Brinton 2015
Brinton 2015
Brinton 2015
Perimenopause as a neurological
transition state
Roberta D. Brinton, Jia Yao, Fei Yin, Wendy J. Mack and Enrique Cadenas
Abstract | Perimenopause is a midlife transition state experienced by women that occurs in the context of a
fully functioning neurological system and results in reproductive senescence. Although primarily viewed as
a reproductive transition, the symptoms of perimenopause are largely neurological in nature. Neurological
symptoms that emerge during perimenopause are indicative of disruption in multiple estrogen-regulated
systems (including thermoregulation, sleep, circadian rhythms and sensory processing) and affect multiple
domains of cognitive function. Estrogen is a master regulator that functions through a network of estrogen
receptors to ensure that the brain effectively responds at rapid, intermediate and long timescales to regulate
energy metabolism in the brain via coordinated signalling and transcriptional pathways. The estrogen
receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition
and, as a corollary, a hypometabolic state associated with neurological dysfunction can develop. For some
women, this hypometabolic state might increase the risk of developing neurodegenerative diseases later
in life. The perimenopausal transition might also represent a window of opportunity to prevent age-related
neurological diseases. This Review considers the importance of neurological symptoms in perimenopause in
the context of their relationship to the network of estrogen receptors that control metabolism in the brain.
Brinton, R. D. et al. Nat. Rev. Endocrinol. advance online publication 26 May 2015; doi:10.1038/nrendo.2015.82
a revealed that both the ovaries and the brain are deter
High High
minants of reproductive life. Notably, neuroendocrine
(endocrine and neurological symptoms)
Neurological symptoms
Low Low Although the clinical definition of perimenopause
Premenopause Perimenopause Postmenopause
focuses on functional changes in the reproductive system,
b the symptoms of perimenopause are largely neurologi
cal in nature (Figure 1b), the documentation of which
Asymptomatic
20% spans continents, cultures and ethnicities.15,27–43 The
complexity of the perimenopausal transition is reflected
Only hot flushes 30% by a range of neurological symptoms, which include
temperature dysregulation, depression, insomnia, pain
Cognitive dysfunction
and cognitive dysfunction.16,31,43 Neurological symptoms
Cognitive dysfunction + insomnia tend to cluster together in occurrence and severity 44
Cognitive dysfunction + mood changes and, in many instances, persist into postmenopause.34,35
Cognitive dysfunction + insomnia The breadth of neurological symptoms that can occur
Perimenopause + mood changes during the perimenopausal transition is indicative of
Hot flushes 70%
Executive function Sensory Default mode network, (minutes to hours) and long (hours to days) to regu
and working memory integration working memory,
ER-α, ER-β ER-β, GPER task preparation late and coordinate multiple systems (Figures 2 and 3).
ER-β Moreover, estrogen signalling through this network of
receptors ensures that neurons can generate sufficient
energy to meet demand.61 Changes in either the avail
OH ability of estrogen or its receptor network can affect
H intracellular signalling and neural circuit function.
While the intricacies of estrogen receptors and signalling
H H
HO
cascades are well characterized, the coordination across
17β-estradiol the network of estrogen receptors necessary for neural
circuit function awaits detailed investigation.
Prefrontal
cortex Thalamus
Posterior
Cellular localization
Hypothalamus cingulate Plasma membrane
Learning
Hippocampus The localization of estrogen receptors facilitates the
Basal
and memory forebrain Amygdala Raphe
sequential activation of estrogen receptors across a net
ER-α, ER-β, GPER
nucleus work, which initiates rapid-response cascades followed
Information processing
Regulation of temperature,
sleep, energy, balance
Locus and short-term memory by an engagement of gene expression for long-term
coeruleus ER-α, ER-β, GPER
and food intake responses (Figure 3). Regardless of their intracellular
ER-α, ER-β, GPER
location, all estrogen receptors are activated by the endo
Emotion and genous estrogen, 17β‑estradiol. Starting at the plasma
motivation
ER-α, ER-β membrane, the first estrogen receptor that can be acti
vated is GPER, which traverses the plasma membrane.
Serotonergic system
affect and mood Activation of GPER triggers rapid signalling cascades.49
ER-α, ER-β The specific localization of GPER remains controversial
Adrenergic system: with some groups reporting localization of GPER at the
attention, arousal and anxiety
ER-α, ER-β plasma membrane,62 and others reporting GPER as being
localized to the membrane of the endoplasmic reticu
lum.49 Estrogen activates monomeric GTPase (Ras)-
Figure 2 | Neurological functions affected by the perimenopausal transition.
Nature Reviews | Endocrinology
Brain regions and their corresponding functions provide a map of the neural circuits
driven signalling cascades through GPER,49 including
regulated by estrogen and a neurobiological basis for the array of symptoms that can cAMP, the PI3K–Akt and MAPK–Erk signalling path
emerge during perimenopause. Nuclear, membrane-associated and mitochondrial ways, the latter of which leads to neurite generation in
estrogen receptors are distributed within each of the neural circuits and can be developing hippocampal neurons.63 In the specialized
present in both neurons and glial cells. While the complete distribution of ER-α and caveolar involutions of the intracellular side of the plasma
ER-β remains to be completely mapped in humans, in rats the location of these membrane, membrane-bound ER‑α and ER‑β (mER‑α
receptors is well documented.45–53 Dysregulation of estrogen signalling, either and mER‑β) are associated with activation of fast-acting
through changes in estrogen concentration or through modifications of estrogen
signalling pathways, such as the PI3K–Akt and MAPK
receptor, will affect neural circuit activation and, thus, neurological function.
Abbreviations: ER, estrogen receptor; GPER, G protein-coupled estrogen receptor.
cascades.48,64 Activation of fast-acting signalling cascades
is one of several mechanisms by which estrogen regu
lates gene transcription (Figure 3). In the case of estrogen
receptors.53 In brain regions that are crucial to learning receptor activation of the PI3K–Akt and MAPK path
and memory, estrogen receptors are present in the pre ways, estrogen binding to its receptor initiates a signalling
frontal cortex, each of the subfields of the hippocampus, cascade that leads to the phosphorylation and activation
the amygdala, the cingulate cortex and the retrosplenial of CREB transcription factors, which upregulate expres
cortex.45,53 The 5‑hydroxytryptaminergic neurons of the sion of genes encoding proteins involved in learning
raphe nucleus are positive for estrogen receptors, as are and memory, synaptic transmission and neural growth
the adrenergic neurons of the locus coeruleus.45,50,54 factors such as brain-derived neurotrophic factor.47,56,65,66
Removal of the ovaries before menopause induces the
neurological symptoms of the perimenopausal transi Mitochondria
tion, whereas restoration of estrogen prevents or reverses ER‑β is also found in mitochondria (referred to as
neurological symptoms.6,47,55–57 Progesterone, which is mtER‑β), where it regulates mitochondrial function
also produced by the ovaries, does not seem to have the and can induce expression of mitochondrial genes
same neuronal effects and, in many instances, antago (Figure 3).67–70 ER‑β is also localized to the mitochondria
nizes the neural actions of estrogen in both preclinical interface and communicates with the endoplasmic reticu
and clinical analyses.58–60 The ovarian–neural estrogen lum, a region also known as mitochondria-associated
axis regulates multiple neurological systems and func membranes.69 mtER‑β within mitochondria is uniquely
tions in the brain through a network of estrogen recep positioned to regulate mitochondria-specific gene
tors; thus, estrogen is a master regulator that ensures expression,71 which enables estrogen to regulate energy
the brain can effectively respond within timescales homeostasis throughout the cell.47 This function of estro
ranging from rapid (seconds to minutes), intermediate gen is particularly important to neurons, which require
Epigenetic
GPER regulation
Signalling Early latent
mER-α pathways response genes
mER-β
Plasma membrane
OH
Cell Intermediate
H response genes
H H
HO
17β-estradiol
Late response
genes
Nucleus
Transcriptional
pathways Mitochondria
Mitochondrial
genes
mtER-β
ER-α ER-β
Nature and
Figure 3 | Estrogen receptor network. The estrogen receptor network integrates cellular responses Reviews | Endocrinology
functions in the
brain. Estrogen binding and activation of the membrane-bound receptors, mER‑α, mER‑β and GPER, leads to activation of
signalling pathways that regulate expression of early and intermediate response genes. Estrogen binding to the nuclear
estrogen receptors, ER‑α and ER‑β, results in activation of transcriptional pathways that regulate expression of late
response genes. Activation and translocation of ER‑β to the mitochondria has been implicated in regulating expression
of mitochondrial genes. Furthermore, estrogen can modulate transcriptional gene expression, activated by either rapid
signalling or transcriptional pathways, via epigenetic regulation. This network of receptors enables the integration of
signals across rapid, intermediate and late response pathways to coordinate a broad spectrum of cellular elements,
including substrate transporters, metabolic enzymes and catalytic processes, which ultimately results in generation of
energy to fuel neurological function. Abbreviations: ER, estrogen receptor; GPER, G‑protein coupled estrogen receptor 1;
mER, membrane estrogen receptor; mtER, mitochondrial estrogen receptor.
ATP for synaptic transmission.47 75% of all ATP gener simplification, as demonstrated by estrogen-mediated
ated in neurons is used to meet the energy demands of regulation of the bioenergetic system of the brain; both
the sodium–potassium pump, which actively pumps both ER‑α and ER‑β in the brain promote expression of
Na+ and K+ against their concentration gradients to re- nuclear encoded genes that are required for glucose trans
establish the neuronal membrane potential necessary to port, glucose metabolism and mitochondrial functions,
respond to the next wave of action potentials.47,56 This while simultaneously suppressing expression of genes
function is particularly important for maintaining the required for ketone body metabolism, inflammation and
high frequency synaptic transmissions that are associated β‑amyloid generation.59,71
with learning and memory function.47,56 Nuclear ER‑α
can also regulate mitochondrial function via modulating Splice variants
the expression of nuclear genes that encode proteins that The complexity of estrogen receptors is extended by
are targeted to the mitochondria.69–71 splice variants of both ER‑α and ER‑β, which typically
have functional differences.72 Three splice variants of
Nucleus ER‑α and one variant of ER‑β have been described in
Estrogen-mediated transcription of genes requires trans the brain.73–75 Some particular splice variants are gen
location of ER‑α and ER‑β into the nucleus. ER‑α and erated during the perimenopausal transition. Splice
ER‑β dimerize and are transported into the nucleus, variants of ER‑α have been detected in the hypothala
which can comprise α or β homodimers or heterodimers mus and hippoc ampus of the human female brain.75
of ER‑α and ER‑β proteins (Figure 3).48 Estrogen recep The ER‑α splice variant MB1 has been detected in the
tors bind directly to specific estrogen response element brain of perimenopausal women (49–50 years) and has
sequences on the DNA or are tethered to other transcrip increased expression throughout the transition, with
tion factors, such as the activator protein 1 (also known as greatest expression in postmenopause (58–94 years of
transcription factor AP‑1), to regulate gene expression.48 age).75 This variant is expressed in neurons, astrocytes
A 1D view of regulation of gene expression by estrogen and endothelia, where it is associated with nitric oxide
receptors is that these transcription factors only promote production required for vasodilation.75 ER‑β splice vari
gene expression.56,71 However, this hypothesis is an over ants are also expressed in select brain regions of the rat,
including the hypothalamus, hippocampus and cerebral menopause and ageing might induce a transcriptionally
cortex.76,77 A well-characterized rodent ER‑β variant, repressive chromatin state that decreases transcription of
ER‑β2, contains an additional 18 amino acids in the memory-related genes has been proposed.80 Epigenetic
ligand-binding domain, which considerably reduces control of genes encoding estrogen receptors, a mecha
the binding affinity of 17β‑estradiol.72 In ovariecto nism well-described in breast cancer cell lines,82 remains
mized rats, protein levels of the ER‑β2 splice variant were undetermined in the female brain under normal and
increased in the hippocampus, which was associated with disease states. Given that onset of puberty can be deter
reduced neurogenesis and an increase in behavioural mined by epigenetic regulation,83,84 these modifications
indicators of depression.77 Expression of ER‑β2 was might also be key drivers of the onset and emergent
reversed when estrogen was administered soon after symptoms of perimenopause.
removal of the ovaries (6 days), as demonstrated by res
toration of neurogenesis and amelioration of depressive Adaption in perimenopause
behaviours in these animals.77 However, the restora Collectively, these findings indicate that the perimeno
tive potential of estrogen was time-dependent, as pausal transition is a dynamic state for signalling via
delay in estrogen replacement (180 days after removal estrogen receptors and is associated with the emergence
of the ovaries) showed no therapeutic benefits for the of estrogen receptor splice variants, changes in protein
ova riectomy-induced decline in neurogenesis and expression and alterations in receptor degradation, as
increase in depressive behaviours.77 well as possible epigenetic reconfigurations. An estrogen
The reduced binding affinity of some ER‑α and ER‑β response network is activated within and across neural
splice variants might partially account for the perimeno networks through a series of membrane-associated,
pausal loss in sensitivity to 17β‑estradiol.22 In addition mitochondrial and nuclear receptors. Although this dis
to splice variants, several polymorphisms in ESR1 are tributed network of estrogen receptors forms the basis
associated with an increased risk of Alzheimer disease of the remarkable effects of estrogen in brain, it can also
in women, particularly when co-occurring with the be a point of vulnerability for the female brain. In many
APOE*e4 allele.61 women, the brain compensates for the changes in levels
of estrogen and its receptors during perimenopause.
Post-translational modifications However, for some women this adaptive compensa
In addition to splice variants and polymorphisms, estro tion is diminished, lacking or only expressed in some
gen signalling is modulated by ubiquitination and subse estrogen-regulated neural networks, which gives rise
quent proteasomal degradation of estrogen receptors.78 to the complex phenotype of neurological symptoms of
Long-term estrogen deprivation results in increased menopause (Figure 2).18,27–43 The extent to which these
interactions between ER‑α and the heat shock 70 kDa changes in the estrogen regulatory network are drivers of
protein 1A/1B, which leads to ubiquitination and pro the perimenopausal transition or an outcome of the tran
teasomal degradation of ER‑α.78 Furthermore, ubiquiti sition remain to be fully explored. Elucidating the spec
nation of ER‑α was specific to the hippocampal neurons trum of compensatory responses that can be induced by
and could be prevented when 17β‑estradiol treatment the perimenopausal transition is still in the early stages.
was administered before, but not after, ovariectomy.78
Estrogen and neural bioenergetics
Epigenetic regulation Estrogen and its network of receptors are strong can
A fairly unexplored area of research in the brain is the didates for being regulators of bioenergetic systems in
control of epigenetic modifications by estrogen during neural circuits of the brain, while simultaneously being
perimenopause and, in turn, epigenetic regulation of affected by the perimenopausal transition.6,47,56,61 Estrogen
expression of the genes encoding the estrogen receptors. utilizes a complex repertoire of receptors and signalling
In young female mice, 17β‑estradiol induced epigenetic pathways to activate and regulate molecular and genomic
changes, such as acetylation and methylation.79 Histone 3 responses required for neurological function at the cel
seems to be a key protein involved in the epigenetic regu lular, organismic and, ultimately, whole-body level.61
lation mediated by 17β‑estradiol; both acetylation and Moreover, biochemical, genomic and bioi nformatic
methylation of histone 3 in neurons of the mouse dorsal data indicate a synergistic interaction between estro
hippocampus regulate 17β‑estradiol-driven enhance gen and insulin signalling pathways exists in the brain.85
ment of memory consolidation.80 17β‑estradiol induces Regulating the bioenergetic capacities within and across
acetylation of histone 3, but not of histone 4, via activa neural circuits could both support the functions of
tion of the ERK signalling pathway in the mouse brain.80 multiple circuits and, concurrently, create an energetic
Moreover, administration of 17β‑estradiol to female connectome between and across neural circuits.47
mice reduced protein expression of histone deacety Within the brain, estrogen signalling contributes to
lase 2, which sustains a permissive chromatin state for processes within the entire bioenergetic system, includ
transcription of genes that are required for hippocampal ing glucose transport, glucose metabolism, mitochondrial
synaptic plasticity and memory consolidation.80,81 DNA respiration and ATP production (Figure 4).47,56,67,71,86,87
methylation of ER‑α at Lys26678 within a critical 3‑h A portion of the bioenergetic system in the mouse
period also seems to be necessary for 17β‑estradiol brain is linked to estrogen, as evidenced by the fact
to enhance memory consolidation.80,81 The idea that that loss of estrogen by surgical removal of the ovaries
OH
H H
HO α-ketoglutarate Succinyl-CoA
17β-estradiol α-KGDH
Cytosol Mitochondria
Isocitrate Succinate
4
TCA
MCT
2 Ketone Ketone Ketone
Aconitase
bodies bodies bodies SCOT NADH NADH e–
Fumarate
GLUT10 Citrate
SDH
5
1 Glucose Glucose-GP Pyruvate Pyruvate Acetyl-CoA
HK PDH Oxaloacetate Malate
Glycolysis O2
GLUT4 H2O IV I
GPER Fatty Fatty e–
3 acids acids
– β-oxidation
H+
ER-α Akt
III
ER-β V
Pl3K ADP
Insulin IRS H+
IGF-1
ATP
Figure 4 | Estrogen-mediated regulation of the bioenergetic system. Estrogen signalling supports Nature and sustains
Reviews glucose
| Endocrinology
metabolism in the brain by regulating expression of glucose transporters, which results in increased glucose uptake, and
by stimulating glucose metabolism, mitochondrial oxidative phosphorylation and ATP generation—collectively referred to as
aerobic glycolysis. Glucose (1) is the primary metabolic fuel for the brain. Estrogen regulates the bioenergetic system in
brain the through the estrogen receptors, GPER, ER‑α and ER‑β, and their activation of PI3K and downstream Akt and
MAPK–ERK signalling pathways. When the glucose pathway is compromised, for example, during starvation, acetyl-CoA can
be generated from ketone bodies via ketogenesis in the liver and transported through the blood to the brain through
monocarboxylate transporters (2) or from fatty acid via β‑oxidation (3). During the perimenopausal transition, neuronal
levels of glucose transporters decline, which is co-incident with the appearance of hypometabolism in the brain. 86 The brain
adapts to this decline in glucose availability by increasing reliance on ketone bodies as an alternative fuel to generate
acetyl-CoA required for entry to the TCA cycle (4) and ultimately generation of ATP via complexes of the mitochondrial redox
carriers (5). Initially, ketone bodies are derived from the periphery by lipid metabolism in the liver. Depletion of peripheral
sources of ketone bodies can result in metabolism of brain-derived fatty acids to generate ketone bodies via β‑oxidation in
glia cells (3). Abbreviations: GP, glucose-6-phosphate; GPER, G protein-coupled estrogen receptor 1; ER‑α, estrogen
receptor α; ER‑β, estrogen receptor β; HK, hexokinase; α-KGDH, α-ketoglutarate dehydrongenase, IGF-1, insulin growth
factor-1; IRS, insulin receptor substrate; MCT, monocarboxylate transporter; PDH, pyruvate dehydrogenase; PI3K,
phosphoinositide 3-kinase; SCOT; succinyl-CoA:3-ketoacid CoA transferase; SDH, succinate dehydrogenase; TCA,
tricarboxylic acid cycle.
or reproductive endocrine ageing results in a 15–25% and complex IV activity,86 which led to impairment of
decline in metabolic function in brain.87,88 During the the mitochondrial energy-conservation systems in these
early stages of reproductive senescence or perimeno animals. Lactate transport and utilization also decreased
pause in the rodent, the neuronal bioenergetic system in parallel to the decline in glucose transport,86 which
undergoes a transformation, which results in a persistent indicates that lactate (which is generated from glucose in
decline in glucose metabolism in the brain.86–89 In female astrocytes) is not used as an alternative fuel source during
mice, hypometabolism in the brain was demonstrated the transition to reproductive senescence. Signs of oxida
by a decline in glucose uptake and hexokinase activity at tive stress and free radical damage to mitochondrial lipid
6–9 months of age (immediately before the transition into membranes are not evident until the animals have tran
reproductive senescence).86 These metabolic changes were sitioned through perimenopause to reproductive senes
accompanied by inactivation of pyruvate dehydrogenase cence.86,89 In the periphery of perimenopausal aged female
mice and rats, dysregulation of the metabolic system was acid metabolism in the brain is indicative of increased
demonstrated by impaired glucose tolerance, which is catabolism of brain-derived lipids, which can disrupt cell
indicative of insulin resistance.86,89 membranes and lipid-rich reservoirs, such as myelin, in
Removal of ovaries in premenopausal mice results in the brain.93
bioenergetic deficits that are similar in magnitude to A shift in metabolism during perimenopause is also
those that occur during reproductive ageing.88 However, evident in women and has been associated with dys
critical distinctions exist between natural endocrine regulated glucose metabolism and insulin resistance.13,61
ageing (that is, changes associated with endocrine func Collectively, preclinical data in rodent models of peri
tion rather than chronological ageing) and surgically menopause and clinical analyses of the human female
induced menopause, and are evident in the differences brain indicate that the perimenopausal transition is
in the bioenergetic systems of animal models of these an ordered and sequential process, during which the
processes. In ovariectomized rodents and nonhuman brain seems to undergo dismantling of the connections
primates, endocrine and ageing programmes seem to between the estrogen receptor network and the bio
be compressed or accelerated, as induction of hypo energetic system.13,20,89,95 The disengagement of the estro
metabolism, mitochondrial dysfunction and oxidative gen receptor network from the bioenergetic system in the
stress occur simultaneously.88,89 The adverse effects of brain is also associated with a release of suppression of
loss of ovarian hormones on the bioenergetic system enzymes required to metabolize ketone bodies.86–89 This
can be prevented by administration of 17β‑estradiol at loss of suppression enables the emergence of an adaptive
the time of ovariectomy.71,88–90 In ovariectomized rhesus compensatory response in the brain that is necessary to
macaque, changes to mitochondrial morphology were utilize ketone bodies as an alternative fuel (Figure 4).86–89
frequently indicative of development of oxidative stress
and occurred with a concomitant decline in number Hypometabolism and neurological systems
of mitochondria within the presynaptic bouton; these If a decline in brain metabolism is a causative factor in
boutons were typically smaller than those of normal the development of neurological symptoms of the peri
ageing in non-ovariectomized monkeys.91 The appear menopausal transition, then hypometabolism in neu
ance of mitochondrial oxidative stress morphology was ronal circuits is expected to proceed or be co-incident
associated with a decline in cognitive function mediated with these symptoms. Moreover, if estrogen is a control
by the prefrontal cortex in ovariectomized animals.91 By ling factor in this process, then women receiving estro
contrast, natural endocrine ageing of the nonhuman gen replacement therapy should exhibit a metabolic
primate prefrontal cortex led to mitochondrial mor profile that is associated with preservation of glucose
phology that was associated with increased respiratory metabolism in the brain. Evidence to support these hypo
capacity, an increased number of presynaptic boutons theses in affected neurological systems does not yet exist;
containing mitochondria, an enlargement of presynap however, multiple studies of brain metabolism suggest an
tic boutons and preservation of cognitive function. 91 association between hypometabolism in the brain and
Administration of estrogen at the time of ovariectomy development of neurological symptoms in women.60,95–97
preserved the normal ageing mitochondrial pheno Notably, the preponderance of available data have been
type and cognitive function in nonhuman primates, derived from studies of women who have transitioned
as well as preventing conversion of mitochondria to a through the menopause,60,95,96 with only a few studies
stress-associated phenotype.91 specifically targeting women of perimenopausal age.38,60
In response to glucose deprivation, the perimenopau In studies of women after menopause, those receiving
sal brain shifts to a bioenergetic response that is indica estrogen replacement therapy have a different pattern of
tive of long-term fasting—that is, the use of ketone brain metabolism to women not receiving estrogen ther
bodies as an alternative energy fuel.86,87,92–94 This res apy.60,95 After the menopause, women who began estro
ponse is indicated by a rise in peripheral levels of gen replacement therapy during perimenopause or their
ketone bodies and their neuronal and astrocytic mono menopausal year, had preserved glucose metabolism in
carboxylate transporters, as well as an increase in brain regions with estrogen-dependent neurological
levels of mitochondrial succinyl-CoA:3-ketoacid CoA functions, such as hippocampus, entorhinal cortex,
transferase (SCOT), which is necessary to metabolize medial temporal cortex and posterior cingulate.60,95,96
ketone bodies. 86,87,94 In addition to use of peripheral After the menopause, glucose metabolism declined in
ketone bodies as an alternative fuel source, a rise in the estrogen-dependent regions of the brain, but increased
levels of proteins required to metabolize fatty acids in in regions, such as pons, caudate and precuneus in
the brain was observed in both mice and rats.87,88,93 These women who did not receive estrogen therapy during
proteins, CPT1‑L (carnitine O‑palmitoyltransferase 1, perimenopause and menopause.96 An important caveat
liver isoform) and HADHA (trifunctional enzyme sub to these studies is that the women who were enrolled
unit alpha, mitochondrial), are required for fatty acid were symptomatic and often compared to women
transport and metabolism by the mitochondria, respec who were premenopausal and or women of a similar
tively.87,88 HADHA converts long-chain fatty acids to age who were asymptomatic. Consequently, the data
acetyl-CoA, which is the primer for ketone body synthe derived from these studies are probably only relevant
sis. As neither cholesterol nor long-chain fatty acids can to symptomatic women and not those undergoing the
pass through the blood–brain barrier, an increase fatty perimenopausal transition who do not have neurological
symptoms. Taken together, these data highlight the adap late perimenopause and continues into postmenopause.95
tive capacity of the perimenopausal female brain and In the SWAN study,104 hot flushes or night sweats were
the need for additional detailed analyses of brain metab strongly associated with dysregulation in glucose metab
olism during perimenopause, with a particular focus on olism, which was indicated by considerably increased
genotype and phenotype of this transition. levels of fasting blood glucose and raised HOMA scores.
The relationship between estrogen receptors and insulin
Hot flushes receptors in the brain is well established and provides
The most frequent, and often defining, feature of the additional evidence for the contribution of decline in
perimenopausal transition is the hot flush, which occurs estrogen levels to dysregulated glucose metabolism.85
in 75–80% women in the perimenopausal period and can Moreover, an association between impairment of the
continue for several decades in ~5% of women.3,98,99 Hot adipokine profile and occurrence of hot flushes early in
flushes can be the only symptom experienced by women the perimenopausal transition has been described, which
undergoing perimenopause (Figure 1b). However, in also supports a link between metabolic dysregulation and
many women, hot flushes co-occur with other neuro hot flushes.61,105 Decreased adiponectin and increased
logical symptoms, including decline in cognitive func leptin levels were associated with increased risk of hot
tion,34,100 insomnia, pain and depression (Figure 1b).44 flushes in early, but not late, stages of the perimenopause
The clinical manifestations of the hot flush have been transition.105 This altered adipokine profile parallels BMI
well documented and are characterized by the onset of a measurements of women with stage-dependent risk of
disturbing and intense rise in body temperature, which hot flashes, such that a high BMI was associated with
is primarily experienced in the upper body (chest, neck increased risk of hot flushes in early, but not late, in the
and head), as well as being accompanied by visible flush perimenopausal transition.105 Increased serum levels of
ing.99 The hot flush is a transient event with sudden and inflammatory cytokine monocyte chemotactic protein 1
rapid onset, and dissipation within seconds to minutes, (also known as C‑C motif chemokine 2) were associ
but can also last up to 60 min. Hot flushes can range from ated with an increased risk of night sweats, regardless
mild to severe in intensity and with a frequency of up to of menopause stage.105 Collectively, these data indicate
50 throughout the day and night; increased severity and a strong association between hot flushes and impaired
frequency during the sleep cycle has also been reported, glucose homeostasis in both the brain and the periphery
which can disrupt sleep and daily activities and cause of women undergoing perimenopause.61
severe stress and anxiety.101
The hypothalamus controls thermoregulation and is, Insomnia
therefore, thought to initiate the hot flush in response to Insomnia is a prevalent symptom of the perimeno
a rise in core temperature (Figure 2).102 The prevailing pausal transition and is frequently associated with hot
conceptualization of the hot flush is that a compression flushes, night sweats, depression and cognitive deficits
of the hypothalamic thermoneutral zone leads to epi (Figure 1b).44,106,107 The hypothalamus is the key nodal
sodic releases of heat in response to a slight increase in complex that regulates sleep–wake cycles (Figure 2).
core body temperature.99 However, although the hypo Interestingly, in the suprachiasmatic nucleus (located
thalamus is undoubtedly involved in the thermoregula within the hypothalamus and a key determinant of
tory response, functional MRI analyses of women in the diurnal rhythms), ER‑β expression follows a diurnal
perimenopausal period indicate activation of the insula rhythm, which is evident in young (aged 3–4 months)
and anterior cingulate cortex during hot flushes, which is and middle aged (aged 11–12 months) rats but not in
coupled to activation of the superior frontal gyrus and old rats (aged 19–24 months).108 In the SWAN study,
is associated with sweating.102 Activation of the insular prevalence of sleep disturbance varied with ethnicity,
cortex is associated with the sensation of ‘rush of heat’.99 with the highest prevalence (40%) occurring in white
These findings advance our understanding of the peri women, intermediate prevalence (31–38%) in Chinese,
menopausal hot flush beyond the temperature regulatory Hispanic and African American women and the lowest
zones of the hypothalamus to include an expanded neural prevalence in Japanese women (28%).107 The SWAN
network that includes subcortical and cortical structures. data indicate that sleep difficulties are maximal during
Increasing evidence also indicates an association of late perimenopause and persist into postmenopause,
the hot flush with altered glucose metabolism.86,103,104 irrespective of vasomotor symptoms.107 Brain imaging
Preclinical studies of bioenergetics using animal models studies in women during the perimenopausal stage who
of the female brain during perimenopause indicate have sleep disturbances remain to be conducted. Having
that the rise in skin temperature is co-incident with increased understanding of the effects of insomnia in this
the onset of reproductive variability and senescence.86 population is particularly important given the emerg
Levels of glucose metabolism in the brain also decline. ing body of data that are indicative of long-term adverse
Furthermore, glucose tolerance is compromised in the consequences of sleep deprivation.109 Multiple studies
periphery (which is indicative of insulin resistance) and have indicated an association between insomnia and
increased use of ketone bodies and fatty acid metabolism reduced brain volume in regions that include the hippo
occurs.86,87,94 Consistent with these preclinical findings, campus and orbitofrontal and parietal grey matter.109
analysis in humans using 18F-FDG-PET indicate a decline Furthermore, in many prospective studies, poor sleep
in brain glucose metabolism in the brain occurs during quality is associated with an increased likelihood of
cognitive impairment and, in some studies, an increased depression can occur early in the transition in women
risk of dementia.109 Sleep deprivation can also induce with no previous history of these symptoms although
β‑amyloid accumulation in the brain.110 depression was more likely to precede hot flushes.36 In
perimenopausal women who had depression, short-term
Cognition 17β‑estradiol treatment had antidepressant efficacy.33
Subjective and objective memory deficits during the Increased risk of major depression has been linked to vari
perimenopause have been well documented (Figure 1).35 ants of ER‑α. For example, in one study, women homo
In 18F-FDG-PET analyses, indicators of hypometabo zygous for the ESR1 rs9340799 variant G had a 1.6-fold
lism in brain regions required for learning and memory increased lifetime risk of major depressive disorder.118
function have been demonstrated.60,95,96 Over a 2‑year Glucose metabolism in brain regions that regu
observation period, hypometabolism was apparent in late depression and anxiety is complex, with different
women undergoing menopause in the hippocampus, metabolic phenotypes in the pons (where the seroto
parahippocampal gyrus and temporal lobe,96 as well as nergic raphe nucleus and locus coeruleus adrenergic
in the medial prefrontal cortex and the posterior cingu systems originate) and frontal cortices (Figure 2).31,97
late cortex.60,95 Estrogen replacement therapy prevented Comp ared with women in postmenopause without
hypometabolism in each of these brain regions and pre depression, those with depression have hypometabolism
served memory function.60,95 In a study that assessed in the pons and hypermetabolism in the middle and
regional cerebral blood flow, women in the postmeno inferior (Broca’s) frontal gyrus.97 In women in post
pausal period who were receiving estrogen had increased menopause aged >65 years without depression, regional
resting state cerebral blood flow in brain regions that are cerebral blood flow was increased in the left pons, which
now recognized as part of the default mode network; suggests a link to metabolism in the pons and an absence
this effect did not occur in women who did not receive of depressive symptoms.96 Timing of the administration
estrogen.96 The default mode network, or resting state of estrogen therapy seems to be critical to the effective
network, is a system of brain regions that includes the ness of treatment for depression, as depression scores
medial prefrontal cortex, the posterior cingulate cortex were not improved in women who received estrogen
and lateral parietal cortices. These regions have a high treatment 5–10 years after perimenopause.31 The long-
degree of functional connectivity during rest, which term effects of perimenopausal depression remain to
consumes a substantial amount of ATP in its continuous be determined; however, extensive epidemiological
activation.111 However, women in the postmenopausal analyses indicate that depression is also a risk factor for
period who were not treated with hormone therapy have Alzheimer disease.119,120
increased cerebral blood flow to brain regions that are
required for motor and spatial function.96,112 Interventions
Women in perimenopause who received hormone Although the outcome of the perimenopause (that is,
therapy (estrogen plus a progestin) also had enhanced reproductive senescence) is inevitable for all women,
activation in the hippocampus combined with decreased the experience of the perimenopausal transition can be
parahippocampal activation, which suggests that this highly variable (Figure 1). Following completion of the
treatment administered during perimenopause increases perimenopause transition, the neurological system is
state-dependent and memory-dependent processes to transformed. Notably, for some women intervention is not
promote verbal recognition performance.113 Analyses of warranted, whereas for others, intervention is appropriate
the default mode network in women in postmenopause and required.
who were neurologically healthy but at risk of Alzheimer Determining the best strategy to sustain neurological
disease indicated that high blood insulin levels were asso bioenergetic capacity in women during the perimeno
ciated with diminished network connectivity.111 Protective pausal and menopausal transition is crucial to sustain
metabolic effects of hormone therapy were most evident brain function. Given that estrogen regulates bioenergetic
in women with low insulin resistance, whereas the same system in brain regions that contribute to perimenopausal
therapy was ineffective in women with increased insulin symptoms, estrogen replacement therapy is a logical
resistance.114 Performance in working memory in both choice. However, many women do not choose this treat
groups of women also paralleled the metabolic response ment, because the data on the benefits and risks of estro
to hormone therapy.114 Glucose metabolism in the brain gen replacement therapy are complicated, controversial
is established as being critical to neurological function and confusing.51,52 Many factors contribute to this con
and that evidence of hypometabolism is apparent several founding state, including unresolved issues regarding the
decades before diagnosis of neurodegenerative diseases timing of intervention, hormone formulation, dose and
such as Alzheimer disease.115–117 route of administration. Optimizing and personalizing
hormone therapy remains an unmet need in women’s
Depression health but is a central issue for precision medicine to treat
Increased risk of depression in perimenopausal women is neurological symptoms that develop during, and persist
supported by evidence from several longitudinal studies beyond, the perimenopause. Given the complexity of the
that have documented odds ratios ranging from 1.8 to perimenopausal transition, women can be grouped into
2.9 of increased risk compared with women in premeno categories according to their symptoms, and clinical trials
pause.33,35,36 During perimenopause, both hot flushes and of new interventions might, therefore, be improved by
targeting specific perimenopausal phenotypes rather than life. Whether the neurological vulnerabilities that can
simply enrolling a heterogeneous population of women. emerge during the perimenopause lead to increased risks
of neurological disease in later life still needs to be deter
Conclusions mined; however, multiple neurological symptoms that
The perimenopausal transition occurs within healthy emerge during the perimenopause are also risk factors
women and initiates a targeted and systematic dis for neurodegenerative disease. The ability to detect both
assembly of the reproductive system and the neural peripheral and neurological indicators of metabolic
substrates controlling its function. As a transition state, dysfunction might enable the prevention of neurologi
the perimenopause is similar to developing neurologi cal disease in later life, and might be achieved by sus
cal dysfunction at puberty.8,121 In this regard, the peri taining bioenergetic capacity during this critical midlife
menopause satisfies the criteria for a critical period in transition in women.
the neuroadaptive landscape of ageing in the female
brain. Many women transition through perimenopause
without long-term adverse effects and are likely to remain Review criteria
healthy. However, a substantial proportion of women are A search for original articles published between 1980
vulnerable to the neurological shifts that can occur during and 2015 and focusing on perimenopause, female brain
this transition and are at increased risk of neurological aging, bioenergetics, transition states was performed
decline. The association between hypometabolism and in MEDLINE and PubMed. All articles identified were
the neurological symptoms of the perimenopause sug English-language, full-text papers. We also searched
gests that, for some women, this critical transition period the reference lists of identified articles for further
relevant papers.
could be a tipping point for neurological disease in later
1. Brinton, R. D. in Brockelhurst’s Textbook of 13. Santoro, N. & Sutton-Tyrrell, K. The SWAN song: 25. Finch, C. E., Felicio, L. S., Mobbs, C. V. &
Geriatric Medicine and Gerontology (eds Fillit, H., Study of Women’s Health Across the Nation’s Nelson, J. F. Ovarian and steroidal influences
Rockwood, K. & Young, J.) 163–171 (Saunders, recurring themes. Obstet. Gynecol. Clin. North on neuroendocrine aging processes in female
2010). Am. 38, 417–423 (2011). rodents. Endocr. Rev. 5, 467–497 (1984).
2. Butler, L. & Santoro, N. The reproductive 14. Burger, H. et al. Nomenclature and 26. Mobbs, C. V., Gee, D. M. & Finch, C. E.
endocrinology of the menopausal transition. endocrinology of menopause and Reproductive senescence in female C57BL/6J
Steroids 76, 627–635 (2011). perimenopause. Expert Rev. Neurother. mice: ovarian impairments and neuroendocrine
3. Harlow, S. D. et al. Executive summary of the 7 (11 Suppl.), S35–S43 (2007). impairments that are partially reversible and
Stages of Reproductive Aging Workshop + 10: 15. Genazzani, A. R. et al. Endocrinology of delayable by ovariectomy. Endocrinology 115,
addressing the unfinished agenda of staging menopausal transition and its brain 1653–1662 (1984).
reproductive aging. Menopause 19, 387–395, implications. CNS Spectr. 10, 449–457 (2005). 27. Maki, P. M. et al. Objective hot flashes are
(2012). 16. Tepper, P. G. et al. Trajectory clustering of negatively related to verbal memory performance
4. Greendale, G. A., Ishii, S., Huang, M. H. & estradiol and follicle-stimulating hormone in midlife women. Menopause 15, 848–856
Karlamangla, A. S. Predicting the timeline to the during the menopausal transition among women (2008).
final menstrual period: the study of women’s in the Study of Women’s Health across the 28. Maki, P. M. et al. Depressive symptoms are
health across the nation. J. Clin. Endocrinol. Nation (SWAN). J. Clin. Endocrinol. Metab. 97, increased in the early perimenopausal stage
Metab. 98, 1483–1491 (2013). 2872–2880 (2012). in ethnically diverse human immunodeficiency
5. United States Census Bureau. World population 17. Bastian, L. A., Smith, C. M. & Nanda, K. Is this virus-infected and human immunodeficiency
by age and sex, [online], http://www.census.gov/ woman perimenopausal? JAMA 289, 895–902 virus-uninfected women. Menopause 19,
population/international/data/worldpop/ (2003). 1215–1223 (2012).
tool_population.php (2014). 18. Avis, N. E. et al. Is there a menopausal 29. Greendale, G. A. et al. Effects of the menopause
6. Brinton, R. D., Gore, A. C., Schmidt, P. J. & syndrome? Menopausal status and symptoms transition and hormone use on cognitive
Morrison, J. H. in Hormones, Brain and Behavior across racial/ethnic groups. Soc. Sci. Med. 52, performance in midlife women. Neurology 72,
2nd edn (eds Pfaff, D. W. et al.) 2199–2222 345–356 (2001). 1850–1857 (2009).
(Elsevier, 2009). 19. Brinton, R. Minireview: translational animal 30. Greendale, G. A. et al. Menopause-associated
7. Burger, H. G., Dudley, E. C., Robertson, D. M. models of human menopause: challenges and symptoms and cognitive performance: results
& Dennerstein, L. Hormonal changes in the emerging opportunities. Endocrinology 153, from the study of women’s health across the
menopause transition. Recent Prog. Horm. Res. 3571–3578 (2012). nation. Am. J. Epidemiol. 171, 1214–1224
57, 257–275 (2002). 20. Finch, C. E. The menopause and aging, a (2010).
8. Paus, T., Keshavan, M. & Giedd, J. N. Why do comparative perspective. J. Steroid Biochem. 31. Rasgon, N., Shelton, S. & Halbreich, U.
many psychiatric disorders emerge during Mol. Biol. 142, 132–141 (2014). Perimenopausal mental disorders: epidemiology
adolescence? Nat. Rev. Neurosci. 9, 947–957 21. Walker, M. L., Gordon, T. P. & Wilson, M. E. and phenomenology. CNS Spectr. 10, 471–478
(2008). Menstrual cycle characteristics of seasonally (2005).
9. Petricka, J. J. & Benfey, P. N. Reconstructing breeding rhesus monkeys. Biol. Reprod. 29, 32. Schmidt, P. J. & Rubinow, D. R. Reproductive
regulatory network transitions. Trends Cell Biol. 841–848 (1983). ageing, sex steroids and depression. J. Br.
21, 442–451 (2011). 22. Weiss, G., Skurnick, J. H., Goldsmith, L. T., Menopause Soc. 12, 178–185 (2006).
10. Chen, L., Liu, R., Liu, Z. P., Li, M. & Aihara, K. Santoro, N. F. & Park, S. J. Menopause and 33. Schmidt, P. J. & Rubinow, D. R. Sex hormones
Detecting early-warning signals for sudden hypothalamic-pituitary sensitivity to estrogen. and mood in the perimenopause. Ann. NY Acad.
deterioration of complex diseases by dynamical JAMA 292, 2991–2996 (2004). Sci. 1179, 70–85 (2009).
network biomarkers. Sci. Rep. 2, 342 (2012). 23. Chen, S., Nilsen, J. & Brinton, R. D. Dose and 34. Weber, M. T., Rubin, L. H. & Maki, P. M. Cognition
11. Wilson, R. S., Leurgans, S. E., Boyle, P. A. & temporal pattern of estrogen exposure in perimenopause: the effect of transition stage.
Bennett, D. A. Cognitive decline in prodromal determines neuroprotective outcome in Menopause 20, 511–517 (2013).
Alzheimer disease and mild cognitive hippocampal neurons: therapeutic implications. 35. Weber, M. T., Maki, P. M. & McDermott, M. P.
impairment. Arch. Neurol. 68, 351–356 (2011). Endocrinology 147, 5303–5313 (2006). Cognition and mood in perimenopause:
12. Ramagopalan, S. V., Dobson, R., Meier, U. C. 24. Mobbs, C. V. et al. Estradiol-induced adult a systematic review and meta-analysis. J. Steroid
& Giovannoni, G. Multiple sclerosis: risk factors, anovulatory syndrome in female C57BL/6J mice: Biochem. Mol. Biol. 142, 90–98 (2014).
prodromes, and potential causal pathways. age-like neuroendocrine, but not ovarian, 36. Freeman, E. W., Sammel, M. D. & Lin, H.
Lancet Neurol. 9, 727–739 (2010). impairments. Biol. Reprod. 30, 556–563 (1984). Temporal associations of hot flashes and
depression in the transition to menopause. neurons of macaques. Psychoneuroendocrinology 73. NCBI AceView. Homo sapiens gene ESR1,
Menopause 16, 728–734 (2009). 27, 431–445 (2002). encoding estrogen receptor 1 [online], http://
37. Bromberger, J. T. et al. Longitudinal change 55. Maki, P. M. The timing of estrogen therapy after www.ncbi.nlm.nih.gov/IEB/Research/Acembly/
in reproductive hormones and depressive ovariectomy--implications for neurocognitive av.cgi?db=human&term=ESR1 (2010).
symptoms across the menopausal transition: function. Nat. Clin. Pract. Endocrinol. Metab. 4, 74. NCBI AceView. Homo sapiens complex locus
results from the Study of Women’s Health 494–495 (2008). ESR2, encoding estrogen receptor 2 (ER beta).
Across the Nation (SWAN). Arch. Gen. Psychiatry 56. Brinton, R. D. The healthy cell bias of estrogen [online], http://www.ncbi.nlm.nih.gov/IEB/
67, 598–607 (2010). action: mitochondrial bioenergetics and Research/Acembly/av.cgi?db=human&term
38. Thurston, R. C., Santoro, N. & Matthews, K. A. neurological implications. Trends Neurosci. 31, =ESR2 (2010).
Adiposity and hot flashes in midlife women: 529–537 (2008). 75. Ishunina, T. A. & Swaab, D. F. Age-dependent
a modifying role of age. J. Clin. Endocrinol. Metab. 57. Rocca, W. A., Grossardt, B. R. & Shuster, L. T. ERα MB1 splice variant expression in discrete
96, E1588–E1595 (2011). Oophorectomy, estrogen, and dementia: areas of the human brain. Neurobiol. Aging 29,
39. Nelson, H. D. Menopause. Lancet 371, a 2014 update. Mol. Cell. Endocrinol. 389, 1177–1189 (2008).
760–770 (2008). 7–12 (2014). 76. Chung, W. C. et al. Detection and localization of
40. Usall, J. et al. Suicide ideation across 58. Brinton, R. D. et al. Progesterone receptors: form an estrogen receptor beta splice variant protein
reproductive life cycle of women. Results from a and function in brain. Front. Neuroendocrinol. 29, (ERβ2) in the adult female rat forebrain and
European epidemiological study. J. Affect Disord. 313–339 (2008). midbrain regions. J. Comp. Neurol. 505,
116, 144–147 (2009). 59. Zhao, L. et al. Continuous versus cyclic 249–267 (2007).
41. Genazzani, A. R., Gambacciani, M. & progesterone exposure differentially regulates 77. Wang, J. M. et al. A dominant negative ERβ splice
Simoncini, T. Menopause and aging, quality of hippocampal gene expression and functional variant determines the effectiveness of early or
life and sexuality. Climacteric 10, 88–96 (2007). profiles. PLoS ONE 7, e31267 (2012). late estrogen therapy after ovariectomy in rats.
42. Genazzani, A. R., Pluchino, N., Luisi, S. & 60. Rasgon, N. L. et al. Prospective randomized trial PLoS ONE 7, e33493 (2012).
Luisi, M. Estrogen, cognition and female ageing. to assess effects of continuing hormone therapy 78. Zhang, Q. G. et al. C terminus of Hsc70-
Hum. Reprod. Update 13, 175–187 (2007). on cerebral function in postmenopausal women interacting protein (CHIP)-mediated degradation
43. Cray, L. A., Woods, N. F. & Mitchell, E. S. at risk for dementia. PLoS ONE 9, e89095 of hippocampal estrogen receptor-α and the
Identifying symptom clusters during the (2014). critical period hypothesis of estrogen
menopausal transition: observations from the 61. Rettberg, J. R., Yao, J. & Brinton, R. D. Estrogen: neuroprotection. Proc. Natl Acad. Sci. USA 108,
Seattle Midlife Women’s Health Study. a master regulator of bioenergetic systems in E617–E624 (2011).
Climacteric 16, 539–549 (2013). the brain and body. Front. Neuroendocrinol. 35, 79. Frick, K. M. Epigenetics, estradiol and
44. Cray, L. A., Woods, N. F., Herting, J. R. & 8–30 (2014). hippocampal memory consolidation.
Mitchell, E. S. Symptom clusters during 62. Tiano, J. P. & Mauvais-Jarvis, F. Importance J. Neuroendocrinol. 25, 1151–1162 (2013).
the late reproductive stage through the early of estrogen receptors to preserve functional 80. Fortress, A. M. & Frick, K. M. Epigenetic
postmenopause: observations from the Seattle β-cell mass in diabetes. Nat. Rev. Endocrinol. 8, regulation of estrogen-dependent memory.
Midlife Women’s Health Study. Menopause 19, 342–351 (2012). Front. Neuroendocrinol. 35, 530–549 (2014).
864–869 (2012). 63. Ruiz-Palmero, I., Hernando, M., Garcia- 81. Zhao, Z., Fan, L., Fortress, A. M., Boulware, M. I.
45. Shughrue, P. J., Lane, M. V. & Merchenthaler, I. Segura, L. M. & Arevalo, M. A. G protein-coupled & Frick, K. M. Hippocampal histone acetylation
Comparative distribution of estrogen receptor- estrogen receptor is required for the regulates object recognition and the estradiol-
alpha and -beta mRNA in the rat central neuritogenic mechanism of 17β-estradiol in induced enhancement of object recognition.
nervous system. J. Comp. Neurol. 388, developing hippocampal neurons. Mol. Cell. J. Neurosci. 32, 2344–2351 (2012).
507–525 (1997). Endocrinol. 372, 105–115 (2013). 82. Zhang, X. et al. Regulation of estrogen receptor α
46. O’Dowd, B. F. et al. Discovery of three novel, 64. Levin, E. R. Extranuclear estrogen receptor’s by histone methyltransferase SMYD2-mediated
G‑protein‑coupled receptor genes. Genomics 47, roles in physiology: lessons from mouse protein methylation. Proc. Natl Acad. Sci. USA
310–313 (1998). models. Am. J. Physiol. Endocrinol. Metab. 307, 110, 17284–17289 (2013).
47. Brinton, R. D. Estrogen-induced plasticity from E133–E140 (2014). 83. Lomniczi, A. et al. Epigenetic control of female
cells to circuits: predictions for cognitive 65. Mannella, P. & Brinton, R. D. Estrogen receptor puberty. Nat. Neurosci. 16, 281–289, (2013).
function. Trends Pharmacol. Sci. 30, 212–222 protein interaction with phosphatidylinositol 84. McCarthy, M. M. A piece in the puzzle of puberty.
(2009). 3‑kinase leads to activation of phosphorylated Nat. Neurosci. 16, 251–253 (2013).
48. Nilsson, S., Koehler, K. F. & Gustafsson, J. A. Akt and extracellular signal-regulated kinase 1/2 85. Mendez, P., Wandosell, F. & Garcia-Segura, L. M.
Development of subtype-selective estrogen in the same population of cortical neurons: Cross-talk between estrogen receptors and
receptor-based therapeutics. Nat. Rev. Drug a unified mechanism of estrogen action. insulin-like growth factor‑I receptor in the brain:
Discov. 10, 778–792 (2011). J. Neurosci. 26, 9439–9447 (2006). cellular and molecular mechanisms. Front.
49. Prossnitz, E. R. & Barton, M. The, 66. Scharfman, H. E. & Maclusky, N. J. Similarities Neuroendocrinol. 27, 391–403 (2006).
G‑protein‑coupled estrogen receptor GPER in between actions of estrogen and BDNF in the 86. Ding, F., Yao, J., Rettberg, J. R., Chen, S. &
health and disease. Nat. Rev. Endocrinol. 7, hippocampus: coincidence or clue? Trends Brinton, R. D. Early decline in glucose transport
715–726 (2011). Neurosci. 28, 79–85 (2005). and metabolism precedes shift to ketogenic
50. Suzuki, H. et al. Involvement of estrogen 67. Simpkins, J. W., Yi, K. D., Yang, S. H. & system in female aging and Alzheimer’s mouse
receptor β in maintenance of serotonergic Dykens, J. A. Mitochondrial mechanisms of brain: implication for bioenergetic intervention.
neurons of the dorsal raphe. Mol. Psychiatry 18, estrogen neuroprotection. Biochim. Biophys. Acta PLoS ONE 8, e79977 (2013).
674–680 (2013). 1800, 1113–1120 (2010). 87. Yao, J., Hamilton, R. T., Cadenas, E. &
51. Brailoiu, E. et al. Distribution and 68. Milner, T. A. et al. Ultrastructural localization of Brinton, R. D. Decline in mitochondrial
characterization of estrogen receptor G protein- estrogen receptor β immunoreactivity in the rat bioenergetics and shift to ketogenic profile
coupled receptor 30 in the rat central nervous hippocampal formation. J. Comp. Neurol. 491, in brain during reproductive senescence.
system. J. Endocrinol. 193, 311–321 (2007). 81–95 (2005). Biochim. Biophys. Acta 1800, 1121–1126
52. Naugle, M. M. et al. G‑protein coupled estrogen 69. Irwin, R. W. et al. Selective estrogen receptor (2010).
receptor, estrogen receptor α, and progesterone modulators differentially potentiate brain 88. Yao, J. et al. Ovarian hormone loss induces
receptor immunohistochemistry in the mitochondrial function. J. Neuroendocrinol. 24, bioenergetic deficits and mitochondrial beta-
hypothalamus of aging female rhesus 236–248 (2012). amyloid. Neurobiol. Aging 33, 1507–1521
macaques given long-term estradiol treatment. 70. Arnold, S., Victor, M. B. & Beyer, C. Estrogen and (2012).
J. Exp. Zool. A Ecol. Genet. Physiol. 321, 399–414 the regulation of mitochondrial structure and 89. Yin, F. et al. The perimenopausal aging transition
(2014). function in the brain. J. Steroid Biochem. Mol. in the female rat brain: decline in bioenergetic
53. McEwen, B. S., Akama, K. T., Spencer- Biol. 131, 2–9 (2012). systems and synaptic plasticity. Neurobiol. Aging
Segal, J. L., Milner, T. A. and Waters, E. M. 71. Nilsen, J., Irwin, R. W., Gallaher, T. K. & http://dx.doi.org/10.1016/j.neurobiolaging.
Estrogen effects on the brain: actions beyond Brinton, R. D. Estradiol in vivo regulation of 2015.03.013.
the hypothalamus via novel mechanisms. brain mitochondrial proteome. J. Neurosci. 27, 90. Zhao, L., Mao, Z., Chen, S., Schneider, L. S. &
Behav. Neurosci. 126, 4–16 (2012). 14069–14077 (2007). Brinton, R. D. Early intervention with an estrogen
54. Bethea, C. L., Mirkes, S. J., Su, A. & 72. Heldring, N. et al. Estrogen receptors: how do receptor β-selective phytestrogenic formulation
Michelson, D. Effects of oral estrogen, raloxifene they signal and what are their targets. Physiol. prolongs survival, improves spatial recognition
and arzoxifene on gene expression in serotonin Rev. 87, 905–931 (2007). memory, and slows progression of amyloid
pathology in a female mouse model of 102. Freedman, R. R., Benton, M. D., Genik, R. J. 2nd memory and hippocampal function later in life.
Alzheimer’s disease. J. Alzheimers Dis. 37, & Graydon, F. X. Cortical activation during Brain Res. 1379, 232–243 (2011).
403–419 (2013). menopausal hot flashes. Fertil. Steril. 85, 114. Rasgon, N. L. et al. Insulin resistance and
91. Hara, Y. et al. Presynaptic mitochondrial 674–678 (2006). medial prefrontal gyrus metabolism in women
morphology in monkey prefrontal cortex 103. Simpkins, J. W., Katovich, M. J. & Millard, W. J. receiving hormone therapy. Psychiatry Res. 223,
correlates with working memory and is improved Glucose modulation of skin temperature 28–36 (2014).
with estrogen treatment. Proc. Natl Acad. Sci. responses during morphine withdrawal in the rat. 115. Mosconi, L. et al. Declining brain glucose
USA 111, 486–491 (2014). Psychopharmacology (Berl.) 102, 213–220 metabolism in normal individuals with a
92. Cahill, G. F. Jr. Fuel metabolism in starvation. (1990). maternal history of Alzheimer disease.
Annu. Rev. Nutr. 26, 1–22 (2006). 104. Thurston, R. C. et al. Vasomotor symptoms and Neurology 72, 513–520 (2009).
93. Yao, J., Rettberg, J. R., Klosinski, L. P., insulin resistance in the study of women’s health 116. Rasgon, N. L. et al. Insulin resistance and
Cadenas, E. & Brinton, R. D. Shift in brain across the nation. J. Clin. Endocrinol. Metab. 97, hippocampal volume in women at risk for
metabolism in late onset Alzheimer’s disease: 3487–3494 (2012). Alzheimer’s disease. Neurobiol. Aging 32,
implications for biomarkers and therapeutic 105. Thurston, R. C., Chang, Y., Mancuso, P. & 1942–1948 (2011).
interventions. Mol. Aspects Med. 32, 247–257 Matthews, K. A. Adipokines, adiposity, and 117. Mosconi, L. et al. Brain imaging of cognitively
(2011). vasomotor symptoms during the menopause normal individuals with 2 parents affected
94. Yao, J. et al. Mitochondrial bioenergetic transition: findings from the Study of Women’s by late-onset AD. Neurology 82, 752–760
deficit precedes Alzheimer’s pathology in Health Across the Nation. Fertil. Steril. 100, (2014).
female mouse model of Alzheimer’s disease. 793–800 (2013). 118. Ryan, J. et al. Estrogen receptor α gene variants
Proc. Natl Acad. Sci. USA 106, 14670–14675 106. Campbell, I. G. et al. Evaluation of the and major depressive episodes. J. Affect Disord.
(2009). association of menopausal status with delta 136, 1222–1226 (2012).
95. Rasgon, N. L. et al. Estrogen use and brain and beta EEG activity during sleep. Sleep 34, 119. Yaffe, K. et al. The epidemiology of Alzheimer’s
metabolic change in postmenopausal women. 1561–1568 (2011). disease: laying the foundation for drug design,
Neurobiol. Aging 26, 229–235 (2005). 107. Kravitz, H. M. & Joffe, H. Sleep during the conduct, and analysis of clinical trials.
96. Maki, P. M. & Resnick, S. M. Longitudinal effects perimenopause: a SWAN story. Obstet. Gynecol. Alzheimers Dement. 8, 237–242 (2012).
of estrogen replacement therapy on PET cerebral Clin. North Am. 38, 567–586 (2011). 120. Norton, S., Matthews, F. E., Barnes, D. E.,
blood flow and cognition. Neurobiol. Aging 21, 108. Wilson, M. E. et al. Age differentially influences Yaffe, K. & Brayne, C. Potential for primary
373–383 (2000). estrogen receptor-α (ERα) and estrogen prevention of Alzheimer’s disease: an analysis
97. Rasgon, N. L., Kenna, H. A., Geist, C., Small, G. receptor-β (ERβ) gene expression in specific of population-based data. Lancet Neurol. 13,
& Silverman, D. Cerebral metabolic patterns in regions of the rat brain. Mech. Ageing Dev. 123, 788–794 (2014).
untreated postmenopausal women with major 593–601 (2002). 121. Deecher, D., Andree, T. H., Sloan, D. &
depressive disorder. Psychiatry Res. 164, 77–80 109. Yaffe, K., Falvey, C. M. & Hoang, T. Connections Schechter, L. E. From menarche to menopause:
(2008). between sleep and cognition in older adults. exploring the underlying biology of depression
98. Santoro, N. Symptoms of menopause: hot Lancet Neurol. 13, 1017–1028 (2014). in women experiencing hormonal changes.
flushes. Clin. Obstet. Gynecol. 51, 539–548 110. Ju, Y. E., Lucey, B. P. & Holtzman, D. M. Sleep Psychoneuroendocrinology 33, 3–17 (2008).
(2008). and Alzheimer disease pathology-—a
99. Freedman, R. R. Menopausal hot flashes: bidirectional relationship. Nat. Rev. Neurol. 10,
Acknowledgements
mechanisms, endocrinology, treatment. 115–119 (2014).
R.D.B. would like to acknowledge the support of
J. Steroid Biochem. Mol. Biol. 142, 115–120 111. Kenna, H. et al. Fasting plasma insulin and the
grants from the National Institute on Aging
(2014). default mode network in women at risk for
(P01AG026572 and R01-AG032236).
100. Maki, P. M. Minireview: effects of different HT Alzheimer’s disease. Neurobiol. Aging 34,
formulations on cognition. Endocrinology 153, 641–649 (2013).
3564–3570 (2012). 112. Yee, L. T., Roe, K. & Courtney, S. M. Selective Author contributions
101 Avis, N. E. et al. Change in health-related quality involvement of superior frontal cortex during R.D.B. researched data for the article and wrote
of life over the menopausal transition in a working memory for shapes. J. Neurophysiol. the manuscript. All authors provided substantial
multiethnic cohort of middle-aged women: 103, 557–563 (2010). contributions to the discussion of content,
Study of Women’s Health Across the Nation. 113. Maki, P. M. et al. Perimenopausal use of generation of figures and reviewed/edited the
Menopause 16, 860–869 (2009). hormone therapy is associated with enhanced manuscript before submission.