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The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
Vol. 84, No. 6
Printed in U.S.A.
CLINICAL REVIEW 108
The Molecular and Neuroanatomical Basis for Estrogen
Effects in the Central Nervous System
BRUCE S. MCEWEN
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University,
New York, New York 10021
With increasing life expectancy during the 20th century,
women are likely to live a substantial part of their lives in a
state of estrogen deficiency. Hot flushes are for many women
the most dramatic and noticeable consequence of loss of
ovarian hormones. Loss of bone calcium and osteoporosis,
developing much more gradually, is another consequence
that has led many women to take estrogen replacement therapy (ERT) at the menopause. Likewise, the loss of protection
of the coronary arteries, leading postmenopausal women to
increased risk for cardiovascular disease, is another result of
estrogen deficiency that has reinforced the value of ERT. Yet,
it is only quite recently that medical science has recognized
that the brain is one of the organs of the body that suffers
from the loss of this circulating hormone.
This has happened despite studies over more than 30 yr
indicating that estrogens target the brain of experimental
animals (for summary, see Ref. 1). However, most of the
animal studies have focused on estrogen actions on the hypothalamus affecting ovulation and reproductive behavior,
and only recently has it become apparent that estrogens exert
many actions outside of the reproductive function, including
actions on brain areas that are important for learning and
memory, emotions and affective state, as well as motor coordination and pain sensitivity. Indeed, some women experience at surgical or natural menopause difficulties in remembering names and other information important for daily
life as well as deficits in fine motor coordination and reaction
times and feelings of depression and anxiety (2). These effects
reflect the actions of estrogens on a large number of brain
areas outside of the hypothalamus. The problem in these
brain regions has been to recognize the receptors and mechanisms by which estrogens produce their effects. This brief
review will focus on two aspects: first, the cellular and molecular mechanisms by which estrogens produce their diverse effects on the brain; and second, the brain regions and
cell types in which estrogens produce their effects, emphasizing new knowledge regarding estrogen actions outside of
the hypothalamus and pituitary gland. Finally, a brief disReceived January 27, 1999. Revision received March 10, 1999. Accepted March 15, 1999.
Address all correspondence and requests for reprints to: Dr. Bruce S.
McEwen, Laboratory of Neuroendocrinology, Rockefeller University,
1230 York Avenue, New York, New York 10021. E-mail:mcewen@
rockvax.rockefeller.edu.
cussion will summarize the potential clinical applications of
this information, particularly in relation to cognitive function
and dementia.
Historical overview
In the early 1960s, putative DNA-binding estrogen receptors (ERs) were identified as proteinaceous binding sites for
tritiated estradiol in the tissue cytosol and cell nuclear compartment (3). Found initially in reproductive tract, putative
ERs were subsequently identified by in vitro cytosol binding
and in vivo uptake and cell nuclear retention in the pituitary
gland and hypothalamus (1). At first, only ERs in the hypothalamus and pituitary gland were studied because they
were the most obvious and also the most obviously related
to estrogen actions on reproduction. Gradually, however,
nerve cells containing putative ERs were recognized in brain
regions such as the hippocampus, cerebral cortex, midbrain,
and brain stem. The introduction of antibodies to ERs and the
cloning of ERs permitted more direct measurements of the
receptor themselves or their messenger ribonucleic acids
(mRNAs) by immunocytochemistry and in situ hybridization
histochemistry, and these newer tools generally confirmed
the older localization of ERs based upon tritiated estrogen
binding and steroid autoradiography. The classical intracellular ER is called the ERa (see Ref. 2 for summary). Recently,
a new form of the intracellular ER, the ERb, was cloned, and
mapping studies are underway in the brain and other tissues
and organs, as summarized below. The localization of this
receptor to new cell types will undoubtedly extend the list of
tissue, organs, and brain regions that are capable of responding to estrogens with a regulation of gene expression.
At the same time that progress with intracellular ERs has
accelerated, other investigations of the functional effects of
estrogens on nerve cell activity and neuroprotection have
uncovered rapid actions of these hormones that cannot involve activation or repression of gene expression, because of
either their extreme rapidity or their structure-activity profile
in relation to the specificity of known intracellular ERs. These
nongenomic actions of estrogens operate in many cases on
the cell surface and affect the excitability of nerve cells and
smooth muscle cells and the movement of the sodium, potassium and calcium ions that create a nerve impulse and
modulate the internal state of neurons. However, we know
very little about the molecular characteristics and the mech-
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anism of action of these nongenomic receptors in cell membranes. Nevertheless, the effects that they mediate are of
sufficient interest to make them an essential component of a
review of estrogen action in brain. We shall now discuss
these issues in greater depth, using a figure and a number of
summary tables to cover material that the reader may find in
more detail in another review (2).
ERs and actions in the central nervous system
The variety of estrogen effects has been expanded to include rapid actions on excitability of neuronal and pituitary
cells, the activation of cAMP- and mitogen-activated protein
kinase (MAP kinase) pathways, effects on calcium channels
and calcium ion entry, and protection of neurons from damage by excitotoxins and free radicals (Table 1 and Fig. 1).
These estrogen actions occur through at least two types of
intracellular receptors as well as a number of other mechanisms involving receptors that have not been characterized.
Indeed, for a number of processes, there are conflicting reports, based upon estrogen structure-activity studies and the
actions of estrogen antagonists, that intracellular receptors
may not be involved. Thus, as summarized in Table 1, for
estrogen actions on some aspects of calcium homeostasis,
certain aspects of second messenger systems and some features of neuroprotection, a novel receptor mechanism is implicated, in which stereospecificity for 17b- over 17a-estradiol is replaced by a broader specificity for the 3-hydroxyl
group on the A ring. Such findings suggest that there are
novel receptor mechanisms not involving the classical intracellular ER. However, before discussing these receptors, we
shall consider the intracellular ER.
Intracellular ERs
ERa shows a characteristic distribution in the nervous
system, with high levels in the pituitary, hypothalamus, the
hypothalamic preoptic area and amygdala and much lower
levels, and a more scattered distribution, in other brain regions. The discovery and cloning of ERb (4 – 6) radically
changed the view of estrogen action and provided, among
other things, a basis for understanding how the knockout of
ERa (aERKO) (7, 8) could have resulted in a viable organism
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and in the continued actions of estrogens on many tissues.
The deletion of the ERb gene was described recently (9), and
bERKO animals are remarkably normal and are even able to
reproduce, although they show some reduction in litter size.
This is in contrast to the aERKO mice, which are sterile and
show altered sexual and other behaviors (see Ref. 2 for
summary).
Measurements of messenger RNA (mRNA) for ERa and
ERb reveal distributions in the body that differ quite markedly from each other, with moderate to high expression of
ERa mRNA in pituitary, kidney, epididymus, and adrenal;
moderate to high expression of ERb mRNA in prostate, lung,
bladder, and brain; and overlapping high expression in
ovary, testis, and uterus (10). Isoforms of ERb have been
identified (see Ref. 2 for summary). The best characterized of
these variants has been termed ERb2. Compared to the originally designated ERb1, this isoform has a lower affinity for
estrogens (11), presumably due to an 18-amino acid insertion
in the ligand-binding domain (12).
In brain, the distribution of ERa is well established, but
there is less certainty and more controversy surrounding the
localization of ERb. The autoradiographic maps of [3H]estradiol uptake and retention in brain (13, 14) are presumed
to reflect binding to all forms of the ER, particularly the ERa
and the ERb1 isoforms, which have similar affinities for
17b-estradiol (10). In situ hybridization data suggest widespread distribution of ERb mRNA throughout much of the
brain, including olfactory bulbs, cerebellum, and cerebral
cortex (15, 16), whereas results from immunocytochemical
studies for ERb indicate a more restricted localization of
detectable protein, although the antisera that are currently
available do not always provide specific signals in some
brain areas (see Ref. 2 for discussion). Thus, it remains a
likely, but unproved, assumption that the presence of ERb
mRNA indicates the presence of some functional ERb receptor protein, even if the [3H]estradiol autoradiography,
mentioned above, has shown very little in the way of functional ER in some of the brain regions where ERb mRNA is
expressed. The possible presence of low levels of intracellular
ER, not detectable by either autoradiography or immunocytochemistry, remains one of the thorniest issues affecting
TABLE 1. Actions of estrogens related to excitability and cell membrane events
Membrane binding sites: identified but not well characterized in pituitary, liver, and endometrium, but not in brain; some membrane sites
may be related to intracellular ER (23, 24).
Genomic effects on membrane events, e.g.: induction of the MINK potassium channel in pituitary via genomic mechanism (58); calcium
channel expression in pituitary and hippocampus (59).
Apparent nongenomic actions, e.g.: rapid excitation of electrical activity in cerebellum, hippocampus, striatum, and cerebral cortex; effects
occur within seconds and are unlikely to involve a transcriptional activation (60).
Second messenger activation
CREB phosphorylation: genomic vs. nongenomic mechanism unclear (25, 26).
MAP kinase activation: possible novel receptor pathway or involvement of classical ER in a novel signaling pathway (27).
Calcium homeostasis
Rapid actions: 17bE is more potent, but tamoxifen is an agonist on Ca21 currents (61).
Rapid actions: 17aE is as potent as 17bE on calcium entry (62).
Possible genomic actions: delayed and sustained increase in Ca channel activity (59).
Neuroprotection
Rapid actions: 17aE is as potent as 17bE vs. oxidative damage (63).
Genomic actions: 17bE is more potent; antiestrogen blockade (64).
Examples are provided for each topic. For detailed summary, see Ref. 2. Note that these estrogen actions are not mutually exclusive, but
may represent different end points of interacting intracellular signaling cascades.
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FIG. 1. Schematic diagram of intracellular estrogen action via ERa
and ERb as well as possible cell surface effects of putative membrane
ERs that produce neuroprotection (top) or affect intracellular signaling (bottom) via the cAMP and MAP kinase pathways. Top panel,
Estradiol exerts its effects intracellularly via two principal receptor
types, ERa and ERb, and these are characterized by a distinct specificity for 17a-estradiol over 17b-estradiol. Estrogens also exert neuroprotective effects in part via a mechanism in which 17a-estradiol
has equal or greater potency than 17b-estradiol. Bottom panel, Estradiol acts either via cell surface receptors or an intracellular ER to
activate two different second messenger pathways, one involving the
MAP kinase cascade and the other involving cAMP. Both pathways
result in activation of gene transcription via at least three possible
response elements: cAMP response element, steroid response element, and AP-1. Note that in the case of intracellular second messengers, there is some uncertainty concerning the involvement of ERa
and ERb in the signaling process vs. the roles of other, as yet uncharacterized, receptors (see text). AC, Adenylate cyclase; CREB-P,
phosphorylated form of cAMP response element-binding protein; ras,
ras oncogene; MAPK, MAP kinase; MAPKK, MAP kinase kinase;
fos-jun, Fos-Jun heterodimer. This figure was reprinted from Ref. 2;
please see this reference for details.
progress in understanding the molecular mechanisms of estrogen action in the nervous system.
ERa and ERb are similar not only in affinity for a number
of estrogens and estrogen antagonists (10), but also in their
ability to regulate genes in which the estrogen response element is the primary site of interaction (17). The major differences between ERa and ERb concern their ability to regulate transcription via the activating protein-1 (AP-1)
response element. With AP-1, 17b-estradiol activated transcription with ERa, whereas it failed to activate transcription
with ERb; in contrast, with AP-1, antiestrogens activated
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transcription with ERb as well as with ERa (17). ERa and ERb
can form heterodimers when expressed in the same cells,
thus giving rise to additional possible variants as far as gene
regulation (6). To date, colocalization of ERa with ERb has
been demonstrated in the hypothalamic preoptic area, bed
nucleus of the stria terminalis, and medial amygdaloid nucleus (18), and the two ER forms probably coexist in cells of
other brain regions.
It has been known for some time that estrogen antagonists
produced agonist-like effects on some parameters in the
brain and antagonize other estrogen actions, and the heterogeneity of these effects has implications for the therapeutic
use of these substances. This has been studied in some detail
for one antagonist, CI-628, a tamoxifen-like estrogen antagonist. The antagonistic effects of CI-628 were first seen by its
blockade of estrogen induction of both progestin receptors
and lordosis behavior (19, 20), whereas the agonist-like effects of CI-628 were seen for induction of choline acetyltransferase, a key enzyme in acetylcholine formation, in basal
forebrain and repression of type A monoamine oxidase in
amygdala (21). Recently, CI-628 was shown to block estrogen-induced synapse formation in the hippocampus (see
below) without having any agonist-like effects (22). One important implication of these findings is that nonsteroidal
antiestrogens, such as CI-628, and possibly also related compounds, such as tamoxifen and raloxifene, will not have
uniformly agonistic or antagonistic effects on the diversity of
actions that estrogens normally produce in the brain. This has
implications for the therapeutic applications of such agents
and requires a careful study of the actions of these agents on
each end point of estrogen action and on integrative neural
processes, such as cognition and affective state, in the event
that these substances may be antagonistic to estrogens on
some processes and exert estrogen-like effects on others. At
the same time, the diverse actions of estrogens and estrogen
antagonists in brain must be explored in terms of the emerging molecular framework of ERs and response elements, as
described above.
Novel estrogen actions
Membrane ERs have been reported on pituitary, uterine,
ovarian granulosa cell, and liver cell membranes, but these
have been only partially characterized in binding studies and
have not yet been shown to be linked to signal transduction
mechanisms (Table 1) (see Ref. 2 for review). Whereas some
of these receptors have a specificity for estrogens that differs
from that of the intracellular ER, there is evidence (23, 24) that
a portion of the intracellular ER can be expressed on the
surface of some cells and participate in second messengerrelated effects. Besides the binding of estrogens to cell surface
sites or the expression of ER on the membrane, there are
reported effects of estrogens on neuronal excitability and
second messenger systems that have been difficult to connect
with either novel receptor mechanisms or genomic receptors.
One reason for these difficulties is a lack, in many cases, of
structure-activity studies that would rule in or rule out the
participation of intracellular ER. However, in a few cases
where such studies have been carried out, there is evidence
for novel types of receptors with a pattern of specificity that
CLINICAL REVIEW
does not discriminate between 17a- and 17b-estradiol (see
Table 1 and Fig. 1) (2).
Noteworthy among these novel actions of estrogens is the
activation of phosphorylation of the transcription regulator,
cAMP response element-binding protein (25, 26), and of the
MAP kinase pathway (27), which represent novel ways in
which estrogens can interact with signaling pathways involving cell surface receptors and thereby participate in cellular events also regulated by growth factors and neurotransmitters. These processes (summarized in Table 1 and
Fig. 1) are often interrelated at the level of intracellular signaling, and thus, studies of these individual estrogen effects
may some day converge when more is known about each of
the mechanisms.
Also important, but equally puzzling for lack of mechanistic details, are the novel ways in which estrogenic compounds protect nerve cells from damage by excitotoxins and
free radicals (Table 1) (see Ref. 2 for review). In this realm,
there are neuroprotective effects that are mediated via classical genomic receptors that can be blocked by estrogen antagonists, but there are also other actions that are not blocked
by estrogen antagonists and which appear to involve a novel
mechanism in which 17a-estradiol is as potent as 17b-estradiol. These actions of estrogens appear to reduce the production or actions of free radicals in cause cell damage and
promoting cell death through apoptosis (for examples, see
Table 1).
Estrogen actions throughout the central nervous system
We now know that ovarian steroids have numerous effects
on the brain throughout life, beginning during gestation and
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continuing on into senescence. Estrogens participate in the
sexual differentiation of the brain during early embryonic or
neonatal life, and these effects undoubtedly involve the intracellular ERs described above. The process of sexual differentiation involves the secretion of testosterone in fetal or
early neonatal life and the actions of testosterone, either
through androgen receptors or via aromatization to estrogen,
in the defeminization and masculinization of brain structures
and function (28, 29). Although initially believed to be confined to the hypothalamus, structural and functional sex
differences have been found in higher cognitive centers and
in sensory and autonomic ganglia as well as in structures of
the limbic system of the brain, midbrain, brain stem, and
basal forebrain structures (see Ref. 2 for review).
Estrogens affect areas of the brain that are not primarily
involved in reproduction, such as the basal forebrain cholinergic system, hippocampus, cerebral cortex, caudate-putamen, midbrain raphe and brain stem locus coeruleus, and
spinal cord (Table 2). These systems are involved in a variety
of estrogen actions on mood, locomotor activity, pain sensitivity, vulnerability to epilepsy, and attentional mechanisms and cognition (Table 3; in each of these tables, key
examples are given with references).
Despite the paucity of ERa outside the hypothalamus,
hypothalamic preoptic region, and amygdala, estrogens
have effects on many other brain regions and neurochemical
systems involved in a host of nonreproductive brain functions. The expression of ERb mRNA in many of these brain
regions has raised the possibility that functional ER may be
expressed in these brain areas (see discussion above). At the
same time, the presence of a few ERa-containing nerve cells
TABLE 2. Brain targets of estrogen (E) action
Basal forebrain cholinergic system: E up-regulated cholinergic markers and NGF receptors, promoting neuronal survival; sex differences
programmed during early development. ERT is an enhancer of the efficacy of tacrine in treatment of cognitive function in dementia (49).
Midbrain serotonergic system: E regulates tryptophan hydroxylase, serotonin transporters, and certain 5HT receptor subtypes; sex
differences in progestin receptor expression and in 5HT turnover (37). ERT is antidepressant and a facilitator of antidepressant actions
of SSRIOs (65).
Midbrain and hypothalamic dopamine system and projections: Incertohypothalamic dopamine neurons show developmentally programmed
sex differences in neuron number and function; PRL and E, via intracellular ER regulate turnover of dopamine in hypothalamic nuclei.
Nigrostriatal and mesolimbic dopamine systems—no known intracellular ER; yet, E facilitates amphetamine- or apomorphinestimulated dopamine release and locomotor activity in rats. In striatum, with males being less responsive to E, there are 4 types of
evidence for E actions not involving the intracellular ER: 1) lack of intracellular ER in striatum; 2) rapidity of E effects; 3)
pharmacological profile of E action, particularly the ineffectiveness of diethylstilbestrol; and 4) the ability of E conjugated to BSA to
mimic effects of free E. One possible explanation is the action of E to reduce L-type calcium channel activity in striatal neurons via a G
protein-coupled receptor (61).
Brain stem catecholaminergic systems: E regulates tyrosine hydroxylase gene and immediate early gene expression, apparently via
intracellular ER. E treatment increases galanin mRNA in some neurons, and this may affect noradrenergic tone by reducing
noradrenaline release (66).
Hippocampus: E induces de novo synapse formation on pyramidal neurons, involving the participation of NMDA receptors. E treatment
transiently down-regulates GABA and BDNF activity in interneurons by a mechanism that is blocked by antiestrogens in a manner that
is consistent with a key role for intracellular ER in inhibitory interneurons. See Refs. 67–70 and 2 for review.
Spinal cord: sex differences and estrogen modulation of nociception in humans (Refs. 71, 72). Sex differences in analgesia have been
reported in mice along with sex-specific effects of E on a form of nonopioid analgesia (73). QTL mapping led to the identification of a
female-specific QTL on chromosome 8 (74). This female-specific mechanism, which is sensitive to E modulation, is consistent with a gene
that is turned off by testosterone exposure during sexual differentiation (75).
Glial cells: E regulates specific genes such as glial fibrillary acidic protein and apolipoprotein E within astrocytes and microglia via
intracellular ER. E regulates morphology of astrocytes in hypothalamus and hippocampus, and these changes may reflect a role of glial
cells in normal synaptic plasticity as well as lesion-induced plasticity.
Cerebral vasculature: Some intracellular ER are expressed in CNS endothelia (76), and E regulates glucose utilization, possibly by
inducing glucose transporter 1 in the endothelial cells of the blood-brain barrier (77).
This summary is confined to the extrahypothalamic targets for estrogen action, with the exception of the incertohypothalamic dopamine
system. For a detailed summary, including a discussion of expression of ER subtypes, see Ref. 2. SSRI, Serotonin reuptake inhibitors; BDNF,
brain-derived neurotropic factor; QTL, quantitative trait locus.
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TABLE 3. Gonadal hormone effects on clinically relevant nonreproductive functions
Affective state and mood: estrogens affect the serotonergic, noradrenergic, dopaminergic, and cholinergic systems, all of which play a role
in affective state and mood. Two disorders are particularly noteworthy, PMS and depressive illness. For PMS, suppression of ovarian
cyclicity reduces mood swings, although specific hormonal mechanisms are not known (78, 79). High doses of estrogens have
antidepressant effects in human subjects (80), and estrogen treatment influences the response to antidepressant drugs in animal models
(81). Estrogen treatment has been reported to enhance the efficacy of Prozac treatment for depression (65).
Cognitive function: estrogens influence short term verbal memory as well as performance on tests of fine motor skills and spatial ability;
sex differences exist in humans and animals for strategies used in solving spatial navigation problems (see Discussion and Ref. 32).
Dementia: estrogen therapy in open trials has been reported to improve cognitive function in Alzheimer’s disease patients (82) and to
prospectively benefit cognitive function in nondemented women (83, 84). There is a reportedly lower prevalence of Alzheimer’s disease as
a cause of death in elderly women who receive estrogen replacement therapy postmenopausally (85, 86).
Motor coordination and movement disorders: estrogens modulate activity of the cerebellum and the nigostriatal and mesolimbic
dopaminergic systems and have effects on normal and abnormal locomotor activity. High levels of estrogens antagonize the dopamine
system and are recognized to exacerbate symptoms of Parkinson’s disease, whereas low estrogen levels facilitate dopaminergic function.
See dopamine entry in Table 2.
Excitability and epilepsy: catamenial epilepsy varies according to the menstrual cycle, with the peak frequency of occurrence
corresponding to the lowest ratio of progesterone to estradiol during the cycle. There are at least 3 potential mechanisms: 1) estrogen
induction of excitatory synapses in hippocampus, leading to decreased seizure thresholds; 2) progesterone actions via the steroid
metabolites, which act via the GABAa receptor to decrease excitability; and 3) hormone actions on the liver to increase clearance rates of
antiseizure medication (87, 88).
Pain: Recent studies in mice indicate that males and females use functionally distinct pain pathways, and that gonadal steroids,
particularly estrogens, play a major role in regulating these pathways (73). See entry under spinal cord in Table 2.
For reviews, see Refs. 2 and 89. PMS, Premenstrual syndrome; GABAa, d-aminobutyric acid-a.
has led to the discovery, for example in the hippocampus,
that these few nerve cells can have powerful transsynaptic
effects on neighboring neurons (see below). In addition, the
rapidity and structure-activity profile of some of these effects
have raised questions about the possible nontraditional and
even nongenomic actions of estrogens in some brain regions.
Treatment of ovariectomized rats with 17b-estradiol induces certain hippocampal neurons to form new synaptic
connections with other nerve cells. These estrogen effects
appear to be attributable to intracellular ERs in inhibitory
interneurons that can influence thousands of pyramidal neurons in their vicinity, although the role of ERb in synapse
formation has not been ruled in or out (see Ref. 2 for summary). Yet, the actions of estrogens in the basal forebrain,
corpus striatum, and nucleus accumbens on dopaminergic
activity appear to be mediated by membrane actions, as there
is no indication for the expression of either ERa or ERb in
these brain regions. On the other hand, estrogen actions on
cholinergic, noradrenergic, serotonergic, and hypothalamic
dopaminergic systems are probably mediated at least in part
by known intracellular ERa or ERb that are expressed in
these brain areas (see Ref. 2 for summary). The spinal cord
also has intracellular ERa and ERb, but the reported effects
on nociception and analgesia do not directly relate to those
receptor sites in enkephalin-expressing spinal neurons (see
Ref. 2 for summary).
Estrogen actions on cognitive function and
memory processes
Among the most novel and fascinating effects of estrogen
are those on cognitive function, and there are at least four
aspects of estrogen and progesterone action in brain that are
especially relevant to memory processes and their alterations
during aging and neurodegenerative diseases (for details, see
Ref. 2).
First, as noted above, studies of female rats show that
estrogens and progestins regulate synaptogenesis in the hippocampus, a brain region important in spatial and declara-
tive learning and memory. During the estrous cycle of a
female rat, these synapses are formed under the influence of
estrogens and are then broken down after the proestrus surge
of progesterone (30). In ovariectomized rats, formation of
new excitatory synapses is induced by estradiol and involves
the participation of a neurotransmitter, glutamic acid, acting
through NMDA receptors (31); progesterone administration
then triggers the disappearance of the newly formed synapses within 12–24 h. Inhibitory interneurons that innervate
thousands of adjacent pyramidal neurons express ERa and
are the most likely transsynaptic regulator of synapse formation on the pyramidal neurons.
Second, there are developmentally programmed sex differences in hippocampal structure that may help to explain
differences in the strategies that male and female rats use to
solve spatial navigation problems. Males use global spatial
cues more effectively than females to locate food in a radial
arm maze or to find a hidden platform in a Morris water
maze. An analogous sex difference in spatial problem-solving ability is reported in humans (32). During the period of
development when testosterone is elevated in the male, aromatase activity and ERs are transiently expressed in hippocampus (33, 34), and recent data on behavior and synapse
induction strongly suggest that this pathway is involved in
the masculinization or defeminization of hippocampal structure and function (35, 36).
Third, ovarian steroids have widespread effects throughout the brain, including brain stem and midbrain catecholaminergic neurons, midbrain serotonergic pathways,
midbrain dopaminergic activity, and the basal forebrain cholinergic system (see Table 2). Whereas basal forebrain cholinergic function is involved in attention, noradrenergic function is involved in arousal, serotonin is involved with mood
and affect, and dopamine is involved with reward (2). Regulation of the serotonergic system appears to be mediated in
part by the presence of estrogen- and progestin-sensitive
neurons in the midbrain raphe and leads to the induction of
tryptophan hydroxylase and the regulation of serotonin
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transporters and serotonergic receptor subtypes (37),
whereas the ovarian steroid influence on cholinergic function
occurs in basal forebrain neurons that express intracellular
ER and leads to the induction of choline acetyltransferase and
acetylcholinesterase according to a sexually dimorphic pattern (38, 39). Noradrenergic and dopaminergic systems also
show sex differences and both direct and indirect effects of
estrogens via conventional ER and by nongenomic mechanisms. Because of the widespread projections of these systems in the forebrain, these various neuronal systems have
important global effects on arousal and attentional mechanisms as well as more specific actions related to learning and
remembering, particularly of verbal information. Thus, it is
not so surprising that ovarian steroids have measurable effects on those aspects of cognition and also on mood and
affect and motor coordination; these effects are evident after
ovariectomy and during the decline of estrogens that occurs
after the menopause and with aging (2). However, as noted
above, one of the fundamental questions is the mechanism by
which these effects occur, whether by traditional intracellular
receptors or by the novel, nongenomic mechanisms that are
referred to above, and as noted, we have seen that the diversity of mechanisms and uncertainties about receptor identity leave us still somewhat in the dark about the exact molecular events.
Fourth, estrogen effects on memory have been reported in
animal models and in studies on humans (2). The memories
affected are ones in which the hippocampus plays a role
along with the basal forebrain cholinergic system; in rats, the
sensitive memories are related to spatial information (40 –
43), whereas in humans, it is verbal memory that is particularly sensitive (44 – 46). Yet, there is some contradiction in
terms of the time course of the effects and the types of
memory affected between the reported estrogen actions and
the known cellular processes, such as estrogen-induced synaptogenesis. For example, estrogen-induced synaptogenesis
in the rat hippocampus occurs within several days, yet the
effects of estrogen on cognitive function in rats and humans
noted above take a number of weeks to be fully manifested.
Moreover, the more rapid actions of estrogens in both rats
and humans (i.e. over the time course of a few days) seem to
be associated with impairment of spatial memory (47, 48).
Thus, much more research is needed to reconcile morphological and neurochemical changes with the behavioral data.
It cannot be overemphasized that rather than one estrogenregulated process or one brain region, many types of estrogen action on a number of neurochemical and neuroanatomical substrates and a number of molecular mechanisms
are likely to underlie the actions of estrogens on cognition
and other aspects of behavior, such as mood, pain perception, and nociception.
Estrogens and neuroprotection in relation to aging
and dementia
There is growing evidence that estrogens not only have
reversible effects to improve memory, affect, and motor coordination in women who suffer from estrogen deficiency
after the menopause, but they also appear to have a neuroprotective effect for Alzheimer’s disease and protect cells
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from damage and destruction by free radicals and b-amyloid
protein. Moreover, the cognitive improvement seen in Alzheimer’s disease patients after treatment with the cholinesterase blocker, tacrine, is reported to be most evident in
women also receiving ERT (49).
There are at least two ways in which estrogens appear to
be able to protect the brain from neurodegeneration. First, as
discussed above and summarized in Table 2, estrogens maintain function of key neural structures, such as the hippocampus and basal forebrain, and the widely projecting dopaminergic, serotonergic, and noradrenergic systems. As estrogen
levels decline over the menopause, these systems and the
cognitive and other behavioral processes that depend upon
them also decline, as least functionally; yet, they appear to
respond to estrogen replacement. It is conceivable that estrogens not only maintain function but also confer resilience
against neural damage by various agents due to their ability
to maintain synaptic connections and promote the activities
of these important neural systems.
The second type of neuroprotective effect of estrogens is
a more direct involvement in blocking the actions of neurotoxic agents or inhibiting their generation. As noted above
and in Table 1, the A ring of the estrogen molecule appears
to have special properties with respect to the formation of
free radicals and special protective effects on cells in culture
that are deprived of serum or exposed to free radical generators (2). In this regard, in vivo studies of estrogen-mediated neuroprotection have reported successful reduction of
lesion size by SILASTIC brand implants (Dow Corning
Corp., Midland, MI) of 17b-estradiol in male rats subjected
to middle cerebral artery occlusion (50). In another study, a
single injection of 17b-estradiol reduced damage to hilar
neurons in the hippocampal dentate gyrus of female rats
caused by kainic acid treatment (51). In addition, estrogen
treatment of cultured nerve decreases formation of the toxic
form of the b-amyloid protein (52). Moreover, estrogen treatment interferes with the toxic effects of the b-amyloid protein
(53) and the human immunodeficiency virus coat protein,
gp120 (54), both of which act via free radical generation.
Besides neurons, the glial cells of the brain are implicated
in aspects of oxidative energy metabolism, brain plasticity,
brain aging, and neuroprotection (see Ref. 2 for more details).
Glial cells and vascular epithelium play a role in the adult
brain in relation to glucose uptake and energy metabolism,
and ovarian steroids regulate the ability of the female brain
to use glucose as its primary energy source. For example, in
studies of postmenopausal women with or without ERT,
there were significant enhancing effects of estrogen on verbal
and figural memory tests as well as enhancements of cerebral
blood flow during the memory tasks (55). Moreover, glial
cells are affected by estrogens in vivo and in vitro, and they
express a number of proteins that are regulated by estrogens,
including apolipoprotein E and glial fibrillary acidic protein;
apolipoprotein E is implicated in membrane formation and
structural plasticity, whereas glial fibrillary acidic protein
expression increases throughout the brain as it ages (2, 56).
Astroglia play a role in synaptic retraction during the ovulatory cycle in the adult hypothalamic arcuate nucleus. During the preovulatory and ovulatory phases of the female rat
estrous cycle, there is a transient disconnection of inhibitory
1796
MCEWEN
synaptic inputs to arcuate nucleus neurons, and this remodeling is mediated in part by soluble factors, such as insulinlike growth factor I (IGF-I) (57). Moreover, there seems to be
a reciprocal interaction between IGF-I and estrogen, and one
speculation is that estrogens may act in arcuate nucleus neurons to regulate the production of a factor, possibly g-aminobutyric acid that, in turn, regulates the expression of IGF-I
by astroglia (tanycytes) in the arcuate nucleus region (57).
The mechanisms of estrogen action on glial cell function
remain unclear, but they may involve some limited expression of both ERa and ERb within astrocytes, oligodendrocytes, and/or microglia (2).
11.
12.
13.
14.
15.
16.
Conclusions
Many regions of the central nervous system respond to
estrogens, and we are rapidly gaining insights into their
diverse cellular and molecular mechanisms of action. Although there is no proof at this time that estrogens are truly
neuroprotective and capable of slowing down Alzheimer’s
disease, they are perhaps the most promising agents yet
devised for this purpose. ERT is already strongly supported
as therpay for osteoporosis and cardiovascular protection,
and protection of the brain, along with benefits in terms of
memory, motor coordination, and affect, would add additional reasons for using ERT.
The question of whether males would also benefit from
ERT is also very important, but to date has not been adequately explored. Likewise, the actions of androgens on the
male brain deserve much more study, particularly with regard to possible neuroprotection as well as beneficial neurocognitive effects. Sex differences in the brain do not preclude the efficacy of ERT in males, but they do indicate the
need for careful and systematic studies of estrogen actions in
men as well as women. The development of novel compounds with specific estrogenic activities, such as the selective estrogen response modulators, offers new hope for benefiting both men and women. However, based upon the
diversity of sites and molecular mechanisms of action of
estrogens in the brain, each novel compound needs to be
carefully evaluated in terms of what it does to a variety of
neural estrogen effects in the central nervous system.
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