REVIEW

EFFECTS OF ENDOGENOUS AND EXOGENOUS ESTROGEN

EXPOSURES IN MIDLIFE AND LATE-LIFE WOMEN ON EPISODIC
MEMORY AND EXECUTIVE FUNCTIONS
V. W. HENDERSON
a,b
* AND R. A. POPAT
a
a
Department of Health Research and Policy (Epidemiology), Stanford
University, Stanford, CA, USA
b
Department of Neurology and Neurological Sciences, Stanford Uni-
versity, Stanford, CA, USA
AbstractCognitive aging affects episodic memory and ex-
ecutive functions, and these vulnerable domains are postulated
to be modulated by endogenous and exogenous estrogen ex-
posures. In midlife and late-life women without dementia, estro-
gen effects on cognition can be examined through associations
with concentrations of serumestrone and estradiol and through
clinical trials of estrogen-containing hormone therapy. To this
end, we reviewed published studies including at least 100
women (larger studies are less prone to publication bias) ad-
dressing associations between estrogen levels and perfor-
mance on neuropsychological tests of episodic memory or ex-
ecutive functions (including working memory; seven studies),
or that reported results of placebo-controlled clinical trials of
hormone therapy with objective measures within these cogni-
tive domains (eight studies). Results were considered sepa-
rately for midlife and late-life (age>65 years) women. There
were no consistent associations between endogenous serum
estrogen concentrations and episodic memory or executive
functions in naturally menopausal midlife women or in older
postmenopausal women. Clinical trial ndings suggested no
substantial impact of exogenous estrogens on episodic mem-
ory or executive functions over time frames of up to several
years. Aquantitative synthesis of clinical trial results supported
the inference of absence of effect. This overall conclusion of no
substantial effect on episodic memory or executive functions
might reassure women concerned by potential adverse cogni-
tive consequences of menopause or of relatively short-term
midlife hormone therapy. There was no apparent window of
opportunity during which exogenous hormones might benet
near-term cognition, but included studies provided limited
power to identify such a window. Conclusions are tempered by
small numbers of studies, imprecise estimates of long-term
estrogen exposures, and narrow range of neuropsychological
tests. Long-term (late-life) cognitive consequence of midlife es-
trogen exposures are poorly addressed by current data, as are
cognitive consequences of surgical menopause and cognitive
consequences of exogenous estrogens during the menopause
transition.
This article is part of a Special Issue entitled: Neuroactive
Steroids: Focus on Human Brain. 2011 IBRO. Published by
Elsevier Ltd. All rights reserved.
Key words: aging, estrogen, executive functions, hormone
therapy, menopause, memory.
Contents
Cognition, cognitive aging, and dementia 130
Review and synthesis of human studies of estrogen
exposures 130
Endogenous exposures 131
Endogenous exposures in midlife women 131
Endogenous exposures in older postmenopausal women 131
Exogenous exposures 131
Exogenous exposures in midlife women 133
Exogenous exposures in older postmenopausal women 134
Quantitative synthesis of clinical trial ndings 134
Unresolved issues 134
Surgical menopause 135
Exogenous estrogen exposures during the menopause
transition 135
Cognitive outcomes in late-life 135
Conclusions 135
References 136
Natural menopause reects the permanent loss of ovarian
follicles, dened clinically by 12 months of amenorrhea
following a nal menstrual period. It represents a near
complete cessation in ovarian hormone secretion (Soules
et al., 2001). Menopause is thus characterized by sharp
decrements in concentrations of the primary ovarian estro-
gens (estradiol and estrone) and progesterone (Trvoux et
al., 1986; Burger et al., 2007). For many women, the
menopause transition is punctuated by uctuations and
instability in serum estrogen levels (Burger et al., 2007).
Such changes in the internal endocrine milieu could po-
tentially affect cognition during midlife and beyond, and are
commonly believed to do so (Hogervorst et al., 2009). An
understanding of potential cognitive consequences for
women, however, is of necessity derived largely from hu-
man observational research, where causality is difcult to
infer. It is possible, however, to address other important
questions about cognition and menopause experimentally.
In particular, evidence for exogenously administered hor-
mones, such as estrogen-containing hormone therapy in
postmenopausal women, is available from placebo-con-
trolled clinical trials.
This review of cognitive effects of estrogens in women
emphasizes endogenous and exogenous exposures that
occur during and after midlife. The focus is on episodic
memory and executive functions, two cognitive domains
*Correspondence to: V. W. Henderson, Stanford University School of
Medicine, 259 Campus Drive, Stanford, CA 94305-5405, USA.
E-mail address: vhenderson@stanford.edu (V. W. Henderson).
Abbreviations: SMD, standardized mean difference; Trails-B, Trail
Making Test, Part B.
Neuroscience 191 (2011) 129138
0306-4522/11 $ - see front matter 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuroscience.2011.05.059
129
viewed as vulnerable to effects of aging (Deary et al.,
2009). Age or temporal proximity to the menopause is
hypothesized to modify some actions of estrogens in the
brain, as reected in the so-called critical window, or win-
dow of opportunity, hypothesis (Resnick and Henderson,
2002; Sherwin, 2009), and we consider studies in midlife
women separately from those of older women.
COGNITION, COGNITIVE AGING, AND
DEMENTIA
The term cognition refers to brain processes by which
knowledge is acquired, stored and used. Cognition encom-
passes attention and concentration, learning and memory,
language, complex perceptual and motor abilities, and plan-
ning, judgment and reasoning. Although brain organization
for cognitive function is not necessarily modular, a rst ap-
proach can consider one cognitive domain as at least partially
independent of another. A caveat is that optimal performance
on a particular cognitive task draws upon various mental
resources, and no neuropsychological test can quantify cog-
nitive function strictly delimited to a single domain.
Cognitive abilities vary with age. In many instances,
age-associated changes involve an erosion of skills. This
is a process that begins insidiously in early adult life or
middle age, accelerates during old age, and affects both
episodic memory and executive functions (Deary et al.,
2009; Salthouse, 2009). Cognitive aging is usually concep-
tualized as differing from pathological processesfor ex-
ample, the accumulation of neurobrillary tangles and neu-
ritic plaques in Alzheimers diseasethat lead to severe
cognitive impairments characteristic of dementia, but the
distinction is not absolute. For both episodic memory and
executive functions, early or excessive decline is viewed
as an early, preclinical indicator of Alzheimers disease
(Albert et al., 2001; Grober et al., 2008).
Episodic memory refers to the ability to recall in a
deliberate manner recent episodes or events. It is often
assessed by delayed recall tasks, such as the ability to
recall items from a word list or narrative details from a
paragraph story, tested after some delay of minutes or
longer. Normal episodic memory performance depends
particularly on integrity of the hippocampus and adjacent
areas of the medial temporal lobes (Squire, 2009). Exec-
utive functions are controlled, non-automatic processes
involved in problem solving and other goal-directed behav-
iors. These include selective attention, judgment, reason-
ing, planning, initiation, inhibition, and monitoring of task
performance. This group of interrelated cognitive pro-
cesses is thought particularly, but not exclusively, to in-
volve the lateral prefrontal cortex (Cummings and Miller,
2007). Working memory, viewed as one aspect of execu-
tive functions, refers to the cognitive demands involved
with the temporary storage and manipulating of informa-
tion. Working memory can be assessed with such tests as
digit span backward, Letter-Number Sequencing, serial
addition, n-back tests, and Brown-Peterson distraction
tests. For the digit span backward test, a woman hears a
string of single-digit numbers, which she immediately re-
peats in reverse order.
Neuropsychological tasks commonly used to assess
other executive functions include the Trail Making Test,
Part B (Trails-B; divided attention and response alterna-
tion) and item generation (uency) tests (initiation and
self-regulation). The former is a timed pencil and paper
task that involves the ability to alternate between circles
labeled sequentially by number and by letter. A common
verbal uency task entails the generation of names of
items belonging to a particular category during a xed time
interval, such as generating as many animal names as
possible over a period of 1 min. Another uency task
requires the generation of names starting with a specied
letter of the alphabet. Other executive function tasks are
maze and tower tests (planning), the Stroop Color Word
Interference Test (selective attention and set changing), the
Wisconsin Card Sorting Test (set changing), and digit-symbol
and symbol-digit substitution tests (scanning and tracking
aspects of attention, and working memory). Details of these
tests are found in standard texts of neuropsychological as-
sessment (Lezak et al., 2004; Spreen et al., 2006).
There is a strong biological rational for considering
estrogen effects on cognitive functions that implicate hip-
pocampus and frontal neocortex. In animal studies, for
example, estradiol inuences synaptic plasticity in the hip-
pocampus and prefrontal cortex and improves aspects of
cognitive function believed to implicate these cortical re-
gions (Woolley and McEwen, 1993; Rapp et al., 2003; Hao
et al., 2006; Mukai et al., 2006; Liu et al., 2008; Foy, 2011).
Other support comes from functional neuroimaging studies
where estrogens appear to modulate medial temporal and
frontal lobe activity during cognitive task performance (Ber-
man et al., 1997; Joffe et al., 2006; Berent-Spillson et al.,
2010; Maki et al., 2011). Animal work supports consider-
ation of whether cognitive effects of estrogen exposures
might vary by age. Effects of estradiol on synaptic plasticity
can differ between young and aged rats (Yildirim et al.,
2008) and primates (Hao et al., 2007), and behavioral
effects of estradiol are inuenced by timing of treatment
initiation after ovariectomy (Daniel et al., 2006; Bohacek
and Daniel, 2010).
REVIEW AND SYNTHESIS OF HUMAN STUDIES
OF ESTROGEN EXPOSURES
We systematically identied two sets of published studies
involving midlife and late-life women, according to criteria
described below. The rst set examined associations be-
tween serum concentrations of estrone or estradiol (en-
dogenous exposures) and cognitive function, and the sec-
ond set reported placebo-controlled trials of estrogen-con-
taining hormone therapy with or without a progestagen
(exogenous exposures). Because smaller studies are more
vulnerable to publication bias (Easterbrook et al., 1991), we
reviewed only reports involving midlife and late-life cohorts of
at least 100 women or clinical trials involving at least 100
postmenopausal women. We pursued a quantitative synthe-
sis where published data rendered this approach feasible.
V. W. Henderson and R. A. Popat / Neuroscience 191 (2011) 129138 130
Studies for review were identied by one author from a
search of the MEDLINE computerized database and biblio-
graphic reviews of relevant articles, and one author indepen-
dently veried eligibility of identied studies.
We considered midlife women separately from late-life
women. Midlife represents the interval between the onset
of the menopause transition (Soules et al., 2001) and the
beginning of old age, commonly taken to be 65 years.
Menopause before age 40 years is viewed as premature,
(Luborsky et al., 2003), and we chose this age as the lower
boundary for mean ages of study participants. Late-life
was dened by a mean participant age of at least 65 years.
Endogenous exposures
For endogenous exposures, we reviewed ndings from
cohorts of at least 100 women not using hormone therapy
and without dementia or other identied cognitive disorder,
also including an objective neuropsychological measure of
episodic memory or executive functions. Seven observa-
tional studies met our selection criteria (Table 1). Because
of heterogeneity in study design and the manner in which
results were reported, we were unable to pool results to
evaluate associations of endogenous estrogen exposures
with cognitive outcomes. A quantitative synthesis was thus
not feasible.
Endogenous exposures in midlife women. Relations
between cognitive function and serum concentrations of
estrone and estradiol have been investigated in three co-
horts of midlife women. These include research in the
population-based Melbourne Womens Midlife Health Proj-
ect (Henderson et al., 2003; Ryan et al., 2011, in press),
the population-based Betula Project in Sweden (Herlitz et
al., 2007) and the Study of Womens Health Across the
Nation, a multi-ethnic voluntary cohort in the United States
(Luetters et al., 2007).
Findings from the Melbourne cohort failed to suggest
strong associations between estrogen levels and episodic
memory or executive functions. Initial analyses of pre-
menopausal and postmenopausal midlife women not using
hormone therapy showed no signicant relations between
episodic memory (word list recall) and the concentration of
total estradiol or the free estradiol index (an index based
on the ratio of estradiol to sex hormone binding globulin)
(Henderson et al., 2003). Analyses 3 years later focused
on midlife women who had by that time undergone natural
menopause (Ryan et al., in press). Principal component
analysis of neuropsychological test scores suggested four
cognitive factors, including verbal episodic memory (word
list recall tasks) and nonverbal episodic memory (face
recognition tasks). Concentrations of estrone, total estra-
diol, and free (nonprotein bound) estradiol were not linked
to these memory factors in cross sectional and 2-year
longitudinal analyses (Ryan et al., in press). In exploratory
follow-up analyses, the estrone concentration was posi-
tively related to scores on one of the executive functions
measures (the Tower of London test) (Ryan et al., 2011).
This nding, however, may have occurred by chance, as
estrogen levels were not associated with other executive
function tests (digit span backward, Letter-Number se-
quencing, Trails-B, category uency, and Symbol Digit
Modalities Test) (Ryan et al., 2011, in press).
Total estradiol levels were similarly unrelated to epi-
sodic memory in midlife women from Sweden (incidental
recall of test materials (Herlitz et al., 2007)) or the United
States (paragraph recall (Luetters et al., 2007)). In these
cohorts, estradiol was also unrelated to executive func-
tions as assessed by digit span backward (Luetters et al.,
2007), category uency (Herlitz et al., 2007), and the Sym-
bol Digit Modalities Test (Luetters et al., 2007).
Endogenous exposures in older postmenopausal women.
Findings for older postmenopausal women are inconsis-
tent (Table 1). A Dutch study reported a positive relation
between serum estradiol and episodic memory (den Heijer
et al., 2003), whereas two US studies suggested no asso-
ciations or inverse associations between some estrogen
measures and some aspects of executive function (Yaffe
et al., 1998; Barrett-Connor and Goodman-Gruen, 1999;
Laughlin et al., 2010).
In the rst of these, the Rotterdam Study, cross sec-
tional analyses described better episodic memory (word
list delayed recall) for women in the two highest tertiles of
bioavailable and free estradiol compared to women in the
lowest tertile; however, associations were not signicant
when estradiol was analyzed as a continuous variable (den
Heijer et al., 2003). The Study of Osteoporotic Fractures
included two executive function measures (Yaffe et al.,
1998). Test scores did not differ by serum estradiol quar-
tile, but women in the higher estrone quartiles had lower
scores on the Digit Symbol Modalities Test compared to
women in lower quartiles. At follow-up, changes in estra-
diol were unrelated to test scores, but reductions in per-
formance on the Trails-B test were larger for women in the
two higher estrone quartiles (Yaffe et al., 1998). Among
women in the Rancho Bernardo retirement community,
estrone and estradiol levels were generally unrelated to
cognitive performance 4 years after serum was obtain for
hormone analyses (Barrett-Connor and Goodman-Gruen,
1999). Follow-up after an additional 4 years (8 years after
serum was obtained) showed higher estrone levels to be
positively associated with greater decline during the sec-
ond 4 year interval on one of two executive function tasks
(category uency but not Trails-B) (Laughlin et al., 2010).
When analyzed categorically, women in the two highest
tertiles of estrone and bioavailable estradiol (bioavailable
estradiol is not bound to sex hormone binding globulin)
showed higher odds of being in the lowest tertile of uency
decline compared to women in the lowest estrogen tertiles
(for each, the odds ratio was 1.8 and 95% condence
intervals were 1.03.1) (Laughlin et al., 2010). Again, there
were no signicant associations with scores on the Trails-B
test.
Exogenous exposures
For exogenous exposures, we selected randomized, pla-
cebo-controlled, double-blind clinical trials of systemic es-
trogen-containing hormone therapy involving at least 100
V. W. Henderson and R. A. Popat / Neuroscience 191 (2011) 129138 131
Table 1. Associations between serum estrogens and tests of episodic memory or executive functions
a
Study Design Type of
menopause
b
Number of
women
Mean age
or range
Estrogen Episodic
memory
Executive functions
Working
memory
Trails-B Fluency Other
Midlife cohort (mean age64 y)
Henderson et al.
(2003)
C Natural 326 57 y E1; total E2 and
free E2 index
NS
Herlitz et al. (2007) C Both 242 4555 y Total E2 NS NS
Luetters et al. (2007) C Natural 1657 50 y Total E2 NS NS NS
Ryan et al. (2011, in
press)
C, L Natural 148 60 y E1; total and free
E2
NS NS NS NS NS; E1
c
Late life cohort (mean age65 y)
Yaffe et al. (1998) C, L Both 532 72 y E1; total E2 NS; E1
d
NS; E1
d
Barrett-Connor and
Goodman-Gruen
(1999)
L Both (presumed) 393 74 y E1; total and
bioavailable E2
NS NS NS NS
den Heijer et al.
(2003)
C Both 210 70 y Total, bioavailable
and free E2
NS; E2
e

Laughlin et al.
(2010)
f
L Both 343 69 y E1; total and
bioavailable E2
NS NS; E1, E2
f

C, cross sectional; E1, estrone; E2, estradiol; L, longitudinal; NS, nonsignicant probability P0.05; Trails-B, Trail Making Test, Part B. Signicant associations between estrogen level and cognitive
test are represented by (positive association) or (negative association).
a
Studies of midlife and late-life women without dementia or identied cognitive disorder, not using hormone therapy, sample size of at least 100 women, and objective measures of episodic memory
or executive functions. Episodic memory tasks were word-list recall of unrelated (Barrett-Connor and Goodman-Gruen, 1999; Henderson et al., 2003; Herlitz et al., 2007; Laughlin et al., 2010; Ryan
et al., in press) or related (Ryan et al., in press) words, paragraph recall (Luetters et al., 2007), incidental recall of verbal information and study tasks (Herlitz et al., 2007), gure recall (Barrett-Connor
and Goodman-Gruen, 1999), and face recognition (Herlitz et al., 2007; Ryan et al., in press). Working memory tasks were digit span backwards (Luetters et al., 2007; Ryan et al., 2011),
Letter-Number Sequencing (Ryan et al., 2011), and serial subtraction of sevens and spelling WORLD backward (Barrett-Connor and Goodman-Gruen, 1999). Other executive function tests were
the Tower of London (Ryan et al., 2011) and digit-symbol or symbol-digit substitution tests (Yaffe et al., 1998; Luetters et al., 2007; Ryan et al., 2011).
b
Surgical menopause was dened by hysterectomy status.
c
Postmenopausal women only; includes women reported in (Henderson et al., 2003). Estrone was positively associated with Tower of London performance (P0.02) on cross sectional analyses;
most executive function associations were nonsignicant.
d
Women in the two higher estrone quartiles had worse Digit Symbol Modalities Test scores compared to women in two lower quartiles in cross sectional analyses (analysis of covariance P0.004).
Women in the two higher estrone quartiles showed greater declines on the Trail Making Test compared to women in the two lower quartiles (analysis of covariance P0.01). Other executive function
associations were not signicant.
e
For bioavailable and free estradiol, but not total estradiol, recall scores were signicantly higher for women in the two higher estradiol tertiles than in the lowest tertile (each P0.05). Other episodic
memory associations were not signicant.
f
Same women reported in (Barrett-Connor and Goodman-Gruen, 1999). Higher baseline estrone was a signicant predictor of greater decline between 4 and 8 y later on category uency
performance (P0.04). Women in the highest tertile of estrone (P0.04) and bioavailable estradiol (P0.04) had a signicantly greater odds of decline in category uency compared to women in
the lowest tertile. Other executive function associations were not signicant.
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women without dementia or other identied cognitive dis-
order, of at least 4 weeks treatment duration and including
an objective neuropsychological measure of episodic
memory or executive functions. Findings in these trials are
more robust for late-life women, where samples sizes
tended to be larger and treatment durations longer, than
for midlife women. Eight clinical trials met selection for
review (Table 2).
We were able to synthesize results from these studies
using meta-analytic methods (Table 3). Different neuro-
psychological tests were used to assess the cognitive
domains of interest. To reduce heterogeneity, we selected
tests that were most frequently used across the eight trials.
For episodic memory, we analyzed word-list learning (de-
layed recall), the most commonly reported test within this
domain (seven trials). For working memory, which repre-
sents one aspect of executive functioning, the most com-
monly reported test was digit span backward (three trials).
Two other executive function tasks were used in at least
two eligible studies, Trails-B (two trials) and verbal uency
(category uency, letter uency, or both; eight trials). The
primary outcome in each of these task-specic analyses
was change in memory or executive function score be-
tween baseline and nal assessment. The effect size of
interest was the standardized mean difference (SMD) in
the change scores between treatment and placebo groups
in these trials. Because studies differed on the interven-
tions used, duration of treatment, and participant charac-
teristics, we calculated a pooled, or summary, SMD using
a random-effects model. Statistical heterogeneity for each
summary SMD was assessed with the Q statistic (Q sta-
tistic with P0.05 is considered heterogeneous) and the I
2
index. This statistic describes the proportion of total vari-
ability between studies due to heterogeneity beyond
chance; I
2
values greater than 50% are considered heter-
ogeneous (Higgins and Thompson, 2002; Borenstein et
al., 2009). We do not report meta-analytic results sepa-
rately for midlife and late-life women, as only two trials
involved midlife women. However, we conducted a sensi-
tivity analysis by excluding the studies of midlife women to
ensure the robustness of our pooled estimates. Analyses
were performed with Comprehensive Meta-Analysis ver-
sion 2 software (Biostat, Englewood, NJ, USA).
Exogenous exposures in midlife women. For midlife
women, only two trials meeting our criteria have been
reported. Both involved naturally menopausal women. Re-
sults from each suggest no signicant treatment effects on
measures of episodic memory or executive functions (Ta-
ble 2). In the rst of these, women 4555 years of age with
cognitive complaints were randomized for 4 months to
active treatment with conjugated equine estrogens com-
Table 2. Hormone therapy and episodic memory or executive functions in women without dementia: randomized placebo-controlled trials
a
Study Type of
menopause
b
Number
of women
Mean
age
Active
treatment
c
Duration Episodic memory Executive functions
Working
memory
Trails-B Fluency
Trials involving predominately midlife women
Maki et al. (2007) Natural 180 52 y CEEMPA 4 mon NS NS NS
Kocoska-Maras et al. (2011) Natural 133
d
59 y E2 4 wk NS NS
Trials involving predominately late life women
Grady et al. (2002) Both 1063 67 y CEEMPA 4 y NS NS CEE
e
Viscoli et al. (2005) Both 461 70 y E2 3 y NS NS NS
Almeida et al. (2006) Surgical 115 74 y E2 20 wk NS; E2
f
NS
Resnick et al. (2006) Natural 1416 71 y CEEMPA 4 y NS; CEE; CEE
g
NS
Yaffe et al. (2006) Natural 417 67 y E2 2 y NS NS NS
Resnick et al. (2009) Surgical 886 74 y CEE 2.7 y NS NS
CEE, conjugated equine estrogens; E2, estradiol; MPA, medroxyprogesterone acetate; NS, non-signicant probability P0.05; Trails-B, Trail
Making Test, Part B. Signicant between-group comparisons are represented by (favoring active treatment) or (favoring placebo treatment).
a
Randomized placebo-controlled trials involving at least 100 midlife or late-life women without dementia or identied cognitive disorder, treatment
duration of at least 4 wk, and objective measures of episodic memory or executive functions. All identied trials used a parallel groups design. Episodic
memory tasks were word-list recall of unrelated (Yaffe et al., 2006; Kocoska-Maras et al., 2011) or related (Almeida et al., 2006; Resnick et al., 2006,
2009; Maki et al., 2007) words, paragraph recall (Yaffe et al., 2006; Maki et al., 2007), incidental recall of naming test items (Viscoli et al., 2005), gure
recall (Resnick et al., 2006, 2009; Yaffe et al., 2006; Maki et al., 2007), or face recognition (Almeida et al., 2006). Working memory tasks were digit
span backwards (Resnick et al., 2006, 2009; Maki et al., 2007), and Disk Spatial Recognition (Viscoli et al., 2005). No executive function tests other
than the Trail Making Test and verbal uency were reported in these studies.
b
Surgical menopause was dened by hysterectomy status.
c
Active treatment was with oral conjugated equine estrogens 0.625 mg/d with (Grady et al., 2002; Resnick et al., 2006; Maki et al., 2007) or without
(Resnick et al., 2009) medroxyprogesterone acetate 2.5 mg/d, oral estradiol 1 mg/d (Viscoli et al., 2005) or 2 mg/d (Almeida et al., 2006;
Kocoska-Maras et al., 2011), or very low dose transdermal estradiol 0.014 mg/d (Yaffe et al., 2006).
d
For this three arm trial; the sample size represents women in the estradiol and placebo arms.
e
Category uency was better in the placebo group (P0.02).
f
Face recognition (immediate recall) was signicantly better in the estradiol group (P0.02), but differences were not signicant on face recognition
(delayed recall) or immediate and delayed recall of unrelated words.
g
Based on annual rates of change, three of four word list recall measures were signicantly better in the placebo group (each P0.02); gure recall
was signicantly better in the conjugated equine estrogens group (P0.01).
V. W. Henderson and R. A. Popat / Neuroscience 191 (2011) 129138 133
bined with medroxyprogesterone acetate or to treatment
with placebo (Maki et al., 2007). Active treatment in the
second study was with oral estradiol; eligible women were
aged 5065 years, and outcomes were assessed at 4
weeks (Kocoska-Maras et al., 2011).
Exogenous exposures in older postmenopausal
women. As with younger women, clinical trial results in
this age older group provide no evidence for important
effects of estrogen-containing hormone therapy on epi-
sodic memory or executive functions (Table 2). Treatment
durations ranged from 4 weeks to 4 years. These trials
included women with pre-existing vascular disease (coro-
nary heart disease (Grady et al., 2002) or ischemic stroke
(Viscoli et al., 2005)), relatively healthy surgically meno-
pausal women (surgical menopause here being dened by
hysterectomy rather than bilateral oophorectomy)
(Almeida et al., 2006; Resnick et al., 2009), and relatively
healthy women who had undergone natural menopause
(Resnick et al., 2006; Yaffe et al., 2006). Two of these trials
were ancillary studies derived from the Womens Health
Initiative (Resnick et al., 2006, 2009).
Quantitative synthesis of clinical trial ndings. Pooled
effect sizes for standardized mean differences were small
and did not provide evidence of a signicant effect of
hormone therapy on episodic memory (word list delayed
recall SMD0.05, 95% condence interval [CI] 0.13,
0.03) or on executive functions (digit span backward
SMD0.04, 95% CI 0.12, 0.05; Trails-B SMD0.02,
95% CI 0.21, 1.66; verbal uency SMD0.06, 95% CI
0.13, 0.02) (Table 3). Sensitivity analyses in which nd-
ings from the two midlife trials were excluded did not
substantially changes these results, implying that effects of
hormone therapy on these particular tasks were similar in
midlife and late-life women.
UNRESOLVED ISSUES
Some populations of women and some cognitive out-
comes are poorly addressed in observational and clinical
trial research described above. Unresolved issues involve
women with induced menopause (especially menopause
induced by bilateral oophorectomy), effects of hormone
exposures during the menopause transition, and long-term
cognitive consequences of midlife estrogen exposures
(Table 4).
Table 3. Meta-analysis of larger randomized placebo-controlled trials of hormone therapy and episodic memory or executive functions in women
without dementia
a
Cognitive domain
(neuropsychological task)
Studies included, (number) Random-effects model
pooled SMD (95% CI),
probability
Q statistic,
probability
I
2
index
Episodic memory (word list
delayed recall)
Grady et al. (2002); Almeida et al. (2006); Viscoli et al.
(2005); Resnick et al. (2006, 2009); Yaffe et al.
(2006); Maki et al. (2007) (seven studies)
0.05 (0.13, 0.03), P0.20 8.5, P0.20 30%
Executive function, working
memory (digit span
backwards)
Resnick et al. (2006); Maki et al. (2007); Resnick et al.
(2009) (three studies)
0.04 (0.12, 0.05), P0.40 1.5, P0.47 0%
Executive function, response
alternation (Trail Making
Test, Part B)
Grady et al. (2002); Yaffe et al. (2006); (two studies) 0.02 (0.21, 0.17), P0.83 2.6, P0.11 62%
b
Executive function, initiation
and self-regulation (verbal
uency; category or letter)
Grady et al. (2002); Almeida et al. (2006); Viscoli et al.
(2005); Resnick et al. (2006); Yaffe et al. (2006);
Maki et al. (2007); Resnick et al. (2009); Kocoska-
Maras et al. (2011) (eight studies)
c,d
0.06 (0.13, 0.02), P0.13 8.8, P0.27 20%
For letter uency only, including Maki et al. (2007); Resnick et al. (2006, 2009); Kocoska-Maras et al. (2011) (four studies): SMD0.05 (95% CI
0.14, 0.04), P0.26; Q3.1, P0.37; I
2
4%. CI, condence interval; SMD, standardized mean difference.
a
See text for selection criteria.
b
Only two studies are included; the I
2
value suggests heterogeneity, even though the Q statistic value does not differ signicantly from chance.
c
For Resnick et al. (2006, 2009), analyses assume correlations between category and letter uencies of 0.5.
d
For category uency only, including Grady et al. (2002); Viscoli et al. (2004); Resnick et al. (2006, 2009); Yaffe et al. (2006) (ve studies):
SMD0.06 (95% CI 0.14, 0.03), P0.20; Q6.6, P0.16; I
2
40%.
Table 4. Cognitive effects of midlife and late-life estrogen exposures:
barriers to understanding
Endogenous exposures and memory or executive function
outcomes
Human research is observational
Restricted range of endogenous estrogen levels
Relatively few studies, especially longitudinal studies
Imprecise estimates of long-term exposures
Executive functions difcult to assess with single tests
Unknown role of neurosteroids
Exogenous estrogens and memory or executive function outcomes
Small number of clinical trials in midlife women
Executive functions difcult to assess with single tests
Complexity due to different hormone interventions
Different estrogens, doses and formulations
Use of a progestagen
Different progestagens, doses and formulations
Different administration schedules (e.g. sequential or
continuous combined)
Issues and populations poorly addressed by existing data
Surgical menopause
Menopause transition
Late-life consequences of midlife exposures
V. W. Henderson and R. A. Popat / Neuroscience 191 (2011) 129138 134
Surgical menopause
In the United States, 28%of women undergo hysterectomy
by age 54 years (Merrill, 2008), and somewhat over half of
these women undergo bilateral oophorectomy at the time
of hysterectomy (Whiteman et al., 2008). Surgically meno-
pausal women are poorly represented in research summa-
rized in Tables 13. Some of these studies involved natu-
rally menopausal women; others co-mingled women with
surgical and natural menopause, or dened surgical meno-
pause by the presence or absence of a uterus.
Distinctions between natural and surgical menopause
include acuity (surgical menopause begins abruptly after
bilateral oophorectomy), age (by denition, surgical meno-
pause is performed during a womans reproductive years,
before the time that natural menopause would have other-
wise occurred), health and life-style factors (women in the
Womens Health Initiative who had undergone hysterec-
tomy were less physically active and more likely to be
obese than women who had experienced natural meno-
pause (Stefanick et al., 2003)), and hormonal effects
(midlife testosterone levels decline after surgical meno-
pause but not after natural menopause (Davison et al.,
2005)). In a rodent model, cognitive effects of an estrogen
differ between surgical and transitional menopause
(Acosta et al., 2010).
No large clinical trials of hormone therapy have been
conducted among women with surgical menopausal de-
ned by bilateral oophorectomy. Signicant benet for ver-
bal episodic memory (paragraph recall (Sherwin, 1988;
Phillips and Sherwin, 1992), verbal paired associate learn-
ing (Phillips and Sherwin, 1992)) but not nonverbal epi-
sodic memory (gure recall (Phillips and Sherwin, 1992)) is
reported from two small trials in which estradiol treatment
began immediately after surgery. Executive functions were
not assessed. Surgical menopause was linked to an ele-
vated risk of late-life cognitive impairment in one observa-
tional study (Rocca et al., 2007) but not in another (Kritz-
Silverstein and Barrett-Connor, 2002).
Exogenous estrogen exposures during the
menopause transition
Many women who initiate hormone therapy for vasomotor
symptoms do so during the menopause transition prior to a
nal menstrual period (Brett and Chong, 2001). These
women are generally not considered for clinical trials with
cognitive outcomes, which have focused exclusively on
postmenpausal women. Exploratory analyses in the Study
of Womens Health Across the Nation and the Melbourne
Womens Midlife Health Project imply that hormone ther-
apy initiated prior to natural menopause may benet epi-
sodic memory (Henderson et al., 2003; Greendale et al.,
2009; Maki et al., 2011) and executive functions (Green-
dale et al., 2009), although benet may not be sustained
after menopause (Greendale et al., 2009).
Cognitive outcomes in late-life
Late-life consequences of midlife estrogen exposures are
of major concern, particularly outcomes pertaining to Alz-
heimers disease and other forms of dementia. The critical
window hypothesis suggests that higher estrogen expo-
sures at a younger age, closer to the time of menopause,
reduce the risk of Alzheimers disease, but exposures later
in life do not (Resnick and Henderson, 2002; Sherwin,
2009); other cognitive outcomes might be affected as well
(MacLennan et al., 2006). In ancillary studies from the
Womens Health Initiative involving women aged 6579
years, randomized allocation to conjugated equine estro-
gens plus medroxyprogesterone acetate increased de-
mentia risk in women with a uterus (hazard ratio 2.1, 95%
CI 1.2, 3.5) (Shumaker et al., 2003); there was a similar
trend after allocation to conjugated equine estrogens alone
in women without a uterus (hazard ratio 1.5, 95% CI 0.8,
2.7) (Shumaker et al., 2004). To the contrary, observa-
tional results generally suggest that early hormone therapy
exposures reduce Alzheimers disease risk (Zandi et al.,
2002; Henderson et al., 2005; Whitmer et al., 2011) but
these associations may be skewed by selection bias
(healthy user bias) or other biases (reviewed in (Hender-
son, 2006)). The lack of heterogeneity for cognitive out-
comes among clinical trials involving midlife and late-life
women (Table 3) fails to support the critical window hy-
pothesis, but the number of trials is small, limiting power to
observe an effect, and the range of cognitive outcomes is
limited. The very long interval between exposure and out-
come indicates that it will be very difcult to assess cog-
nitive effects of midlife hormone therapy on such late-life
outcomes as episodic memory, executive functions, or
Alzheimers disease incidence.
CONCLUSIONS
Observational research on endogenous estrogen expo-
sures and clinical trial research on exogenous exposures
suggest two general conclusions regarding cognitive
outcomes.
First, there are no convincing associations between
endogenous serum estrogen concentrations and episodic
memory or executive functions in naturally menopausal
midlife women or in older postmenopausal women (Table
1). Hints in older women that endogenous estrogen levels
have an inverse association with cognition (e.g., Laughlin
et al., 2010) are contradicted by other ndings and require
conrmation. Second, randomized clinical trials in midlife
and late-life women without dementia do not show a sig-
nicant impact of exogenous estrogensbenecial or
harmfulon neuropsychological measures of episodic
memory or executive functions over time frames ranging
from 4 weeks to 4 years (Table 2). A quantitative synthesis
of trial results similarly failed to discern signicant effects
within these cognitive domains (Table 3). This overall con-
clusion of no effect may be reassuring to women con-
cerned by potential adverse cognitive effects of meno-
pause but disappointing to women seeking cognitive aug-
mentation from hormone therapy. Findings support current
guidelines, which do not recommend hormone therapy to
improve cognition or prevent dementia (Board of the Inter-
V. W. Henderson and R. A. Popat / Neuroscience 191 (2011) 129138 135
national Menopause Society et al., 2007; North American
Menopause Society, 2010).
There are limitations to even these modest conclusions
(Table 4). For endogenous exposures, the number of stud-
ies is relatively small; study designs are often cross sec-
tional or hormone concentrations are often assessed at a
single point in time; and neuropsychological tests in these
studies may be insufciently sensitive to episodic memory
and executive functions skills. Indeed, performances on
executive function tasks are not necessarily strongly cor-
related (Kafer and Hunter, 1997; Miyake et al., 2000; Ryan
et al., 2011), and studies incorporating only one or two
executive function tests may fail to capture important as-
pects of what is understood by this term. For episodic
memory, even a widely validated task such as word list
delayed recall may be insensitive to aspects of this domain
(Bird and Burgess, 2008), and delayed recall performance
may be inuenced by attentional, language and planning
disturbances, in addition to memory impairment. More-
over, because most women in these studies are postmen-
pausal, conclusions pertain only to the range of relatively
low levels of estrone and estradiol typical of the postmeno-
pausal state. Another caveat is that hormone levels at one
point in time provide an imprecise estimate of long-term,
cumulative hormone exposures. Among women with os-
teoporosis, bone mineral density, a marker of cumulative
estrogen exposures, is positively associated with better
cognitive outcomes (Yaffe et al., 1999).
For clinical trial results, there are similar limitations with
respect to number of studies and selection of neuropsy-
chological instruments. Interpretations are potentially lim-
ited as well by use in different trials of different formulations
of different estrogens at differing doses, administered on
differing schedules for differing durations. A progestagen,
used in some trials but not others, has the potential to
modify cognitive effects of an estrogen in women (Rice et
al., 2000) and laboratory animals (Lowry et al., 2010). For
midlife women in particular, trial durations have thus far
been relatively short. Results anticipated from two larger,
longer duration hormone therapy trials may provide addi-
tional insights on estrogen effects in midlife women. These
are the Early versus Late Intervention Trial with Estrogen
(ELITE, clinicaltrials.gov identier NCT00114517) and the
Kronos Early Estrogen Prevention Study (KEEPS, clinical-
trials.gov identier NCT00623311).
In understanding these largely negative observational
and clinical trial results, it may be important that estradiol is
not only an ovarian steroid, it is also a neurosteroid syn-
thesized within the central nervous system (Mukai et al.,
2010; Srivastava et al., 2010). The widespread distribution
of aromatase in neurons in the hippocampus and neocor-
tex supports the view that local estrogen synthesis contrib-
utes to synaptic plasticity (Yague et al., 2008). At least
theoretically, brain-synthesized estradiol may be at least
as important in modulating cognition as ovarian derived
endogenous estrogens or exogenous estrogens in hor-
mone therapy. Circulating levels may therefore be weak
predictors of neural effects that modulate cognition.
There remains a pressing need for preclinical and hu-
man studies on the relationship between the menopause
transition and midlife exposures to estrogens, progesta-
gens and related compounds, and the risks of age-related
cognitive disorders (Asthana et al., 2009). Future studies
of estrogen exposures and cognition might consider how to
incorporate these ndings into the design and interpreta-
tion of observational and experimental research. Under-
studied populations include women with induced meno-
pause and women in the menopause transition. Potential
effects of midlife hormone exposures on Alzheimers dis-
ease risk and other late-life cognitive outcomes merit fur-
ther study.
Note added in proof: Two other large studies in late-life women
describe associations between serum estrogens and tests of ep-
isodic memory or executive functions. Almeida et al. (2005) re-
ported no signicant associations between total estradiol or es-
trone and episodic memory (word list recall) or executive functions
(uency). Yaffe et al. (2007) reported no signicant association
between tertiles of bioavailable estradiol and episodic memory
(word list recall), but women in the highest tertile were signicantly
less likely to show decline two years later than women in the
lowest tertile.
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(Accepted 24 May 2011)
(Available online 6 June 2011)
V. W. Henderson and R. A. Popat / Neuroscience 191 (2011) 129138 138