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JPET #237412
TITLE PAGE
Estrogen signaling as a therapeutic target in neurodevelopmental disorders
Amanda Crider and Anilkumar Pillai
Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta
University, Augusta, GA 30912.
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RUNNING TITLE PAGE
Running Title: Estrogen signaling, ASD and schizophrenia
Address for Correspondence:
Anilkumar Pillai, Ph.D.
CA-3143
1462 Laney Walker Blvd
Augusta University
Augusta, GA 30912
Phone – (706) 446-0325
Word count:
Abstract: 142
Manuscript: 5878
Number of Tables: 1
Number of Figures: 1
Abbreviations: ADHD, Attention Deficit Hyperactivity Disorder; ASD, autism spectrum disorder; BDNF, brain derived neurotrophic factor; DHEA, didehydroepiandrosterone; ER, estrogen receptor; GPR30, g-protein coupled receptor 30; GPER, g-protein coupled estrogen receptor; FXS, Fragile X syndrome; IFN-g, interferon-g; IL, interleukin; MPP, 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PPT, 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol; PSD-95, postsynaptic density protein 95; SERM, synthetic estrogen receptor modulator.
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ABSTRACT
Estrogens, the primary female sex hormones, were originally characterized through their
important role in sexual maturation and reproduction. However, recent studies have shown that
estrogens play critical roles in a number of brain functions including cognition, learning and
memory, neurodevelopment and adult neuroplasticity. A number of studies from both clinical as
well as preclinical research suggest a protective role of estrogen in neurodevelopmental disorders
including autism spectrum disorder (ASD) and schizophrenia. Alterations in the levels of
estrogen receptors (ERs) have been found in subjects with ASD or schizophrenia, and
adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of
schizophrenia. This review summarizes the findings on the role of estrogen in the
pathophysiology of neurodevelopmental disorders with a focus on ASD and schizophrenia. We
also discuss the potential of estrogen as a therapeutic target in the above disorders.
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INTRODUCTION
Estrogen was first isolated and characterized in 1929 by Tadeus Reichstein, Adolf
Butenandt, and Edward Adelbert Doisy (Tata, 2005). The field of endocrinology progressed
rapidly and in the 1950s, it was discovered that there was major interaction between the
endocrine and central nervous systems, coordinating activities of metabolic and developmental
processes in response to the environment (Tata, 2005). In the 1960s, it was found that hormones
affect transcription and translation of mRNA and protein. Estrogen was specifically implicated in
transcriptional activation in the 1970s and 1980s by Pierre Chambon and Bert O’Malley (Tata,
2005). Along with the discovery of hormonal regulation of genes came the knowledge of
hormone receptors.
Estrogen is produced centrally by the brain and peripherally by the ovaries and other
tissues (Nelson and Bulun, 2001; Gruber et al., 2002). Estrogen plays different roles in each
tissue and is involved in puberty, fertility, estrus cycle, brain development, and neuroprotection
(Cui et al., 2013). Estrogen is produced from testosterone in the ovaries, corpus luteum, and
placenta in premenopausal women (Cui et al., 2013). It can also be produced in the liver, heart,
skin, adipose tissue, and brain (Nelson and Bulun, 2001; Gruber et al., 2002; Cui et al., 2013).
Estradiol is the bioactive form of estrogen, but other forms of estrogen are produced by females
(estrone and estriol). Aromatase catalyzes the final step in estradiol synthesis and is widely
expressed in many tissues, but many tissue-specific forms exist (Simpson et al., 1997). Similar to
peripheral synthesis, brain estrogen synthesis can occur from testosterone, but it can also be
produced de novo (Cui et al., 2013). In the brain, estrogen is produced in many regions including
the hippocampus, cortex, cerebellum, hypothalamus, and amygdala (Cui et al., 2013). Neurons
are the primary site of estrogen synthesis in the brain, but it can also be produced by astrocytes,
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but not microglia or oligodendrocytes (Azcoitia et al., 2011). Estrogen synthesis and aromatase
expression are involved in neural development, synaptic plasticity, and cell survival (Azcoitia et
al., 2011). The specificity of aromatase expression and therefore estradiol production in certain
cell types and brain regions suggests that local production of estradiol is important for specific
brain processes (Cui et al., 2013).
A number of recent studies have shown that estrogen plays a critical role in the
pathophysiology of neurodevelopmental disorders. ASD is a neurodevelopmental disorder that
affects 1 in 68 children in America and approximately 1% of the worldwide population.
Individuals with ASD exhibit a wide range of symptoms including anxiety, depression, repetitive
and obsessive behaviors, language and communication deficits, and social deficits. These
symptoms occur over a spectrum of severity and can appear in a heterogeneous fashion in
patients with the disorder. ASD appears to be gender specific, affecting boys 5x more often than
girls, which rises to 10x more often in Asperger’s syndrome, a high-functioning form of ASD.
The increased risk for males to develop ASD suggests a potential role of sex hormones in the
pathophysiology of this disorder. Schizophrenia is another neuropsychiatric disorder with
neurodevelopmental origin (Hoftman et al., 2016; Lewis and Levitt, 2002; Weinberger, 1995).
Subjects with schizophrenia typically present with three types of symptoms: positive (in addition
to normal behavior), negative (deficits), and cognitive (Kulkarni et al., 2012). These symptom
sets include hallucinations, delusions, catatonic behavior, disorganized speech, depression, flat
affect, and social deficits in early adulthood (Association, 2013; NAMI, 2013; McGrath et al.,
2008). Schizophrenia can also present earlier in life, which is denoted as childhood-onset
schizophrenia. This disorder affects about 1% of individuals during their lifespan (McGrath et
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al., 2008). A number of comorbid conditions including substance abuse, reduced lifespan, and
suicide are often seen in subjects with schizophrenia (Kulkarni et al., 2012).
Many factors appear to be significant in the development of ASD and schizophrenia. A
number of factors, both genetic and environmental have been implicated in the pathogenesis of
these two disorders. Understanding the pathophysiology is very critical for the development of
novel therapeutics and long-term treatment management of ASD and schizophrenia. This article
will provide an overview of the recent progress of our understanding in the role of estrogen in
neurodevelopmental disorders with a focus on ASD and schizophrenia.
ESTROGEN SIGNALING AND BRAIN FUNCTION
There are three known receptors for estrogen, estrogen receptor alpha (ERα), estrogen
receptor beta (ERβ), and g-protein coupled receptor 30 (GPR30), which is also known as g-
protein coupled ER1 (GPER). ERα (then known as ER) was discovered to specifically bind
estrogen in 1986 (Green et al., 2006; Greene et al. 1986). In 1995, an additional estrogen
receptor was cloned and named ERβ (Kuiper et al., 1996), explaining why estrogen effects were
still seen in ERα knockout mice. A third receptor with homology to g-protein coupled receptors
is a membrane-bound receptor that binds estrogen and possibly other ligands (Maggiolini and
Picard, 2010).
ERα is thought to be responsible for modulating neurobiological reproductive systems
such as sexual characteristics and puberty (Behl, 2002; De Fossé, 2004). ERβ is important in
modulating non-reproductive neurobiological systems that are involved in anxiety, locomotion,
fear, memory, and learning (Krezel et al., 2001). ERβ is the principal estrogen receptor
expressed in cortex, hippocampus, and cerebellum (Bodo and Rissman, 2006). A number of
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cofactors have been shown to regulate the expression of ERα and ERβ at the transcriptional
level. Some of these include: steroid receptor coactivator-1 (SRC-1), transcriptional
mediators/intermediary factor 2 (TIF2), amplified in breast 1 (AIB1), CREB binding protein
(CBP), and CBP-associated facto (CAF), which are coactivators, as well as silencingmediator for
retinoid and thyroid hormone receptors (SMRT) and nuclear receptor corepressor (nCOR) which
are corepressors (Bodo and Rissman, 2006). Estrogen receptors can also regulate the production
of proteins through genetic loci called estrogen response elements (EREs). These regions allow
direct binding of estrogen receptors to the DNA at specific loci, which can alter gene expression.
GPER appears to mediate many of the rapid, non-genomic actions of estrogen and typically
involve regulation of membrane bound and cytoplasmic regulatory proteins. (Huang et al., 2016).
GPER is expressed in the plasma membrane (Filardo and Thomas, 2005; Filardo and Thomas,
2012; Cheng et al., 2011), endoplasmic reticulum and trans-Golgi network (Revankar et al.,
2005). Moreover, its plasma membrane localization is stabilized by association with scaffolding
proteins containing PDZ (Dlg homologous region or (glycine-leucine-glycine-phenylalanine
domain) binding domains, such as post synaptic density protein 95 and synapse associated
protein 97, as well as with other g-protein coupled receptors (GPCRs) (Akama et al., 2013;
Waters et al., 2015; Broselid et al., 2014). In the brain, GPER is widely expressed in
hippocampus, cortex and hypothalamus (Prossnitz and Arterburn, 2015).
Neuroprotective effects of estrogen
Estrogen is largely thought to be neuroprotective. The bioactive form of estrogen known as 17β-
estradiol (E2) has been implicated in neuroprotection, cognitive functioning, and synaptic
plasticity (Yang et al., 2010). On the other hand, chronic estrogen deprivation has also been
shown to increase risk of neurological disorders such as stroke, Alzheimer’s disease, Parkinson’s
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disease (Scott et al., 2012). The neuroprotective effects of estrogen occur through genomic and
non-genomic signaling, antioxidant functions, and the maintenance of neuronal adenosine
triphosphate (ATP) through estrogen receptors (Brann et al., 2007). Estrogens can upregulate
antiapoptotic genes and downregulate proapoptotic genes through diffusion of estradiol through
the cell membrane and translocation and binding of estrogen receptors to genes in the nucleus,
promoting or inhibiting transcription (Scott et al., 2012; Choi et al., 2004; Dubal et al., 1999).
This regulation seems to be largely dependent on ERα and occurs on the scale of hours (Scott et
al., 2012; Dubal et al., 2001). Estrogen also exerts neuroprotective function through nongenomic
signaling and localize in the plasma membrane of cortical and hippocampal neurons (Scott et al.,
2012; Dubal et al., 2001). These receptors are thought to be involved in more rapid estrogen
signaling including regulation of kinases, calcium signaling, and other pathways that occur on
the scale of minutes to hours (Scott et al., 2012). Estradiol also protects the brain through its
ability to increase cerebral blood flow, facilitation of glucose metabolism (Brinton, 2008; Yao et
al., 2012), and enhancement of electron transport chain activity to supply energy to neurons
(Choi et al., 2004; Yao et al. 2010). It is important to note that there appear to be “critical
periods” or periods of effectiveness for estrogen neuroprotection (Choi et al., 2004; Sherwin,
2009). The critical period hypothesis states that estrogen therapy must be given within a certain
period of time following menopause (Sherwin, 2009). This theory follows hand in hand with the
healthy cell bias theory of estrogen which states that estrogen therapy is only effective when
applied to healthy neurons (Brinton, 2005). Animal studies have shown that estrogen can exert
neuroprotective effects against ischemic damage if it is replaced immediately after injury, but not
at 10 weeks post-ovariectomy (Scott et al., 2012). Also, long-term estrogen deprivation causes
tissue-specific reduction in ERα levels in hippocampus, altering its sensitivity to estrogen,
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explaining the need for immediate estrogen replacement for neuroprotection to be effective
(Scott et al., 2012). A similar reduction in ERα has been shown to occur naturally during the
aging process, altering hippocampal sensitivity to estrogen (Scott et al., 2012).
Estrogen is known to promote the synthesis of neurotrophins and protects the brain
against inflammation and stress. Accumulating evidence suggest that estrogen regulates the
expression of brain derived neurotrophic factor (BDNF), a key molecule involved in neuronal
survival, differentiation, and synaptic plasticity (Blurton-Jones et al., 2003, Numakawa et al.,
2010, Solum and Handa, 2002 and Zhou et al., 2005). ER mediated transcription has been shown
to be potentiated by full length TrkB, the receptor for BDNF (Wong et al., 2013). Estrogen has
also been shown to regulate BDNF mRNA and protein expression (Solum and Handa, 2002). In
addition, estrogen treatment has been shown to restore the reduced expression of BDNF mRNA
in the midbrain area of ovariectomized mice (Yi et al., 2016). Estradiol has also been shown to
exert anti-inflammatory activity on activated macrophages and microglia (Dodel et al., 1999;
Drew and Chavis, 2000; Bruce-Keller et al., 2000, Vegeto et al., 2001, Vegeto et al., 2003 and
Vegeto et al., 2004). Estrogen is known to reduce endoplasmic reticulum stress, an inducer of
inflammation, through a synovilin 1-dependent mechanism (Kooptiwut et al., 2014; Rajapaksa et
al., 2014). It has been shown that ovariectomy is associated with changes in the peripheral
immune response as evidenced by increased levels of inflammatory markers such as TNF-α, IL-
1β, macrophage inflammatory protein-1, and macrophage colony-stimulating factor (Benedusi et
al., 2012 and Cenci et al., 2000). The NF-kB family of transcription factors regulates many genes
that play important roles in the function of the innate and adaptive immune systems. Moreover,
estrogen-induced activation of the ER results in a reduction in the levels of nuclear DNA-binding
activity of NF-kB (Kalaitzidis and Gilmore, 2005), which in turn regulates the expression of
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inflammatory genes (O’Neill and Kaltschmidt, 1997). Interestingly, treatment of ovariectomized
mice with 17α-ethinylestradiol has been shown to suppress NF-KB-induced inflammatory genes
(Evans et al., 2001). Moreover, treatment with estrogen modulators has been shown to reduce
levels of NFkB and the activation of t-cells (Bebo et al., 2009; Lee et al., 2008). Studies
conducted using ERα knockout and ERβ knockout mice have reported that both ERα and ERβ
regulate proinflammatory cytokine and chemokine production in the brain through E2-dependent
and E2-independent mechanisms (Brown et al., 2010). This evidence suggest anti-inflammatory
action as a potential mechanism in mediating the neuroprotective effects of estrogen.
Estrogen in neurodevelopment and plasticity
Estradiol is extremely important in brain development. The fetal brain is exposed to
maternal estradiol, and that which is locally produced by the fetus (McCarthy, 2008). The
developing brain shows high expression levels of estrogen receptors, which regulate gene
expression and signal transduction (McCarthy, 2008). This expression is somewhat sex-specific
and varies over time as brain development progresses (McCarthy, 2008; Yokosuka et al., 1997).
Estrogen’s effects on learning and memory occur through rapid, non-genomic signaling
pathways. Acute treatment with 17β-estradiol rapidly increased the activation of extracellular
signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) (Fernandez et al., 2008;
Fan et al., 2010). Estradiol is necessary for hippocampal, frontal cortex, cerebellar, and basal
forebrain-based learning and spatial memory in rats (Luine et al., 1998; Shang et al., 2010;
Andreescu et al., 2007). Also, ovariectomized rats have shown impaired performance in working
memory and spatial navigation tasks, and acute activation of estrogen signaling using 17β-
estradiol or other potent estrogens, including synthetic estrogen receptor modulators (SERMs)
could reverse the above deficits (Daniel et al., 1997; Bimonte and Denenberg, 1999; Gibbs,
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2007; Gibbs and Johnson, 2008; Sherwin and Henry, 2008; Singh et al., 1994). In male mice,
administration of 17β-estradiol has been shown to improve performance in inhibitory and water
maze learning tasks (Frye et al., 2005). Estradiol can alter epigenetic processes within minutes to
improve consolidation of hippocampal memories (Bi et al., 2000, Fernandez et al., 2008). In
vitro studies have shown that estradiol activation of some of the same epigenetic pathways also
promotes dendritic spine remodeling, which suggests a link between spinogenesis and memory
consolidation (Hasegawa et al., 2015; Kramár et al., 2009). The knowledge that estradiol can be
produced locally in the hippocampus further suggests that rapid estrogen signaling contributes to
memory formation (Kretz et al., 2004; Prange-Kiel et al., 2006).
Aromatase, encoded by the cyp19 gene, is the rate-limiting step in the biosynthesis of
estrogens, and is widely distributed in different regions of the brain including hypothalamus,
hippocampus, and cortex (Rune and Frotscher, 2005; Yague et al., 2006; Boon et al., 2010;
Azcoitia et al., 2011; Saldanha et al., 2011). It is expressed in both neurons and glial cells (Kretz
et al., 2004; Yague et al., 2008). Mice deficient in aromatase show impairments in spatial
reference memory (Martin et al., 2003). Interestingly, treatment with estradiol benzoate and
dihydrotestosterone propionate has been shown to restore social recognition abilities in castrated
aromatase KO mice (Pierman et al., 2008) further suggesting the important role of estrogen in
behavior.
Studies focused on specific estrogen receptor isoforms have further established the role of
estrogen signaling in brain functions. Accumulating literature suggest that ERβ primarily
regulates non-reproductive components of estrogen signaling in the brain (Weiser et al., 2008;
Bodo and Rissman, 2006). ERα knockout (KO) mice show severe deficits in reproduction and
some alterations in learning (Rissman et al., 1999). ERβ KO mice show normal sexual behavior
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and only slight reproductive deficits, but severe memory and learning deficits (Rissman et al.,
2002). Modulation of ERβ enhances spatial memory while ERα facilitates sexual behavior
(Rhodes et al., 2006). It has been shown that ERα KO, but not ERβ KO, mice showed an
improvement in cognitive function following treatment with 17β-estradiol further indicating a
critical role for ERβ in mediating rapid estrogenic regulation of cognitive function (Liu et al.,
2008). ERβ is also important for motor learning by potentiating cerebellar plasticity and
synaptogenesis (Khan et al., 2014).
A key mechanism involved in the effects of estrogen on improving cognitive function is
through the regulation of synaptic structure and function (Srivastava et al., 2013). Seminal
studies by McEwan and colleagues have shown that 17β-estradiol treatment could restore
ovariectomy-induced loss of dendritic spine density in the hippocampal pyramidal neurons
(Gould et al., 1990; Woolley et al., 1990). Additional studies have demonstrated that 17β-
estradiol increases spine number on cortical neurons in the prefrontal cortex of ovariectomized
rhesus monkeys (Hao et al., 2007; Dumitriu et al., 2010). The above findings from in vivo studies
on the effects of 17β-estradiol on spine density are further supported by in vitro studies. It has
been shown that the decrease in synapse number in response to GABA(A) receptor blockade by
bicuculline was restored by estradiol treatment in hippocampal neurons (Zhou et al., 2007).
Similarly, aromatase inhibition using androstatrienedione has been shown to reduce dendritic
spine density in cortical pyramidal neurons further suggesting an important role of estrogen in
modulating spine density (Srivastava et al., 2008). In addition to estradiol, ERβ-selective agonist
(WAY-200070, 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol) has also shown to increase
the number of spines in cortical neurons (Srivastava et al., 2010). A recent study has reported
that estradiol-induced spine changes in the dorsal hippocampus and medial prefrontal cortex are
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mediated through ERK and mTOR signaling mechanisms in ovariectomized mice (Tuscher et al.,
2016). Together, these findings suggest that estrogen signaling plays a critical role in synaptic
function and plasticity.
ESTROGEN AND ASD
Many studies over the years have shown that increased testosterone exposure during
pregnancy (Xu et al., 2015; Whitehouse et al., 2010; Auyeung et al., 2009; Auyeung et al., 2012;
Tordjman et al., 1997; Palomba et al., 2012), decreased aromatase expression (Chakrabarti et al.,
2009; Crider et al., 2014, Pfaff et al., 2011), and reduced estrogen or estrogen receptor
expression (Crider et al., 2014; Chakrabarti et al., 2009) are significantly correlated with the
development of ASD. Testosterone’s effects on behavior and the brain have been well
characterized in human and animal studies. Increased prenatal testosterone exposure appears to
be significantly more correlated than postnatal exposure with development of ASD. Increased
testosterone during prenatal periods can result in social anxiety (Pfaff et al., 2011), reduced
empathy and social development (Knickmeyer et al., 2006), and language development
(Whitehouse et al., 2010). ASD and cognitive dysfunction have been correlated with precocious
puberty, which is also caused by increased testosterone load (Tordjman et al., 1997).
The other side of the coin of increased testosterone is reduced estrogen signaling. In
rodents, sex differences in the brain are largely driven by estradiol, which is produced locally by
conversion of testosterone by aromatase (Wu et al., 2009). It follows that estradiol is also very
important for proper brain development and cognition. Unlike testosterone, the effects of
estrogen seem to be more profound postnatally. Reduction in estrogen signaling in adult mice
through blocking aromatase or estrogen receptors has been shown to increase susceptibility to
cognitive impairments due to repeated stress in rats (Wei et al., 2014). Adult females with low
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estrogen have also been shown to have impaired extinction and retrieval in fear extinction
paradigms in rodents and humans (Milad et al., 2009; Milad et al., 2010). Reduced estrogen
receptor expression in ASD has only been established very recently (Amin et al., 2005; Ostlund
et al., 2003; Österlund et al., 2001; Chakrabarti et al., 2009; Crider et al., 2014). ERβ gene was
found significantly associated with autism traits as measured by the Autism Spectrum Quotient
and the Empathy Quotient in ASD subjects (Chakrabarti et al., 2009). In a recent study using
postmortem brain samples from ASD and control subjects, we found that ERβ mRNA and
protein levels are lower in the middle frontal gyrus of ASD subjects as compared to age- and
gender-matched controls (Crider et al., 2014). In addition, significant reductions in aromatase
(CYP19A1) mRNA and protein levels were observed in ASD subjects. CYP19A1 is enriched at
synapses and localizes to presynaptic structures in neurons (Srivastava et al., 2010), suggesting
that brain-synthesized estrogen plays an important role in neuronal function (Balthazart and Ball,
2006). The reductions in CYP19A1 could lead to impaired conversion of testosterone to estradiol
resulting in increased levels of testosterone as observed in ASD subjects (Baron-Cohen et al.,
2011). It is known that estrogen-ER complex recruits a variety of co-regulators that result in the
activation or repression of target genes by modifying chromatin structure (Behl, 2002). We
observed significant decreases in ER co-activators such as SRC-1, CBP and P/CAF mRNA
levels in ASD subjects relative to controls (Crider et al., 2014). Together, these studies suggest
that a coordinated regulation of ER and associated molecules plays an important role in ER
signaling in the brain, and that this network may be impaired in subjects with ASD.
ESTROGEN AND SCHIZOPHRENIA
Schizophrenia is another major neurodevelopmental disorder where gender plays a very
important role in the pathophysiology. Men with schizophrenia show a higher incidence, earlier
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onset, and different symptomatology than women (Jablensky et al., 2000; Kulkarni et al., 2013).
Women are not only less likely to develop the disorder, they are less likely to experience
negative symptoms, substance abuse, and depression than men with schizophrenia (Conus et al.,
2007). Men also show a higher incidence of conduct disorders, aggression, antisocial personality
traits, higher levels of psychopathology, lower levels of treatment adherence, and lower levels of
response to antipsychotics (Cotton et al., 2009; Morgan et al., 2008).
Along with the gender specificity of the disorder, there is evidence suggesting that
estrogen levels correlate with the symptoms of schizophrenia. Several clinical studies have
reported correlation between low plasma estrogen levels and an increase in the risk for
schizophrenic symptoms in women (Mahé and Dumaine, 2001). An inverse correlation between
the plasma estrogen levels across the menstrual cycle and psychopathological symptoms has
been found in women with schizophrenia (Riecher-Rössler et al., 1994). Moreover, low rates of
relapse have been observed in women with schizophrenia during pregnancy, when plasma
estrogen levels are high (Chang and Renshaw, 1986 and Kendell et al., 1987). Additional studies
have shown that serum levels of estradiol are associated with heightened well-being and
improved cognition in healthy (Hampson, 1990) as well as schizophrenia subjects (Hampson,
1990; Akhondzadeh et al., 2003; Ko et al., 2006; Hoff et al., 2001). Two independent studies
showed positive correlation between peripheral estrogen and cognitive performance in women
with schizophrenia (Hoff et al., 2001; Ko et al., 2006). Another study using functional magnetic
resonance imaging (fMRI) showed a significant positive correlation between sex steroid levels
and brain activity in both women with schizophrenia and healthy men (Mendrek et al., 2011).
Evidence also suggest estrogen may be the protective factor for women that reduce symptom
severity and susceptibility (Kulkarni et al., 2012). For women who suffer from schizophrenia,
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symptoms have been shown to be increased during the early follicular phase of the menstrual
cycle, a phase where estrogen is particularly low (Bergemann et al., 2007; Rubin et al., 2010). In
addition, the later onset of schizophrenia in women has been attributed to the protective effects
of estrogen (Kulkarni et al., 2012; Stevens, 2002).
In addition to the findings on altered peripheral levels of estrogen in schizophrenia,
evidence also indicates alterations in the brain’s response to these hormones. Both men and
women with schizophrenia show reduced mRNA levels of ERα in hippocampus (Perlman et al.,
2005) and reduced mRNA levels and decreased frequency of wild-type ERα mRNA in frontal
cortex (Perlman et al., 2005; Weickert et al 2008). There are several single nucleotide
polymorphisms (SNPs) that have been associated with schizophrenia. Weickert et al., (2008)
found eighteen splice variants of ERα, one of which encoded a premature stop codon. This
variant produced a truncated version of ERα that lacked the majority of its estrogen binding
domain. This receptor acted as a dominant negative version which attenuated gene expression at
estrogen response elements (EREs), but had no estrogen signaling function. The altered forms of
ERα mRNA have been found to work as a dominant negative form of the receptor, which blocks
the activity of the wild-type (Weickert et al., 2008). These studies show that the schizophrenic
brain may have an attenuated response to estrogen. This along with altered blood levels of
estrogen may work together to significantly blunt estrogen response in schizophrenia.
Previous studies have shown that low levels of estrogen in women with schizophrenia are
correlated with increased relapse vulnerability and reduced sensitivity to antipsychotics (Arad
and Weiner, 2009). A rodent study using the latent inhibition model of selective attention deficits
in schizophrenia showed that estrogens are at least in part responsible for haloperidol sensitivity
(Almey et al., 2013). Another study in rats showed that low levels of estrogen leads to a “pro-
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psychotic” state and increased resistance to typical antipsychotic treatment (Arad and Weiner,
2009). In addition to their effects on HPA axis as evidenced by changes in cortisol levels (Piriu
et al., 2015; Arad and Weiner, 2009; Haddad and Wieck, 2004), antipsychotics are also known to
alter estradiol levels. One study in 64 male patients who were taking either risperidone (19
subjects) or clozapine (30 subjects) and met Diagnostic and Statistical Manual of Mental
Disorders IV (DSM-IV) criteria for schizophrenia or healthy controls (15 subjects) showed that
both drugs reduced circulating estradiol (Piriu et al., 2015). Stimulation of ERα with 4,4',4''-(4-
Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and antagonism with 1,3-Bis(4-
hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole (MPP) led to a dose-
dependent increase or decrease in basal prepulse inhibition (PPI), respectively in male mice
(Labouesse et al., 2015). Estrogen signaling plays an important role in modulating the activity of
dopamine, serotonin, GABA and glutamate, the key neurotransmitters implicated in
schizophrenia. Rodent studies have revealed that estradiol increases serotonin concentrations
(Sanchez et al., 2013) and enhances glutamate receptors (Meitzen and Mermelstein, 2011) and
dopamine synthesis, release and turnover in cortical and striatal regions (Bethea et al., 1999;
Hiroi et al., 2006; Pasqualini et al., 1995; Becker, 2000; Becker, 1990; Pecins-Thompson et al.,
1996; Seeman, 1987; Xiao and Becker, 1994; Adams et al., 2004). Moreover, ovariectomy has
been shown to reduce dopamine receptor 1 (D1) receptors in frontal cortex and striatum as well
as D2 receptors in striatum in rats (Bossé, and DiPaolo, 1996). These changes were seen along
with alterations in GABAA receptors in the substantia nigra pars reticulata, striatum, nucleus
accumbens, and entopeduncular nucleus post-ovariectomy. Moreover, treatment with estradiol
for 2 weeks restored the changes in D1, D2, and GABAA receptors suggesting an important role
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of estrogen in neurotransmitter receptor regulation (Bosse and DiPaolo, 1996; Schotte et al.,
1996).
ESTROGEN AND OTHER NEURODEVELOPMENTAL DISORDERS
Attention Deficit Hyperactivity Disorder (ADHD)
In addition to ASD and schizophrenia, estrogen has been implicated in the
pathophysiology of many other neurodevelopmental disorders. Attention Deficit Hyperactivity
Disorder (ADHD) is a neurodevelopmental disorder that occurs more often in men than women.
ADHD is marked by reduced attention, hyperactivity, and impulsivity and is often mistaken for
ASD. Males are twice as likely to be diagnosed with ADHD as their female counterparts
(American Psychiatric Association, 2013), but the factors that contribute to the gender disparity
are largely unknown. Bisphenol A (BPA) is a xenoestrogen compound that has been shown to
have some effects on behavioral outcomes when children are exposed to high levels of the
compound (Casas et. al., 2015; Schug et al., 2015). BPA binds to estrogen receptors altering
estrogen signaling and disrupting downstream effects of estrogen receptors (Schug et al., 2015).
One study showed a significant association with increased BPA exposure and risk for
development of ADHD-hyperactivity symptoms at 4 years of age, though this effect disappeared
by 7 years of age (Casas et al., 2015). Another study showed that gestational exposure to BPA
resulted in an increased risk for development of hyperactivity and aggressive behavior in
children (Perera et al., 2012). The effect was stronger in girls than their male counterparts (Perera
et al., 2012). Also, an aromatase gene (CYP19) variant is correlated with increased hyperactivity
in boys (Miodovnik et al., 2012), suggesting alterations in the estrogen-testosterone balance has
significant behavioral outcomes.
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Tourette’s Syndrome
Tourette’s Syndrome is a neurodevelopmental disorder characterized by vocal and motor
tics. The severity of the disorder peaks around puberty and shows a gender bias in which it
affects 3-4 times as many males as females (Martino et al., 2013). Studies involving humans and
rodents have reported that increased exposure to androgens during development can raise the risk
of development of Tourette’s (Martino et al., 2013). Studies also show that tic severity in women
is increased during the premenstrual reduction in estrogen levels (Martino et al., 2013; Kompoliti
et al., 2001).
Fragile X syndrome (FXS)
Fragile X syndrome (FXS) is a genetic disorder resulting in mental retardation,
hyperactivity, attention deficits, and language deficits. FXS results from an expansion of a CGG
repeat in the FMR1 gene. The disorder affects both genders, but males typically show more
severe symptoms due to the location of the mutation on the X chromosome. A study of the FXS
mouse model has shown reduced ER� signaling due to the genetic mutation in FMR1 (Yang et
al., 2015). Additional evidence of hormonal alterations related to FMR1 mutations has been
shown in women with premutations of FMR1. Women who carry the premutation allele (which
is defined as 55-200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism
(Sherman et al., 2014). These women stop menstruating before age 40 and show ovarian
dysfunction, subfertility, and increased risk of medical conditions related to reduction in estrogen
levels (Sherman et al., 2014).
Bipolar Disorder
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Bipolar Disorder has recently been reconsidered as a neurodevelopmental disorder
(Roybal et al., 2012; Sanches et al., 2008). Bipolar disorder is characterized by cycles of mania
and depression, but often presents as a fairly heterogeneous disorder. Females present with
symptoms later in life than men and have more rapid cycling, mixed mania, and depressive
episodes than men (Arnold, 2003). Bipolar II disorder, which is more predominantly composed
of depressive episodes, is also more common in women than men (Arnold, 2003). Studies have
shown that reduced levels of estrogen, for example postpartum, result in increased psychosis
(Arnold, 2003).
ESTROGEN AS A THERAPEUTIC TARGET IN NEURODEVELOPMENTAL
DISORDERS
The above observations suggest that an optimal balance of estrogen levels and their
receptors are necessary for proper brain development and function (Table 1). The profound
effects of reduced estrogen signaling on ASD or schizophrenia phenotype and the potential of
estrogen/estrogen receptor modulating agents to rescue behavioral deficits in rodents suggest that
estrogen signaling, more specifically ER� agonism, is a potential therapeutic target for ASD and
other neurodevelopmental disorders.
As with any hormone therapy, efficacy in males and females should outweigh the risk of
sexual and other side effects. When estrogen therapy is given, men can show major side effects
including feminization, gynecomastia as well as other side effects such as headache and nausea
(Sherwin et al., 2011). There are also concerns that estrogen therapies increase cancer risk and
reduce fertility in men. A small study showed no increased risk of cancer in female to male
transsexual men who were being administered estrogen therapy, but no large studies that are
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applicable to the general population have been performed (Asscheman et al., 2011). For women,
the risks are less pronounced, but some potentially detrimental side effects are still observed. Pre
and postmenopausal women who are given estrogen therapy risk the development of venous
thrombosis (Hayes et al., 2000). With both men and women showing side effects from estrogen
therapy, do the benefits outweigh the risks?
Estrogen has shown effectiveness in improving verbal memory loss (Beer et al., 2006),
and reducing depression, aggression, anxiety, and psychotic symptoms in men with dementia
(Kyomen et al., 1999; Kyomen et al., 2002). In schizophrenia, 17β-estradiol administration has
been shown to improve speech comprehension in women with schizophrenia (Bergemann et al.,
2008). In contrast, Kulkarni and colleagues (2015) have shown that transdermal estradiol patch
therapy in women with treatment-resistant schizophrenia significantly improves their psychotic
symptoms, but no effect on cognitive function was observed (Wilk et al., 2002). In addition to
estradiol, a number of studies have investigated the beneficial effects of DHEA, an intermediate
in the synthesis of sex steroids, in schizophrenia. However, some studies showed improvement in
attention and skill learning (Ritsner et al., 2006a; Ritsner et al., 2006b), whereas others reported
no beneficial effects (Ritsner et al., 2010; Strous et al., 2007) following DHEA treatment in
schizophrenia. Based on these observations, the important question here is whether a receptor-
selective therapy is more beneficial than estradiol treatment? SERMs are chemicals that
modulate estrogen signaling through receptors, providing a more specific therapy than estrogen
administration. These molecules were developed to avoid peripheral effects of estrogen therapy
while still stimulating estrogen signaling in the brain (Weickert et al., 2015). Raloxifene
hydrochloride is a selective estrogen receptor modulator with mixed agonist and antagonist
activity (Shang and Brown, 2002). Raloxifene has been shown to improve attention and memory,
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reduce cognitive impairment, and increase learning in individuals with schizophrenia (Weickert
et al., 2015; Huerta-Ramos et al., 2014; Gogos et al., 2015; Kindler et al., 2015). These outcomes
have been shown to occur without feminizing effects in males. Raloxifene mimics estrogen
effects on dopamine and serotonin neurotransmission, age-related attention and verbal memory
loss, cognitive decline, and brain activity (Landry et al., 2002; Bethea et al., 2002; Cyr et al.,
2000; Weickert et al., 2005; Goekoop et al., 2006). In a recent study, Kulkarni and colleagues
(2016) have shown that Raloxifene hydrochloride treatment for 12 weeks (120 mg/d) reduces
illness severity and increases the probability of a clinical response in women with refractory
schizophrenia. That being said, the exact neurobiological mechanism of raloxifene has not been
fully elucidated, so additional studies are warranted to prove the safety and effectiveness of this
drug in long-term treatment management of schizophrenia. In particular, subjects with
schizophrenia should be screened for the potential risks associated with raloxifene-induced
thromboembolic events at the time of their enrolment in the study (Barrett-Connor et al., 2009;
Adomaityte et al., 2008).
Very few studies have been performed to explore the efficacy of estrogen or related
hormone therapies in subjects with ASD, ADHD, FXS, or Tourette’s syndrome. A few recent
studies have shown that administration of tamoxifen as an adjunct to mood stabilizer medications
or monotherapy improves symptoms in adults with bipolar disorder (Kulkarni et al., 2014; Yildiz
et al., 2008; Talaei et al., 2016). Tamoxifen has also been shown to reduce mania and depression
in children and adolescents with acute mania when added to lithium treatment (Fallah et al.,
2016). The sample sizes in the above studies are small, but the results indicate some beneficial
effects of tamoxifen as an effective rapid acting antimanic agent. However, the increased risk of
thromboembolic events and endometrial cancer (Fisher et al., 1994; Kedar et al., 1994) limit the
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potential use of tamoxifen in long-term treatment in neurodevelopmental disorders. Although
tamoxifen has mixed estrogen receptor agonist and antagonist activity depending on the target
tissue, it has a number of receptor-independent effects, including inhibition of protein kinase C
(PKC) (O’Brian et al. 1986). Since abnormalities in PKC signaling are known in manic states
(Hahn and Friedman, 1999), additional studies are warranted to address the mechanisms of
action of tamoxifen in bipolar disorder.
CONCLUSIONS
As stated above, estrogen can have tremendous effects on cognition, mood, and synaptic
plasticity. Estrogen receptors are most densely located in the cortex, hippocampus, and
amygdala, which are regions that control cognitive function and mood. This control is highly
relevant to neurodevelopmental disorders because higher order functions such as memory,
learning, impulse control, and language are often impaired in these disorders. Mood is also
impaired in both ASD and schizophrenia where subjects who suffer from ASD or schizophrenia
show increased anxiety and depression. These factors make estrogen receptors an enticing
therapeutic target for neurological and neurodevelopmental disorders. Treating with SERMs
could eliminate most sexual side effects seen in treatment with estradiol or less specific estrogen
modulators (Figure 1). Although SERMS have been clinically tested in a number of studies in
schizophrenia subjects, their therapeutic potential in children with ASD still needs to be
determined. In addition, how estrogen and estrogen receptors are developmentally dysregulated
in the above neurodevelopmental disorders is largely unknown. The role of genetic and/or
epigenetic mechanisms in the regulation of estrogen receptors, the effects of immune activation
during development on estrogen signaling, the possible cross talk of estrogen receptors and/or
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cofactors with other candidate genes implicated in ASD or schizophrenia are some other areas of
research which need further investigation.
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AUTHORSHIP CONTRIBUTION
Wrote or contributed to the writing of the manuscript: Crider, Pillai
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FOOTNOTES: This work was supported by funding from National Institute of Health (NIH)/National Institute
of Mental Health (NIMH) to Dr. Pillai [Grant R01 MH 097060].
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LEGENDS FOR FIGURES
Figure 1. Schematic representation of the effects of estrogen on brain functions through estrogen
receptors, ERα and ERβ. ERα activation promotes a number of cellular events including
sociosexual development, activation of GABA signaling, neuroprotection and cognitive effects.
ERβ activation leads to mainly neuroprotective and neurobehavioral effects. ERβ stimulation
also inhibits endoplasmic reticulum stress-induced changes in mRNA transcription and protein
translation via synovilin 1 dependent mechanism. Raloxifene is an agonist of both ERα and ERβ
where as PPT is an ERα specific agonist. MPP is an ERα specific antagonist.
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TABLES AND FIGURES
Table 1. Summary of the studies published on the effects of estrogen on various cellular
functions in brain and periphery
BRAIN PERIPHERY
Memory (Kretz et al., 2004; Prange-Kiel et al., 2006)
Spatial Memory (Rhodes et al., 2006; Khan et al., 2014)
Motor Control (Martino et al., 2013; Kompoliti et al., 2001)
Language (Whitehouse et al., 2010; Beer et al., 2006; )
Learning (Rissman et al., 1999; Rissman et al 2002; Weickert et al., 2015; Huerta-Ramos et al., 2014; Gogos et al., 2015; Kindler et al., 2015)
Inflammation NFkB (Bebo et al 2009; Kalaitzidis and Gilmore, 2005; Evans et al., 2001; )
T-cell Activation (Lee et al 2008)
Endoplasmic Reticulum Stress (Kooptiwut et al., 2014)
Neuroprotection Plasticity (Hasegawa et al., 2015; Kramár et al., 2009)
Neurotrophic factors (Yi et al., 2016; Wong et al., 2011; Solum and Handa, 2002; Golden et al., 2010)
Inflammation (Dodel et al., 1999; Drew and Chavis, 2000; Bruce-Keller et
Sexual Characteristics and Reproduction
Sociosexual Development (Rhodes et al., 2006)
Puberty (Tordjman et al, 1997; Rissman et al, 2002; Shermal et al., 2015)
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al., 2000; Vegeto et al., 2001; Vegeto et al., 2003; Vegeto et al., 2004)
Cognition (Hoff et al, 2001; Ko et al 2006)
Mood (Ostlund et al., 2003; Pfaff et al., 2011; Conus et al., 2007; Kyomen et al., 1999; Kyomen et al., 2002)
Brain Activity (Mendrek et al., 2011)
Social Development (Tordjman et al., 1997; Knickmeyer et al., 2006)
Drug Response Antipsychotics (Cotton et al., 2009; Morgan et al., 2008)
Neurotransmission Dopamine (Bosse and DiPaolo, 1996; Landry et al., 2002)
Serotonin (Bethea et al., 2002; Amin et al. 2005)
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