Review

Action of estrogens in the aging brain: Dementia and cognitive aging

Victor W. Henderson
Departments of Health Research and Policy (Epidemiology) and of Neurology and Neurological Sciences, Stanford University School of Medicine, 259 Campus Drive, Stanford,
CA 94305-5405, USA
a b s t r a c t a r t i c l e i n f o
Article history:
Received 25 July 2009
Received in revised form 20 October 2009
Accepted 2 November 2009
Available online 12 November 2009
Keywords:
Aging
Alzheimer's disease
Cognition
Dementia
Estrogen
Hormone therapy
Background: Menopause is associated with sharp declines in concentrations of circulating estrogens. This
change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive
aging.
Scope of review: Focused review of published results of randomized clinical trials of estrogen-containing
hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on
cognition across the menopause transition, and observational research on the association of hormone
therapy and Alzheimer's disease risk.
Major conclusions: Clinical trial evidence supports conclusions that estrogen therapy does not improve
dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy
initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older
postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone
exposures are less well studied. There is no strong indication of short-term cognitive benet of hormone use
after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after
surgical menopause; limited clinical trial data imply short-term benet of prompt initiation at the time of
oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or
cognitive aging much later in life is unanswered by available data. Observational results raise the possibility
of long-term cognitive benet, but bias is a concern in interpreting these ndings.
General signicance: Estrogen-containing hormone therapy should not be initiated after age 65 to prevent
dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term
cognitive effects of estrogen exposures closer to the age of menopause.
2009 Elsevier B.V. All rights reserved.
Estrogen receptorsestrogen receptor alpha and estrogen receptor
betaare members of a nuclear receptor superfamily that includes
receptors for androgen, progesterone, glucocorticoids, and miner-
alocorticoids. Within mammalian brain, these receptors have delim-
ited topographic distributions unique to each hormone. Estrogen
receptor alpha, for example, is the predominant receptor subtype of
cholinergic neurons in the basal forebrain, whereas estrogen receptor
beta is more abundantly expressed in the hippocampus and cerebral
cortex [1,2]. These receptors function as ligand-activated transcription
factors that bind hormone response elements on the genome to
modulate the expression of nearby target genes. In addition, putative
G-protein-coupled estrogen receptors are associated with the plasma
membrane, one role of which appears to be regulation of intracellular
signaling cascades and mediation of rapid actions not involving
genomic activation [3,4]. The brain is affected secondarily by
estrogens acting on non-neural tissues, which in turn inuence
normal and pathological processes within the central nervous system.
Examples are estrogen effects on vascular endothelium and the
immune system [5,6].
Menopause represents the permanent loss of ovarian follicles,
which during a woman's reproductive years cyclically produce
estrogens and progesterone. Menopause is thus associated with
sharp declines in concentrations of circulating estradiol and estrone
[7], the two primary ovarian estrogens, as well as progesterone. This
change in endocrine milieu has the potential to affect a variety of brain
functions during midlife and beyond. From animal models based on
ovariectomy or on reproductive senescence, it is clear that estradiol
can facilitate or enhance aspects of learning and memory [8-11]. Some
types of memory are clearly not aided, however; striatal-dependent
motor learning, for example, may be impeded by estradiol adminis-
tration after ovariectomy [11].
There is great interest in whether reduced levels of sex hormones
due to specically to menopause or, in the case of men, related more
generally to ageaffect cognition. In the late nineteenth and early
twentieth centuries, the clinical focus was on testosterone and
cognitive function in older men [12]. Although a century later
testosterone is now again a topical area of investigation, greater
attention during the past decade and a half has been paid to estrogen
and cognitive aging in women. This line of research was engendered
by emerging interests during the 1970s and 1980s in menopause,
climacteric symptoms, and women's health [13-15] and by parallel
Biochimica et Biophysica Acta 1800 (2010) 10771083
Fax: +1 650 725 6951.
E-mail address: vhenderson@stanford.edu.
0304-4165/$ see front matter 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbagen.2009.11.005
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
j our nal homepage: www. el sevi er. com/ l ocat e/ bbagen
advances in the psychology and neurology of human sex differences
[16,17].
The following sections consider effects of estrogens on severe
cognitive decrement characteristic of dementia and on minor
cognitive decrement associated with usual aging.
1. Dementia
Dementia can be dened as major cognitive impairment, where
cognitive decits interfere substantially with social or occupational
function. The term implies decline from a premorbid level at which
there were no functional limitations as well as the presence of an
underlying pathobiological substrate. In the United States and Europe,
Alzheimer's disease is by far the most common cause of dementia in
old age [18,19]. In some Asian countries, vascular dementia may be
more prevalent, although the reported higher frequency could be due
to methodological differences in case ascertainment [20]. Overlapping
pathologies (e.g., co-existing changes of both Alzheimer's disease and
vascular disease) are increasingly recognized and may be more
common than so-called pure cases [21]. Cognitive loss in Alzheimer's
disease begins insidiously and progresses gradually over a period of
years. It is rare before age 60 years and increases in incidence and
prevalence into the ninth and tenth decades of life. A consistent early
symptom reecting impairment in episodic memory is loss of the
ability to recall recent events or recently encountered information
[22]. Other cognitive skills are also affected, but typically less
noticeably so, especially early in the disease course.
Observations that women with Alzheimer's disease may have
relatively greater difculty with cognitive skills sometimes viewed as
female-advantaged (verbal uency, naming, verbal episodic memory)
[23] led to inquiries on the relation between estrogen and this
dementing disorder. Early observational studies revealed an associ-
ation between a woman's use of estrogen-containing hormone
therapy and a reduced risk of later developing Alzheimer's disease
[24,25]. Subsequent case-control and cohort studies generally
reinforced the view that estrogens used after menopause could
reduce Alzheimer risk [26-34] (Table 1), with meta-analyses
indicating signicant risk reductions in the range of 30 to 40 percent
[35,36]. These clinical ndings were supported by strong biological
plausibility. Estradiol facilitates hippocampal long-term potentiation
[37] (a physiological process believed to be important in episodic
memory formation) in awake ovariectomized rats and, similarly, it
enhances long-term potentiation in hippocampal slice preparations
derived from a transgenic mouse model of Alzheimer's disease [38].
Estradiol also reduces the formation of -amyloid [39] and hyperpho-
sphorylated tau protein [40], key biochemical abnormalities in brains
of Alzheimer patients. In addition, estradiol is neuroprotective in
models of ischemia, oxidative stress, excitatory neurotoxicity, and
apoptosis [41-43]; and it has tropic effects in promoting neurite
growth and synapse formation [44,45]. Mitochondrial actions of
estradiol enhance glycolytic metabolism in the brain [46].
Two lines of clinical research, however, have challenged the
implication that estrogen-containing hormone therapy might have a
therapeutic role with respect to Alzheimer risk. First, randomized
trials of estrogens for women with mild-to-moderate symptoms of
Alzheimer's disease generally failed to show improvement in
dementia symptoms [47-50]. The largest of these found no
between-group differences on most functional and cognitive compar-
isons after 1 year of unopposed conjugated equine estrogens [48].
Second, an ancillary study of the Women's Health Initiative, the
Women's Health Initiative Memory Study (WHIMS), showed that
hormone therapy actually increased dementia risk [51]. WHIMS
examined effects of a widely used oral hormone preparation on
incident dementia in postmenopausal women age 65 to 79 years.
Baseline cognitive assessment in this randomized controlled trial
excluded women with pre-existing dementia. Participants were
randomly assigned to receive conjugated equine estrogens
(0.625 mg/day) or placebo. Women with a uterus in the estrogen
group also received a progestogen (medroxyprogesterone acetate
2.5 mg/day) in a continuous combined formulation. During the course
of the WHIMS trials, 61 women with a uterus and 47 women without
a uterus developed dementia. For women with a uterus, the hazard
ratio (a measure of relative risk) of developing dementia was doubled
for women receiving the estrogen-progestogen formulation (2.05,
95% condence interval 1.2 to 3.5) [51]. For women who had
undergone hysterectomy, the relative risk for women receiving
estrogens alone was increased by half (hazard ratio 1.5, 95%
condence interval 0.8 to 2.7) [52].
It is clear that in vitro effects vary among different estrogens (e.g.,
estradiol or estrone [53]) and different progestogens (e.g., progester-
one or medroxyprogesterone acetate [54]), and clinical outcomes
might be inuenced by these differences. However, hormone
formulations used by women in observational studies of Alzheimer
risk often contained the same estrogens and same progestogen
selected for the Women's Health Initiative clinical trials. In WHIMS,
Alzheimer's disease was the specic diagnosis in half of the dementia
cases [52], but because of the small sample size separate results for
Alzheimer's disease were not reported. Women who were older at the
start of the WHIMS trials were signicantly more apt to become
demented, regardless of treatment arm [52]. The same association
was seen for women with lower cognitive test scores at the start of the
trial [52], perhaps implying that some women diagnosed with
dementia during the trial already had subclinical disease at trial
onset. Consistent with most prior observational studies on hormone
therapy and Alzheimer's disease risk [35,36], WHIMS participants
who had used hormone therapy before enrolling in Women's Health
Initiative studies were less likely to develop dementia during the
WHIMS trial, regardless of treatment arm [34,52]. Interestingly, in a
large clinical trial conducted among postmenopausal women with
Table 1
Hormone therapy and Alzheimer's disease risk: observational studies in which information on hormone exposure was obtained before dementia onset.
Study [Ref.] Source of exposure information Number of cases Number of controls Relative risk Condence interval
Brenner et al [26] Pharmacy records
a
107 120 1.1 0.6-1.8
Paganini-Hill and Henderson [27] Self-report 248 1193 0.65 0.5-0.9
Tang et al [28] Self-report 167 957 0.5 0.25-0.9
Kawas et al [29] Self-report 34 438 0.5 0.2-1.0
Waring et al [30]
b
Medical records 222 222 0.4 0.2-0.96
Roberts et al [33]
b
Medical records 245 245 1.1 0.6-1.9
Seshadri et al [31] Pharmacy records
a
59 221 1.2 0.6-2.4
Zandi et al [32] Self-report 84 1866 0.6 0.4-0.96
WHIMS [34]
c
Self-report 53 7047 0.4 0.2-0.85
WHIMS= Women's Health Initiative Memory Study.
a
Pharmacy records for studies of Brenner et al [26] and Seshadri et al [31] were available from approximately the preceding decade.
b
Separate, independent Mayo Clinic case-control studies, with cases from 1980-1984 (Waring et al [30]) and 1985-1989 (Roberts et al [33]).
c
Hormone therapy increased dementia risk during WHIMS trials irrespective of prior hormone exposures [52].
1078 V.W. Henderson / Biochimica et Biophysica Acta 1800 (2010) 10771083
osteoporosis, higher doses of raloxifene, a selective estrogen receptor
modulator, reduced the incidence of mild cognitive impairment and
dementia [55].
1.1. Reconciling apparent differences between results of the WHIMS
trial and results of observational research
In trying to understand WHIMS results in the context of prior
research on Alzheimer risk, at least two points should be considered
[56]: bias and external validity. First, observational studies of
hormone therapy probably have provided biased estimates of
Alzheimer risk reduction. Exposure misclassication is a concern in
studies where information on hormone use is collected retrospec-
tively, after the onset of dementia. Where hormone usage was based
on self-report before dementia diagnosis, women who were cogni-
tively impaired at baselineand thus more likely to be diagnosed with
frank dementia latermay have underreported prior usage compared
to women without cognitive impairment at baseline [57]. Further,
prior users of hormone therapy may be healthier than women who
never used hormone therapy [58], and healthy life style practices
unrelated to hormone use may have contributed to protective
associations.
On the other hand, it should be considered that women in the
WHIMS clinical trials differed from women in observational studies,
and WHIMS ndings might not generalize to women ineligible to
participate in the clinical trials. A key difference was the age at which
women initiated and used hormone therapy [56]. Because hormone
therapy is most often used around the time of menopause for
vasomotor symptoms, hormone use in observational studies more
often than not occurred at a relatively young age. In contrast, WHIMS
trial participants were at least 65 years of age at the time of
randomization to study medication.
Is this difference in timing relevant?
There is indirect support for an interaction based on age or based
on timing of hormone initiation. Estrogen effects on atherosclerosis
progression, as an example, may vary according to a woman's age or
the length of time since menopause. Earlier hormone use may retard
atherosclerosis; later use in the presence of pre-existing atheroscle-
rosis may promote adverse outcomes [5,59-61]. However, the clinical
import of timing with respect to coronary heart disease has been
challenged [62].
Some have speculated that estrogen effects on Alzheimer risk
might also vary, depending on whether hormones are initiated or
used during some critical period dened by young age or close
proximity to menopause. In a Danish follow-up study, middle-age
participants in three randomized trials of hormone therapy for
osteoporosis prevention were assessed after a mean interval of
11 years. Women originally randomized to hormone therapy were
signicantly less likely to have cognitive impairment at follow-up
than women assigned to placebo [63]. These results suggest a
cognitive protective effect of short-term midlife hormone therapy
over a decade later. This inference is additionally supported by
observations in one case-control study that hormone therapy was
associated with reductions in Alzheimer risk only among younger
postmenopausal women, where hormone use necessarily occurred at
a younger age [64], and observations in a prospective cohort study
that current hormone usein contrast to past usewas not linked to
reduced risk [32].
Based on evidence discussed above, it remains at present unclear
whether use of estrogens during the menopausal transition or early
postmenopause affects Alzheimer risk and, if so, whether the effect is
protective (as suggested by some observational research ndings) or
harmful (as extrapolated from WHIMS clinical trial ndings).
2. Cognitive aging
Beginning in midlife or earlier, decrements are apparent in many
areas of cognitive function [65], and the term cognitive aging is often
used to describe this age-related phenomenon. By convention, when
the threshold for dementia is reached, one is no longer dealing with
cognitive aging. The concept of cognitive aging also excludes forms of
mild cognitive impairment (MCI, [66]), usually viewed as a transi-
tional stage between normal and dementia, representing very early
clinical manifestations of a dementing disorder such as Alzheimer's
disease. Although unitary explanatory factors, such as slowed neural
processing or impaired working memory, have been invoked to
account for cognitive aging, it is more likely that multiple processes
are involved [67]. The trajectory of cognitive aging is variable [68], and
many even among the oldest old remain cognitively competent [69].
A decline in episodic memory performance may precede the
clinical diagnosis of Alzheimer's disease, but episodic memory is
among the cognitive domains impactedalbeit more modestlyby
usual aging as well. In the clinical setting, this form of memory is
tested by tasks that require exposures to new material (e.g., a list of
words or a paragraph-length story) followed by conscious recollec-
tion of this material. Almost all studies of estrogen and aging have
included memory tasks; other cognitive domains have been assessed
less reliably.
Many women complain of forgetfulness or poor memory around
the time of the menopausal transition [70]. Forgetfulness, however, is
a common symptom at any age, and serum estradiol levels at midlife
are unrelated to memory performance or performance in other
cognitive domains [71-73]. Moreover, observational ndings from
well-characterized midlife cohorts suggest that natural menopause
does not lead to measurable change in midlife cognition [71,72,74,75]
(Table 2). However, there is some suggestion that learning may be less
Table 2
Objective cognitive outcomes across the natural menopause transition
a
.
Study [Ref.] Cohort description Number Mean age Memory Other cognitive scores
Henderson et al [71] Population-based, Melbourne, Australia 326 57 years NS
Fuh et al [75] Population-based, Kinmen, Taiwan 495 48 years NS Most NS
b
Kok et al [74] Population-based, United Kingdom birth cohort 997 53 years NS Slower search speed
c
Herlitz et al [72] Population-based, Umea, Sweden 242 49 years NS NS
Luetters et al [73]
d
Ethnically-diverse convenience sample, United States 1657 50 years NS NS
Greendale [76]
d
Ethnically-diverse convenience sample, United States 2362 46 years NS
e
NS
e
NS= non-signicant probability pN 0.05.
a
Includes cross-sectional and longitudinal analyses.
b
Lower verbal uency for women transitioning to perimenopause compared to premenopause; no differences on digit span forward or backward, or on Trail Making Test, Part A
or B.
c
Trend for slower visual search on a letter cancellation task across pre-peri-and postmenopausal groups, with lower scores in the postmenopause.
d
Women in Leutters et al [73] represent a subset of women in the sample of Greendale et al [76].
e
No differences based on menopause transition stage. Non-signicant (0.05b pb 0.1) trend for lower rate of improvement on verbal recall scores across annual visits for women
in early and late perimenopausebut not postmenopausecompared to premenopause. Non-signicant trend for lower rate of improvement on processing speed (Symbol Digit
Modality Test) for women in late perimenopause compared to premenopause.
1079 V.W. Henderson / Biochimica et Biophysica Acta 1800 (2010) 10771083
efcient during the uctuating hormonal milieu of the perimeno-
pause in comparison to the premenopause or postmenopause [76].
During midlife, memory complaints often appear more closely related
to mood than to objective memory decits [77].
2.1. Cognitive aging: clinical trials in women below age 65
There is a growing experimental literature on cognitive effects of
menopausal hormone therapy. This literature is more substantial for
older postmenopausal women than for women closer to the age of
menopause, where smaller studies of estrogen-containing hormone
therapy have often lacked statistical power to detect important
cognitive effects. Most trials conducted among midlife women have
not reported signicant treatment effects [78], a nding predicted on
the basis of observational studies of the natural menopause transition
[71-75] (Table 2). The largest clinical trial of younger postmeno-
pausal women randomized 180 volunteers 45 to 55 years of age [79]
(Table 3). Participants had undergone natural menopause, and active
treatment was with conjugated equine estrogens combined with
medroxyprogesterone acetate. Findings at 4 months revealed no
signicant benet on tests of episodic memory or other cognitive
abilities.
2.2. Cognitive aging: clinical trials in women age 65 and older
Clinical trial ndings on cognitive outcomes among women in the
early postmenopause are limited. Trial data are ampler for women in
the late postmenopause [78]. Results in this older age group provide
no evidence for cognitive improvement from late initiation or use of
hormone therapy. Indeed, there are some hints of cognitive harmafter
several years of use [80] associated with reduced brain volume [81].
However, the magnitude of mean decrement on neuropsychological
tests, when detected at all, is probably too small to be clinically
apparent. In the WHIMS trials discussed above with respect to
dementia outcomes, scores on a modied version of the Mini-Mental
State examination, a test of global cognition, were slightly lower
among women randomized to hormone therapy after treatment
durations averaging 4.2 years (women with a uterus [82]) or 5.4 years
(women without a uterus [83]). Mean differences between treatment
groups were about a quarter of a point on a 100-point scale (effect size
of approximately 0.05). These small differences were further
attenuated after women with incident dementia, MCI, or stroke
were excluded [83]. An ancillary study in the WHIMS cohort found the
combined estrogen-progestogen preparation slightly improved mem-
ory for a visual design but slightly impaired memory for a list of words
[80] (Table 3).
Cognitive abilities have been assessed in other fairly large clinical
trials in this age group, with mean treatment durations as long as
4 years. Two such trials focused on women with known vascular
disease, either coronary heart disease [84] or stroke or transient
ischemic attack [85] (Table 3). Active treatment used conjugated
equine estrogens with medroxyprogesterone acetate [84] or oral
estradiol [85]. Two other large trials involved women believed to be
healthy. In these studies, active treatment was with oral estradiol [86]
or very low-dose transdermal estradiol [87] (Table 3). None of these
trials demonstrated improvements in memory, and none suggested
overall cognitive benet or harm.
2.3. Is surgical menopause different?
Natural menopause occurs at a mean age of 51 years [88], and
fewer than 2% of women experience menopause after age 55 [89]. In
the United States, hysterectomy is the second most common major
surgery among women ages 18 to 44 years, surpassed only by
cesarean section. By age 54 years, 28% of women have undergone
hysterectomy [90]. Bilateral oophorectomy is performed at the time of
hysterectomy somewhat more than half of the time [91].
Surgical menopause begins abruptly after bilateral oophorectomy
performed during a woman's reproductive years which, by denition,
occurs before the age that natural menopause would have otherwise
occurred. Cognitive consequences of surgical menopausewhere the
ovarian production of estrogens and progesterone, as well as
androgens, ceases abruptlymay differ from those of natural meno-
pause occurring at a later age. Surgical menopause, for example, has
been linked with heightened risk of late-life cognitive impairment
[92] and Alzheimer's disease [93], but it is also reported not to be
related to cognitive function later in life [94].
Few clinical trials have assessed cognitive effects of estrogens in
surgically menopausal women. Signicant cognitive benet is
reported from two very small trials [95,96]. In these, participating
women were relatively young (mean ages of 45 and 48 years), and
therapy was initiated immediately after surgery. Supportive ndings
fromthe same investigative group come froma trial conducted among
even younger women (mean age 34 years) treated with a gonado-
tropin-releasing hormone agonist to suppress ovarian function [97].
In this study, women began oral conjugated estrogens or placebo after
3 months, while continuing to receive the gonadotropin-releasing
hormone agonist. Cognitive testing 2 months later showed signi-
cantly better test scores in the estrogen group, although cognitive
Table 3
Hormone therapy and objective cognitive outcomes in women without dementia: large randomized placebo-controlled trials
a
.
Trial Reproductive stage
b
Menopause type
b
Number Mean age Duration Memory Other cognitive scores
Grady et al [84] Late Both 1063 67 years 4 years NS Most NS
c
Rapp et al [82]
d
Late Natural 4381 6579 years
e
4 years NS
Espeland et al [83]
d
Late Surgical 2808 6579 years
e
5 years NS
Viscoli et al [85] Late Both 461 70 years 3 years NS NS
Almeida et al [86] Late Surgical 115 74 years 5 months NS NS
Resnick et al [80]
d
Late Natural 1416 71 years 4 years Variable
f
NS
Yaffe et al [87] Late Natural 417 67 years 2 years NS NS
Maki et al [79] Early Natural 180 52 years 4 months NS NS
NS= non-signicant probability, pN0.05.
a
Restricted to randomized placebo-controlled trials in postmenopausal women without dementia, sample size of at least 100, duration of at least 1 month, and objective measures
of cognitive outcomes.
b
Early=early postmenopause [104], Late=late postmenopause [104], Natural =natural menopause, Surgical =surgical menopause based on hysterectomy status,
Both=natural and surgical menopause.
c
Better verbal uency in placebo group; no differences for global cognition, naming, or executive function (Trail Making Test, Part B).
d
Women's Health Initiative Memory Study of women with [80, 82] or without [83] a uterus. Rapp et al. [82] and Espeland et al. [83] report global cognition on the Modied Mini-
Mental State examination. Resnick et al. [80] report more detailed cognitive analyses on a subset of women with a uterus; these women are included in the sample of Rapp et al. [82].
See text for details.
e
Age range; mean ages not stated.
f
Based on annual rates of change, verbal memory was better in placebo group, and nonverbal memory was better in hormone group.
1080 V.W. Henderson / Biochimica et Biophysica Acta 1800 (2010) 10771083
benet was restricted to verbal memory performance [97]. This
nding of domain-specic cognitive improvement is consistent with
results in surgically menopausal women [96].
Other trials of surgically menopausal women found no cognitive
improvement [80,82,86,98,99], including trials conducted as part of
the Women's Health Initiative [80,82]. Surgical menopause in these
negative trials was dened by hysterectomy status and not oopho-
rectomy status, and only one of thesea 3-month crossover trial of 62
Finish women [98]involved primarily midlife women. Verbal
memory was not assessed in this trial [98].
Similar issues are raised by early menopause induced by
irradiation or adjuvant cancer chemotherapy. Cognitive complaints,
which are common in this clinical setting, undoubtedly have multiple
determinants. Treatment-induced menopause may be associated with
short-term cognitive decits [100], although potential consequences
of early menopause are difcult to disambiguate from those of
therapy per se. Among breast cancer survivors, tamoxifen, a selective
estrogen receptor modulator, and aromatase inhibitors such as
anastrozole, exemestane, and letrozole raise particular concerns. It
is not clear, however, that resultant hormonal changes substantially
impact cognitive skills, at least in the short-term [101,102], although
data remain sparse and much remains to be determined.
3. Estrogens, dementia, and cognitive aging: a summing up
Despite convincing demonstration that estrogens affect brain
tissues and brain processes in ways expected to reduce dementia risk
and improve the course of cognitive aging, clinical ndings have been
disappointing. There are, of course, important differences between in
vitro and in vivo laboratory models and clinical practice. A major issue
is the question of timing: are estrogen effectsfor example, on key
biochemical perturbations of Alzheimer's disease [39,40]modied by
use during a so-called critical window dened by age or temporal
propinquity to menopause [56]? One clinical trial (WHIMS) indicates
that hormones increase dementia rate [51]; many (but not all)
observational studies imply that hormones reduce the rate of
Alzheimer's disease (Table 1). Major differences in ages at time of
hormone exposures (at least 65 years of age for women in WHIMS,
but generally much younger in observational studies), lend credence
to this view. If correct, this nding begs the important question of
mechanism by which the hormone effect is modied by age.
Some of the apparent discrepancy between research ndings
might also be ascribed to competing risks. Whereas some estrogenic
effects on the vasculature are clearly protective [5,60,61], other
actions are harmful. Estrogens have complex, competing effects on
pathways involved in inammation, thrombosis and thrombolysis,
brinolysis, and the formation and rupture of atherosclerotic vascular
plaques. Because the clinical manifestations of Alzheimer neuropa-
thology depend in part on the presence or absence of vascular disease
and other brain pathology [21], the net cognitive outcome is not easily
predicted from short-term laboratory experiments in models that at
best only approximate the human situation.
It is important to appreciate that some clinical issues now appear
to be resolved, thanks to new clinical research informed by basic
laboratory investigation. This was not the case a decade ago. It now
seems apparent that starting estrogen-containing hormone therapy in
women with Alzheimer's disease probably does not benet dementia
symptoms, and hormone initiation after about age 65 years increases
rather than reduces dementia risk. Further, hormones, when used
over periods of up to several years, do not provide net benet to
cognitive aging in this older age group (Table 3). For women closer to
the age of menopause, clinical data are less robust; but among
naturally menopausal women, there is no strong evidence that short-
term use of hormone therapy augments cognitive skills [78].
In contrast, there remains some indication that estrogens might
improve aspects of cognitive function among women who have had
menopause induced before the age at which natural menopause
would have otherwise occurred. Further study will be needed to
conrm or disprove this inference. Whether midlife estrogen
exposures affect dementia risk or cognitive aging much later in life
cannot be answered by present data. Well-designed cohort studies,
appropriate animal models, and long-term clinical trialsperhaps
using surrogate biomarkers of brain function and brain pathology
will help provide less ambiguous answers to these important, vexing
questions [103].
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