormone therapy: the estrogen-alone trial of conjugated equine
estrogen (CEE) therapy in women with a prior hysterectomy and the estrogen
plus progestin trial of CEE combined with medroxyprogesterone acetate (CEE
plus MPA) in women with an intact uterus.13 The
Women's Health Initiative Memory Study (WHIMS) was designed as an ancillary
study to evaluate the effect of either estrogen-alone or estrogen plus progestin
on cognitive outcomes in an analysis pooled across the 2 trials.14
We previously reported that CEE plus MPA increased the risk of probable
dementia and provided no benefit for global cognition.15,16 On
March 1, 2004, the estrogen-alone trial of the WHI was terminated due to an
excess risk of stroke and the lack of a significant effect on other cardiovascular
disease outcomes.17
In this study, we evaluated the effect of postmenopausal hormone therapy
on global cognition in the estrogen-alone trial and, consistent with the original
design of WHIMS, in the pooled estrogen-alone and estrogen plus progestin
cohorts. (An accompanying article reports the effects of estrogen plus progestin
and estrogen-alone on incidence of probable dementia and mild cognitive impairment.18) This analysis was not specified in the original
protocol but was conducted to help interpret the findings with respect to
dementia.
The study design, eligibility criteria, and recruitment procedures of
the WHI estrogen plus progestin trial have been described.13,19 Women
enrolled in the WHI estrogen-alone trial who were aged 65 to 79 years and
free of dementia as ascertained by the WHIMS protocol14 were
eligible and asked to enroll. Participating women provided written informed
consent. Thirty nine of 40 WHI clinical centers participated in WHIMS. Early
in the trial, follow-up was suspended by the main trial in 1 center and 47
women from this center were excluded from this study. The National Institutes
of Health and institutional review boards for all participating institutions
approved the WHI and WHIMS protocols and consent forms.
Of the 3200 women in the WHI estrogen-alone trial who were approached
for WHIMS participation, 2947 (92.1%) consented and enrolled. To analyze the
change in cognitive scores, we included only participants with at least 1
valid postbaseline Modified Mini-Mental State Examination (3MSE) score. We
also excluded the relatively few women who were enrolled 6 months or more
after initiation of their assigned WHI therapy, because treatment effects
may be under way by this time. These exclusions were also applied to reanalyses
of the estrogen plus progestin trial data, eliminating 37 women who were included
in our earlier study.16
The main outcome measure was global cognitive function measured annually
with the 3MSE.20 Scores 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
moderate internal consistency and temporal reliability,21,22 with
good sensitivity and specificity for detecting cognitive impairment.21-28 The α
coefficient of the 3MSE at baseline was .55.16
The 3MSE was administered during a WHI screening visit and annually
thereafter by a technician who was trained and certified in its administration
and masked to randomization assignment and reports of symptoms. 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. Women who scored below cut points based on education level
were asked to complete an expanded neuropsychological battery and a neuropsychiatric
clinical examination to classify their dementia status.18 These
cut points were initially a score of 72 or lower for women with 8 years or
less of education and a score of 76 or lower for women with at least 9 years
of education. After 16 months, the protocol was altered to increase these
cut points to a score of 80 or lower and 88 or lower, respectively. Enrolled
participants continued to be scheduled for their annual 3MSE assessments regardless
of adjudicated dementia status.
Information on demographic, health, and behavioral factors and physical
measurements were collected at baseline as previously described.14 These
included menopausal symptoms (hot flashes and night sweats) experienced during
the prior 4-week period to assess presence and severity of vasomotor symptoms
(none, mild, moderate, severe). Prior cardiovascular disease was defined by
self-report of myocardial infarction, stroke, angina, percutaneous transluminal
coronary angioplasty, or coronary artery bypass graft surgery. Regular use
of aspirin was queried and use of 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (statins) was ascertained by a medication inventory. Incidence
of strokes during the trial was based on central adjudication of medical records.
Changes from baseline 3MSE score across follow-up were compared between
treatment groups using Wald tests from linear models fitted by maximum likelihood,
with first-order autoregressive structure for the longitudinal correlation
within study participants.29 Treatment assignment
was included in the model as a fixed effect to compare the mean difference
in these changes between treatment groups over time. We decided to evaluate
mean changes rather than rates of change (which were the basis of the earlier
estrogen plus progestin trial analyses), because the changes in scores over
the extended estrogen-alone trial were markedly nonlinear and thus not well
described by rates of change. We report analyses of untransformed scores because
they allow more interpretable expressions of changes (and yielded inferences
similar to the analyses of transformed scores). To parallel analyses defined
by the WHIMS protocol for its primary outcome of probable dementia, we also
pooled data from the estrogen-alone and estrogen plus progestin trials to
estimate an overall effect of hormone therapy and assess by using interaction
terms whether relative treatment effects varied between therapies.
Our main analyses follow a modified intent-to-treat approach. Women
were analyzed according to randomization assignment; however, analyses were
limited to women who consented to WHIMS, whose consent was obtained within
6 months of WHI randomization, and who took the 3MSE at least once after baseline.
We also performed an analysis of only those women who were adherent to treatment
assignment (a participant was defined as nonadherent by stopping study medication,
taking <80% of study medications, or taking independently prescribed hormones).
In other supporting analyses, we examined the balance of treatment assignment
across subgroups defined by 17 factors expected to affect measured cognitive
status (and ascribed potential importance only to comparisons associated with
a nominal P<.01): age, education, ethnicity, family
income, body mass index (calculated as weight in kilograms divided by the
square of height in meters), smoking status, alcohol intake, prior vascular
disease, hypertension, diabetes mellitus, moderate or severe vasomotor symptoms,
prior hormone therapy, age at hysterectomy, bilateral oophorectomy, use of
statins, regular use of aspirin, and baseline 3MSE score. We described the
consistency of treatment effects across these subgroups, using interaction
terms for inference.
We examined whether changes in 3MSE scores of various magnitudes occurred
more frequently among women assigned to CEE and pooled CEE and CEE plus MPA,
by computing whether a woman's 3MSE scores had changed by 2, 4, 6, 8, 10,
or 12 units from baseline at any time during follow-up. We used logistic regression
to estimate the odds ratio of these changes between treatment groups and adjusted
the odds ratio to approximate the relative risk.30 Baseline
3MSE score and follow-up time were included as covariates in these analyses.
Figure 1 depicts the enrollment
and follow-up status of the WHIMS estrogen-alone trial. The 139 WHIMS participants
(4.7%) excluded from analyses due to enrollment 6 months or more after randomization
(17 assigned to CEE and 13 assigned to placebo) or absence of follow-up data
(60 assigned to CEE and 49 assigned to placebo) were equally distributed between
groups. Women excluded in the analysis had lower mean baseline 3MSE scores
than women who were included (mean [SD], 92.73 [5.80] vs 94.68 [4.64]; P<.001) and, among all the remaining characteristics
considered in this analysis, the women excluded only differed in a higher
rate of current (9.9% vs 7.2%) and former (41.4% vs 36.6%) smoking (P<.001). These women were included in the analyses of
WHIMS primary outcomes.18
The baseline data for the WHIMS estrogen-alone trial participants that
were included in these analyses are shown in Table 1. Approximately 45% were aged 65 to 69 years and two thirds
had some education after high school. Most women (62%) had 3MSE scores of
95 or higher; 9.6% scored at or below the preset WHIMS screening cut points.
The mean time between first and last 3MSE examinations was 5.4 years (range,
0.9-7.6) and was similar in both groups (P = .86).
Women participated in 1 (4.0%), 2 (4.2%), 3 (5.3%), 4 (7.2%), 5 (23.5%), 6
(42.7%), 7 (12.9%), or 8 (0.2%) follow-up examinations. Overall, women assigned
to CEE or placebo had comparable distributions of demographic, socioeconomic,
and clinical characteristics. The only statistically significant difference
was regular use of aspirin at baseline, which was slightly more common among
women assigned to placebo (31.1% vs 27.5%; P = .04).
The analyses for the companion estrogen plus progestin trial, which
excluded 14 women assigned to CEE plus MPA and 23 assigned to placebo who
consented to WHIMS more than 6 months after WHI treatment assignment, involved
4344 women (2131 assigned to CEE plus MPA and 2213 assigned to placebo) who
were followed up for a mean of 4.2 years (range, 0.9-6.4 years). The baseline
characteristics for the estrogen plus progestin trial were described previously.16 As self-described, women in the estrogen-alone trial,
in addition to having had a hysterectomy, tended to be relatively less educated
and were more likely to be from an ethnic minority. Compared with women in
the estrogen plus progestin trial, women in the estrogen-alone trial reported
lower family incomes; weighed more; consumed less alcohol; had more cardiovascular
disease, hypertension, diabetes mellitus, and vasomotor symptoms; and reported
more use of hormone therapy in the past and for longer periods. The baseline
mean (SD) 3MSE scores were 94.68 (4.64) and 95.69 (4.04), respectively, for
the estrogen-alone and estrogen plus progestin trials (P<.001); this difference remained statistically significant after
adjusting for the factors mentioned above, excluding hysterectomy. The overall
mean (SD) 3MSE score across trials was 95.2 (4.3).
Table 2 shows that in both
the CEE and placebo groups, 3MSE scores tended to increase with time on study
during the first 4 years, and the placebo group tended to have slightly higher
mean scores compared with the CEE group.
Figure 2 portrays mean 3MSE
estimates from linear models using intraparticipant longitudinal correlations
to address the varying patterns of examination times among women. Means (SEs)
by treatment assignment are provided for both trials, separately and combined.
Across all treatment assignments, mean 3MSE scores initially increased from
baseline throughout the first 3 to 5 years after randomization, with greater
increases in the placebo groups. During longer follow-up in the estrogen-alone
trial, the initial increases in mean 3MSE scores declined. Differences between
active and placebo therapy emerged after 2 years.
During follow-up, the mean (baseline subtracted) 3MSE scores were 0.26
(SE, 0.13) units lower among women assigned to CEE compared with placebo in
analyses without covariate adjustment (P = .04; Table 3). Similarly, in the estrogen plus
progestin trial (P = .58), differences averaged 0.18
(0.10) units (P = .055). In the 2 trials combined,
women assigned to hormone therapy had lower on-study mean (SE) 3MSE scores
of 0.21 (0.08) units (P = .006).
Adherence to study medication in the estrogen-alone trial was greater
among women assigned to the placebo group. Cumulative drop-out rates for CEE
and placebo were 10.9% vs 8.0% (year 1), 20.5% vs 17.3% (year 2), 27.9% vs
24.4% (year 3), 34.7% vs 31.8% (year 4), 42.3% vs 38.8% (year 5), 49.5% vs
46.3% (year 6), and 59.4% vs 54.2% (year 7), respectively. During follow-up,
some women (8.5% in CEE group and 11.0% in placebo group by year 6) initiated
hormone therapy through their health care physicians. Baseline 3MSE score
was inversely related to subsequent nonadherence (P<.001),
based on logistic regression. Similar trends have already been reported for
the estrogen plus progestin trial.16 When data
were censored at the first occurrence of any nonadherence, mean (SE) 3MSE
differences between treatment groups were slightly less (0.25 [0.14] for estrogen-alone
trial [P = .07] and 0.14 [0.10] for estrogen plus
progestin trial [P = .17], and 0.19 [0.08] overall
[P = .02]). Again, differences between trials were
not statistically significant (P = .51).
At baseline, 24 (1.7%) and 21 (0.99%) women in the active groups, and
29 (2.0%) and 42 (1.9%) women in the placebo groups of the estrogen-alone
and estrogen plus progestin trials, respectively, reported a history of stroke.
During follow-up, 33 (2.4%), 37 (1.7%), 39 (2.8%), and 32 (1.4%) women, respectively,
had strokes. In analyses limited to women with no history of stroke and with
follow-up censored after on-study strokes, the mean (SE) differences in 3MSE
scores between treatment groups were 0.32 (0.14) for estrogen-alone trials
(P = .02) and 0.18 (0.10) for estrogen plus progestin
trials (P = .055), and 0.24 (0.08) for the pooled
trials (P = .002). During follow-up, 88 women (6.5%)
and 82 women (3.9%) in the active groups, and 62 women (4.5%) and 61 women
(2.8%) in the placebo groups of the estrogen-alone and estrogen plus progestin
trials, respectively, were classified as having probable dementia or mild
cognitive impairment. Differences were moderated when follow-up was censored
at the first 3MSE leading to such classifications (mean [SE], 0.14 [0.11]
for estrogen-alone trials [P = .22] and 0.09 [0.08]
for estrogen plus progestin trials [P = .30], and
0.11 [0.07] overall [P = .11], with little difference
between trials [P = .71]).
The largest declines in 3MSE scores from baseline tended to occur more
frequently among women assigned to active therapy. Figure 3 contrasts treatment groups with respect to odds ratio for
increases and declines in 3MSE scores, from baseline at any time during follow-up.
For the estrogen-alone and the pooled trials, the odds ratios for declines
of 8 points or more in 3MSE scores were 37% to 62% higher in the active treatment
groups.30 The estimated relative risk corresponding
to and developed by adjustment of the odds ratio of the 10-unit decrease was
1.47 (95% confidence interval, 1.04-2.07).
As shown in Table 3, both
within the estrogen-alone and estrogen plus progestin trials and overall,
hormone therapy had a relatively greater adverse effect for women whose baseline
3MSE scores were lowest (all P<.01). No other
factors appeared to markedly influence the treatment effects of CEE or pooled
hormone therapy.
We found that women aged 65 years or older assigned to CEE therapy had
a slightly but significantly lower average cognitive function compared with
women assigned to placebo, as measured by serial 3MSE scores during 5 to 7
years of follow-up. These differences appeared to emerge 1 to 2 years after
initiation of therapy and persisted throughout the trial. The estimated magnitude
of the difference attributable to CEE therapy was slightly smaller when analyses
were limited to women who adhered to the study protocol. This adherence-related
effect may be attributable to a tendency for women whose cognitive function
is declining to become nonadherent, perhaps an effect of incident comorbidity
or social stress. Baseline 3MSE score was a strong predictor of subsequent
nonadherence, which supports this conjecture. The difference was not materially
affected when data from women with a history of stroke or who experienced
a stroke during the study were eliminated, suggesting that clinical strokes
are not entirely responsible for the lower cognitive function we observed
in the active treatment groups. However, when women who developed cognitive
impairment or dementia were excluded, the mean difference was moderated and
was no longer statistically significant.
Cognition has been reported to be influenced by exogenous progestins3,31 and differently by CEE and CEE plus
MPA therapy.32,33 We found similar
effects on 3MSE scores for CEE and CEE plus MPA therapy, although women in
the 2 trials differed according to many factors at baseline, including cognitive
function. The similarity of these effects, both overall and across many subgroups,
support pooled analysis, as was described in the original study protocol for
the primary end point of probable dementia. The WHI found a similar increased
risk of stroke for CEE and CEE plus MPA, although the overall incidence rates
of strokes differed between the 2 trials.34 A
possible resonance between the adverse effects of hormone therapy on atherosclerotic
and thrombotic cerebrovascular effects and cognitive outcomes may be further
reflected in the higher numbers of women experiencing relatively large declines
in 3MSE scores. For example, 54 (3.89%) of 1387 women assigned to CEE had
declines in 3MSE scores of at least 12 units compared with 42 (2.96%) of 1421
women assigned to placebo in the estrogen-alone trial.
The adverse effect of hormone therapy appeared to be consistent across
many subgroups. Only baseline 3MSE score was associated with differential
treatment effects. Among women whose scores exceeded 95, the mean decrement
was small and not statistically different from 0. The mean decrement increased
for lower 3MSE scores and was largest for those women who were below study
3MSE screening cut points; to enter the study, women must have been classified
as not having probable dementia at that time according to additional testing
and a standardized protocol.18 This finding
occurred in both the estrogen-alone and estrogen plus progestin trial cohorts.
Considering the age of these women, some degree of cerebrovascular disease
and/or neuropathologic changes may have preceded their participation in WHIMS,
and hormone therapy may have accelerated progress of underlying disease. Although
we cannot address this question directly, the findings from an ancillary magnetic
resonance imaging study currently under way will test whether subclinical
cerebrovascular pathological changes are more prevalent among women assigned
to active hormone therapy.
The WHIMS findings stand in contrast to a considerable body of literature
suggesting that exogenous estrogen helps to protect cognitive function in
postmenopausal women. Many of these studies are observational in which, unlike
our randomized trial, estrogen users may have reflected the so-called healthy
user bias (ie, postmenopausal women who choose to take estrogen are generally
healthier, better educated, and of a higher socioeconomic status than those
who do not take estrogen).35 Such demographic
factors are independently associated with cognitive decline and dementia and
thereby may confound the interpretation of observational study findings.
A second possible explanation for inconsistencies between prior studies
and WHIMS is that estrogen has been reported to enhance verbal memory, with
no effect on other domains of cognition.7 Although
the 3MSE is a reliable and valid measure of global cognitive function, it
does not capture performance in individual domains of cognition. It remains
possible that differential beneficial (and/or detrimental) effects of estrogen
on specific cognitive functions (eg, verbal memory) were not detected when,
in fact, they had actually occurred. The results of the Women's Health Initiative
Study of Cognitive Aging will help to address this important issue.
A third explanation may relate to a critical period during which hormone
therapy must be initiated to protect cognitive functioning. Laboratory animal
models36,37 suggest that giving
estrogen 3 months not 10 months after ovariectomy produces memory performance
similar to that of young control animals. Similarly, among older women, initiation
of hormone therapy at menopause may be associated with significantly less
cognitive decline 20 years later compared with nonusers, whereas recent estrogen
exposure may not be beneficial.38 Former early
users of estrogen but not current users may have a reduced risk of Alzheimer
disease.39 Unfortunately, this theory cannot
be addressed in WHIMS because participants were all aged 65 years or older
when they were recruited and treated. However, 45% of women in the estrogen-alone
trial reported previous hormone therapy use, and they did not have higher
scores than women reporting no prior use. In addition, results from the observational
studies cited may be biased due to healthy user effects.
Although the difference in mean (SE) 3MSE scores between the CEE and
placebo group was statistically significant (P =
.04), the actual magnitude of the difference (0.26 [0.13] units) is too small
to have relevance in clinical practice. This was also true for between-group
differences in 3MSE scores in the CEE plus MPA16 and
pooled CEE plus MPA and CEE-alone analyses. However, the statistically significant,
albeit small, difference in mean 3MSE scores was robust across treatments
and many subgroups, and indicates that in these large randomized clinical
trials, hormone therapy did not improve global cognition in older postmenopausal
women. In addition, both the CEE and pooled analyses showed that women receiving
hormone therapy were significantly more likely to experience a marked decrease
(≥8 units) in 3MSE scores compared with the placebo group. Such a decrease
is meaningful and would likely alert a clinician to explore this further.
Although WHIMS participants were generally healthy and well educated,
there is no compelling reason to believe that the results are not applicable
to other women in this age group with similar demographic and health status
characteristics. The WHI study tested only CEE and CEE plus MPA, the most
commonly used postmenopausal hormone therapy preparations in the United States
when WHI was designed.40 Outcomes of treatment
might differ with other doses, formulations, or routes of delivery. The longer
follow-up time of the estrogen-alone trial compared with the estrogen plus
progestin trial indicated that the apparent practice (eg, learning) effect
observed in both trials is overcome in time, yielding curved patterns for
longitudinal scores. In adopting an analytical strategy more appropriate to
data from the estrogen-alone trial, we decreased slightly the power for analyses
of data from the estrogen plus progestin trial, in which the more parsimonious
linear assumption was warranted. Overall, however, the 2 different analytical
approaches to the estrogen plus progestin data yielded congruent results.
Finally, as a brief screen for cognitive impairment, the 3MSE provides a coarser
estimate than would a more detailed and comprehensive evaluation of cognitive
functioning.
In conclusion, this large randomized clinical trial indicates that CEE,
initiated in the late postmenopausal period, does not improve global cognitive
function and may even adversely affect this outcome. The effects on cognition
were similar to those observed with CEE plus MPA. Our results suggest that
neither CEE nor CEE plus MPA should be initiated in older women for the purpose
of protecting cognitive function. Furthermore, at least 1 subgroup of women
was at particularly high risk for the adverse effects of hormone therapy on
cognition—women with relatively low baseline cognitive function.
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