Available via license: CC BY 4.0
Content may be subject to copyright.
International Journal of
Molecular Sciences
Review
The Role of Estrogen Receptors and Their Signaling across
Psychiatric Disorders
Wu Jeong Hwang 1, Tae Young Lee 2,3,*, Nahrie Suk Kim 2and Jun Soo Kwon 1,4
Citation: Hwang, W.J.; Lee, T.Y.; Kim,
N.S.; Kwon, J.S. The Role of Estrogen
Receptors and Their Signaling across
Psychiatric Disorders. Int. J. Mol. Sci.
2021,22, 373. https://doi.org/
10.3390/ijms22010373
Received: 30 November 2020
Accepted: 28 December 2020
Published: 31 December 2020
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional clai-
ms in published maps and institutio-
nal affiliations.
Copyright: © 2020 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University,
Seoul 08826, Korea; hwj7942@gmail.com (W.J.H.); kwonjs@snu.ac.kr (J.S.K.)
2Department of Psychiatry, Pusan National University Yangsan Hospital, Yangsan 50612, Korea;
nahriekim@gmail.com
3Research Institute for Convergence of Biomedical Science and Technology, Pusan National University
Yangsan Hospital, Yangsan 50612, Korea
4Department of Psychiatry, Seoul National University College of Medicine, Seoul 03080, Korea
*Correspondence: leetaey@gmail.com; Tel.: +82-55-360-2468
Abstract:
Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across
psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but
are also highly involved in a wide range of brain functions, such as cognition, memory, neurode-
velopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-
inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric
disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric
disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of
estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple
neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their
disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further,
in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated
to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.
Keywords:
estrogen; estrogen receptors; schizophrenia; bipolar disorder; major depression disorder;
autism; attention-deficit/hyperactivity disorder; raloxifene; hypothalamic-pituitary-gonadal axis
1. Introduction
Globally, one in seven people (equivalent to 11–18% of the population) suffers from
mental or substance use disorders [
1
]. Despite many efforts, the prevalence of mental disor-
ders remains high, and interestingly, there exist gender disparities. Women have a higher
prevalence than men [
1
]. Indeed, multiple psychiatric disorders display sex differences
in their symptoms, age of onset, and prevalence. In general, males are more susceptible
to neurodevelopmental disorders, including schizophrenia, autism spectrum disorder
(ASD), and attention-deficit/hyperactivity disorder (ADHD), whereas females are more
susceptible to depressive, anxiety, and eating disorders. Multiple factors, such as social
and environmental factors, via various pathways and circuits in the brain, play a role in
creating these sex differences. However, accumulated evidence suggests biological factors
as one of the strongest candidates underlying this phenomenon and a closer examination
of sex hormones—in particular, estrogen.
Estrogens have traditionally been known to have their effects on reproductive be-
haviors, such as sexual receptivity and maternal behaviors [
2
]. However, over the past
twenty years of extensive research, both in animals and humans, it is now known that
estrogens, via their signaling mechanisms and interactions with multiple neurotransmit-
ter systems in our brain, including dopamine, serotonin, and glutamate, have heavy
involvement in cognition and mood [
3
–
5
]. Recent investigations have revealed pronounced
Int. J. Mol. Sci. 2021,22, 373. https://doi.org/10.3390/ijms22010373 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2021,22, 373 2 of 21
interactions of estrogens with the dopaminergic system, a highly implicated system in
the pathophysiology of multiple psychiatric and neurodegenerative disorders, and that
they modulate executive functions, such as working memory and reward processing [
6
–
8
].
Further, the roles of estrogen receptors and estrogen signaling have been highlighted,
with studies reporting their neuroprotective effects on the brain by promoting neurotrophins
synthesis and protecting the brain from inflammation and stress [
9
–
11
]. To add more,
investigations revealed, in animal models of psychiatric disorders and in patients, that es-
trogen and estrogen signaling are disturbed and that they are associated with not only
the cognitive deficits but, also, the manifestations of the symptoms, which could also be
reversed with estrogen administration or treatments targeting estrogen-signaling path-
ways [
11
–
13
]. Thus, together with much evidence on estrogen signaling disruptions in
psychiatric disorders, recently, their effects have been taken under examination in multiple
clinical trials for the critical assessment and evaluation of their efficacy as a new treatment
for psychiatric patients [
14
–
18
]. Altogether, accumulating evidence suggests that estrogen
and estrogen signaling may be highly implicated in the pathophysiology of psychiatric
disorders, warranting a comprehensive and integrated understanding of estrogen and
estrogen signaling across multiple levels of the brain system architecture from cellular and
molecular to systemic to elucidate the mechanisms involved in its therapeutic effects in
psychiatric disorders.
In this review, we first describe estrogen receptor signaling by providing summarized
information of the literature on estrogen receptor signaling; distributions of estrogen
receptors in the brain; their mechanisms of actions on major neurotransmitters of our
brain, including dopaminergic, serotonergic, and glutamatergic; and their cognitive and
neuroprotective effects. Next, we critically assess the recent progress of our understanding
of the role of estrogen receptor signaling and its therapeutic effects in psychiatric disorders,
including schizophrenia, bipolar disorder, major depressive disorder (MDD), ASD, ADHD,
general anxiety disorder (GAD), post-traumatic stress disorder (PTSD), eating disorders,
and substance use disorder, with an aim to provide and highlight the importance of
estrogen singling in major psychiatric disorders, thereby possibly providing guidance as to
finding new therapeutic targets.
2. Estrogen Receptor Signaling
2.1. Estrogen
The estrogen family is a steroid hormone and consists of one benzene ring, a phe-
nolic hydroxyl group, and a ketone group, and, depending on the number of hydroxyl
groups, the estrogens are named estrone (zero groups, E1), estradiol (one group, E2),
estriol (two groups, E3), and estetrol (three groups, E4). While females produce estrogens
all during their lives, however, for the predominance during the reproductive years and
high relevance to physiology, the word estrogen in the literature commonly refers to E2
(or 17
β
-estradiol). Estrogens have been traditionally reported to have physiological func-
tions involved in the development of breast tissue and sexual organs, regulations of the
menstrual cycle and reproduction, and maintenance of our bone density. However, recent re-
ports suggest its cognitive [
3
,
19
] and neuroprotective effects [
10
] and anti-inflammatory
roles [
20
]. Estrogens are also present in males at low levels [
21
], and in men, they are
involved in reproduction, such as spermatogenesis, erectile function, and libido [
22
].
Estrogens are produced primarily in ovaries from testosterone but can also be produced in
the liver, adipose tissue, heart, and, most importantly, the brain [
23
]. In the brain, there ex-
ists regional specifics in estrogen production, suggesting their selective involvement of the
brain functions. Reports show that estrogens are produced in the hippocampus, cerebellum,
hypothalamus, amygdala, and cortex [24] by neurons and astrocytes [25].
2.2. Estrogen Receptors and Their Signaling Mechanisms
Estrogens exert their effects via estrogen receptors. There currently are three known
classes of receptors, estrogen receptor alpha (ER
α
), estrogen receptor beta (ER
β
), and G
Int. J. Mol. Sci. 2021,22, 373 3 of 21
protein-coupled receptor 30 (GPER). With GPER being relatively recently discovered [26],
ER
α
and ER
β
are the most widely studied in the literature. ER
α
and ER
β
are composed
of various functional domains and have several structural regions in common, the amino-
terminal domain (NTD) and estrogen response elements (ERE). Since estrogens are steroid
hormones, they can exert their direct effects by entering the plasma membrane and tak-
ing estrogen receptor complexes to the cell nucleus and interacting and binding directly
onto the ERE of intracellular ER
α
and ER
β
. Otherwise, they can indirectly exert their
effects by activating intracellular signaling cascades via interacting with estrogen receptors.
Thus, estrogen signaling can be divided into genomic (direct binding onto ERE) and nonge-
nomic (activation of an intracellular signaling cascade). Recent reports suggest that 35%
of genes that are regulated by estrogen receptors lack EREs, in which only nongenomic
estrogen signaling can be conducted [
27
]. There exist multiple signal transduction path-
ways in response to estrogen, and the same estrogen binding can lead to different, or even
opposite [
28
,
29
], responses in ER
α
and ER
β
(See Fuentes et al., 2019 [
30
] for a detailed re-
view). Generally, ER
α
is known to modulate neurobiological reproductive systems, such as
those involved in sexual characteristics and puberty. ER
β
is known to be involved in the
modulation of nonreproductive systems, such as anxiety, locomotion, fear, and memory
and learning.
2.3. Estrogen Receptors in the Brain
Along with estrogens, ER
α
and ER
β
are widely distributed in our brain, including
the hippocampus, hypothalamus, amygdala, thalamic connectivity system regions [
31
] of
the thalamus, cerebellum, and cortex, as well as the cortico-striato-thalamo-cortical (CSTC)
circuit-related regions of the basal ganglia and striatum. GPERs are also expressed in the
hippocampus, cortex, and hypothalamus [
32
]. Revealed by extensive neuroimaging studies,
interestingly, these areas are the most frequently reported regions of deficits in psychiatric
patients, and below, we provide a brief description of estrogen receptor distributions.
The receptors possess different dominance in different brain regions (Figure 1).
Describing the distribution in all brain regions may be unpractical for this article. However,
to provide a brief description, in the cortex, ER
α
and ER
β
are present particularly at the
prefrontal and temporal cortexes in humans. In rats, reports show the existence of ER
α
in
the medial prefrontal cortex [
33
] and the colocalization of ER
α
and ER
β
in sensorimotor
areas [
34
], with the density of ER
β
being greater than that of ER
α
[
35
]. In the temporal
cortex of humans, a report showed a higher density of ER
α
in the nuclei and ER
β
in the
cytoplasm [
36
]. In the hippocampus, the pivotal region of the cognitive functioning of
learning and memory in our brain, ER
β
is expressed at moderately high levels at the
regions of the subiculum, cornu ammonis 1-2 (CA1-CA2), and CA3 dentate gyrus [
35
,
37
,
38
]
and is a primary regulator of the region in both rats and humans. In the amygdala,
ER
α
is the primary regulator of the region; thus, they are predominantly expressed [
39
].
In humans, ERαis found the highest at the periamygdala cortex, amygdala-hippocampal
area, and posterior cortical nucleus [
37
,
40
]. The co-expression of both receptors is the
highest at the medial posterior-dorsal nucleus [
39
]. ER
α
is also a primary regulator
of the hypothalamus. In humans, the ER
α
is expressed the highest at the supraoptic,
paraventricular, arcuate, and periventricular nuclei [
37
]. The regions both ER
α
and ER
β
are co-expressed, although beta is expressed at low levels, at the supraoptic, paraventricu-
lar, arcuate, and ventromedial nuclei [
37
]. The expression of ER
α
and ER
β
are found in
the major node of the CSTC circuit in our brain, the basal ganglia, where also dopamine
cell bodies reside. Reports show the expression of estrogen receptors in dopamine neu-
rons in rodents [
35
,
41
] and even the modulation of dopamine neurotransmission by
estrogen [
42
–
44
]. In rodents, reports have found ER
α
and ER
β
expressions in the striatum,
with estrogen receptors being expressed low at the nuclei and high at the extracellular
sites [
45
]. However, ER
α
and ER
β
expressions have not, so far, been detected in the human
striatum [
40
]. Further evidence of ER
α
and ER
β
exists in the center node of the thalamic
connectivity system: the thalamus and the cerebellum. Both regions are primarily regulated
Int. J. Mol. Sci. 2021,22, 373 4 of 21
by ER
β
[
46
]. In the thalamus, in humans, low levels of ER
β
are found in the paratenial and
paraventricular nuclei, and ER
α
is found in the posterior nuclei only [
47
]. Interestingly,
sex differences in these areas have been shown, with men expressing a higher density of
nuclear ERβreceptors than women [47].
Figure 1.
A schematic diagram of distributions of estrogen receptor alpha and estrogen receptor
beta in our brains. The receptors have a different predominance of expression in distinct regions.
ER
α
is predominantly expressed in the amygdala and hypothalamus, whereas ER
β
is predominantly
expressed in the somatosensory cortex, hippocampus, thalamus, and cerebellum.
2.4. Mechanism of Actions on Neurotransmitter Systems
Mounting evidence from both clinical and preclinical studies suggests the modulation
of estrogen, via estrogen receptor signaling, on neurotransmitter systems in our brains,
such as dopaminergic, serotonergic, and glutamatergic, the key neurotransmitter systems
implicated in major psychiatric disorders. Estrogens exert effects on neurotransmitter
systems by targeting and regulating the expressions of specific subtypes of neurotrans-
mitter system receptors in a region-specific manner, contributing to our cognition, mood,
and behavioral responses. For example, estrogens present selectivity in exerting effects on
serotonin receptor subtypes that have high implications to cognitive functions commonly
disrupted across multiple psychiatric disorders, such as learning, memory, and cognitive
flexibility [
48
,
49
]. Mounting reports suggest a strong modulatory effect of estrogen on major
neurotransmitter systems in our brain, and extensive studies have found neuroleptic-like
properties of estrogen [15] similar to atypical antipsychotics used in psychiatric disorders
on dopaminergic, serotonergic, and glutamatergic systems. Thus, a better understanding
of the nature of these interactions is suggested for assessing the therapeutic potential
of estrogen. To maintain the scope of this article, brief descriptions will be provided in
this article, but we recommend Krolick and her colleagues for a detailed review of the
interactions [50].
Preclinical studies have extensively revealed many profound yet complex effects
of estrogens on dopaminergic neurotransmissions [
42
]. Briefly, the current literature
reports that (1) estrogens increase dopamine synthesis in the nucleus accumbens,
induce presynaptic dopamine release in the striatum, and decrease the turnover in the
nucleus accumbens [
51
–
56
]. (2) Evidence suggests the regulation of D1 and D2 receptor
densities and functions by estrogens [
57
–
60
]. (3) Estrogens prolong neurotransmissions
by reducing dopamine transporters in the nucleus accumbens [
61
–
63
]. Similarly, exten-
sive studies report the effects of estrogens on the serotonergic neurotransmission system.
Specifically, current evidence suggests that (1) estrogens upregulate the expression and
activity of TPH to increase 5HT biosynthesis [
51
,
64
] and (2) regulate 5HT receptors 5HT2A
and 2C, the receptors of which have high implications in depression [
65
–
70
]. (3) Estrogens
Int. J. Mol. Sci. 2021,22, 373 5 of 21
regulate 5HT autoinhibition via the 5HT1A auto-receptor, resulting in an antidepressant-
like activity [
71
]. (4) Estrogen treatments reduce the 5HT uptake to presynaptic cells and
prolong neurotransmissions [
72
]. (5) Estrogens decrease 5HT metabolism via degrada-
tion by monoamine oxidase inhibitors (MAO) after 5HT is taken up into the presynaptic
neurons [
68
,
73
,
74
]. It has also been shown that estrogens exert their effects on the gluta-
matergic neurotransmitter system, which facilitates most of our neurotransmissions in
our brain and mediates our cognitive functions. Current reports suggest that estrogens
affect N-Methyl-D-aspartic acid (NMDA) glutamate receptors and upregulate and increase
their distributions [
75
–
77
]. Notably, reports revealed the neuroprotective effects of es-
trogen on cortical and hippocampal neurons against the effects of glutamate-mediated
neurotoxicity [78,79].
2.5. Estrogen Receptors and Cognition
Extensive reports depict the effects of estrogens on cognition. In humans, it has been
reported that verbal memory impairments and menopause-related cognitive decline can
be rescued by estradiol replacement therapy [80,81]. Studies have been reporting varying
the results of outcomes of estradiol replacement therapy, depending on the dosage, du-
ration, and type of the treatment; however, in general, estrogens have beneficial impacts
on cognitive functioning [
81
]. Finer details of the relationship have been thoroughly in-
vestigated in preclinical studies. Studies have reported the distinguished characteristics
of estrogen receptors; ER
β
knockout mice show severely disruptive behaviors in mem-
ory and learning [
82
], and ER
α
knockout mice show severe deficits in reproduction [
83
].
Further, their distributions and expressions in our brain regions converge onto most cog-
nitively relevant brain regions, and, via estrogen signaling, they also exert effects on the
synaptic formation [
84
]. For example, in a recent study, it was reported that ER
β
plays a
crucial role in motor learning in the cerebellum by potentiating the neuronal plasticity and
synaptogenesis in that brain region [85].
Extensive reports suggest the particular involvement of estrogen on the working
memory [
86
,
87
]. In an ovariectomy performed on rodents, both spatial and nonspatial
working memory deficits were observed, and the estradiol treatment also rescued those
deficits [88]. In humans, high estradiol levels during menstrual phases in healthy women
and estrogen replacement therapy (ERT) in postmenopausal women have been shown to
improve the spatial working memory [
89
,
90
]. Their notable actions on the hippocampus
and prefrontal cortex, in particular, have also been reported. It has been reported, in rodents,
that exogenous estradiol administration reverses the decreases in the dendritic spine density
of neurons in the hippocampus and prefrontal cortex caused by an ovariectomy, as well as
improving the memory [
91
–
93
]. The detailed actions are yet to be thoroughly elucidated;
however, their receptor distributions are wide across brains, and complex interactions with
multiple neurotransmitter systems, as described in previous sections, conveniently place
them as a key player in cognitive functioning.
Beneficial Effects of Selective Estrogen Receptor Modulators (SERMs) on Cognition
Estrogen signaling and its effects on cognition are particularly relevant to psychi-
atric disorders, as they display global cognitive deficits; particularly the disorders pos-
sess different degrees of executive dysfunctions [
94
,
95
]. Nonetheless, despite vigor-
ous effort, the currently available pharmaceutical treatments for psychiatric disorders—
particularly, schizophrenia—do not show satisfactory results in treating the cognitive
deficits. In schizophrenia, despite the cognitive deficits being related to the patient’s func-
tional impairment, there exist mixed results in pharmaceutical treatments for cognitive
deficits [
96
,
97
]. The alpha-7-nicotinic receptor agonist has shown significant beneficial
effects with small effect sizes on the CogState battery [
98
,
99
]. However, both the alpha-7-
nicotinic receptor agonist and modafinil have been found insignificant on the Measurement
and Treatment Research to Improve Cognition in Schizophrenia [
100
,
101
]. Thus, currently,
Int. J. Mol. Sci. 2021,22, 373 6 of 21
it is very urgent to identify novel pharmacological targets, and amongst many targets,
estrogenic treatments have been showing highly promising results.
ERTs, which have beneficial effects on the domains of verbal memory, speech, abstract
reasoning, and information processing in postmenopausal women, come with the side
effects of increased risks of thromboembolism, hot flashes, and breast hyperplasia when
used long term, and most importantly, the therapy is prohibited for use in men due to
feminizing effects [
102
]. Thus, recent studies have been focusing on another class of drugs
that act on the estrogen receptor, selective estrogen receptor modulators (SERMs), which
have antagonistic effects in the breasts and uterus and agonistic effects in the bone and
brain. There are two classes of SERMs: triphenylethylene, which includes tamoxifen,
clomiphene, toremifene, and GW5407, and benzothiophene, which includes raloxifene,
arzoxifene, bazedoxifene, and lasofoxifene. Each has different properties and treatment
effects, depending on the estrogen receptor subtypes, coactivators, and corepressors in the
brain region. Reports show SERMs interact with ER
α
, Er
β
, and, also, GPER and can activate
both genomic and nongenomic cascades, such as cAMP/PKA, MAPK/ERKs, PI3K/Akt,
and Wnt/
β
-catenin, which are major signaling pathways in our brain for cognition and
neuroprotection [
103
–
105
]. However, different SERMs, for their distinct properties, result
in different actions in our brains. For example, tamoxifen, a first-generation SERM initially
developed for the treatment of breast cancer, and raloxifene have shown a similar affinity
for both ER
α
and ER
β
, whereas raloxifene, a second-generation SERM developed for osteo-
porosis treatment, has a four-times higher affinity for ER
α
[
106
]. Thus, unlike their initial
developmental purposes, studies found beneficial effects in cognition—particularly in the
memory—as well as neuroprotective and antioxidizing effects in SERMs, both in healthy
and injured brains [
85
,
107
–
110
]. Raloxifene, in particular, has been reported, via various
cell signaling cascades, to regulate plasticity; improve memory; and exert neuroprotective,
antioxidative, and anti-inflammatory effects [
85
,
107
,
108
]. Therefore, multiple clinical trials
assessing their efficacies and effects on cognition have been conducted across multiple
psychiatric disorders, described in the following sections.
2.6. Estrogen and Its Neuroprotective Effects
Converging lines of evidence report that estrogens, via estrogen signaling, are im-
plicated in neuroprotection [
111
,
112
]. Evidence suggests their implications in synaptic
plasticity, antioxidative effects, apoptosis, and protection against excitotoxicity [
113
–
116
].
Reports also have shown estrogens facilitate glucose metabolism by having a regulatory
role in the cerebral blood flow and can enhance the electron transport chain activity to
provide more energy to neurons [117].
Further, estrogens provide neuroprotection by having anti-inflammatory effects [
118
,
119
].
They regulate and promote the synthesis of neurotrophins, such as brain-derived neu-
rotrophic factor (BDNF), which is a highly implicated molecule to various psychiatric
disorders for its pertinent roles in neuronal survival, differentiation, and synaptic plas-
ticity [
120
]. Further, reports have shown that ER
α
and ER
β
have regulatory roles in the
production of proinflammatory cytokines and chemokines and that this can occur either
through estrogen-dependent or -independent mechanisms [
121
]. However, there exist
“critical periods” for estrogens to exert their neuroprotective effects. It has been reported
that estrogen therapies need to be given immediately after brain injuries, as the treat-
ment loses the effect when given ten weeks post-ovariectomy [
122
]. In the same study,
long-term estrogen deprivation caused a reduction in ER
α
receptors in the hippocampus,
and the “critical period” is suggested to be due to tissue-specific reductions of estrogen
receptors [122].
3. Estrogen Receptor and Psychiatric Disorders
3.1. Schizophrenia
Schizophrenia is a severely debilitating disorder that affects 1% of the population.
It has, largely, three symptom domains of positive symptoms, negative symptoms, and cog-
Int. J. Mol. Sci. 2021,22, 373 7 of 21
nitive deficits. Sex differences in the pathophysiology are well-documented in the literature.
Compared to women, in males, evidence shows higher incidence rates, early-onset, and dif-
ferent symptoms [
123
]. Men have earlier onset and higher incidence rates of the disorder
than women, as well as present more symptoms of conduct disorders, aggression, antisocial
personality traits, and higher levels of psychopathology. Women have a higher incidence
of negative symptoms, substance abuse, and depression. Further, there exist differences
in the number of peaks in the age of onset between the sexes. Men have a single peak
between 21 and 25 years of age, and women have two, the first after menarche and the
second postmenopause [
124
]. This has led to the “estrogen hypothesis” in schizophrenia,
which posits that estrogens provide neuroprotective effects against the disorder in regards
to the onset, progression, and symptom severity, as well as the promotion of healthy brain
development [125–127].
Studies revealed and confirmed detailed correlations between estrogen levels and
schizophrenia symptoms. Low plasma estrogen levels have been correlated with increased
risks for schizophrenia symptoms in women [
128
], and estrogen levels across the menstrual
cycle have been inversely correlated with psychopathological symptoms in women with
schizophrenia [
129
]. Menstrual cycle irregularities in schizophrenia patients have also been
reported to be a predictor of lower cognitive performance in areas of psychomotor speed,
verbal fluency, and verbal memory, suggesting that cognitive deficits in schizophrenia are
partly attributed to estrogens [
130
]. During pregnancy, when in the surge of estrogen levels,
patients have shown low rates of relapse of the disorder [
131
]. Studies also have found
that the early timing of menarche has beneficial effects in providing neuroprotective effects
against psychosis deterioration [
132
], and a recent neuroimaging study revealed that an
earlier age at menarche (i.e., earlier availability of estrogens) results in more normative
hippocampal connectivity in high risk for psychosis youths [
133
]. A study also suggested
the neuroprotective role of estrogen in reducing symptom severity and susceptibility [
134
].
Studies have also revealed the effects of estrogens on cognitive deficits seen in
schizophrenia patients. Both in healthy populations and in schizophrenia patients,
studies have shown that estrogen levels correlate with well-being and cognitive func-
tioning. Further, reports have demonstrated low estradiol phases are associated with
poorer verbal and spatial memory, as well as perceptual-motor speed [
135
]. A neuroimag-
ing study using functional magnetic resonance imaging (fMRI) also reported that there is a
significant positive correlation between sex steroid levels and brain activity in both female
schizophrenia patients and healthy males [
136
]. In preclinical studies, using rodent models
of schizophrenia, a few studies have examined the molecular and genetic details of such
cognitive disruptions seen in patients. The studies yielded promising results that estrogens
can be used to ameliorate working memory deficits. Different models exist, but most
tried to implement the cognitive deficits observed in schizophrenia by manipulating the
NMDA receptors. Celia Moreira Borella and colleagues [
137
] reported working memory
and prepulse inhibition (PPI) deficits when estrogen levels are the lowest and normal
behaviors when the levels are the highest in a model using a neonatal N-Methyl-D-aspartic
acid receptor (NMDAR) blockade with ketamine. Gogos and colleagues [
138
,
139
] reported
the effects of estrogen or selective estrogen receptor modulators on PPI deficits caused by
MK801 or apomorphine in ovariectomized rats. Further, in a recent study, Gogos and col-
leagues [
140
] reported that chronic treatment with estrogens reversed the PPI disruptions
and the increased dopamine D2 receptor-binding densities in Poly(I:C)-treated rodents,
suggesting that the beneficial effects may be mediated by selective changes in densities of
dopamine D2 receptors.
Mounting evidence exists reporting subnormal estrogen levels in both treated and
untreated schizophrenia patients and high risk for psychosis subjects [
136
,
141
,
142
]. In addi-
tion to the aforementioned deficits observed peripherally, studies exist reporting alterations
in the brain’s response to these hormones. It has been reported that both men and women
with schizophrenia have reduced mRNA levels of ER
α
in the hippocampus [
143
]. The
ER
α
gene and its mRNA expression has further been reported to be associated with
Int. J. Mol. Sci. 2021,22, 373 8 of 21
schizophrenia [
144
]. Further, reports have also shown that women with schizophrenia
often are hypoestrogenic, and converging evidence suggests this may be the consequential
effect of hyperprolactinemia, a common side effect of antipsychotic mediation [
145
]. It has
been suggested that, as increased levels of prolactin suppress the hypothalamic-pituitary-
gonadal (HPG) axis in a negative feedback manner, estrogen and testosterone levels become
decreased, resulting in hypoestrogenism observed in schizophrenia patients. However,
recent lines of investigation revealed that hyperprolactinemia alone cannot be a full explain-
ing factor of hypoestrogenism in schizophrenia [
146
] and that hyperprolactinemia is also
independent of antipsychotics [
147
–
150
] (see Du and Hill, 2019 for a detailed review [
151
]).
Thus, currently, clinical trials are being conducted to test estrogen as a new target
of therapy. Initially, studies focused on rescuing the estrogen level itself. The direct ad-
ministration of estrogens showed improvements in the speech comprehension of female
schizophrenia patients [
152
]. Transdermal estradiol patch therapy also demonstrated
beneficial effects and significantly improved the psychotic symptoms in female patients
with schizophrenia; however, no positive effects were found in their cognitive function-
ing [
153
]. Recent research paradigms have shifted towards assessing SERMs—in particular,
raloxifene—on symptom amelioration and cognition enhancements in schizophrenia pa-
tients for their lack of sensitization and feminization and selective action as potent estrogens
only in the bone and brain.
Raloxifene has shown promising results in the improvement of the cognitive
impairment—particularly, attention, memory, and learning—seen in schizophrenia.
Further, raloxifene improves symptoms in schizophrenia patients. Recent studies have
found that raloxifene improves both positive and negative symptoms in women and nega-
tive symptoms in men [
11
]. Its effects were also assessed in multiple clinical trials in which
its beneficial effects on multiple domains of executive functions and psychopathology were
confirmed in various subgroups of schizophrenia patients, such as men and women with
schizophrenia, treatment-resistant young women with schizophrenia, and postmenopausal
women with schizophrenia [
154
–
157
]. Further, in one study, the beneficial effects were
maintained even when the dose was reduced to half [
156
,
158
]. However, more studies are
needed to elucidate the mechanisms of raloxifene, and the current literature shows varying
degrees of improvements by raloxifene on cognition and psychopathology, suggesting
further clinical trials.
3.2. Bipolar Disorder
Bipolar disorder is characterized by cycles of mania and depression. The disorder
can be classified into Bipolar I disorder, which is characterized by much severer mood
episodes, from mania to depression, and Bipolar II disorder, which is characterized by
milder episodes of hypomania and alternate with severe depression. There exist gender
differences in the disorder in that women present with symptoms later in life than men and
have faster cycling of mania and depression than men. Gender differences are also seen
amongst the subtypes. Bipolar II disorder is more common in women than men. Numerous
reports show that women with bipolar disorder, during periods of hormonal fluctuation,
are associated with increased vulnerability to developing depression and increased risk of
affective dysregulation.
Increased levels of GPER-1 were recently reported in euthymic outpatients of bipolar
disorder, the results of which were not influenced by medications [
159
]. So far, the two
studies that have examined the relationship between ER
α
, ER
β
, and bipolar disorder
have found negative results [
160
,
161
], unlike in schizophrenia. Despite there being a
limited number of studies examining the associations between estrogens and estrogen
receptors in bipolar disorder, reports show high associations between the symptomatic
course in patients with bipolar disorder and the periods of hormonal fluctuations. It has
been reported that bipolar disorder patients who experience premenstrual exacerbation
are more likely to have a worse course of illness, a shorter time to relapse, and increased
severity in their symptoms [
162
]. Further, in a recent study, the bipolar patients who report
Int. J. Mol. Sci. 2021,22, 373 9 of 21
reproductive cycle event-related worsening of their mood were associated with rapid
cycling, comorbid anxiety, and mixed mood episodes [
163
]. Taken together, the current
lines of evidence show that disruptions in estrogen and estrogen signaling and estrogen
fluctuations are associated with the symptoms.
Several clinical trials on SERMs have been showing promising effects in the treatment
of bipolar disorder. Tamoxifen has been shown to have effects in reducing mania and
depression when used together with a lithium treatment in children and adolescents with
acute mania [
164
]. The study also reported the high efficacy of tamoxifen despite the small
sample size. In a meta-study, tamoxifen adjuvant therapy was reported to reduce the
frequency of manic episodes in bipolar patients [
165
]. However, tamoxifen is known to
have side effects of thromboembolic events and increasing risks of endometrial cancer.
Thus, efforts have been put into understanding and elucidating the detailed mechanisms of
the actions of the drug. Animal studies have reported that the beneficial effects of tamoxifen
on mania from the coadministration of lithium and tamoxifen come partly from lithium and
tamoxifen changing the protein kinase C signaling pathway [
166
]. The current literature,
however, lacks the long-term effects of tamoxifen, and further studies are warranted.
3.3. MDD
MDD can be chronic or recurrent, and its impacts on mood and behavior are associated
with poor health and mortality. Gender differences exist in MDD, like other psychiatric
disorders, and women have a higher prevalence than men.
It is speculated, with multiple lines of evidence, that alterations in hormones play
a crucial role in the pathophysiology of the disorder. Reports show high associations
between the symptomatic course in patients with MDD and the periods of hormonal
fluctuations. The patients, when in periods of ovarian hormone withdrawal, such as
a postpartum period or menopause, have increased risks of mood symptoms and the
occurrence of MDD [
167
]. At a molecular level, the GPER level has been reported to be
elevated in MDD compared to healthy subjects, which also correlated with depression
scores [
168
]. Using the data from one million Danish women, oral contraceptive uses were
associated with an increased risk of a depression diagnosis, antidepressant treatments,
and suicidal acts [
169
,
170
]. Further elucidation into detailed mechanisms involved in such
a phenomenon was made in animal studies. During low-estradiol times of the cycles,
rodents showed more profound depressive-like behaviors [
171
]. Further, ovariectomy
caused an enhanced feeling of despair and was rescued with the estradiol administration
in rodents [172].
ERTs are currently used to treat peri- or post-MDD patients. However, currently avail-
able clinical trials examining moods in pre- and postmenopausal women treated with
hormone replacement have yielded mixed results for wide variations in the symptomatol-
ogy of recruited samples and treatment timing postmenopause across studies [
17
]. It was
revealed in a study that the early treatment of ERT has a cardioprotective effect, whereas the
same treatment when treated 10 years after menopause exerted risk-enhancing effects [
173
].
3.4. ASD
ASD is a neurodevelopmental disorder that begins early in childhood. The disorder is
characterized by dysfunctions in communicating and interacting with others, as well as
learning disabilities. With the prevalence ratio of 4:1, men are more highly likely to develop
this disorder [
174
]. Reports have long been made for the association between ASD devel-
opment and increased testosterone exposure during pregnancy [
175
]. Studies associate
testosterone levels to various symptoms and cognitive deficits manifested in ASD, such as
social anxiety and reduced empathy, as well as deficits in social and language develop-
ments in ASD patients [
68
,
176
]. These led to the “extreme male brain” (EBM) theory [
177
],
which proposes that ASD patients, due to elevated prenatal testosterone levels, can be
considered as having an extreme of the normal male profile for their cognition and show a
strong predominance of systemizing over empathizing.
Int. J. Mol. Sci. 2021,22, 373 10 of 21
The literature also describes estrogen-signaling disruptions in ASD. Aromatase,
CYP19A1, which converts testosterone to estradiol, as well as estrogen and estrogen
receptors, are reported to be decreased in ASD patients [
178
–
180
]. There exist significant
associations between the ER
β
gene and autism trait, measured by the Autism Spectrum
Quotient and the Empathy Quotient in ASD patients [
180
]. Further, in a recent study,
ER
β
mRNA and protein levels were reported to be reduced at the middle frontal gyrus
in the postmortem brains of ASD subjects. In the same study, ER coactivators were also
reported to be disrupted in ASD. There were impairments in the steroid receptor coactivator-
1, CREB-Binding Protein (CBP), and P/mRNA levels in ASD patients [
179
]. With recent
studies reporting disruptions in estrogen and estrogen signaling in ASD, thus, it may
potentially be that abnormal levels of testosterone and the testosterone-associated cognitive
deficits and symptoms may be representing one of the factors of ASD risk. Put together,
the consideration of both testosterone and estrogen, for their close relationship, may benefit
identifying the risk factors of ASD.
3.5. ADHD
ADHD is a neurodevelopmental disorder characterized by marked deficits in attention,
hyperactivity, and impulsivity. Gender disparities in this disorder include males having
twice as likely prevalence than females and ADHD females having increased inattentive
symptoms than males [181], although the underlying factors are not well-elucidated.
Despite the associations between ADHD and estrogen signaling remaining relatively
unexplored yet, a few case studies support the association. ADHD symptoms exacerbate a
week before menstruation and become alleviated during pregnancy [
182
]. A recent study
investigating serum estrogen and GPER levels in children with ADHD reported comparable
serum estrogen levels but reduced GPER in ADHD children [
183
]. Much literature lies in the
investigation of bisphenol A (BPA). BPA is a xenoestrogen compound that binds to estrogen
receptors and affects the downstream cell signaling cascade [
184
]. Evidence supports
associations between BPA and ADHD-like symptoms, occurring via disrupting multiple
neurotransmitter systems of catecholaminergic, dopaminergic, and serotonergic signaling
systems [
185
,
186
]. It has shown effects in behavioral outcomes in ADHD children when
used in high doses [
187
]. Further, a study reported a significant positive association
between BPA exposure and ADHD risk at four years of age, although the effect disappeared
by seven years of age [
187
]. A recent meta-analysis examined the prenatal exposure to
BPA in ADHD children and rodent models. Early BPA exposure was associated with
increased hyperactivity in male rodents and both males and females in humans [
188
].
Given the contribution of estrogen to executive function, a possible marker of ADHD,
the current literature warrants further studies exploring the contributions of estrogen in
ADHD pathophysiology.
3.6. Anxiety Disorders
3.6.1. Generalized Anxiety Disorder (GAD)
GAD is characterized by excessive, ongoing anxiety and worry that interferes with
daily functioning. The disorder is twice more prevalent amongst women than men [
189
],
and interestingly, it is developed and manifested after puberty [
190
], suggesting contribut-
ing roles of hormones—particularly, estrogen—to the disorder pathophysiology.
Indeed, studies report disruptions of estrogen signaling in GAD. A study reported
increased GPER levels in GAD, which further correlated with the anxiety severity in
patients irrespective of gender [
191
]. In rodents, GPER-deficient rats showed anxiety-like
behaviors, as well as low corticosterone [
192
]. Interestingly, reports show ER
β
signaling
has anxiolytic effects [
193
], and in mice, ER
β
deficiency has been associated with social and
mood-related behavioral disturbances via the oxytocin and arginine-vasopressin signaling
pathways [
194
]. A recent report investigated interactions with the glutamatergic system
and estrogen and showed that, for the estrogen mitigation of anxiety-related behaviors in
rats, mGlu5 activation is necessary [195].
Int. J. Mol. Sci. 2021,22, 373 11 of 21
3.6.2. PTSD
PTSD is developed after experiencing a traumatic event and is characterized by se-
vere anxiety, flashbacks, and nightmares of the trauma. Women have a twice-higher
prevalence of the disorder than men following trauma [
196
]. Further, a meta-analytic
study of 48 studies reported women to have better treatment responses than men [
197
].
Although the characteristics of the traumatic events may be different amongst the gen-
ders (e.g., women experience a greater number of interpersonal and sexual violence
events, while men experience a greater number of industrial accidents and war), these are
not completely explanative of the disparities. Recent studies suggest a high involve-
ment of sex hormones—particularly, estrogen—in the pathophysiology and treatment of
PTSD [198,199].
Reports have shown that PSTD symptoms fluctuate with estrogen levels. One study
reported increased phobic anxiety and depression at cycles of low estrogen levels [
200
].
Multiple genetic studies further support the implications of estrogen signaling in PTSD.
The pituitary adenylate cyclase-activating peptide receptor gene has been reported to be
associated with PSTD symptom severity in women but not men [
201
]. DNA methylation
of the histone deacetylase 4 (HDAC4) gene, which is estrogen-dependent, is associated
with fear learning and memory in PTSD [
202
]. It has also identified the implications of the
ER
α
genes rs2234639 and rs9340799 in PTSD [
203
,
204
]. Recently, a neuroimaging study,
using functional magnetic resonance imaging, administered blocks of the fear condition
and extinction training to PTSD patients and measured their responses to fear with a
skin conductance response. The study revealed the modulatory role of estrogens in PTSD
severity and the arousal response, such that higher estrogens have protective effects against
the negative impacts of PTSD symptoms [
205
]. This evidence, taken together, suggests a
promising outlook towards using estrogen or the estrogen-signaling pathway as a putative
pharmacological adjunctive treatment [199].
3.7. Eating Disorders
Eating disorders comprise the development of unhealthy eating habits due to psy-
chological conditions. There exist gender disparities in the disorders, in that females
have 3-10 times higher prevalence than men [
206
]. Sociocultural factors, indeed, are a
significant factor driving the huge disparity; however, animal studies have shown pro-
nounced differences in the disorder phenotypes occurring during puberty, supporting a
big part of the biological factors—particularly, hormones—contributing to the disorder
pathophysiology [207,208].
Preclinical studies have revealed that perinatal exposure to testosterone causes the
sexual differences in behaviors of food intake, as well as the preference for sweet tastes [
209
].
In a study where the genetic influences on binge eating in girls were examined, it was
found that girls with relatively high estrogen levels had minimal genetic influences of
binge eating. On the other hand, girls with relatively low estrogen levels have greater
genetic influences on binge eating [
210
], suggesting a protective role of estrogen against
the genetically-mediated eating disorder. Further, genetics studies have identified risk
the genes for an eating disorder. The ER
α
gene has been identified as being associated
with an eating disorder, and a study reported that the decreased gene activity increased
the risk of developing an eating disorder [
211
]. Further, the HDAC4 gene, of which DNA
methylation is dependent on estrogen, was found also associated with eating disorders by
changing feeding behaviors in mice [
211
]. Nonetheless, the pharmacological treatments for
eating disorders, including estrogen or estrogen signaling target treatments, have, so far,
been underexplored [212].
3.8. Substance Use Disorder
Substance use disorders are characterized by the inability to control using legal or ille-
gal drugs or medication, such as marijuana, stimulants, and heroin, as well as nicotine, and
alcohol. Men have a higher tendency to use illicit drugs and alcohol than women. Further
Int. J. Mol. Sci. 2021,22, 373 12 of 21
differences lie in the treatment adherence, illness course, and comorbidities. For example,
women generally seek help earlier and have a higher prevalence of comorbid psychiatric
disorders than men [213].
Alcohol Use Disorder
Amongst the different substances in substance use disorders, most literature ex-
ists in investigating alcohol use disorder. Men and women have different reasons for
binge drinking. Women drink for self-medication and soothing mood disturbances [
213
].
Further, women often have worse health outcomes from the abuse, including liver disease
and brain damage [214,215].
Studies have reported estrogen and estrogen signaling involved in alcohol-abusing
behaviors. The estrogen level is positively associated with alcohol consumption [
216
]
in humans and in rodents [
217
]. Further, a recent study showed that ER
α
promotes
the ethanol response of ventral tegmental area neurons, the process of which requires
mGLuR1 activity. To add more, the study observed a more dramatic effect of ER
α
re-
duction in the ventral tegmental area (VTA) on binge-like drinking behavior than ER
β
.
However, the effect was only observed in female mice and not male mice, providing evi-
dence that alcohol use disorder treatments may need to take into account genders [218].
4. Conclusions
Extensive literature supports estrogen and estrogen-signaling disruptions across the
psychiatric illnesses of schizophrenia, bipolar disorder, MDD, ASD, ADHD, GAD, PTSD,
eating disorders, and substance use disorders. Estrogens and estrogen signaling play
a pertinent role in the regulation of neurotransmitter systems, such as dopaminergic,
serotonergic, and glutamatergic, and actively participate in cognitive functioning—most
importantly, memory. Further, they provide neuroprotective and anti-inflammatory effects.
Estrogen and estrogen signaling are disrupted in multiple psychiatric disorders, with vary-
ing degrees of disruptions affecting different downstream cell cascades. Future studies
elucidating estrogen and estrogen-signaling disruptions and possible novel treatment
strategies in major psychiatric disorders are warranted.
Author Contributions:
W.J.H. contributed to performing the literature search, analyzing the data,
and drafting the article. T.Y.L. contributed to planning the literature search, analyzing the data, and
editing the manuscript. N.S.K. contributed to performing the literature search and drafting the article.
J.S.K. contributed to planning the literature search and editing the manuscript. All authors have read
and agreed to the published version of the manuscript.
Funding:
This research was supported by a grant of the Korea Health Technology R&D Project
through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of
Health & Welfare, Republic of Korea (grant number: HI19C1080), and the Brain Research Program
and Basic Science Research Program through the National Research Foundation of Korea (NRF)
funded by the Ministry of Science, ICT & Future Planning (grant numbers: 2017M3C7A1029610
and 2019R1A2B5B03100844), and the Research Institute for Convergence of Biomedical Science and
Technology, Pusan National University Yangsan Hospital (20-2020-009).
Data Availability Statement:
Please refer to suggested Data Availability Statements in section “MDPI
Research Data Policies” at https://www.mdpi.com/ethics.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Mol. Sci. 2021,22, 373 13 of 21
Abbreviations
ADHD Attention-deficit hyperactivity disorder
Akt Protein kinase B
ASD Autism spectrum disorder
BDNF Brain-derived neurotrophic factor
BPA Bisphenol A
CA1 Cornu ammonis 1
CA2 Cornu ammonis 2
CA3 Cornu ammonis 3
cAMP Cyclic adenosine monophosphate
CSTC Cortico-striato-thalamo-cortical
ERαEstrogen receptor alpha
ERβEstrogen receptor beta
ERE Estrogen response elements
ERK Extracellular signal-regulated kinase
ERT Estrogen replacement therapy
fMRI Functional magnetic resonance imaging
GPER G-protein coupled receptor 30
HDAC4 Histone deacetylase 4
MAPK Mitogen-activated protein kinase
NTD Amino-terminal domain
PI3K Phosphatidylinositol 3-kinase
PKA Protein kinase A
SERMs Selective estrogen receptor modulators
Wnt Wingless-int
References
1.
Our World in Data. Global Mental Health: Five Key Insights Which Emerge from the Data. Available online: https://
ourworldindata.org/global-mental-health (accessed on 29 November 2020).
2.
Findlay, J.K.; Liew, S.H.; Simpson, E.R.; Korach, K.S. Estrogen Signaling in the Regulation of Female Reproductive Functions.
Handb. Exp. Pharmacol. 2010,198, 29–35.
3.
Colzato, L.S.; Hommel, B. Effects of estrogen on higher-order cognitive functions in unstressed human females may depend on
individual variation in dopamine baseline levels. Front. Neurosci. 2014,8, 65. [CrossRef] [PubMed]
4.
Almey, A.; Milner, T.A.; Brake, W.G. Estrogen receptors in the central nervous system and their implication for dopamine-
dependent cognition in females. Horm. Behav. 2015,74, 125–138. [CrossRef] [PubMed]
5.
Frizell, B.; Dumas, J.A. Examining the Relationship Between Neurosteroids, Cognition, and Menopause With Neuroimaging
Methods. Curr. Psychiatry Rep. 2018,20, 96. [CrossRef]
6.
Gasbarri, A.; Pompili, A.; D’Onofrio, A.; Cifariello, A.; Tavares, M.C.; Tomaz, C. Working memory for emotional facial expressions:
Role of the estrogen in young women. Psychoneuroendocrinology 2008,33, 964–972. [CrossRef]
7.
Dreher, J.-C.; Schmidt, P.J.; Kohn, P.; Furman, D.; Rubinow, D.; Berman, K.F. Menstrual cycle phase modulates reward-related
neural function in women. Proc. Natl. Acad. Sci. USA 2007,104, 2465–2470. [CrossRef]
8.
Jacobs, E.; D’Esposito, M. Estrogen shapes dopamine-dependent cognitive processes: Implications for women’s health. J. Neurosci.
Off. J. Soc. Neurosci. 2011,31, 5286–5293. [CrossRef]
9. Saldanha, C.J. Estrogen as a Neuroprotectant in Both Sexes: Stories From the Bird Brain. Front. Neurol. 2020,11, 497. [CrossRef]
10.
Azcoitia, I.; Barreto, G.E.; Garcia-Segura, L.M. Molecular mechanisms and cellular events involved in the neuroprotective actions
of estradiol. Analysis of sex differences. Front. Neuroendocrinol. 2019,55, 100787. [CrossRef]
11.
McGregor, C.; Riordan, A.; Thornton, J. Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective
mechanisms. Front. Neuroendocrinol. 2017,47, 19–33. [CrossRef]
12.
Gogos, A.; Ney, L.J.; Seymour, N.; Van Rheenen, T.E.; Felmingham, K.L. Sex differences in schizophrenia, bipolar disorder,
and post-traumatic stress disorder: Are gonadal hormones the link? Br. J. Pharmacol.
2019
,176, 4119–4135. [CrossRef] [PubMed]
13.
Crider, A.; Pillai, A. Estrogen Signaling as a Therapeutic Target in Neurodevelopmental Disorders. J. Pharmacol. Exp. Ther.
2017
,
360, 48–58. [CrossRef] [PubMed]
14.
Cho, M.; Lee, T.Y.; Kwak, Y.B.; Yoon, Y.B.; Kim, M.; Kwon, J.S. Adjunctive use of anti-inflammatory drugs for schizophrenia:
A meta-analytic investigation of randomized controlled trials. Aust. N. Z. J. Psychiatry 2019,53, 742–759. [CrossRef] [PubMed]
15.
Kulkarni, J.; Butler, S.; Riecher-Rössler, A. Estrogens and SERMS as adjunctive treatments for schizophrenia. Front. Neuroendocrinol.
2019,53, 100743. [CrossRef]
16.
Çakici, N.; van Beveren, N.J.M.; Judge-Hundal, G.; Koola, M.M.; Sommer, I.E.C. An update on the efficacy of anti-inflammatory
agents for patients with schizophrenia: A meta-analysis. Psychol. Med. 2019,49, 2307–2319. [CrossRef]
Int. J. Mol. Sci. 2021,22, 373 14 of 21
17.
Dwyer, J.B.; Aftab, A.; Radhakrishnan, R.; Widge, A.; Rodriguez, C.I.; Carpenter, L.L.; Nemeroff, C.B.; McDonald, W.M.;
Kalin, N.H. Hormonal Treatments for Major Depressive Disorder: State of the Art. Am. J. Psychiatry
2020
,177, 686–705. [CrossRef]
18.
Jeppesen, R.; Christensen, R.H.B.; Pedersen, E.M.J.; Nordentoft, M.; Hjorthøj, C.; Köhler-Forsberg, O.; Benros, M.E. Efficacy and
safety of anti-inflammatory agents in treatment of psychotic disorders—A comprehensive systematic review and meta-analysis.
Brain Behav. Immun. 2020,90, 364–380. [CrossRef]
19.
Sherwin, B.B. Estrogen and Cognitive Functioning in Women: Lessons We Have Learned. Behav Neurosci.
2012
,126, 123–127.
[CrossRef]
20. Liang, J.; Shang, Y. Estrogen and cancer. Annu. Rev. Physiol. 2013,75, 225–240. [CrossRef]
21. Sayed, Y.; Taxel, P. The use of estrogen therapy in men. Curr. Opin. Pharmacol. 2003,3, 650–654. [CrossRef]
22.
Schulster, M.; Bernie, A.M.; Ramasamy, R. The role of estradiol in male reproductive function. Asian J. Androl.
2016
,18, 435–440.
[PubMed]
23.
Gruber, C.J.; Tschugguel, W.; Schneeberger, C.; Huber, J.C. Production and actions of estrogens. N. Engl. J. Med.
2002
,346, 340–352.
[CrossRef] [PubMed]
24.
Denley, M.C.S.; Gatford, N.J.F.; Sellers, K.J.; Srivastava, D.P. Estradiol and the Development of the Cerebral Cortex: An Unexpected
Role? Front. Neurosci. 2018,12, 245. [CrossRef] [PubMed]
25.
Azcoitia, I.; Arevalo, M.-A.; De Nicola, A.F.; Garcia-Segura, L.M. Neuroprotective actions of estradiol revisited. Trends Endocrinol.
Metab. 2011,22, 467–473. [CrossRef] [PubMed]
26.
Prossnitz, E.R.; Sklar, L.A.; Oprea, T.I.; Arterburn, J.B. GPR30: A novel therapeutic target in estrogen-related disease.
Trends Pharmacol. Sci. 2008,29, 116–123. [CrossRef] [PubMed]
27.
Vrtaˇcnik, P.; Ostanek, B.; Mencej-Bedraˇc, S.; Marc, J. The many faces of estrogen signaling. Biochem. Med.
2014
,24, 329–342.
[CrossRef] [PubMed]
28.
Liu, M.-M.; Albanese, C.; Anderson, C.M.; Hilty, K.; Webb, P.; Uht, R.M.; Price, R.H., Jr.; Pestell, R.G.; Kushner, P.J. Opposing
action of estrogen receptors alpha and beta on cyclin D1 gene expression. J. Biol. Chem. 2002,277, 24353–24360. [CrossRef]
29.
Marino, M.; Galluzzo, P.; Ascenzi, P. Estrogen signaling multiple pathways to impact gene transcription. Curr. Genom.
2006
,7,
497–508. [CrossRef]
30. Fuentes, N.; Silveyra, P. Estrogen receptor signaling mechanisms. Adv. Protein Chem. Struct. Biol. 2019,116, 135–170.
31.
Hwang, W.J.; Cho, K.I.K.; Kwak, Y.B.; Lee, J.; Kim, M.; Lee, T.Y.; Kwon, J.S. Intact thalamic microstructure in asymptomatic
relatives of schizophrenia patients with high genetic loading. Schizophr. Res. 2020. [CrossRef]
32.
Prossnitz, E.R.; Arterburn, J.B. International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen
Receptor and Its Pharmacologic Modulators. Pharmacol. Rev. 2015,67, 505–540. [CrossRef] [PubMed]
33.
Montague, D.; Weickert, C.S.; Tomaskovic-Crook, E.; Rothmond, D.A.; Kleinman, J.E.; Rubinow, D.R. Oestrogen receptor alpha
localisation in the prefrontal cortex of three mammalian species. J. Neuroendocrinol. 2008,20, 893–903. [CrossRef] [PubMed]
34.
Kritzer, M.F. Regional, laminar, and cellular distribution of immunoreactivity for ER alpha and ER beta in the cerebral cortex of
hormonally intact, adult male and female rats. Cereb. Cortex 2002,12, 116–128. [CrossRef] [PubMed]
35.
Shughrue, P.J.; Lane, M.V.; Merchenthaler, I. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat
central nervous system. J. Comp. Neurol. 1997,388, 507–525. [CrossRef]
36.
González, M.; Cabrera-Socorro, A.; Pérez-García, C.G.; Fraser, J.D.; López, F.J.; Alonso, R.; Meyer, G. Distribution patterns of
estrogen receptor alpha and beta in the human cortex and hippocampus during development and adulthood. J. Comp. Neurol.
2007,503, 790–802. [CrossRef]
37.
Ostlund, H.; Keller, E.; Hurd, Y.L. Estrogen receptor gene expression in relation to neuropsychiatric disorders.
Ann. N. Y. Acad. Sci.
2003,1007, 54–63. [CrossRef]
38.
Simerly, R.B.; Chang, C.; Muramatsu, M.; Swanson, L.W. Distribution of androgen and estrogen receptor mRNA-containing cells
in the rat brain: An in situ hybridization study. J. Comp. Neurol. 1990,294, 76–95. [CrossRef]
39.
Osterlund, M.K.; Gustafsson, J.A.; Keller, E.; Hurd, Y.L. Estrogen receptor beta (ERbeta) messenger ribonucleic acid (mRNA)
expression within the human forebrain: Distinct distribution pattern to ERalpha mRNA. J. Clin. Endocrinol. Metab.
2000
,85,
3840–3846.
40.
Osterlund, M.K.; Keller, E.; Hurd, Y.L. The human forebrain has discrete estrogen receptor alpha messenger RNA expression:
High levels in the amygdaloid complex. Neuroscience 2000,95, 333–342. [CrossRef]
41.
Purves-Tyson, T.D.; Handelsman, D.J.; Double, K.L.; Owens, S.J.; Bustamante, S.; Weickert, C.S. Testosterone regulation of sex
steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra. BMC Neurosci.
2012
,13, 95.
[CrossRef]
42.
Sánchez, M.G.; Bourque, M.; Morissette, M.; Di Paolo, T. Steroids-dopamine interactions in the pathophysiology and treatment of
CNS disorders. CNS Neurosci Ther. 2010,16, e43–e71. [CrossRef]
43.
Yoest, K.E.; Cummings, J.A.; Becker, J.B. Oestradiol influences on dopamine release from the nucleus accumbens shell: Sex differ-
ences and the role of selective oestradiol receptor subtypes. Br. J. Pharmacol. 2019,176, 4136–4148. [CrossRef]
44.
Wang, J.-X.; Zhuang, J.-Y.; Fu, L.; Lei, Q.; Fan, M.; Zhang, W. How ovarian hormones influence the behavioral activation and
inhibition system through the dopamine pathway. PLoS ONE. 2020,15, e0237032.
45.
Küppers, E.; Beyer, C. Expression of estrogen receptor-alpha and beta mRNA in the developing and adult mouse striatum.
Neurosci Lett. 1999,276, 95–98. [CrossRef]
Int. J. Mol. Sci. 2021,22, 373 15 of 21
46.
Mitra, S.W.; Hoskin, E.; Yudkovitz, J.; Pear, L.; Wilkinson, H.A.; Hayashi, S.; Pfaff, D.W.; Ogawa, S.; Rohrer, S.P.; Schaeffer, J.M.;
et al. Immunolocalization of estrogen receptor beta in the mouse brain: Comparison with estrogen receptor alpha. Endocrinology
2003,144, 2055–2067. [CrossRef] [PubMed]
47.
Kruijver, F.P.M.; Balesar, R.; Espila, A.M.; Unmehopa, U.A.; Swaab, D.F. Estrogen-receptor-beta distribution in the human
hypothalamus: Similarities and differences with ER alpha distribution. J. Comp. Neurol.
2003
,466, 251–277. [CrossRef] [PubMed]
48.
Bacqué-Cazenave, J.; Bharatiya, R.; Barrière, G.; Delbecque, J.-P.; Bouguiyoud, N.; Di Giovanni, G.; Cattaert, D.;
De Deurwaerdère, P. Serotonin in Animal Cognition and Behavior. Int. J. Mol. Sci. 2020,21, 1649. [CrossRef] [PubMed]
49. Buhot, M.C. Serotonin receptors in cognitive behaviors. Curr. Opin. Neurobiol. 1997,7, 243–254. [CrossRef]
50.
Krolick, K.N.; Zhu, Q.; Shi, H. Effects of Estrogens on Central Nervous System Neurotransmission: Implications for Sex
Differences in Mental Disorders. Prog. Mol. Biol. Transl. Sci. 2018,160, 105–171. [PubMed]
51.
Pecins-Thompson, M.; Brown, N.A.; Kohama, S.G.; Bethea, C.L. Ovarian steroid regulation of tryptophan hydroxylase mRNA
expression in rhesus macaques. J. Neurosci. Off. J. Soc. Neurosci. 1996,16, 7021–7029. [CrossRef]
52.
Maharjan, S.; Serova, L.I.; Sabban, E.L. Membrane-initiated estradiol signaling increases tyrosine hydroxylase promoter activity
with ER alpha in PC12 cells. J. Neurochem. 2010,112, 42–55. [CrossRef]
53.
Becker, J.B. Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during
microdialysis. Neurosci. Lett. 1990,118, 169–171. [CrossRef]
54.
Becker, J.B.; Ramirez, V.D. Experimental studies on the development of sex differences in the release of dopamine from striatal
tissue fragments in vitro. Neuroendocrinology 1981,32, 168–173. [CrossRef]
55.
Becker, J.; Ramirez, V.D. Dynamics of endogenous catecholamine release from brain fragments of male and female rats.
Neuroendocrinology 1980,31, 18–25. [CrossRef]
56.
Hernández, M.L.; Fernández-Ruiz, J.J.; de Miguel, R.; Ramos, J.A. Time-dependent effects of ovarian steroids on tyrosine
hydroxylase activity in the limbic forebrain of female rats. J. Neural Transm. Gen. Sect. 1991,83, 77–84. [CrossRef]
57.
Wallin-Miller, K.G.; Chesley, J.; Castrillon, J.; Wood, R.I. Sex differences and hormonal modulation of ethanol-enhanced risk
taking in rats. Drug Alcohol. Depend. 2017,174, 137–144. [CrossRef]
58.
Hruska, R.E.; Nowak, M.W. Estrogen treatment increases the density of D1 dopamine receptors in the rat striatum. Brain Res.
1988,442, 349–350. [CrossRef]
59.
Czoty, P.W.; Riddick, N.V.; Gage, H.D.; Sandridge, M.; Nader, S.H.; Garg, S.; Bounds, M.; Garg, P.K.; Nader, M.A. Effect of
menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys. Neuropsychopharmacol. Off. Publ.
Am. Coll. Neuropsychopharmacol. 2009,34, 548–554. [CrossRef]
60.
Bazzett, T.J.; Becker, J.B. Sex differences in the rapid and acute effects of estrogen on striatal D2 dopamine receptor binding.
Brain Res. 1994,637, 163–172. [CrossRef]
61. Disshon, K.A.; Boja, J.W.; Dluzen, D.E. Inhibition of striatal dopamine transporter activity by 17beta-estradiol. Eur. J. Pharmacol.
1998,345, 207–211. [CrossRef]
62.
Rehavi, M.; Goldin, M.; Roz, N.; Weizman, A. Regulation of rat brain vesicular monoamine transporter by chronic treatment with
ovarian hormones. Brain Res. Mol. Brain Res. 1998,57, 31–37. [CrossRef]
63.
Chavez, C.; Hollaus, M.; Scarr, E.; Pavey, G.; Gogos, A.; van den Buuse, M. The effect of estrogen on dopamine and serotonin
receptor and transporter levels in the brain: An autoradiography study. Brain Res. 2010,1321, 51–59. [CrossRef]
64.
Bethea, C.L.; Mirkes, S.J.; Shively, C.A.; Adams, M.R. Steroid regulation of tryptophan hydroxylase protein in the dorsal raphe of
macaques. Biol Psychiatry 2000,47, 562–576. [CrossRef]
65.
Sumner, B.E.; Fink, G. Testosterone as well as estrogen increases serotonin2A receptor mRNA and binding site densities in the
male rat brain. Brain Res. Mol. Brain Res. 1998,59, 205–214. [CrossRef]
66.
Sumner, B.E.; Fink, G. Effects of acute estradiol on 5-hydroxytryptamine and dopamine receptor subtype mRNA expression in
female rat brain. Mol. Cell. Neurosci. 1993,4, 83–92. [CrossRef]
67.
Biegon, A.; Reches, A.; Snyder, L.; McEwen, B.S. Serotonergic and noradrenergic receptors in the rat brain: Modulation by chronic
exposure to ovarian hormones. Life Sci. 1983,32, 2015–2021. [CrossRef]
68.
Cyr, M.; Bossé, R.; Di Paolo, T. Gonadal hormones modulate 5-hydroxytryptamine2A receptors: Emphasis on the rat frontal
cortex. Neuroscience 1998,83, 829–836. [CrossRef]
69.
Gundlah, C.; Pecins-Thompson, M.; Schutzer, W.E.; Bethea, C.L. Ovarian steroid effects on serotonin 1A, 2A and 2C receptor
mRNA in macaque hypothalamus. Brain Res. Mol. Brain Res. 1999,63, 325–339. [CrossRef]
70.
Rivera, H.M.; Santollo, J.; Nikonova, L.V.; Eckel, L.A. Estradiol increases the anorexia associated with increased 5-HT(2C) receptor
activation in ovariectomized rats. Physiol. Behav. 2012,105, 188–194. [CrossRef]
71.
Singh, A.; Lucki, I. Antidepressant-like activity of compounds with varying efficacy at 5-HT1A receptors. Neuropharmacology
1993,32, 331–340. [CrossRef]
72.
Hoffman, B.J.; Hansson, S.R.; Mezey, E.; Palkovits, M. Localization and dynamic regulation of biogenic amine transporters in the
mammalian central nervous system. Front. Neuroendocrinol. 1998,19, 187–231. [CrossRef]
73.
Holschneider, D.P.; Kumazawa, T.; Chen, K.; Shih, J.C. Tissue-specific effects of estrogen on monoamine oxidase A and B in the
rat. Life Sci. 1998,63, 155–160. [CrossRef]
Int. J. Mol. Sci. 2021,22, 373 16 of 21
74.
Ortega-Corona, B.G.; Valencia-Sánchez, A.; Kubli-Garfias, C.; Anton-Tay, F.; Salazar, L.A.; Villarreal, J.E.; Ponce-Monter, H.
Hypothalamic monoamine oxidase activity in ovariectomized rats after sexual behavior restoration. Arch. Med. Res.
1994
,25,
337–340.
75.
Gazzaley, A.H.; Weiland, N.G.; McEwen, B.S.; Morrison, J.H. Differential regulation of NMDAR1 mRNA and protein by estradiol
in the rat hippocampus. J. Neurosci. Off. J. Soc. Neurosci. 1996,16, 6830–6838. [CrossRef]
76.
Adams, M.M.; Fink, S.E.; Janssen, W.G.M.; Shah, R.A.; Morrison, J.H. Estrogen modulates synaptic N-methyl-D-aspartate receptor
subunit distribution in the aged hippocampus. J. Comp. Neurol. 2004,474, 419–426. [CrossRef]
77.
Woolley, C.S.; Weiland, N.G.; McEwen, B.S.; Schwartzkroin, P.A. Estradiol increases the sensitivity of hippocampal CA1 pyramidal
cells to NMDA receptor-mediated synaptic input: Correlation with dendritic spine density. J. Neurosci. Off. J. Soc. Neurosci.
1997
,
17, 1848–1859. [CrossRef]
78.
Kurata, K.; Takebayashi, M.; Morinobu, S.; Yamawaki, S. beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone
sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms.
J. Pharmacol. Exp. Ther. 2004,311, 237–245. [CrossRef]
79.
Kajta, M.; Laso´n, W. Oestrogen effects on kainate-induced toxicity in primary cultures of rat cortical neurons. Acta Neurobiol. Exp.
2000,60, 365–369.
80.
Fischer, B.; Gleason, C.; Asthana, S. Effects of hormone therapy on cognition and mood. Fertil. Steril.
2014
,101, 898–904.
[CrossRef]
81.
Verghese, J.; Kuslansky, G.; Katz, M.J.; Sliwinski, M.; Crystal, H.A.; Buschke, H.; Lipton, R.B. Cognitive performance in surgically
menopausal women on estrogen. Neurology 2000,55, 872–874. [CrossRef]
82.
Rissman, E.F.; Heck, A.L.; Leonard, J.E.; Shupnik, M.A.; Gustafsson, J.-A. Disruption of estrogen receptor beta gene impairs
spatial learning in female mice. Proc. Natl. Acad. Sci. USA 2002,99, 3996–4001. [CrossRef]
83.
Rissman, E.F.; Wersinger, S.R.; Fugger, H.N.; Foster, T.C. Sex with knockout models: Behavioral studies of estrogen receptor alpha.
Brain Res. 1999,835, 80–90. [CrossRef]
84.
Hara, Y.; Waters, E.M.; McEwen, B.S.; Morrison, J.H. Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse.
Physiol Rev. 2015,95, 785–807. [CrossRef]
85.
Khan, M.M.; Wakade, C.; de Sevilla, L.; Brann, D.W. Selective estrogen receptor modulators (SERMs) enhance neurogenesis and
spine density following focal cerebral ischemia. J. Steroid Biochem. Mol. Biol. 2015,146, 38–47. [CrossRef]
86.
Lu, Y.; Sareddy, G.R.; Wang, J.; Wang, R.; Li, Y.; Dong, Y.; Zhang, Q.; Liu, J.; O’Connor, J.C.; Xu, J.; et al. Neuron-Derived Estrogen
Regulates Synaptic Plasticity and Memory. J. Neurosci. 2019,39, 2792–2809. [CrossRef]
87. Hampson, E. Estrogens, Aging, and Working Memory. Curr. Psychiatry Rep. 2018,20, 109. [CrossRef]
88.
Bastos, C.P.; Pereira, L.M.; Ferreira-Vieira, T.H.; Drumond, L.E.; Massensini, A.R.; Moraes, M.F.D.; Pereira, G.S. Object recognition
memory deficit and depressive-like behavior caused by chronic ovariectomy can be transitorialy recovered by the acute activation
of hippocampal estrogen receptors. Psychoneuroendocrinology 2015,57, 14–25. [CrossRef]
89.
Duff, S.J.; Hampson, E. A Beneficial Effect of Estrogen on Working Memory in Postmenopausal Women Taking Hormone
Replacement Therapy. Horm. Behav. 2000,38, 262–276. [CrossRef]
90.
Hussain, D.; Hanafi, S.; Konishi, K.; Brake, W.G.; Bohbot, V.D. Modulation of spatial and response strategies by phase of the
menstrual cycle in women tested in a virtual navigation task. Psychoneuroendocrinology 2016,70, 108–117. [CrossRef]
91.
Wallace, M.; Luine, V.; Arellanos, A.; Frankfurt, M. Ovariectomized rats show decreased recognition memory and spine density
in the hippocampus and prefrontal cortex. Brain Res. 2006,1126, 176–182. [CrossRef]
92.
Tuscher, J.J.; Luine, V.; Frankfurt, M.; Frick, K.M. Estradiol-Mediated Spine Changes in the Dorsal Hippocampus and Medial
Prefrontal Cortex of Ovariectomized Female Mice Depend on ERK and mTOR Activation in the Dorsal Hippocampus. J. Neurosci.
Off. J. Soc. Neurosci. 2016,36, 1483–1489. [CrossRef]
93.
Engler-Chiurazzi, E.B.; Singh, M.; Simpkins, J.W. Reprint of: From the 90’s to now: A brief historical perspective on more than
two decades of estrogen neuroprotection. Brain Res. 2016,1645, 79–82. [CrossRef]
94.
Hwang, W.J.; Lee, T.Y.; Shin, W.-G.; Kim, M.; Kim, J.; Lee, J.; Kwon, J.S. Global and Specific Profiles of Executive Functioning in
Prodromal and Early Psychosis. Front. Psychiatry 2019,10, 356. [CrossRef]
95.
Bloemen, A.J.P.; Oldehinkel, A.J.; Laceulle, O.M.; Ormel, J.; Rommelse, N.N.J.; Hartman, C.A. The association between executive
functioning and psychopathology: General or specific? Psychol. Med. 2018,48, 1787–1794. [CrossRef]
96.
Sinkeviciute, I.; Begemann, M.; Prikken, M.; Oranje, B.; Johnsen, E.; Lei, W.U.; Hugdahl, K.; Kroken, R.A.; Rau, C.; Jacobs, J.D.;
et al. Efficacy of different types of cognitive enhancers for patients with schizophrenia: A meta-analysis. NPJ Schizophr.
2018
,4,
1–14. [CrossRef]
97.
Goff, D.C.; Hill, M.; Barch, D. The treatment of cognitive impairment in schizophrenia. Pharmacol. Biochem. Behav.
2011
,99,
245–253. [CrossRef]
98.
Keefe, R.S.E.; Meltzer, H.A.; Dgetluck, N.; Gawryl, M.; Koenig, G.; Moebius, H.J.; Lombardo, I.; Hilt, D.C. Randomized, Double-
Blind, Placebo-Controlled Study of Encenicline, an
α
7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive
Impairment in Schizophrenia. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2015,40, 3053–3060. [CrossRef]
99.
Pietrzak, R.H.; Olver, J.; Norman, T.; Piskulic, D.; Maruff, P.; Snyder, P.J. A comparison of the CogState Schizophrenia Battery and
the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive
impairment in chronic schizophrenia. J. Clin. Exp. Neuropsychol. 2009,31, 848–859. [CrossRef]
Int. J. Mol. Sci. 2021,22, 373 17 of 21
100.
Nuechterlein, K.H.; Green, M.F.; Kern, R.S.; Baade, L.E.; Barch, D.M.; Cohen, J.D.; Essock, S.; Fenton, W.S.; Frese, F.J., 3rd;
Gold, J.M.; et al. The MATRICS Consensus Cognitive Battery, part 1: Test selection, reliability, and validity. Am. J. Psychiatry
2008
,
165, 203–213. [CrossRef]
101.
Michalopoulou, P.G.; Lewis, S.W.; Drake, R.J.; Reichenberg, A.; Emsley, R.; Kalpakidou, A.K.; Lees, J.; Bobin, T.; Gilleen, J.K.;
Pandina, G.; et al. Modafinil combined with cognitive training: Pharmacological augmentation of cognitive training in schizophre-
nia. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 2015,25, 1178–1189. [CrossRef]
102.
Harper-Harrison, G.; Shanahan, M.M. Hormone Replacement Therapy. In StatPearls; StatPearls Publishing: Treasure Is-
land, FL, USA, 2020; Available online: http://www.ncbi.nlm.nih.gov/books/NBK493191/ (accessed on 29 November 2020).
103.
Abdelhamid, R.; Luo, J.; Vandevrede, L.; Kundu, I.; Michalsen, B.; Litosh, V.A.; Schiefer, I.T.; Gherezghiher, T.; Yao, P.; Qin, Z.; et al.
Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.
ACS Chem. Neurosci. 2011,2, 256–268. [CrossRef] [PubMed]
104.
Bourque, M.; Morissette, M.; Di Paolo, T. Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect
dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice. Neurobiol. Aging
2014
,35, 2347–2356. [CrossRef]
[PubMed]
105.
Salgado, I.K.; Torrado, A.I.; Santiago, J.M.; Miranda, J.D. Tamoxifen and Src kinase inhibitors as neuroprotective/neuroregenerative
drugs after spinal cord injury. Neural Regen. Res. 2015,10, 385–390. [PubMed]
106.
Kuiper, G.G.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van der Saag, P.T.; van der Burg, B.; Gustafsson, J.A. Interaction
of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology
1998
,139, 4252–4263. [CrossRef] [PubMed]
107.
Yaz˘gan, B.; Yaz˘gan, Y.; Övey, ˙
I.S.; Nazıro˘glu, M. Raloxifene and Tamoxifen Reduce PARP Activity, Cytokine and Oxidative Stress
Levels in the Brain and Blood of Ovariectomized Rats. J. Mol. Neurosci. 2016,60, 214–222. [CrossRef]
108.
Ishihara, Y.; Itoh, K.; Ishida, A.; Yamazaki, T. Selective estrogen-receptor modulators suppress microglial activation and neuronal
cell death via an estrogen receptor-dependent pathway. J. Steroid Biochem. Mol. Biol. 2015,145, 85–93. [CrossRef]
109.
DonCarlos, L.L.; Azcoitia, I.; Garcia-Segura, L.M. Neuroprotective actions of selective estrogen receptor modulators.
Psychoneuroendocrinology 2009,34 (Suppl. S1), S113–S122. [CrossRef]
110.
Arevalo, M.A.; Santos-Galindo, M.; Lagunas, N.; Azcoitia, I.; Garcia-Segura, L.M. Selective estrogen receptor modulators as brain
therapeutic agents. J. Mol. Endocrinol. 2011,46, R1–R9. [CrossRef]
111.
Brann, D.W.; Dhandapani, K.; Wakade, C.; Mahesh, V.B.; Khan, M.M. Neurotrophic and neuroprotective actions of estrogen:
Basic mechanisms and clinical implications. Steroids 2007,72, 381–405. [CrossRef]
112.
Lu, Y.; Sareddy, G.R.; Wang, J.; Zhang, Q.; Tang, F.-L.; Pratap, U.P.; Tekmal, R.R.; Vadlamudi, R.K.; Brann, D.W. Neuron-Derived
Estrogen Is Critical for Astrocyte Activation and Neuroprotection of the Ischemic Brain. J. Neurosci.
2020
,40, 7355–7374. [CrossRef]
113.
Babayan, A.H.; Kramár, E.A. Rapid Effects of Oestrogen on Synaptic Plasticity: Interactions with Actin and its Signaling Proteins.
J. Neuroendocrinol. 2013,25, 1163–1172. [CrossRef] [PubMed]
114.
Lewis-Wambi, J.S.; Jordan, V.C. Estrogen regulation of apoptosis: How can one hormone stimulate and inhibit? Breast Cancer Res.
2009,11, 206. [CrossRef] [PubMed]
115.
Goodman, Y.; Bruce, A.J.; Cheng, B.; Mattson, M.P. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative
injury, and amyloid beta-peptide toxicity in hippocampal neurons. J. Neurochem. 1996,66, 1836–1844. [CrossRef] [PubMed]
116.
Behl, C.; Widmann, M.; Trapp, T.; Holsboer, F. 17-beta estradiol protects neurons from oxidative stress-induced cell death
in vitro
.
Biochem. Biophys. Res. Commun. 1995,216, 473–482. [CrossRef]
117.
Rettberg, J.R.; Yao, J.; Brinton, R.D. Estrogen: A master regulator of bioenergetic systems in the brain and body. Front. Neuroen-
docrinol. 2014,35, 8–30. [CrossRef]
118.
Villa, A.; Vegeto, E.; Poletti, A.; Maggi, A. Estrogens, Neuroinflammation, and Neurodegeneration. Endocr. Rev.
2016
,37, 372–402.
[CrossRef]
119.
Zhang, Z.; Qin, P.; Deng, Y.; Ma, Z.; Guo, H.; Guo, H.; Hou, Y.; Wang, S.; Zou, W.; Sun, Y.; et al. The novel estrogenic receptor
GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation. J. Neuroinflamm.
2018
,15, 206. [CrossRef]
120.
Hill, R.A.; van den Buuse, M. Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice. Brain
Res. 2011,1384, 51–60. [CrossRef]
121.
Brown, C.M.; Mulcahey, T.A.; Filipek, N.C.; Wise, P.M. Production of proinflammatory cytokines and chemokines during
neuroinflammation: Novel roles for estrogen receptors alpha and beta. Endocrinology 2010,151, 4916–4925. [CrossRef]
122.
Scott, E.; Zhang, Q.; Wang, R.; Vadlamudi, R.; Brann, D. Estrogen neuroprotection and the critical period hypothesis.
Front. Neuroendocrinol. 2012,33, 85–104. [CrossRef]
123.
Jablensky, A.; McGrath, J.; Herrman, H.; Castle, D.; Gureje, O.; Evans, M.; Carr, V.; Morgan, V.; Korten, A.; Harvey, C.
Psychotic disorders in urban areas: An overview of the Study on Low Prevalence Disorders. Aust. N. Z. J. Psychiatry
2000
,34,
221–236. [CrossRef] [PubMed]
124.
Huber, T.J.; Rollnik, J.; Wilhelms, J.; von zur Mühlen, A.; Emrich, H.M.; Schneider, U. Estradiol levels in psychotic disorders.
Psychoneuroendocrinology 2001,26, 27–35. [CrossRef]
125.
Biegon, A.; McEwen, B.S. Modulation by estradiol of serotonin receptors in brain. J. Neurosci.
1982
,2, 199–205. [CrossRef]
[PubMed]
126. Goldstein, J.M.; Link, B.G. Gender and the expression of schizophrenia. J. Psychiatr. Res. 1988,22, 141–155. [CrossRef]
Int. J. Mol. Sci. 2021,22, 373 18 of 21
127.
Riecher-Rössler, A. Oestrogens, prolactin, hypothalamic-pituitary-gonadal axis, and schizophrenic psychoses. Lancet Psychiatry
2017,4, 63–72. [CrossRef]
128. Mahé, V.; Dumaine, A. Oestrogen withdrawal associated psychoses. Acta Psychiatr. Scand. 2001,104, 323–331. [CrossRef]
129.
Riecher-Rössler, A.; Häfner, H.; Stumbaum, M.; Maurer, K.; Schmidt, R. Can estradiol modulate schizophrenic symptomatology?
Schizophr. Bull. 1994,20, 203–214. [CrossRef]
130.
Gurvich, C.; Gavrilidis, E.; Worsley, R.; Hudaib, A.; Thomas, N.; Kulkarni, J. Menstrual cycle irregularity and menopause status
influence cognition in women with schizophrenia. Psychoneuroendocrinology 2018,96, 173–178. [CrossRef]
131. Chang, S.S.; Renshaw, D.C. Psychosis and pregnancy. Compr. Ther. 1986,12, 36–41.
132.
Wei, S.-M.; Berman, K.F. Ovarian hormones, genes, and the brain: The case of estradiol and the brain-derived neurotrophic factor
(BDNF) gene. Neuropsychopharmacology 2019,44, 223–224. [CrossRef]
133.
Damme, K.S.F.; Ristanovic, I.; Vargas, T.; Mittal, V.A. Timing of menarche and abnormal hippocampal connectivity in youth at
clinical-high risk for psychosis. Psychoneuroendocrinology 2020,117, 104672. [CrossRef] [PubMed]
134.
Kulkarni, J.; Gavrilidis, E.; Worsley, R.; Hayes, E. Role of estrogen treatment in the management of schizophrenia. CNS Drugs
2012,26, 549–557. [CrossRef] [PubMed]
135.
Hoff, A.L.; Kremen, W.S.; Wieneke, M.H.; Lauriello, J.; Blankfeld, H.M.; Faustman, W.O.; Csernansky, J.G.; Nordahl, T.E.
Association of Estrogen Levels With Neuropsychological Performance in Women With Schizophrenia. Am. J. Psychiatry
2001
,158,
1134–1139. [CrossRef] [PubMed]
136.
Mendrek, A.; Lakis, N.; Jiménez, J. Associations of sex steroid hormones with cerebral activations during mental rotation in men
and women with schizophrenia. Psychoneuroendocrinology 2011,36, 1422–1426. [CrossRef]
137.
Célia Moreira Borella, V.; Seeman, M.V.; Carneiro Cordeiro, R.; Vieira dos Santos, J.; Romário Matos de Souza, M.;
Nunes de Sousa Fernandes, E.; Santos Monte, A.; Maria Mendes Vasconcelos, S.; Quinn, J.P.; de Lucena, D.F.; et al.
Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine.
Dev. Neurobiol. 2016,76, 519–532. [CrossRef]
138.
Gogos, A.; Kwek, P.; van den Buuse, M. The role of estrogen and testosterone in female rats in behavioral models of relevance to
schizophrenia. Psychopharmacology 2012,219, 213–224. [CrossRef]
139.
Gogos, A.; van den Buuse, M. Comparing the effects of 17
β
-oestradiol and the selective oestrogen receptor modulators, raloxifene
and tamoxifen, on prepulse inhibition in female rats. Schizophr. Res. 2015,168, 634–639. [CrossRef]
140.
Sbisa, A.; Kusljic, S.; Zethoven, D.; van den Buuse, M.; Gogos, A. The effect of 17
β
-estradiol on maternal immune activation-
induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats. Schizophr. Res.
2020
,223,
249–257. [CrossRef]
141.
Riecher-Rössler, A.; Kulkarni, J. Estrogens and Gonadal Function in Schizophrenia and Related Psychoses. In Biological Basis
of Sex Differences in Psychopharmacology; Current Topics in Behavioral Neurosciences; Neill, J.C., Kulkarni, J., Eds.; Springer:
Berlin/Heidelberg, Germany, 2011; pp. 155–171. [CrossRef]
142.
Da Silva, T.L.; Ravindran, A.V. Contribution of sex hormones to gender differences in schizophrenia: A review. Asian J. Psychiatry
2015,18, 2–14. [CrossRef]
143.
Perlman, W.R.; Tomaskovic-Crook, E.; Montague, D.M.; Webster, M.J.; Rubinow, D.R.; Kleinman, J.E.; Weickert, C.S. Alteration in
estrogen receptor alpha mRNA levels in frontal cortex and hippocampus of patients with major mental illness. Biol. Psychiatry
2005,58, 812–824. [CrossRef]
144.
Weickert, C.S.; Miranda-Angulo, A.L.; Wong, J.; Perlman, W.R.; Ward, S.E.; Radhakrishna, V.; Straub, R.E.; Weinberger, D.R.;
Kleinman, J.E. Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia. Hum. Mol. Genet.
2008,17, 2293–2309. [CrossRef] [PubMed]
145.
Kinon, B.J.; Gilmore, J.A.; Liu, H.; Halbreich, U.M. Prevalence of hyperprolactinemia in schizophrenic patients treated with
conventional antipsychotic medications or risperidone. Psychoneuroendocrinology 2003,28 (Suppl. S2), 55–68. [CrossRef]
146.
Canuso, C.M.; Goldstein, J.M.; Wojcik, J.; Dawson, R.; Brandman, D.; Klibanski, A.; Schildkraut, J.J.; Green, A.I. Antipsychotic
medication, prolactin elevation, and ovarian function in women with schizophrenia and schizoaffective disorder. Psychiatry Res.
2002,111, 11–20. [CrossRef]
147.
Aston, J.; Rechsteiner, E.; Bull, N.; Borgwardt, S.; Gschwandtner, U.; Riecher-Rössler, A. Hyperprolactinaemia in early psychosis-
not only due to antipsychotics. Prog. Neuropsychopharmacol. Biol. Psychiatry 2010,34, 1342–1344. [CrossRef] [PubMed]
148.
Ittig, S.; Studerus, E.; Heitz, U.; Menghini-Müller, S.; Beck, K.; Egloff, L.; Leanza, L.; Andreou, C.; Riecher-Rössler, A. Sex differ-
ences in prolactin levels in emerging psychosis: Indication for enhanced stress reactivity in women. Schizophr. Res.
2017
,189,
111–116. [CrossRef] [PubMed]
149.
Petrikis, P.; Tigas, S.; Tzallas, A.T.; Archimandriti, D.T.; Skapinakis, P.; Mavreas, V. Prolactin levels in drug-naïve patients with
schizophrenia and other psychotic disorders. Int. J. Psychiatry Clin. Pract. 2016,20, 165–169. [CrossRef] [PubMed]
150.
Riecher-Rössler, A.; Rybakowski, J.K.; Pflueger, M.O.; Beyrau, R.; Kahn, R.S.; Malik, P.; Fleischhacker, W.W.; EUFEST Study Group.
Hyperprolactinemia in antipsychotic-naive patients with first-episode psychosis. Psychol. Med. 2013,43, 2571–2582.
151.
Du, X.; Hill, R.A. Hypothalamic-pituitary-gonadal axis dysfunction: An innate pathophysiology of schizophrenia?
Gen. Comp. Endocrinol. 2019,275, 38–43. [CrossRef]
Int. J. Mol. Sci. 2021,22, 373 19 of 21
152.
Bergemann, N.; Parzer, P.; Jaggy, S.; Auler, B.; Mundt, C.; Maier-Braunleder, S. Estrogen and comprehension of metaphoric speech
in women suffering from schizophrenia: Results of a double-blind, placebo-controlled trial. Schizophr. Bull.
2008
,34, 1172–1181.
[CrossRef]
153.
Kulkarni, J.; Gavrilidis, E.; Wang, W.; Worsley, R.; Fitzgerald, P.B.; Gurvich, C.; Van Rheenen, T.; Berk, M.; Burger, H. Estradiol for
treatment-resistant schizophrenia: A large-scale randomized-controlled trial in women of child-bearing age. Mol. Psychiatry
2015
,
20, 695–702. [CrossRef]
154.
Khodaie-Ardakani, M.-R.; Khosravi, M.; Zarinfard, R.; Nejati, S.; Mohsenian, A.; Tabrizi, M.; Akhondzadeh, S. A Placebo-
Controlled Study of Raloxifene Added to Risperidone in Men with Chronic Schizophrenia. Acta Med. Iran.
2015
,53, 337–345.
[PubMed]
155.
Kulkarni, J.; Gavrilidis, E.; Gwini, S.M.; Worsley, R.; Grigg, J.; Warren, A.; Gurvich, C.; Gilbert, H.; Berk, M.; Davis, S.R. Effect of
Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial. JAMA Psychiatry
2016,73, 947–954. [CrossRef] [PubMed]
156.
Weickert, T.W.; Weinberg, D.; Lenroot, R.; Catts, S.V.; Wells, R.; Vercammen, A.; O’Donnell, M.; Galletly, C.; Liu, D.; Balzan, R.;
et al. Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol. Psychiatry
2015,20, 685–694. [CrossRef] [PubMed]
157.
Huerta-Ramos, E.; Labad, J.; Cobo, J.; Núñez, C.; Creus, M.; García-Parés, G.; Cuadras, D.; Franco, J.; Miquel, E.; Reyes, J.C.; et al.
Effects of raloxifene on cognition in postmenopausal women with schizophrenia: A 24-week double-blind, randomized, parallel,
placebo-controlled trial. Eur. Arch. Psychiatry Clin. Neurosci. 2020,270, 729–737. [CrossRef]
158.
Shivakumar, V.; Venkatasubramanian, G. Successful use of adjuvant raloxifene treatment in clozapine-resistant schizophrenia.
Indian J. Psychiatry 2012,54, 394. [CrossRef]
159.
Orhan, F.Ö.; Kuruta¸s, E.B.; Do ˘ganer, A.; Türker, E.; Özcü, S.¸S.T.; Güngör, M.; Çakmak, S. Serum levels of GPER-1 in euthymic
bipolar patients. Neuropsychiatr. Dis Treat. 2018,14, 855–862. [CrossRef]
160.
Middle, F.; Jones, I.; Robertson, E.; Morey, J.; Lendon, C.; Craddock, N. Variation in the coding sequence and flanking splice
junctions of the estrogen receptor alpha (ERalpha) gene does not play an important role in genetic susceptibility to bipolar
disorder or bipolar affective puerperal psychosis. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr.
Genet. 2003,118B, 72–75. [CrossRef]
161.
Kealey, C.; Reynolds, A.; Mynett-Johnson, L.; Claffey, E.; McKeon, P. No evidence to support an association between the oestrogen
receptor beta gene and bipolar disorder. Psychiatr. Genet. 2001,11, 223–226. [CrossRef]
162.
Dias, R.S.; Lafer, B.; Russo, C.; Del Debbio, A.; Nierenberg, A.A.; Sachs, G.S.; Joffe, H. Longitudinal follow-up of bipolar disorder
in women with premenstrual exacerbation: Findings from STEP-BD. Am. J. Psychiatry 2011,168, 386–394. [CrossRef]
163.
Perich, T.A.; Roberts, G.; Frankland, A.; Sinbandhit, C.; Meade, T.; Austin, M.-P.; Mitchell, P.B. Clinical characteristics of women
with reproductive cycle-associated bipolar disorder symptoms. Aust. N. Z. J. Psychiatry 2017,51, 161–167. [CrossRef]
164.
Fallah, E.; Arman, S.; Najafi, M.; Shayegh, B. Effect of Tamoxifen and Lithium on Treatment of Acute Mania Symptoms in Children
and Adolescents. Iran. J. Child Neurol. 2016,10, 16–25. [PubMed]
165.
Palacios, J.; Yildiz, A.; Young, A.H.; Taylor, M.J. Tamoxifen for bipolar disorder: Systematic review and meta-analysis.
J. Psychopharmacol. Oxf. Engl. 2019,33, 177–184. [CrossRef] [PubMed]
166.
Valvassori, S.S.; Dal-Pont, G.C.; Resende, W.R.; Varela, R.B.; Peterle, B.R.; Gava, F.F.; Mina, F.G.; Cararo, J.H.; Carvalho, A.F.;
Quevedo, J. Lithium and Tamoxifen Modulate Behavior and Protein Kinase C Activity in the Animal Model of Mania Induced by
Ouabain. Int. J. Neuropsychopharmacol. 2017,20, 877–885. [CrossRef] [PubMed]
167.
Bäckström, T.; Sanders, D.; Leask, R.; Davidson, D.; Warner, P.; Bancroft, J. Mood, sexuality, hormones, and the menstrual cycle. II.
Hormone levels and their relationship to the premenstrual syndrome. Psychosom. Med. 1983,45, 503–507. [CrossRef] [PubMed]
168.
Findikli, E.; Kurutas, E.B.; Camkurt, M.A.; Karaaslan, M.F.; Izci, F.; Fındıklı, H.A.; Karda¸s, S.; Dag, B.; Altun, H. Increased Serum
G Protein-coupled Estrogen Receptor 1 Levels and Its Diagnostic Value in Drug Naïve Patients with Major Depressive Disorder.
Clin. Psychopharmacol. Neurosci. Off. Sci. J. Korean Coll. Neuropsychopharmacol. 2017,15, 337–342. [CrossRef] [PubMed]
169.
Skovlund, C.W.; Mørch, L.S.; Kessing, L.V.; Lange, T.; Lidegaard, Ø. Association of Hormonal Contraception with Suicide
Attempts and Suicides. Am. J. Psychiatry 2018,175, 336–342. [CrossRef] [PubMed]
170.
Skovlund, C.W.; Mørch, L.S.; Kessing, L.V.; Lidegaard, Ø. Association of Hormonal Contraception with Depression.
JAMA Psychiatry 2016,73, 1154–1162. [CrossRef]
171.
Frye, C.A.; Walf, A.A. Changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test
behavior of proestrous rats. Horm. Behav. 2002,41, 306–315. [CrossRef]
172.
Rachman, I.M.; Unnerstall, J.R.; Pfaff, D.W.; Cohen, R.S. Estrogen alters behavior and forebrain c-fos expression in ovariectomized
rats subjected to the forced swim test. Proc. Natl. Acad. Sci. USA 1998,95, 13941–13946. [CrossRef]
173.
Hodis, H.N.; Mack, W.J.; Henderson, V.W.; Shoupe, D.; Budoff, M.J.; Hwang-Levine, J.; Li, Y.; Feng, M.; Dustin, L.; Kono, N.; et al.
Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N. Engl. J. Med.
2016
,374, 1221–1231. [CrossRef]
174.
Loomes, R.; Hull, L.; Mandy, W.P.L. What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and
Meta-Analysis. J. Am. Acad. Child Adolesc. Psychiatry 2017,56, 466–474. [PubMed]
175.
Baron-Cohen, S.; Auyeung, B.; Nørgaard-Pedersen, B.; Hougaard, D.M.; Abdallah, M.W.; Melgaard, L.; Cohen, A.S.;
Chakrabarti, B.; Ruta, L.; Lombardo, M.V. Elevated fetal steroidogenic activity in autism. Mol. Psychiatry
2015
,20, 369–376.
[CrossRef] [PubMed]
Int. J. Mol. Sci. 2021,22, 373 20 of 21
176.
Crespi, B.J. Oxytocin, testosterone, and human social cognition. Biol. Rev. Camb. Philos. Soc.
2016
,91, 390–408. [CrossRef]
[PubMed]
177. Baron-Cohen, S. The extreme male brain theory of autism. Trends Cogn. Sci. 2002,6, 248–254. [CrossRef]
178.
Srivastava, D.P.; Woolfrey, K.M.; Liu, F.; Brandon, N.J.; Penzes, P. Estrogen receptor ß activity modulates synaptic signaling and
structure. J. Neurosci. Off. J. Soc. Neurosci. 2010,30, 13454–13460. [CrossRef]
179.
Crider, A.; Thakkar, R.; Ahmed, A.O.; Pillai, A. Dysregulation of estrogen receptor beta (ER
β
), aromatase (CYP19A1), and ER
co-activators in the middle frontal gyrus of autism spectrum disorder subjects. Mol. Autism 2014,5, 46. [CrossRef]
180.
Chakrabarti, B.; Dudbridge, F.; Kent, L.; Wheelwright, S.; Hill-Cawthorne, G.; Allison, C.; Banerjee-Basu, S.; Baron-Cohen, S.
Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and As-
perger syndrome. Autism Res. Off. J. Int. Soc. Autism Res. 2009,2, 157–177. [CrossRef]
181.
Rucklidge, J.J. Gender differences in attention-deficit/hyperactivity disorder. Psychiatr. Clin. N. Am.
2010
,33, 357–373. [CrossRef]
182.
Quinn, P.O. Treating adolescent girls and women with ADHD: Gender-specific issues. J. Clin. Psychol.
2005
,61, 579–587.
[CrossRef]
183.
Sahin, N.; Altun, H.; Kuruta¸s, E.B.; Fındıklı, E. Evaluation of estrogen and G protein-coupled estrogen receptor 1 (GPER) levels in
drug-naïve patients with attention deficit hyperactivity disorder (ADHD). Bosn. J. Basic Med. Sci. 2018,18, 126–131. [CrossRef]
184.
Schug, T.T.; Blawas, A.M.; Gray, K.; Heindel, J.J.; Lawler, C.P. Elucidating the links between endocrine disruptors and neurodevel-
opment. Endocrinology 2015,156, 1941–1951. [CrossRef] [PubMed]
185.
Matsuda, S.; Matsuzawa, D.; Ishii, D.; Tomizawa, H.; Sutoh, C.; Nakazawa, K.; Amano, K.; Sajiki, J.; Shimizu, E. Effects of perinatal
exposure to low dose of bisphenol A on anxiety like behavior and dopamine metabolites in brain. Prog. Neuropsychopharmacol.
Biol. Psychiatry 2012,39, 273–279. [CrossRef] [PubMed]
186.
Wilens, T.E. Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder.
J. Clin. Psychopharmacol. 2008,28 (Suppl. S2), S46–S53. [CrossRef] [PubMed]
187.
Casas, M.; Forns, J.; Martínez, D.; Avella-García, C.; Valvi, D.; Ballesteros-Gómez, A.; Luque, N.; Rubio, S.; Julvez, J.; Sunyer, J.;
et al. Exposure to bisphenol A during pregnancy and child neuropsychological development in the INMA-Sabadell cohort.
Environ. Res. 2015,142, 671–679. [CrossRef] [PubMed]
188.
Rochester, J.R.; Bolden, A.L.; Kwiatkowski, C.F. Prenatal exposure to bisphenol A and hyperactivity in children: A systematic
review and meta-analysis. Environ. Int. 2018,114, 343–356. [CrossRef] [PubMed]
189.
McLean, C.P.; Asnaani, A.; Litz, B.T.; Hofmann, S.G. Gender differences in anxiety disorders: Prevalence, course of illness,
comorbidity and burden of illness. J. Psychiatr. Res. 2011,45, 1027–1035. [CrossRef] [PubMed]
190.
Hayward, C.; Sanborn, K. Puberty and the emergence of gender differences in psychopathology. J. Adolesc. Health
2002
,30 (Suppl.
S1), 49–58. [CrossRef]
191.
Fındıklı, E.; Camkurt, M.A.; Karaaslan, M.F.; Kurutas, E.B.; Altun, H.; ˙
Izci, F.; Fındıklı, H.A.; Kardas, S. Serum levels of G
protein-coupled estrogen receptor 1 (GPER1) in drug-naive patients with generalized anxiety disorder. Psychiatry Res.
2016
,244,
312–316. [CrossRef]
192.
Zheng, Y.; Wu, M.; Gao, T.; Meng, L.; Ding, X.; Meng, Y.; Jiao, Y.; Luo, P.; He, Z.; Sun, T.; et al. GPER-Deficient Rats Exhibit Lower
Serum Corticosterone Level and Increased Anxiety-Like Behavior. Neural Plast. 2020,2020, 8866187. [CrossRef]
193.
Solomon, M.B.; Herman, J.P. Sex differences in psychopathology: Of gonads, adrenals and mental illness. Physiol. Behav.
2009
,97,
250–258. [CrossRef]
194.
Dombret, C.; Naulé, L.; Trouillet, A.-C.; Parmentier, C.; Hardin-Pouzet, H.; Mhaouty-Kodja, S. Effects of neural estrogen receptor
beta deletion on social and mood-related behaviors and underlying mechanisms in male mice. Sci. Rep.
2020
,10, 6242. [CrossRef]
[PubMed]
195.
Miller, C.K.; Krentzel, A.A.; Patisaul, H.B.; Meitzen, J. Metabotropic glutamate receptor subtype 5 (mGlu5) is necessary for
estradiol mitigation of light-induced anxiety behavior in female rats. Physiol. Behav. 2020,214, 112770. [CrossRef] [PubMed]
196.
Kessler, R.C.; Aguilar-Gaxiola, S.; Alonso, J.; Benjet, C.; Bromet, E.J.; Cardoso, G.; Degenhardt, L.; de Girolamo, G.; Dinolova, R.V.;
Ferry, F.; et al. Trauma and PTSD in the WHO World Mental Health Surveys. Eur. J. Psychotraumatol.
2017
,8(Suppl. S5), 1353383.
[CrossRef] [PubMed]
197.
Wade, D.; Varker, T.; Kartal, D.; Hetrick, S.; O’Donnell, M.; Forbes, D. Gender difference in outcomes following trauma-focused
interventions for posttraumatic stress disorder: Systematic review and meta-analysis. Psychol. Trauma Theory Res. Pract. Policy
2016,8, 356–364. [CrossRef]
198.
Ney, L.J.; Matthews, A.; Bruno, R.; Felmingham, K.L. Modulation of the endocannabinoid system by sex hormones: Implications
for posttraumatic stress disorder. Neurosci. Biobehav. Rev. 2018,94, 302–320. [CrossRef]
199.
Glover, E.M.; Jovanovic, T.; Norrholm, S.D. Estrogen and Extinction of Fear Memories: Implications for Posttraumatic Stress
Disorder Treatment. Biol. Psychiatry 2015,78, 178–185. [CrossRef]
200.
Nillni, Y.I.; Pineles, S.L.; Patton, S.C.; Rouse, M.H.; Sawyer, A.T.; Rasmusson, A.M. Menstrual cycle effects on psychological
symptoms in women with PTSD. J. Trauma. Stress 2015,28, 1–7. [CrossRef]
201.
Lind, M.J.; Marraccini, M.E.; Sheerin, C.M.; Bountress, K.; Bacanu, S.-A.; Amstadter, A.B.; Nugent, N.R. Association of Post-
traumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta-Analysis. J. Trauma. Stress
2017
,30, 389–398.
[CrossRef]
Int. J. Mol. Sci. 2021,22, 373 21 of 21
202.
Maddox, S.A.; Kilaru, V.; Shin, J.; Jovanovic, T.; Almli, L.M.; Dias, B.G.; Norrholm, S.D.; Fani, N.; Michopoulos, V.; Ding, Z.; et al.
Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. Mol. Psychiatry
2018
,23, 658–665.
[CrossRef]
203.
Feng, Y.; Su, M.; Si, Y.J.; Guo, Q.W.; Lin, J.; Cao, T.; Zhang, X.; Fan, M.; Fang, D.Z. Longitudinal interplays of estrogen receptor
alpha gene rs9340799 with social-environmental factors on post-traumatic stress disorder in Chinese Han adolescents after
Wenchuan earthquake. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr. Genet.
2018
,177, 337–345.
[CrossRef]
204.
Feng, Y.; Lin, J.; Su, M.; Zhang, X.; Fang, D.Z. Interplays of estrogen receptor alpha gene rs2234693 with post-traumatic stress
disorder influence serum glucose and lipids profiles in Chinese adolescents. J. Clin. Neurosci. Off. J. Neurosurg. Soc. Australas
2019
,
61, 36–43. [CrossRef] [PubMed]
205.
Sartin-Tarm, A.; Ross, M.C.; Privatsky, A.A.; Cisler, J.M. Estradiol Modulates Neural and Behavioral Arousal in Women with
Posttraumatic Stress Disorder During a Fear Learning and Extinction Task. Biol. Psychiatry Cogn. Neurosci. Neuroimaging
2020
,5,
1114–1122. [PubMed]
206.
Udo, T.; Grilo, C.M. Prevalence and Correlates of DSM-5-Defined Eating Disorders in a Nationally Representative Sample of U.S.
Adults. Biol. Psychiatry 2018,84, 345–354. [CrossRef] [PubMed]
207.
Culbert, K.M.; Sinclair, E.B.; Hildebrandt, B.A.; Klump, K.L.; Sisk, C.L. Perinatal testosterone contributes to mid-to-post pubertal
sex differences in risk for binge eating in male and female rats. J. Abnorm. Psychol. 2018,127, 239–250. [CrossRef]
208.
Mikhail, M.E.; Culbert, K.M.; Sisk, C.L.; Klump, K.L. Gonadal hormone contributions to individual differences in eating disorder
risk. Curr. Opin. Psychiatry 2019,32, 484–490. [CrossRef]
209.
Asarian, L.; Geary, N. Sex differences in the physiology of eating. Am. J. Physiol. Regul. Integr. Comp. Physiol.
2013
,305,
R1215–R1267. [CrossRef]
210.
Klump, K.L.; Fowler, N.; Mayhall, L.; Sisk, C.L.; Culbert, K.M.; Burt, S.A. Estrogen moderates genetic influences on binge eating
during puberty: Disruption of normative processes? J. Abnorm. Psychol. 2018,127, 458–470. [CrossRef]
211.
Lutter, M.; Khan, M.Z.; Satio, K.; Davis, K.C.; Kidder, I.J.; McDaniel, L.; Darbro, B.W.; Pieper, A.A.; Cui, H. The Eating-Disorder
Associated HDAC4A778T Mutation Alters Feeding Behaviors in Female Mice. Biol. Psychiatry 2017,81, 770–777. [CrossRef]
212.
McElroy, S.L.; Guerdjikova, A.I.; Mori, N.; Keck, P.E. Psychopharmacologic treatment of eating disorders: Emerging findings.
Curr. Psychiatry Rep. 2015,17, 35. [CrossRef]
213. Brady, K.T.; Randall, C.L. Gender differences in substance use disorders. Psychiatr. Clin. N. Am. 1999,22, 241–252. [CrossRef]
214.
Agabio, R.; Campesi, I.; Pisanu, C.; Gessa, G.L.; Franconi, F. Sex differences in substance use disorders: Focus on side effects.
Addict. Biol. 2016,21, 1030–1042. [CrossRef] [PubMed]
215.
Szabo, G. Women and alcoholic liver disease-warning of a silent danger. Nat. Rev. Gastroenterol. Hepatol.
2018
,15, 253–254.
[CrossRef] [PubMed]
216.
Martel, M.M.; Eisenlohr-Moul, T.; Roberts, B. Interactive effects of ovarian steroid hormones on alcohol use and binge drinking
across the menstrual cycle. J. Abnorm. Psychol. 2017,126, 1104–1113. [CrossRef] [PubMed]
217.
Satta, R.; Hilderbrand, E.R.; Lasek, A.W. Ovarian Hormones Contribute to High Levels of Binge-Like Drinking by Female Mice.
Alcohol. Clin. Exp. Res. 2018,42, 286–294. [CrossRef]
218.
Vandegrift, B.J.; Hilderbrand, E.R.; Satta, R.; Tai, R.; He, D.; You, C.; Chen, H.; Xu, P.; Coles, C.; Brodie, M.S.; et al.
Estrogen Receptor
α
Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice.
J. Neurosci. Off. J. Soc. Neurosci. 2020,40, 5196–5207. [CrossRef]
