A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings

Review ArticleA Role for Estrogen in SchizophreniaClinical and Preclinical Findings

Andrea Gogos1 Alyssa M Sbisa12 Jeehae Sun12 Andrew Gibbons1

Madhara Udawela1 and Brian Dean1

1Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville VIC 3010 Australia2School of Psychology and Public Health La Trobe University Bundoora VIC 3086 Australia

Correspondence should be addressed to Andrea Gogos andreagogosfloreyeduau

Received 1 July 2015 Revised 21 August 2015 Accepted 23 August 2015

Academic Editor Haifei Shi

Copyright copy 2015 Andrea Gogos et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroidsare strongly attributed to this phenomenon Of the various hormones implicated the estrogen hypothesis has been the most widelyresearched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severityof the illness In this review we comprehensively analyse studies that have investigated the effects of estrogen in particular 17120573-estradiol in clinical animal andmolecular researchwith relevance to schizophrenia Specifically we discuss the current evidence onestrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment inschizophrenia patients Preclinical research that has used animal models and molecular probes to investigate estradiolrsquos underlyingprotective mechanisms is also substantially discussed with particular focus on estradiolrsquos impact on the major neurotransmittersystems implicated in schizophrenia namely the dopamine serotonin and glutamate systems

1 Introduction

Schizophrenia is a complex neuropsychiatric disorder whichwill affect approximately 07 of the population during theirlifetime [1] Schizophrenia is a profoundly debilitating illnesscurrently ranking among the top 10 causes of long-termdisabilityworldwide [2] which imposes a significant financialburden on public health services as it is one of the mostfinancially costly psychiatric disorders to manage [3] Theprofound impact of the disorder is reflected in the fact thatapproximately 70ndash92 of patients with schizophrenia areunemployed [4] Additionally people with schizophrenia are13-fold more likely to die by suicide than are members of thegeneral population [5] and also have a life expectancy 10ndash25years less even after accounting for suicide [6] Schizophreniais a disorder characterised by severe impairment of cognitionemotions and behaviour [2] with symptomatology beingclassified within threemain clusters positive symptoms neg-ative symptoms and cognitive deficits [7] Positive symptoms(additive to normal healthy function) include hallucinations

and delusions whilst negative symptoms (deficits) includeblunted drive and affect (ie asociality alogia and avolition)[8] The heterogeneity of symptoms reflects the diagnosis ofschizophrenia defined as a syndrome of disorders therebysignifying that there may be a need to identify differingaetiologies for different diseases within the syndrome ofschizophrenia which currently remain largely unknown [9]

The numerous neurotransmitter systems implicated inschizophrenia (eg dopaminergic glutamatergic and sero-tonergic systems) add to the difficulty in effectively treat-ing the disorder [10] Presently the primary treatment forschizophrenia is antipsychotic medications [11] which pre-dominantly target the dopaminergic system [12] Howeverantipsychotics have reduced efficacy on the negative and cog-nitive symptoms of schizophrenia [11] and with respect to thepositive symptoms are not efficacious for 20ndash30 of patientswith the disorder [10 13] This has led to the explorationof potential adjunctive treatments such as treatment withestrogen [14] to extend the current therapeutic benefits ofantipsychotic drugs Importantly the gender differences in

Hindawi Publishing CorporationInternational Journal of EndocrinologyVolume 2015 Article ID 615356 16 pageshttpdxdoiorg1011552015615356

2 International Journal of Endocrinology

onset symptom severity and outcome of schizophrenia arenow thought to support the hypothesis that sex hormonesmay also have a role in the aetiology as well as treatment ofschizophrenia

Estrogen is a gonadal hormone that can exert powerfuleffects in numerous regions of the brain consequently affect-ing mood cognition and behaviour [15] Research over thelast two decades has established a clear neuromodulatory roleof estrogen in the pathogenesis and therapeutics of neuropsy-chiatric disorders including schizophrenia Estrogen is oftenconsidered the primary ldquofemalerdquo sex hormone although it ispresent in both sexes [16] Reference to estrogen can broadlyrefer to numerous estrogenic compounds including estradiolestrone estriol equilin and ethinylestradiol In this reviewreference to estrogen refers to the most potent endogenousform 17120573-estradiol unless otherwise stated 17120573-estradiol hasa role in the development of secondary sex characteristicsin women and reproduction in men and in both sexes hasperipheral effects in areas including the liver and bone [17]While 17120573-estradiol is primarily produced in the ovaries toregulate menstrual cycle in females it is also created bynonendocrine tissues including fat breast and importantlythe brain [18] Estrogen has neuroprotective properties and ithas been suggested that it can exert its effects over the entirelifetime protecting the brain from certain insults [19] Accu-mulating evidence has led to the hypothesis that recurringhormone influxes in women serve as a protective factor inthe initial development of schizophrenia [14] Thus in recentyears an increasing amount of literature has explored estrogentherapy as a potential form of treatment for schizophrenia[20 21]

This literature review aims to critically analyse therelevance of estrogen in relation to the pathogenesis andtherapeutics of schizophrenia in a clinical settingThis reviewwill also report on preclinical research and the molecularmechanisms that may underlie the therapeutic effects ofestrogen in schizophrenia

2 Clinical Findings

21 Gender Differences in Schizophrenia A rich literatureelaborately describes gender differences in schizophreniarelating to disease risk course and outcome [22ndash24] Thereis a difference in the age-at-onset of schizophrenia betweenthe sexes whereby men reach a peak onset at the ages of 18ndash24 years whereas for women it occurs up to 4 years later[25 26]This is awell-replicated finding and occurs regardlessof the definition of onset used it is consistent across culturesand is not due to differences in symptoms or social roleFurthermore only in females with schizophrenia is there asecond peak age-at-onset at 45ndash50 years of age [27] There isan increased incidence rate in men (14 1 ratio) which hasbeen verified by 2 independent meta-analyses and remainseven after controlling for various confounding factors suchas age range diagnostic criterion and hospital bias [28 29]There is a plethora of studies based in different countries andcultures supporting the notion that women with schizophre-nia present with a less severe course of the illness comparedto men [24 30 31] For example women with schizophrenia

present with less severe negative symptoms but exhibit morepositive and affective symptoms [32] In women a laterage-at-onset and presentation of affective symptoms havepredicted a better prognosis whereas in men an earlier onsetand presentation of primarily negative symptoms predict aworse course of illness and outcome [22] Females showa more favourable antipsychotic treatment response thanmales [33 34] have fewer hospitalisations better adapt tothe illness and present less disability (particularly with self-care) Women also have an improved outcome and improvedquality of life for example they aremore likely to bemarriedremain employed and keep in contact with family andfriends [24] Men have more brain structural abnormalitiesthan females including enlarged ventricles and decreasedtemporal lobe volume [35ndash37]

22 Estrogen Hypothesis of Schizophrenia In light of thegender differences described above it has been hypothesizedthat gonadal steroids may play a role in buffering femalesagainst the development of schizophrenia [32 38] This isconsistent with the existence of a second peak of onset infemales after the age of 40 which may be associated withmenopause a time of rapidly declining sex hormone levels[25 39] Further premenopausal women with schizophreniaexperience a better course of illness with less negativesymptoms and respond better to antipsychotic treatment(ie require lower doses) than older women [34] The mostcommon interpretation of these gender differences is thewell-described ldquoestrogen hypothesisrdquo which postulates thatestrogen plays a protective role against schizophrenia [14 40]However it is important to note that the studies describinggender differences in schizophrenia suggest sex steroid dys-function not necessarily only estrogen dysfunction A num-ber of reproductive hormones may be implicated includingtestosterone progesterone or luteinising hormone and thusit is important to acknowledge that there is a complexinterplay of hormones occurring For example progesteroneand estrogen naturally vary with each other over endogenoushormonal cycles therefore the influence of progesterone oran interaction between the two hormones on the observedphenomena cannot be excluded However this review willfocus on estrogen as the estrogen hypothesis has been well-supported by molecular animal and clinical studies [41ndash43]

23 Evidence for Estrogen Dysfunction in Patients withSchizophrenia An early study reported that of the sam-ple of 276 women admitted to psychiatric hospitals 46were admitted during or immediately before menstruationa period of low circulating estrogen levels [44] Furtherpsychotic symptoms were reported to improve during preg-nancy [45] but worsened postpartum [46] More recentlycase reports and clinical studies have shown that womenwith schizophrenia demonstrate increased symptom severitygreater relapse rates and more hospital admissions duringtimes of low circulating sex hormones including the earlyfollicular phase of the menstrual cycle postpartum andpostmenopause [47ndash50] In contrast rates of relapse areless frequent and symptom severity is reduced during timesof high circulating sex hormones including pregnancy and

International Journal of Endocrinology 3

the mid-luteal stage of the menstrual cycle [47 51] Forexample Hallonquist et al [52] assessed the variation insymptom severity in female outpatients with schizophreniaduring two phases of the menstrual cycle The authorsfound that symptom scores as measured by the AbbreviatedSymptom Checklist were distinctly low during the mid-luteal phase but high during the early follicular phase [52]Similarly Rubin et al [50] reported that female patients withchronic schizophrenia showed less severe positive symptomsand general psychopathology (measured using the Positiveand Negative Syndrome Scale PANSS) during the mid-lutealphase versus the early follicular phase whereas negativesymptom severity did not change across the cycle [50]Some studies have specifically shown that there is a negativecorrelation between circulating estrogen levels and symp-toms of schizophrenia particularly the positive symptoms[39 53] In 125 premenopausal women with schizophreniaBergemann and colleagues [53] assessed psychopathologyscores three times during the menstrual cycle Using thePANSS and Brief Psychiatric Rating Scale they found asignificant improvement in psychotic symptoms during theluteal phase which was associated with estradiol plasmalevels [53] A positive relationship has also been discoveredbetween later menarche higher negative symptom scores(as measured by the Scales for Assessment of NegativeSymptoms) and greater functional impairment in womenwith schizophrenia suggesting that earlier puberty mightpredict improved clinical outcome [54] Similarly a negativeassociation has been discovered between age at menarcheand first psychotic symptoms and first hospitalisation morespecifically a relationship has been identified between earlierpuberty and later onset of illness in women with schizophre-nia [38]

Women with schizophrenia are often hypoestrogenicthat is their circulating levels of estrogen are much lowerthan the normal reference range and they tend to experi-ence menstrual irregularities [48 49 55] Importantly somestudies showing reduced estrogen levels in women withschizophrenia were conducted during the preantipsychoticera [56 57] Since the introduction of antipsychotic drugtreatment reduction in estrogen levels is correlated with anincreased risk of symptoms and is found regardless of the typeof antipsychotic treatment [47 58]This is important as someantipsychotics can cause hyperprolactinaemia which leads toa reduction in estrogen levels [59] Hyperprolactinaemia ismainly associated with antipsychotics such as risperidonewhich predominantly block the dopamine D2 receptor thereceptor that modulates prolactin release from the pituitary[60]

An important question is whether estrogen dysfunctionoccurs prior to or after the onset of schizophrenia Earlypuberty has been associated with a late onset of the dis-order [38] suggesting that physiological estrogens mightdelay the onset of schizophrenia [56] Many clinical studiesexamining plasma estrogen levels and symptomatology inschizophrenia patients require their participants to have ahistory of regular menstrual cycles therefore it cannot beinferred from these samples whether gonadal dysfunction ismerely a state or a trait of the disorder Schepp [61] attempted

to explore this question by investigating premenopausalfirst-episode schizophrenia patients In comparison to age-matched healthy controls schizophrenia patients had latermenarche mid-cycle bleeding mild bleeding hirsutism andmore tendency to be infertile [56 61] This study demon-strates evident gonadal dysfunction in a sample of first-timeadmitted patients however a longitudinal experiment exam-ining endocrinological function inclusive of prepubescentparticipants is necessary to sufficiently answer whetherpremorbid hypoestrogenism occurs

24 Clinical Trials of Adjunctive Estrogen in SchizophreniaA growing body of double-blind placebo-controlled ran-domized trials provides evidence that estrogen treatmentadministered in conjunction with antipsychotics is benefi-cial for schizophrenia particularly in reducing the positivesymptoms [20 62 63] An initial pilot study by Kulka-rni et al [64] discovered that the synthetic 17120573-estradiolderivative ethinylestradiol taken orally daily for eight weekssignificantly improved positive symptoms in premenopausalwomen with schizophrenia Later trialling a transdermalmethod of administration Kulkarni et al [20 63] foundthatwomenwith schizophrenia receiving adjunctive estradiolhad significant improvements in the positive symptoms andgeneral psychopathology (PANSS) ratings [20 63] In theirlargest study to date Kulkarni and colleagues [20] tested 183premenopausal women with schizophrenia who were receiv-ing transdermal 17120573-estradiol (100 120583gday or 200120583gday for8 weeks) together with their prescribed antipsychotic Thelargest effect was found in the women receiving 200120583g ofestradiol who showed reduced scores on the positive subscaleof the PANSS [20] Another group found similar benefi-cial effects where 8 weeks of adjunctive haloperidol andethinylestradiol treatment resulted in reduced positive gen-eral and total PANSS scores compared to the haloperidol-only group [62] On the other hand a study by Bergemannand colleagues [65] failed to replicate the beneficial effect ofestradiol in their placebo-controlled double-blind studywith46 hypoestrogenic women finding there was no difference inPANSS scores relapse rates or antipsychotic dose betweentreatment and placebo This may be due to the use of acombined 17120573-estradiol (1ndash4mg) and progestin treatmentwith doses varying dependent on the phase ofmenstrual cycle[65] In comparison Kulkarni et al [20 63] administeredonly estrogen treatment and at a consistent daily dose for theduration of the experiment

One cross-sectional study compared postmenopausalwomenwith schizophreniawhowere either users or nonusersof hormone replacement therapyThey found that the womentaking hormones required a lower dose of antipsychoticsand had less severe negative symptoms [66] Research thusfar has primarily concerned females evidently due to thepremise for estrogen therapy relying on observation ofhypoestrogenism in women One study that examined theeffects of estradiol in men with schizophrenia found thatafter two weeks of oral estradiol treatment in conjunctionwith antipsychotics the estrogen group experienced morerapid reduction in general psychopathology compared to theplacebo group [67] Although there is concern regarding


the potentially feminising side effects of estradiol estrogentherapy is currently used inmales for other clinical conditions(eg prostate cancer) and the results of the Kulkarni et al[67] study suggest exploration of estrogen treatment in menwith schizophrenia is warranted

Other forms of estrogen have also shown some beneficialeffects on schizophrenia symptoms although perhaps not aspotent as the effects of 17120573-estradiol In a double-blind ran-domized placebo-controlled trial 32 premenopausal womenwith chronic schizophrenia were treated with conjugatedestrogens for 4 weeks in addition to their antipsychotictreatment Participants experienced a significant decreasein positive negative general and total PANSS scores [68]In a similar study however Louza et al [69] found nosignificant difference between the treatment and placebogroups although there was a trend for the conjugated estro-gen group to show greater improvement [69] The selectiveestrogen receptor modulator raloxifene has also been trialledin women with schizophrenia with favourable results forthe positive [70 71] negative [72] and cognitive symptoms[73 74]

Clinical research specifically concerning the influence ofestradiol on cognition in schizophrenia patients is limitedWith relevance to endogenous estrogen research has foundestradiol can improve certain cognitive functions in womenwith schizophrenia Hoff et al [75] determined there was apositive correlation with serum estradiol levels and a globalcognitive score including six cognitive domains with verbaland spatial memory and perceptual motor speed being themost strongly related Ko and colleagues [76] stratified theirsample of women with schizophrenia into low or high estro-gen groups by using the normal serum reference ranges forestradiol during the follicular phase of the menstrual cycleSimilar to the results ofHoff et al [75] they found diminishedperformance in verbal memory and executive function inthe low estradiol group compared to the high estradiolgroup Studies administering estradiol treatment provide lessconsistent results Bergemann and colleagues [77] foundoral 17120573-estradiol and adjunctive antipsychotic treatmentfor women with schizophrenia improved metaphoric speechbut had no effect on word fluency and verbal ability In anexperiment examining transdermal 17120573-estradiol Kulkarniet al [20] found there were no significant differences betweenor within groups in cognitive domains including attentionlanguage visuospatialconstructional ability and memoryThese studies employed different neurocognitive batteriesand different methods of administering estradiol which mayaccount for dissimilar outcomes

The diverse results in the aforementioned estradiol trialsmay be due to a variety of inconsistent factors includingdissimilarmeasures severity of symptoms variable treatmentduration additional pharmacotherapy (ie antipsychoticsbenzodiazepines) oral versus transdermal administrationand pharmacological and pharmacokinetic variation in estro-gen Additionally despite its putative effect on the positivesymptoms of schizophrenia estradiol at the efficacious doseis unfortunately not feasible for long-term management ofschizophrenia due to the associated health risks (eg throm-boembolism endometrial hyperplasia) Evidently estradiol

treatment in men with schizophrenia also remains con-troversial due to potential feminising side effects [20 67]Nevertheless overall the epidemiological and clinical datapresented provide strong support for the notion that estradiolis protective in women with schizophrenia particularly forthe positive symptoms

3 Mechanisms of EstrogenAction in Schizophrenia

The molecular mechanisms of how estrogen may affectschizophrenia symptoms remain largely unknown Perhapsthe simplest explanation is that estrogen can regulate thedopaminergic system of the central nervous system (CNS) byaffecting the expression and function of dopamine receptorsand transporters [78 79] However there are several otherpossible mechanisms by which estradiol can exert the effectsin the CNS some of which have been well defined and othersare yet to be characterised Estradiol actions are generallycategorised as either genomic or nongenomic Genomicactions are delayed in onset and prolonged in duration suchas those likely to occur after chronic estradiol treatmentThese effects occur through binding of intracellular estradiolto the estrogen receptor (ER) which belongs to the nuclearreceptor superfamily Upon binding the receptors dimeriseand then translocate to the nucleuswhere they bind to specificDNA sequences called estrogen response elements (EREs)found in the promotor region of estrogen-responsive genesor to activator protein 1 (AP-1) sites via FosJun interactionsresulting in transcriptional activation ofmanydifferent genesThe nongenomic actions occur through activation of intra-cellular second messenger pathways such as the MAP kinaseand cAMP to elicit a more rapid response including cell-excitability synaptic transmission and antioxidant effects[80ndash82] These are believed to be mediated via either ERsinteracting with other proteins to form a large complexanchored to the plasmamembrane or an alternativeG proteincoupled receptor GPR30 [83 84] (see Figure 1)

Gene profiling of the mouse brain after treatment withestradiol has revealed changes in genes associated withbiosynthesis growth synaptic potentiation and myelinationlipid synthesis and metabolism cell signalling pathwaysand epigenetic modifications [85 86] In the primate pre-frontal cortex estrogen treatment caused changes in genesinvolved in transcription regulation neurotransmission cellsignalling cell cycle control and proliferation and differenti-ation [87] These effects could be a result of either genomicor nongenomic actions [88] Thus estrogen can have far-reaching and diverse effects on the brain Interestingly onegroup studied the gene expression profile of a cell linetreated with 18 different antipsychotics and found a commonsignature shared by antipsychotics and estrogen receptormodulators lipid homeostasis [89] It is theorised that theestrogen pathway may be involved in the therapeutic effectof antipsychotics [89]

31 Estrogen Receptors The first ER ER120572 was cloned in1986 [90] and the second subtype ER120573 was not discovered


ER120572 ER120573or

Transcription activation

EREAP-1

Transcription factors

Second messengers

Genomic actions

Nongenomicactions

MAPKcAMP

GPR30

Estrogen

mERs

Figure 1 Putative mechanisms of estrogen action in the cell Estrogen can act via either genomic or nongenomic mechanisms Genomicmechanisms involve activation of the estrogen receptors (ERs) by estrogen which then translocate to the cell nucleus as hetero- orhomodimers to bind to estrogen response elements (EREs) or to activator protein 1 (AP-1) sites resulting in transcription activationNongenomic actions occur via binding of estrogen to ERs or to a G protein coupled receptor GPR30 either intracellularly or at the plasmamembrane (mERs) to activate second messenger systems such as those involving mitogen-activated protein kinase (MAPK) or cyclicadenosine 3101584051015840-monophosphate (cAMP) pathways which can also activate transcription or have other effects

until 1996 [91] The two receptor subtypes are encoded byseparate genes ESR1 and ESR2 respectively A splice variantof ER120573 was later identified ER1205732 [92] which shows a muchlower affinity to 17120573-estradiol than ER120572 and ER1205731 [93]but can competitively bind at EREs and as such can act asa negative regulator of estrogen-dependent transcriptionalactivation [94] As expected ER120572 is highly expressed in areasof the CNS that are implicated in the control of reproductivefunctions such as the hypothalamus and preoptic areas [84]and receptor levels tend to be higher in the female rats than inmales [95ndash97] ER120573 expression showsmuch overlapwith ER120572but appears to be more widely distributed showing strongexpression in areas such as the hippocampus in mice ratsand humans [91 98] while ER120572mRNA is abundantly foundin the prefrontal cortex of nonhuman primates [87 99 100]indicating both these receptors are involved in potentiatingthe nonreproductive estrogen actions such as learning andmemory

For many years there was uncertainty surrounding therole of ERs in nongenomic actions of estrogen While ER120572and ER120573 were shown to activate nongenomic signallingthrough crosstalk with other signal transduction proteins[84] these receptors could not fully account for observeddownstream effects of estrogen such as its antioxidantproperties [101] and it was speculated that another receptor

could be involved GPR30 previously an orphan receptorwas recently renamed G protein coupled estrogen receptor1 (GPER) following evidence that estrogen can bind to andactivate the receptor [102 103] It is found to be expressedin multiple regions of the rat CNS [104] including thehippocampus frontal cortex and substantia nigra [94 104]Several studies indicate that this receptor is localised to thecytoplasm [104] specifically the endoplasmic reticulum andGolgi apparatus [90 105 106] However there is also evidencethat it is expressed at the plasma membrane and dendriticspines of rat hippocampal neurons [104 107ndash109] suggestingthat localisation may be cell type-specific or influencedby state This receptor can rapidly activate multiple kinasepathways involved in nongenomic estrogen actions [110] andappears tomediatemany of the effects of estrogen in neuronalcells [111] including calcium oscillations and luteinisinghormone-releasing activity in primate neurons [112] WhileCNS expression patterns do not appear to differ betweenthe adult male and female rat [104 105 113] the receptor isimplicated in sexual dimorphism of immune response in theGPER knock-out mouse [114] Importantly there is emergingevidence for GPERs role in learning and memory [115ndash117]as well as neuronal plasticity [118] Several new membersand isoforms of estrogen receptors have also recently beenidentified some of which are expressed in the CNS such as


ER-X which could be involved in the nongenomic actions ofestrogen [119] however these have yet to bewell characterised[120]

32 Estrogen Receptors andCognition Therole of estrogen oncognition is of particular importance for schizophrenia as thecognitive deficits associated with the disease are consideredthe most debilitating symptoms for patients to assimilate intosociety [121] and these symptoms are poorly treated usingcurrent antipsychotics [122] Sinopoli and colleagues [123]showed that a low dose of estradiol injected directly intothe hippocampus or a high dose injected into the prefrontalcortex could improve radial arm maze performance (spatialworking memory task) in rats [123] Several studies havedemonstrated contradicting findings on the roles of ER120572and ER120573 on cognition Viral delivery of ER120572 into the hip-pocampus has been shown to rescue memory deficits in ER120572knock-out mice [124] In contrast another study has shown anegative effect of ER120572 on memory where estradiol treatmentimpaired acquisition of spatial memory but not cue discrim-ination in the Morris water maze in ovariectomised wild-typemice but not ER120572 knock-outmice [123]This suggests anER120572-dependent mechanism of estradiol in impairing spatialtask performance [125] Recently mice with ER120573 knock-down showed improved spatial learning which could bereversed by viral delivery of ER120573 to the hippocampus [126]By contrast treatment with selective ER120573 agonist diarylpro-pionitrile (DPN) in female ovariectomised rats enhancedrecognition memory but had no effect following treatmentwith ER120572-selective agonist propyl pyrazole triol (PPT) [127]Results suggest that ER120573 mediates the subchronic and acuteeffects of estrogen on recognition memory Molecular workby the same authors showed that memory enhancements viaDPN are likely to occur through alterations in monoaminesin the hippocampus and prefrontal cortex [127] In a differentspecies Phan et al [128] found that acute PPT treatmentenhanced object and place recognition in ovariectomisedmice whilst DPN at the same dose did not affect objectrecognition and only slightly facilitated place recognition[128] Collectively research demonstrates that different estro-gen agonists estrogen receptors and brain regions have theability to mediate dissimilar forms of learning and memoryIt is currently difficult to isolate specific actions of ERs inrelation to cognitive function Not only does function changedependent on the cognitive task but factors such as agesex and treatment duration can also alter outcomes Thelatter is of particular importance due to the influence oftreatment period on genomic versus nongenomic outcomesand consequently mediation via different estrogen receptors[129] More preclinical research is necessary to further clarifythe specific role of ERs in relation to cognition especiallywithspecific relevance to schizophrenia

33 Estrogen Effects on Brain Structure Schizophrenia isassociated with various structural brain changes such asprogressive decline in global gray and white matter vol-ume in multiple brain regions followed by continuousventricular enlargement [130] Abnormal cytoarchitecture

also commonly occurs including neuronal soma and neu-ropil volume reductions irregular synaptic organization andectopic neurons [131 132] The effects of estrogen treatmenton brain structure have been well documented includingthe modulation of neurogenesis synaptic density plasticityand connectivity and axonal sprouting (reviewed in [84])Of particular relevance to cognition estradiol treatmenthas been shown to enhance hippocampal synaptic plasticityin young ovariectomised rats [133] induce dendritic spineformation in CA1 pyramidal neurons [134] and stimulateneurogenesis of granule cells in the dentate gyrus of adultfemale rats [135] Estrogen can also modulate neurotrophicfactors [136] as well as neurotransmission [15 137] whichcan secondarily promote neuronal survival and prolifera-tion Thus in women with schizophrenia lower circulatingestradiol levels [51 65] may contribute to the observedbrain pathology associated with the disorder Based on thesefindings we would expect to see sex differences in brainabnormalities in people with schizophrenia Indeed twoMRIstudies reported more severe abnormalities in males thanin females with the disorder when compared to age- andsex-matched controls particularly in regard to ventricularenlargement [37] and temporal lobe volume [35] Howeverthere are some conflicting reports where a similarMRI studyshowed no difference [138] Overall these studies suggest thatestrogen levels could influence the brain structure differencesthat occur in the CNS of people with schizophrenia

34 Neuroprotection by Estrogen Neuroprotective effects areanother key component of estrogen action that is relevantto schizophrenia [84] Early cell culture studies showedincreased neuronal survival upon treatment with estrogenunder serum deprivation [139ndash142] and subsequent studieshave shown estrogen protection against injury from excito-toxicity [143ndash145] oxidative stress [101 146] inflammation[147 148] and apoptosis [149] Some of these protectiveactions have been attributed to the ability of estrogen toreduce the generation of free radicals [150] More recentlyit has been suggested that the neuroprotective actions ofestrogen are mediated through maintaining mitochondriafunction [151] and there is growing evidence of mitochon-drial dysfunction playing a role in schizophrenia [152] Takentogether these findings indicate that low estrogen levels mayleave the brain vulnerable to insult or age-related changesleading to development of schizophrenia or increased symp-tom severity and could explain the observed differencesin disease onset and severity between males and femalesTreatment with estrogen may therefore help to protect thebrain from disease progression

35 Changes in Estrogen Signaling in Schizophrenia In 2005Perlman and colleagues showed that while ER120572 mRNA wasnot different in the dorsolateral prefrontal cortex of peoplewith schizophrenia in the dentate gyrus region of the hip-pocampus ER120572 expression levels were lower in schizophreniacompared to healthy controls [153] This has implicationsin estrogen driven synaptic plasticity and neurogenesis asthis region of the hippocampus is important for control ofthese activities Further lower receptor levels are unlikely


to be the result of lower circulating estradiol levels as lowlevels of hormone would be expected to upregulate receptorexpression [154] Perlman et al [153] study also detecteda negative correlation between ER120572 mRNA expression inthe dentate gyrus and age-at-onset suggesting ER120572 levelsmay confer vulnerability to the disease Furthermore theirfinding appeared to be diagnosis specific as people withmajor depressive disorder and bipolar disorder showed nodifference in ER120572 expression compared to control [153]On the other hand ER120572 mRNA levels were lower in theamygdala in major depressive disorder and bipolar disorderbut not in schizophrenia compared to control while sexdifferences were detected in the dorsolateral prefrontal cortexof people withmajor depressive disorder that was not presentin control These findings illustrate that alterations in ER120572expression in the CNS across major mental illnesses arespecific to sex region and diagnosis [153] More recentlyER gene variation has also been implicated in schizophreniarisk Weickert et al [155] showed a SNP in intron 1 of theESR1 gene was more prevalent in people with schizophreniaMoreover this SNP was associated with lower expressionlevels of ER120572 in the prefrontal cortex among people with thedisorder [155]Thus ER120572 expression levels in the CNS appearto play an important role in schizophrenia pathophysiologyand may explain some of the cognitive deficits associatedwith disorder particularly in those CNS regions that areimplicated in cognition such as the hippocampus [156] andprefrontal cortex [157]

36 Estrogen Effects on Major Neurotransmitter Systems Tar-geted by Antipsychotics Several converging lines of evidencefrom clinical and animal studies suggest that estrogen can actto modulate the activity of the neurotransmitter systems tar-geted by current antipsychotics [30 79 83 158] Understand-ing the nature of these interactions is important for address-ing the therapeutic potential of estrogen and of compoundsthat target estrogen signalling Researchers have labelledestradiol as neuroprotective and antipsychotic implicatingnumerous neurotransmitter systems in this mechanism [30]The strongest evidence for estrogen modulation of neu-rotransmitter systems comes from studies examining thedopamine serotonin and glutamate systems examples ofthese studies are described below

361 Estrogen Interaction with Dopamine As stated earlierthe most direct route by which estrogen could influencesymptom severity in schizophrenia could be by modulatingdopaminergic activity in the CNS as hyperactivation ofthe dopamine signalling system is thought to be a centralmechanism affected in schizophrenia [12 159] Central to thishypothesis are observations that typical antipsychotics suchas haloperidol are potent antagonists of dopamine D2 recep-tors [160] and can reduce positive symptoms of schizophrenia[161] The stimulatory effect of estrogen on the activity ofdopaminergic neurons particularly those in the striatum andnucleus accumbens is well documented (see [79]) Rodentstudies have demonstrated that phases of dopaminergictransmission vary during the estrous cycle [162] Removal of

the primary source of estradiol via ovariectomy evokes a per-manent loss of dopamine neuron density in the substantianigra in nonhuman primates [163] Estradiol treatment canmodulate the levels of dopamine transporters and receptors(pre- and postsynaptic) and dopamine synthesis releaseand turnover in both cortical and striatal regions [162 164ndash167] For example ovariectomy in rats has been shown toreduce protein levels of the dopamine active transporter(which reuptakes dopamine into the neuron for recycling ordegradation) and increase levels of dopamine D2 receptorin the nucleus accumbens and caudate nucleus [78] Sub-sequent treatment in ovariectomised rats with 17120573-estradiolreversed the loss of dopamine transporter levels and reduceddopamine D2 receptor levels below that of intact control lev-els [78] Chronic 17120573-estradiol treatment of ovariectomisedmonkeys increased dopamine transporter expression lev-els in the caudate putamen compared to vehicle-treatedmonkeys [168] and also led to a downstream activation ofthe AktGSK3 signalling pathway which is thought to beimpaired in schizophrenia [169] Ovariectomised macaquesshowed increased numbers of neurons expressing dopamine120573 hydroxylase (DBH) an enzyme involved in metabolisingdopamine across all layers of the dorsolateral prefrontalcortex Treating ovariectomised macaques with 17120573-estradiolreturned the number of DBH-immunoreactive neurons tolevels comparable to intact animals Furthermore cotreatingovariectomised macaques with 17120573-estradiol and proges-terone did not produce a greater effect than 17120573-estradiolalone suggesting this effect is primarilymediated by estrogen[170] One study treated ovariectomised rats with an ER120573-selective agonist and found increased brain monoaminelevels in the prefrontal cortex including a marked increasein dopamine levels its metabolite homovanillic acid (HVA)and HVAdopamine ratio [127] In humans a PET study didnot show any significant variation in striatal D2 receptordensity throughout the menstrual cycle [171] However post-menopausal women receiving estrogen replacement therapyfollowing hysterectomy or oophorectomy showed increaseddopamine responsiveness to apomorphine [172]

Rodent behaviour studies also show marked protectiveeffects of estrogen on the dopaminergic system For examplewemeasured a behavioural endophenotype of schizophreniaprepulse inhibition in ovariectomised female rats treatedwith estrogen and its analogues [173] We showed that 17120573-estradiol raloxifene and tamoxifen prevented the disruptionof prepulse inhibition induced by the dopamine D1D2receptor agonist apomorphine [173] In another animalbehaviour relevant to schizophrenia 17120573-estradiol treat-ment in combination with chronic antipsychotic haloperi-dol reduced amphetamine-induced locomotor hyperactiv-ity in ovariectomised amphetamine-sensitized female rats[174] Interestingly this effect of estradiol was not observedwhen paired with saline treatment suggesting that estradiolexerts antipsychotic properties that further potentiate thefunctional efficacy of haloperidol However the lack of ahaloperidol treatment-only group in this study makes itdifficult to ascertain this facilitatory effect In contrast to thesestudies in female rats the treatment of male rats with 17120573-estradiol following gonadectomy has not been shown to effect


the mRNA expression of enzymes involved in dopaminesynthesis and metabolism [175] This is in contrast to theincreased expression of these enzymes seen in response totestosterone suggesting that estrogenrsquos effect on dopaminesignalling may be sex-specific [175] Overall these stud-ies suggest a protective action of estrogen particularly infemales on the dopaminergic system

362 Estrogen Interaction with Serotonin The advent ofclinically effective atypical antipsychotics which have ahigher affinity for serotonin receptors compared to typicalantipsychotics has highlighted a role for the serotonergicsystem in schizophrenia [160 176 177] Further postmortemstudies have reported altered levels of several serotoninreceptors in cortical and subcortical regions of the CNSin people with schizophrenia [178ndash182] Sex differences inthe regulation of serotonin signalling have been reportedby some where serotonin 5-HT1A receptor mRNA levelswere lower in the amygdala and hypothalamus of femalerats compared to males whilst 5-HT2A receptor bindingwas higher in the female hippocampus [183] Treating femalerats with 17120573-estradiol has been found to improve spatialworking memory and increase the levels of serotonin inthe prefrontal cortex [184] PET studies of postmenopausalwomen showed that estradiol replacement therapy increasedserotonin 5-HT2A receptor levels in the prefrontal cortex[185 186] However serotonin 5-HT1A receptor levels werenot altered following estradiol replacement therapy [187]suggesting estradiolrsquos selective action on serotonin receptorsubtypes Another study reported a trend toward elevatedplasma serotonin levels in postmenopausal women followingestradiol replacement therapy although this effect failedto reach statistical significance [188] Furthermore clinicalstudies in postmenopausal women showed that removingtryptophan (a biochemical precursor for serotonin synthesis)from the diet prior to but not after estradiol treatment canreduce dorsolateral prefrontal and cingulate cortex activationduring working memory tasks [189] Interestingly a PETstudy conducted in healthy men found a positive correlationbetween the levels of the serotonin 5-HT2A receptor ligand[18F]altanserin and plasma levels of estradiol [190]

The effects of estradiol on serotonin receptor signallingmay result from its capacity to modulate serotonin biosyn-thesis In vitro studies in raphe cells have shown that ER120573acts as a transcription factor for the tryptophan hydroxylase-2 gene which encodes the enzyme involved in biosynthesisof serotonin from tryptophan [191] Interestingly it has beensuggested that changes in serotonin biosynthesis in responseto estradiol may vary following a prolonged disruption ofestradiol signalling Studies in macaques ovariectomised for3 years report reductions in neurons positive for serotonin5-HT1A receptor serotonin transporter and tryptophanhydroxylase-2 gene expression [192] These changes werelargely absent in macaques 5 months after ovariectomywhile another study reported increased numbers of serotoninpositive neurons in macaques 4ndash7 months after ovariec-tomy [170] suggesting reduced serotonergic signalling maybecome more pronounced with chronic loss of estradiol

[193] Using the behavioural paradigm prepulse inhibitionwe found that treatment of female ovariectomised rats with17120573-estradiol prevented a serotonin 5-HT1A receptor agonist-induced disruption of prepulse inhibition [21 173 194]Similarly we found that in healthy women pretreatmentwith estradiol prevented the disruption of prepulse inhibitioninduced by a partial serotonin 5-HT1A receptor agonistbuspirone [195] Further in these same women we foundthat estradiol pretreatment prevented a further buspirone-induced potentiation in loudness dependence of the auditoryevoked potential (LDAEP) [196] This is a measure of earlysensory processing that is thought to be primarily mediatedby central serotonin function (reviewed in [197]) A highLDAEP which is indicative of low serotonin neurotrans-mission has been found to be tightly associated with thenegative symptoms of schizophrenia [198] These results aretherefore suggestive of a protective role of estradiol againstthe sensory processing or gating deficits typically observed inschizophrenia patients Overall the above studies collectivelysubstantiate the idea of estradiol interacting with multiplefacets of the serotonergic system through which it mightexert protective actions against the cognitive positive andnegative symptom domains of schizophrenia

363 Estrogen InteractionwithGlutamate Glutamate signalsthrough two classes of receptors the ionotropic receptorswhich include the NMDA receptor kainate receptor andAMPA receptor subtypes the metabotropic receptors whichinclude mGluR1-mGluR8 subtypes The psychomimeticactions of drugs such as ketamine and phencyclidine whichare antagonists of the NMDA receptor implicate the glu-tamatergic system in the pathophysiology of schizophrenia[199 200] Thus glutamatersquos role in schizophrenia has beenproposed to involve NMDA receptor hypofunction [201]Postmortem studies of brains frompeoplewith schizophreniashow regionally discrete increases and decreases in both thelevels of NMDA receptor [202ndash204] and the levels of otherionotropic and metabotropic glutamate receptors [202 203205 206] Furthermore regionally specific differences in theexpression of the subunit components of these receptors arealso reported in people with schizophrenia which couldaffect receptor activity [202 207 208] Chronic treatmentwith 17120573-estradiol has been shown to modulate glutamateNMDA and AMPA receptor density in the rat brain [209]Further studies showing treatment with 17120573-estradiol orselective estrogen modulators can alter the NMDA receptorsubunit levels in the rat hippocampus [209 210] suggestthat estrogen may have varying effects on different areasof the brain in schizophrenia However these findings arecontrasted by studies in macaques showing treating ovariec-tomised animals with 17120573-estradiol does not alter hippocam-pal AMPA receptor or NMDA receptor subunit expression[211] Studies examining estradiolrsquos effects on neurodegenera-tion anddamage in cortical andhippocampal neuron cultureshave shown that estradiol can be neuroprotective againstthe effects of glutamate mediated neurotoxicity further sup-porting a role for estradiol in the modulation of glutamatesignalling [212 213] Endogenous estradiol has been shownto enhance basal glutamatergic transmission and facilitate


synaptic plasticity in the mouse medial prefrontal cortex[214]

Our understanding of how estradiol regulates glutamatesignalling in the CNS has been advanced by recent in vitrostudies examining how the glutamate pathways are affectedby selective estrogen receptor modulators Tamoxifen whichhas both agonist and antagonist properties on ERs in differenttissues has been shown to increase glutamate reuptake [215]suggesting that estradiol could affect the broad changes inionotropic and metabotropic glutamate receptor activity inschizophrenia by regulating the availability of glutamate inthe synaptic cleft Excitatory amino acid transporters (EAAT)control the uptake of surplus glutamate from the synapticcleft In primary astrocyte cultures tamoxifen and raloxifeneare both able to upregulate themRNA and protein expressionof the astrocytic glutamate transporters EAAT1 and EAAT2via NFkB mediated pathways [216] The increase in EAAT2expression in response to raloxifene has been shown tocorrespond to an increase in glutamate uptake suggestingthat the increase in EAAT levels results in a functionalincrease in EAAT activity [217 218] This upregulation ofglutamate transporter gene expression by tamoxifen andraloxifene is mediated via ER120572 and ER120573 receptors as wellas GPER via extracellular signal-regulated kinases the epi-dermal growth factor receptor and cAMP response element-binding protein-mediated regulation of the NF-120581B pathway[217 218] Treating astrocytic cells with estradiol has alsobeen shown to increase EAAT1 and EAAT2 mRNA andprotein expression an effect that is attenuated by the estrogenreceptor antagonist ICI Therefore the effects of tamoxifenand raloxifene on astrocytic glutamate uptake are likely toresult from the activation of the estrogen receptors and thusare comparable to the actions of estradiol [219]

Animal behavioural studies suggest estradiolrsquos effectson glutamatergic signalling may be involved in behavioursrelevant to schizophrenia Estradiol is protective againstNMDA receptor antagonist-induced impairments in thenovel object recognition task [220 221] suggesting thatestradiol has the potential to affect glutamatergic dysfunctionin schizophrenia Postweaning social isolation in rats hasbeen shown to result in increased prepulse inhibition andstartle response aswell as cognitive rigidity which is reflectiveof schizophrenia-like symptoms In male rats these symp-toms are associated with a dysregulation of the serotoninand dopaminergic system in the CNS By contrast socialisolation in female mice has been shown to downregulatethe expression of the NR1 NMDA receptor subunit and theGluR1AMPA receptor subunit andPSD95 aswell as synapsinwhich is involved in glutamate release [222] Whilst suchstudies suggest that estradiol plays a role in glutamatergicdysfunction in schizophrenia estradiol treatment has notbeen shown to reduce deficits in prepulse inhibition in ratscaused by the NMDA receptor antagonist MK-801 [21]Thus further evidence is needed to support a therapeuticeffect of estradiol on glutamate dysfunction in schizophreniaOverall whilst substantial evidence supports the role ofestradiol in modulating the glutamatergic system at themolecular level how these mechanisms make an impact at

the phenotypic level remains elusive and thus requires morein-depth investigation

4 Summary and Conclusions

In summary schizophrenia is a neuropsychiatric disorderthat has shown robust gender differences in numerous aspectsof the illness including an earlier age of onset a more severecourse of illness poorer antipsychotic treatment responseand adaptability to illness inmale patients with schizophreniacompared to that of women This review has highlighted theresearch that has been invested to understand the potentiallyprotective effects of estradiol with respect to these gender dif-ferences in schizophrenia The extent of this research rangesfrom molecular investigations that have clearly evidencedestradiolrsquos intricate interactions with the major neurotrans-mitter systems in the brain and especially those implicatedin schizophrenia to preclinical models of the illness that haveshown estradiolrsquos potential in either enhancing cognitionand memory or reversing deficits that are reflective of thepositive negative and cognitive symptoms of schizophreniaRecent clinical trials have provided a promising outlook onthe use of estradiol and the more recent use of selectiveestradiol receptor modulators as an adjunctive treatment toantipsychotics for schizophrenia patients of both gendersFuture studies investigating themechanism underlying estra-diolrsquos protective action in schizophrenia are warranted suchresearch is also necessary in other psychiatric disorderswheregender differences are observed including depression andanxiety

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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[2] K TMueser andDV JesteClinicalHandbook of SchizophreniaGuilford Press New York NY USA 2011

[3] M Knapp ldquoSchizophrenia costs and treatment cost-effect-ivenessrdquo Acta Psychiatrica Scandinavica vol 102 no 407 pp15ndash18 2000

[4] M S Ritsner Handbook of Schizophrenia Spectrum DisordersTherapeutic Approaches Comorbidity and Outcomes SpringerNew York NY USA 2011

[5] S Saha D Chant and J McGrath ldquoA systematic review ofmortality in schizophrenia is the differential mortality gapworsening over timerdquo Archives of General Psychiatry vol 64no 10 pp 1123ndash1131 2007

[6] T J R Lambert and J W Newcomer ldquoAre the cardiometaboliccomplications of schizophrenia still neglected Barriers to carerdquoMedical Journal of Australia vol 190 no 4 article 39 2009

[7] K T Mueser and S R McGurk ldquoSchizophreniardquo The Lancetvol 363 no 9426 pp 2063ndash2072 2004


[8] R Tandon W Gaebel D M Barch et al ldquoDefinition anddescription of schizophrenia in the DSM-5rdquo SchizophreniaResearch vol 150 no 1 pp 3ndash10 2013

[9] C A Tamminga ldquoAccelerating new knowledge in schizophre-niardquoTheAmerican Journal of Psychiatry vol 165 no 8 pp 949ndash951 2008

[10] H Steeds R L Carhart-Harris and J M Stone ldquoDrug modelsof schizophreniardquo Therapeutic Advances in Psychopharmacol-ogy vol 5 no 1 pp 43ndash58 2015

[11] F J Acosta E Chinea J L Hernandez et al ldquoInfluence ofantipsychotic treatment type and regimen on the functionalityof patientswith schizophreniardquoNordic Journal of Psychiatry vol68 no 3 pp 180ndash188 2014

[12] P Seeman ldquoAll roads to schizophrenia lead to dopaminesupersensitivity and elevated dopamine D2(high) receptorsrdquoCNSNeuroscienceampTherapeutics vol 17 no 2 pp 118ndash132 2011

[13] H Y Meltzer ldquoTreatment-resistant schizophreniamdashthe role ofclozapinerdquo Current Medical Research and Opinion vol 14 no 1pp 1ndash20 1997

[14] M V Seeman ldquoThe role of estrogen in schizophreniardquo Journalof Psychiatry and Neuroscience vol 21 no 2 pp 123ndash127 1996

[15] G Fink B E H Sumner R Rosie O Grace and J PQuinn ldquoEstrogen control of central neurotransmission effecton mood mental state and memoryrdquo Cellular and MolecularNeurobiology vol 16 no 3 pp 325ndash344 1996

[16] Y Sayed and P Taxel ldquoThe use of estrogen therapy in menrdquoCurrent Opinion in Pharmacology vol 3 no 6 pp 650ndash6542003

[17] J Cui Y Shen and R Li ldquoEstrogen synthesis and signalingpathways during aging from periphery to brainrdquo Trends inMolecular Medicine vol 19 no 3 pp 197ndash209 2013

[18] M J Legato Principles of Gender-Specific Medicine AcademicPress New York NY USA 2009

[19] M L Rao and H Kolsch ldquoEffects of estrogen on braindevelopment and neuroprotectionmdashimplications for negativesymptoms in schizophreniardquo Psychoneuroendocrinology vol28 supplement 2 pp 83ndash96 2003

[20] J Kulkarni E Gavrilidis W Wang et al ldquoEstradiol fortreatment-resistant schizophrenia a large-scale randomized-controlled trial in women of child-bearing agerdquo MolecularPsychiatry vol 20 pp 695ndash702 2015

[21] A Gogos P Kwek andM van den Buuse ldquoThe role of estrogenand testosterone in female rats in behavioral models of rele-vance to schizophreniardquo Psychopharmacology vol 219 no 1 pp213ndash224 2012

[22] K M Abel R Drake and J M Goldstein ldquoSex differences inschizophreniardquo International Review of Psychiatry vol 22 no5 pp 417ndash428 2010

[23] J A Markham ldquoSex steroids and schizophreniardquo Reviews inEndocrineampMetabolic Disorders vol 13 no 3 pp 187ndash207 2012

[24] S Ochoa J Usall J Cobo X Labad and J Kulkarni ldquoGenderdifferences in schizophrenia and first-episode psychosis acomprehensive literature reviewrdquo Schizophrenia Research andTreatment vol 2012 Article ID 916198 9 pages 2012

[25] H Hafner ldquoGender differences in schizophreniardquo Psychoneu-roendocrinology vol 28 no 2 pp 17ndash54 2003

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explanation of the gender difference in age at first onset ofschizophreniardquo Psychological Medicine vol 23 no 4 pp 925ndash940 1993

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[36] K L Narr P M Thompson T Sharma et al ldquoThree-dimensional mapping of temporo-limbic regions and the lateralventricles in schizophrenia gender effectsrdquo Biological Psychia-try vol 50 no 2 pp 84ndash97 2001

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[38] R Z CohenMV SeemanAGotowiec and L Kopala ldquoEarlierpuberty as a predictor of later onset of schizophrenia inwomenrdquoThe American Journal of Psychiatry vol 156 no 7 pp 1059ndash1064 1999

[39] R Halari V Kumari R Mehrotra M Wheeler M Hines andT Sharma ldquoThe relationship of sex hormones and cortisol withcognitive functioning in schizophreniardquo Journal of Psychophar-macology vol 18 no 3 pp 366ndash374 2004

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[41] E Hayes E Gavrilidis and J Kulkarni ldquoThe role of oestrogenand other hormones in the pathophysiology and treatmentof schizophreniardquo Schizophrenia Research and Treatment vol2012 Article ID 540273 8 pages 2012

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[43] A Wieck ldquoOestradiol and psychosis clinical findings andbiological mechanismsrdquo Current Topics in Behavioral Neuro-sciences vol 8 pp 173ndash187 2011


[44] K Dalton ldquoMenstruation and acute psychiatric illnessesrdquoBritish Medical Journal vol 1 no 5115 pp 148ndash149 1959

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[47] N Bergemann P Parzer I Nagl et al ldquoAcute psychiatric admis-sion and menstrual cycle phase in women with schizophreniardquoArchives of Womenrsquos Mental Health vol 5 no 3 pp 119ndash1262002

[48] N Bergemann C Mundt P Parzer et al ldquoPlasma concen-trations of estradiol in women suffering from schizophre-nia treated with conventional versus atypical antipsychoticsrdquoSchizophrenia Research vol 73 no 2-3 pp 357ndash366 2005

[49] A Riecher-Rossler H Rossler M Stumbaum K Maurer andR Schmidt ldquoCan estradiol modulate schizophrenic symptoma-tologyrdquo Schizophrenia Bulletin vol 20 no 1 pp 203ndash214 1994

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[51] T JHuberM BorsutzkyU Schneider andHM Emrich ldquoPsy-chotic disorders and gonadal function evidence supporting theoestrogen hypothesisrdquo Acta Psychiatrica Scandinavica vol 109no 4 pp 269ndash274 2004

[52] J D Hallonquist M V Seeman M Lang and N A RectorldquoVariation in symptom severity over the menstrual cycle ofSchizophrenicsrdquo Biological Psychiatry vol 33 no 3 pp 207ndash209 1993

[53] N Bergemann P Parzer B Runnebaum F Resch and CMundt ldquoEstrogen menstrual cycle phases and psychopathol-ogy in women suffering from schizophreniardquo PsychologicalMedicine vol 37 no 10 pp 1427ndash1436 2007

[54] K M Hochman and R R Lewine ldquoAge of menarche andschizophrenia onset in womenrdquo Schizophrenia Research vol 69no 2-3 pp 183ndash188 2004

[55] T J Huber J Rollnik J Wilhelms A von Zur Muhlen HM Emrich and U Schneider ldquoEstradiol levels in psychoticdisordersrdquo Psychoneuroendocrinology vol 26 no 1 pp 27ndash352001

[56] N Bergemann and A Riecher-Rossler Estrogen Effects inPsychiatric Disorders Springer New York NY USA 2005

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[58] J H Zhang-Wong and M V Seeman ldquoAntipsychotic drugsmenstrual regularity and osteoporosis riskrdquoArchives ofWomenrsquosMental Health vol 5 no 3 pp 93ndash98 2002

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a double-blind randomized and placebo-controlled trialrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 6 pp 1007ndash1012 2003

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[65] N Bergemann C Mundt P Parzer et al ldquoEstrogen as anadjuvant therapy to antipsychotics does not prevent relapsein women suffering from schizophrenia results of a placebo-controlled double-blind studyrdquo Schizophrenia Research vol 74no 2-3 pp 125ndash134 2005

[66] L A Lindamer D C Buse J B Lohr and D V JesteldquoHormone replacement therapy in postmenopausal womenwith schizophrenia positive effect on negative symptomsrdquoBiological Psychiatry vol 49 no 1 pp 47ndash51 2001

[67] J Kulkarni A de Castella B Headey et al ldquoEstrogens andmen with schizophrenia is there a case for adjunctive therapyrdquoSchizophrenia Research vol 125 no 2-3 pp 278ndash283 2011

[68] E Ghafari M Fararouie H G Shirazi A Farhangfar FGhaderi and A Mohammadi ldquoCombination of estrogenand antipsychotics in the treatment of women with chronicschizophrenia a double-blind randomized placebo-controlledclinical trialrdquo Clinical Schizophrenia and Related Psychoses vol6 no 4 pp 172ndash176 2013

[69] M R Louza A P Marques H Elkis D Bassitt M Diegoliand W F Gattaz ldquoConjugated estrogens as adjuvant therapyin the treatment of acute schizophrenia a double-blind studyrdquoSchizophrenia Research vol 66 no 2-3 pp 97ndash100 2004

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[71] J Kulkarni C Gurvich S J Lee et al ldquoPiloting the effectivetherapeutic dose of adjunctive selective estrogen receptor mod-ulator treatment in postmenopausal women with schizophre-niardquo Psychoneuroendocrinology vol 35 no 8 pp 1142ndash11472010

[72] J Usall E Huerta-Ramos R Iniesta et al ldquoRaloxifene asan adjunctive treatment for postmenopausal women withschizophrenia a double-blind randomized placebo-controlledtrialrdquoThe Journal of Clinical Psychiatry vol 72 no 11 pp 1552ndash1557 2011

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[74] T W Weickert D Weinberg R Lenroot et al ldquoAdjunctiveraloxifene treatment improves attention and memory in menand women with schizophreniardquo Molecular Psychiatry vol 20no 6 pp 685ndash694 2015

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[76] Y-H Ko S-H Joe W Cho et al ldquoEstrogen cognitive functionand negative symptoms in female schizophreniardquo Neuropsy-chobiology vol 53 no 4 pp 169ndash175 2006


[77] N Bergemann P Parzer S Jaggy B Auler C Mundtand S Maier-Braunleder ldquoEstrogen and comprehension ofmetaphoric speech in women suffering from schizophreniaresults of a double-blind placebo-controlled trialrdquo Schizophre-nia Bulletin vol 34 no 6 pp 1172ndash1181 2008

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[80] A P V Dantas R C A Tostes Z B Fortes S G Costa DNigro andM H C Carvalho ldquoIn vivo evidence for antioxidantpotential of estrogen in microvessels of female spontaneouslyhypertensive ratsrdquo Hypertension vol 39 no 2 pp 405ndash4112002

[81] A Kumar and T C Foster ldquo17120573-estradiol benzoate decreasesthe AHP amplitude in CA1 pyramidal neuronsrdquo Journal ofNeurophysiology vol 88 no 2 pp 621ndash626 2002

[82] M Wong and R L Moss ldquoLong-term and short-term electro-physiological effects of estrogen on the synaptic properties ofhippocampal CA1 neuronsrdquoThe Journal of Neuroscience vol 12no 8 pp 3217ndash3225 1992

[83] B McEwen K Akama S Alves et al ldquoTracking the estrogenreceptor in neurons implications for estrogen-induced synapseformationrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 13 pp 7093ndash7100 2001

[84] B S McEwen and S E Alves ldquoEstrogen actions in the centralnervous systemrdquo Endocrine Reviews vol 20 no 3 pp 279ndash3071999

[85] K K Aenlle A Kumar L Cui T C Jackson and T C FosterldquoEstrogen effects on cognition and hippocampal transcriptionin middle-aged micerdquo Neurobiology of Aging vol 30 no 6 pp932ndash945 2009

[86] G I Humphreys Y S Ziegler and A M Nardulli ldquo17120573-estradiol modulates gene expression in the female mousecerebral cortexrdquo PLoS ONE vol 9 no 11 Article ID e1119752014

[87] J Wang C M Cheng J Zhou et al ldquoEstradiol alters tran-scription factor gene expression in primate prefrontal cortexrdquoJournal of Neuroscience Research vol 76 no 3 pp 306ndash3142004

[88] A Pedram M Razandi M Aitkenhead C C W Hughesand E R Levin ldquoIntegration of the non-genomic and genomicactions of estrogen membrane-initiated signaling by steroidto transcription and cell biologyrdquo The Journal of BiologicalChemistry vol 277 no 52 pp 50768ndash50775 2002

[89] M H Polymeropoulos L Licamele S Volpi et al ldquoCommoneffect of antipsychotics on the biosynthesis and regulationof fatty acids and cholesterol supports a key role of lipidhomeostasis in schizophreniardquo Schizophrenia Research vol 108no 1ndash3 pp 134ndash142 2009

[90] S Green P Walter V Kumar et al ldquoHuman oestrogen receptorcDNA sequence expression and homology to v-erb-ArdquoNaturevol 320 no 6058 pp 134ndash139 1986

[91] G G Kuiper E Enmark M Pelto-Huikko et al ldquoCloning of anovel receptor expressed in rat prostate and ovaryrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 93 no 12 pp 5925ndash5930 1996

[92] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[93] B Hanstein H Liu M C Yancisin andM Brown ldquoFunctionalanalysis of a novel estrogen receptor-120573 isoformrdquo MolecularEndocrinology vol 13 no 1 pp 129ndash137 1999

[94] K Maruyama H Endoh H Sasaki-Iwaoka et al ldquoA novelisoform of rat estrogen receptor beta with 18 amino acidinsertion in the ligand binding domain as a putative dominantnegative regulator of estrogen actionrdquo Biochemical and Biophys-ical Research Communications vol 246 no 1 pp 142ndash147 1998

[95] P J Shughrue C D Bushnell and D M Dorsa ldquoEstrogenreceptor messenger ribonucleic acid in female rat brain duringthe estrous cycle a comparison with ovariectomized femalesand intact malesrdquo Endocrinology vol 131 no 1 pp 381ndash3881992

[96] R B Simerly and B J Young ldquoRegulation of estrogen receptormessenger ribonucleic acid in rat hypothalamus by sex steroidhormonesrdquoMolecular Endocrinology vol 5 no 3 pp 424ndash4321991

[97] Y Zhou P J Shughrue and D M Dorsa ldquoEstrogen receptorprotein is differentially regulated in the preoptic area of thebrain and in the uterus during the rat estrous cyclerdquo Neuroen-docrinology vol 61 no 3 pp 276ndash283 1995

[98] PMicevych and R Dominguez ldquoMembrane estradiol signalingin the brainrdquo Frontiers in Neuroendocrinology vol 30 no 3 pp315ndash327 2009

[99] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Molecular Brain Research vol 76 no 2 pp 191ndash204 2000

[100] T C Register C A Shively and C E Lewis ldquoExpressionof estrogen receptor 120572 and 120573 transcripts in female monkeyhippocampus and hypothalamusrdquo Brain Research vol 788 no1-2 pp 320ndash322 1998

[101] C Behl T Skutella F Lezoualcrsquoh et al ldquoNeuroprotectionagainst oxidative stress by estrogens structuremdashactivity rela-tionshiprdquo Molecular Pharmacology vol 51 no 4 pp 535ndash5411997

[102] CM Revankar D F Cimino L A Sklar J B Arterburn and ER Prossnitz ldquoA transmembrane intracellular estrogen receptormediates rapid cell signalingrdquo Science vol 307 no 5715 pp1625ndash1630 2005

[103] P Thomas Y Pang E J Filardo and J Dong ldquoIdentity of anestrogen membrane receptor coupled to a G protein in humanbreast cancer cellsrdquo Endocrinology vol 146 no 2 pp 624ndash6322005

[104] E Brailoiu S L Dun G C Brailoiu et al ldquoDistributionand characterization of estrogen receptor G protein-coupledreceptor 30 in the rat central nervous systemrdquo The Journal ofEndocrinology vol 193 no 2 pp 311ndash321 2007

[105] K Matsuda H Sakamoto H Mori et al ldquoExpression andintracellular distribution of the G protein-coupled receptor 30in rat hippocampal formationrdquo Neuroscience Letters vol 441no 1 pp 94ndash99 2008

[106] C Otto B Rohde-Schulz G Schwarz et al ldquoG protein-coupledreceptor 30 localizes to the endoplasmic reticulum and is notactivated by estradiolrdquo Endocrinology vol 149 no 10 pp 4846ndash4856 2008


[107] K T Akama L I Thompson T A Milner and B S McEwenldquoPost-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30) an estrogen receptor thatcan be identified in hippocampal dendritic spinesrdquoThe Journalof Biological Chemistry vol 288 no 9 pp 6438ndash6450 2013

[108] T Funakoshi A Yanai K Shinoda M M Kawano andY Mizukami ldquoG protein-coupled receptor 30 is an estrogenreceptor in the plasmamembranerdquo Biochemical and BiophysicalResearch Communications vol 346 no 3 pp 904ndash910 2006

[109] R Hammond D Nelson and R B Gibbs ldquoGPR30co-localizes

with cholinergic neurons in the basal forebrain and enhancespotassium-stimulated acetylcholine release in the hippocam-pusrdquo Psychoneuroendocrinology vol 36 no 2 pp 182ndash192 2011

[110] H Tang Q Zhang L Yang et al ldquoReprint of lsquoGPR30 mediatesestrogen rapid signaling and neuroprotectionrsquordquo Molecular andCellular Endocrinology vol 389 no 1-2 pp 92ndash98 2014

[111] M Maggiolini and D Picard ldquoThe unfolding stories ofGPR30 a new membrane-bound estrogen receptorrdquo Journal ofEndocrinology vol 204 no 2 pp 105ndash114 2010

[112] S D Noel K L Keen D I Baumann E J Filardo andE Terasawa ldquoInvolvement of G protein-coupled receptor 30(GPR30) in rapid action of estrogen in primate LHRHneuronsrdquoMolecular Endocrinology vol 23 no 3 pp 349ndash359 2009

[113] K Takanami H Sakamoto K-I Matsuda et al ldquoExpressionof G protein-coupled receptor 30 in the spinal somatosensorysystemrdquo Brain Research vol 1310 pp 17ndash28 2010

[114] C Wang B Dehghani I J Magrisso et al ldquoGPR30 contributesto estrogen-induced thymic atrophyrdquoMolecular Endocrinologyvol 22 no 3 pp 636ndash648 2008

[115] R Hammond R Mauk D Ninaci D Nelson and R B GibbsldquoChronic treatment with estrogen receptor agonists restoresacquisition of a spatial learning task in young ovariectomizedratsrdquo Hormones and Behavior vol 56 no 3 pp 309ndash314 2009

[116] R Hammond D Nelson E Kline and R B Gibbs ldquoChronictreatment with a GPR30 antagonist impairs acquisition of aspatial learning task in young female ratsrdquo Hormones andBehavior vol 62 no 4 pp 367ndash374 2012

[117] W R Hawley E M Grissom N M Moody G P Dohanichand N Vasudevan ldquoActivation of G-protein-coupled receptor30 is sufficient to enhance spatial recognition memory inovariectomized ratsrdquo Behavioural Brain Research vol 262 pp68ndash73 2014

[118] C Gabor J Lymer A Phan and E Choleris ldquoRapid effects ofthe G-protein coupled oestrogen receptor (GPER) on learningand dorsal hippocampus dendritic spines in female micerdquoPhysiology amp Behavior vol 149 pp 53ndash60 2015

[119] C D Toran-Allerand X Guan N J MacLusky et al ldquoER-X anovel plasmamembrane-associated putative estrogen receptorthat is regulated during development and after ischemic braininjuryrdquo The Journal of Neuroscience vol 22 no 19 pp 8391ndash8401 2002

[120] K Soltysik and P Czekaj ldquoMembrane estrogen receptorsmdashis itan alternative way of estrogen actionrdquo Journal of Physiology andPharmacology vol 64 no 2 pp 129ndash142 2013

[121] M F Green ldquoWhat are the functional consequences of neu-rocognitive deficits in schizophreniardquoThe American Journal ofPsychiatry vol 153 no 3 pp 321ndash330 1996

[122] R Tandon M S Keshavan and H A Nasrallah ldquoSchizophre-nia lsquoJust the Factsrsquo what we know in 2008 Part 1 overviewrdquoSchizophrenia Research vol 100 no 1ndash3 pp 4ndash19 2008

[123] K J Sinopoli S B Floresco and L A M Galea ldquoSystemic andlocal administration of estradiol into the prefrontal cortex orhippocampus differentially alters working memoryrdquoNeurobiol-ogy of Learning and Memory vol 86 no 3 pp 293ndash304 2006

[124] T C Foster A Rani A Kumar L Cui and S L Semple-Rowland ldquoViral vector-mediated delivery of estrogen receptor-120572 to the hippocampus improves spatial learning in estrogenreceptor-120572 knockoutmicerdquoMolecularTherapy vol 16 no 9 pp1587ndash1593 2008

[125] HN Fugger S G Cunningham E F Rissman and T C FosterldquoSex differences in the activational effect of ER120572 on spatiallearningrdquo Hormones and Behavior vol 34 no 2 pp 163ndash1701998

[126] X Han K K Aenlle L A Bean et al ldquoRole of estrogen receptor120572 and 120573 in preserving hippocampal function during agingrdquoTheJournal of Neuroscience vol 33 no 6 pp 2671ndash2683 2013

[127] L F Jacome C Gautreaux T Inagaki et al ldquoEstradiol andER120573 agonists enhance recognition memory and DPN an ER120573agonist alters brain monoaminesrdquo Neurobiology of Learningand Memory vol 94 no 4 pp 488ndash498 2010

[128] A Phan K E Lancaster J N Armstrong N J MacLuskyand E Choleris ldquoRapid effects of estrogen receptor 120572 and 120573selective agonists on learning and dendritic spines in femalemicerdquo Endocrinology vol 152 no 4 pp 1492ndash1502 2011

[129] V N Luine ldquoEstradiol and cognitive function past present andfuturerdquo Hormones and Behavior vol 66 no 4 pp 602ndash6182014

[130] L E DeLisi K U Szulc H C Bertisch M Majcher and KBrown ldquoUnderstanding structural brain changes in schizophre-niardquo Dialogues in Clinical Neuroscience vol 8 no 1 pp 71ndash782006

[131] L A Flashman andM F Green ldquoReview of cognition and brainstructure in schizophrenia profiles longitudinal course andeffects of treatmentrdquo Psychiatric Clinics of North America vol27 no 1 pp 1ndash18 2004

[132] S Iritani ldquoNeuropathology of schizophrenia a mini reviewrdquoNeuropathology vol 27 no 6 pp 604ndash608 2007

[133] MM Adams R A ShahW GM Janssen and J HMorrisonldquoDifferent modes of hippocampal plasticity in response toestrogen in young and aged female ratsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 98 no 14 pp 8071ndash8076 2001

[134] C S Woolley and B S McEwen ldquoRoles of estradiol andprogesterone in regulation of hippocampal dendritic spinedensity during the estrous cycle in the ratrdquo The Journal ofComparative Neurology vol 336 no 2 pp 293ndash306 1993

[135] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo The Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[136] C D Toran-Allerand ldquoThe estrogenneurotrophin connectionduring neural development is co-localization of estrogen recep-tors with the neurotrophins and their receptors biologicallyrelevantrdquo Developmental Neuroscience vol 18 no 1-2 pp 36ndash48 1996

[137] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[138] J Lauriello A Hoff M H Wieneke et al ldquoSimilar extentof brain dysmorphology in severely ill women and men withschizophreniardquoTheAmerican Journal of Psychiatry vol 154 no6 pp 819ndash825 1997


[139] Y Arimatsu and H Hatanaka ldquoEstrogen treatment enhancessurvival of cultured fetal rat amygdala neurons in a definedmediumrdquo Brain research vol 391 no 1 pp 151ndash159 1986

[140] J Bishop and J W Simpkins ldquoEstradiol treatment increasesviability of glioma and neuroblastoma cells in vitrordquoMolecularand Cellular Neurosciences vol 5 no 4 pp 303ndash308 1994

[141] J A Chowen I Torres-Aleman and L M Garcia-SeguraldquoTrophic effects of estradiol on fetal rat hypothalamic neuronsrdquoNeuroendocrinology vol 56 no 6 pp 895ndash901 1992

[142] A Faivre-Bauman E Rosenbaum J Puymirat D Grouselleand A Tixier-Vidal ldquoDifferentiation of fetal mouse hypothala-mic cells in serum-free mediumrdquo Developmental Neurosciencevol 4 no 2 pp 118ndash129 1981

[143] Y Goodman A J Bruce B Cheng and M P Mattson ldquoEstro-gens attenuate and corticosterone exacerbates excitotoxicityoxidative injury and amyloid120573-peptide toxicity in hippocampalneuronsrdquo Journal of Neurochemistry vol 66 no 5 pp 1836ndash1844 1996

[144] P S Green K E Gridley and J W Simpkins ldquoEstradiolprotects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cellsrdquo Neuroscience Letters vol218 no 3 pp 165ndash168 1996

[145] C A Singer K L Rogers T M Strickland and D M DorsaldquoEstrogen protects primary cortical neurons from glutamatetoxicityrdquo Neuroscience Letters vol 212 no 1 pp 13ndash16 1996

[146] C Behl MWidmann T Trapp and F Holsboer ldquo17-120573 estradiolprotects neurons from oxidative stress-induced cell death invitrordquo Biochemical and Biophysical Research Communicationsvol 216 no 2 pp 473ndash482 1995

[147] M Sarvari I Kallo E Hrabovszky et al ldquoEstradiol replacementalters expression of genes related to neurotransmission andimmune surveillance in the frontal cortex of middle-agedovariectomized ratsrdquo Endocrinology vol 151 no 8 pp 3847ndash3862 2010

[148] S Suzuki CM Brown CDDela Cruz E YangD A Bridwelland P M Wise ldquoTiming of estrogen therapy after ovariectomydictates the efficacy of its neuroprotective and antiinflammatoryactionsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 14 pp 6013ndash6018 2007

[149] L M Garcia-Segura P Cardona-Gomez F Naftolin and J AChowen ldquoEstradiol upregulates Bcl-2 expression in adult brainneuronsrdquo NeuroReport vol 9 no 4 pp 593ndash597 1998

[150] A D Mooradian ldquoAntioxidant properties of steroidsrdquo TheJournal of Steroid Biochemistry and Molecular Biology vol 45no 6 pp 509ndash511 1993

[151] J W Simpkins K D Yi S-H Yang and J A Dykens ldquoMito-chondrial mechanisms of estrogen neuroprotectionrdquo Biochim-ica et Biophysica ActamdashGeneral Subjects vol 1800 no 10 pp1113ndash1120 2010

[152] M Manatt and S B Chandra ldquoThe effects of mitochondrialdysfunction in schizophreniardquo Journal of Medical Genetics andGenomics V vol 3 no 5 pp 84ndash94 2011

[153] W R Perlman E Tomaskovic-Crook D M Montague etal ldquoAlteration in estrogen receptor 120572 mRNA levels in frontalcortex and hippocampus of patients with major mental illnessrdquoBiological Psychiatry vol 58 no 10 pp 812ndash824 2005

[154] N G Weiland C Orikasa S Hayashi and B S McEwenldquoDistribution and hormone regulation of estrogen receptorimmunoreactive cells in the hippocampus of male and femaleratsrdquoThe Journal of Comparative Neurology vol 388 no 4 pp603ndash612 1997

[155] C S Weickert A L Miranda-angulo J Wong et al ldquoVariantsin the estrogen receptor alpha gene and its mRNA contribute torisk for schizophreniardquo Human Molecular Genetics vol 17 no15 pp 2293ndash2309 2008

[156] J D Sweatt ldquoHippocampal function in cognitionrdquo Psychophar-macology vol 174 no 1 pp 99ndash110 2004

[157] A M Owen ldquoThe functional organization of working memoryprocesses within human lateral frontal cortex the contributionof functional neuroimagingrdquo The European Journal of Neuro-science vol 9 no 7 pp 1329ndash1339 1997

[158] M Cyr F Calon M Morissette and T Di Paolo ldquoEstrogenicmodulation of brain activity implications for schizophreniaand Parkinsonrsquos diseaserdquo Journal of Psychiatry andNeurosciencevol 27 no 1 pp 12ndash27 2002

[159] O D Howes and S Kapur ldquoThe dopamine hypothesisof schizophrenia version IIImdashthe final common pathwayrdquoSchizophrenia Bulletin vol 35 no 3 pp 549ndash562 2009

[160] F P Bymaster D O Calligaro J F Falcone et al ldquoRadioreceptorbinding profile of the atypical antipsychotic olanzapinerdquo Neu-ropsychopharmacology vol 14 no 2 pp 87ndash96 1996

[161] I Creese D R Burt and S H Snyder ldquoDopamine receptorbinding predicts clinical and pharmacological potencies ofantischizophrenic drugsrdquo Science vol 192 no 4238 pp 481ndash483 1976

[162] T Di Paolo ldquoModulation of brain dopamine transmission bysex steroidsrdquo Reviews in the Neurosciences vol 5 no 1 pp 27ndash41 1994

[163] C Leranth R H Roth J D Elswoth F Naftolin T L Horvathand D E Redmond ldquoEstrogen is essential for maintainingnigrostriatal dopamine neurons in primates implications forParkinsonrsquos disease and memoryrdquo Journal of Neuroscience vol20 no 23 pp 8604ndash8609 2000

[164] M Cyr F Calon M Morissette M Grandbois S Callierand T Di Paolo ldquoDrugs with estrogen-like potency and brainactivity potential therapeutic application for the CNSrdquo CurrentPharmaceutical Design vol 6 no 12 pp 1287ndash1312 2000

[165] C Pasqualini V Olivier B Guibert O Frain and V LevielldquoAcute stimulatory effect of estradiol on striatal dopaminesynthesisrdquo Journal of Neurochemistry vol 65 no 4 pp 1651ndash1657 1995

[166] M Pecins-Thompson N A Brown S G Kohama and C LBethea ldquoOvarian steroid regulation of tryptophan hydroxylasemRNA expression in rhesus macaquesrdquo The Journal of Neuro-science vol 16 no 21 pp 7021ndash7029 1996

[167] L Xiao and J B Becker ldquoQuantitative microdialysis deter-mination of extracellular striatal dopamine concentration inmale and female rats effects of estrous cycle and gonadectomyrdquoNeuroscience Letters vol 180 no 2 pp 155ndash158 1994

[168] M G Sanchez M Morissette and T Di Paolo ldquoEffect ofa chronic treatment with 17120573-estradiol on striatal dopamineneurotransmission and the AktGSK3 signaling pathway in thebrain of ovariectomized monkeysrdquo Psychoneuroendocrinologyvol 37 no 2 pp 280ndash291 2012

[169] E S Emamian ldquoAKTGSK3 signaling pathway and schizophre-niardquo Frontiers in Molecular Neuroscience vol 5 article 33 2012

[170] M F Kritzer and S G Kohama ldquoOvarian hormones differen-tially influence immunoreactivity for dopamine120573- hydroxylasecholine acetyltransferase and serotonin in the dorsolateral pre-frontal cortex of adult rhesus monkeysrdquo Journal of ComparativeNeurology vol 409 no 3 pp 438ndash451 1999


[171] A-LNordstromHOlsson andCHalldin ldquoAPET study ofD2dopamine receptor density at different phases of the menstrualcyclerdquo Psychiatry ResearchmdashNeuroimaging vol 83 no 1 pp 1ndash6 1998

[172] M C Craig W J Cutter H Wickham et al ldquoEffect oflong-term estrogen therapy on dopaminergic responsivity inpost-menopausal womenmdasha preliminary studyrdquo Psychoneu-roendocrinology vol 29 no 10 pp 1309ndash1316 2004

[173] A Gogos P Kwek C Chavez andM van den Buuse ldquoEstrogentreatment blocks 8-Hydroxy-2-Dipropylaminotetralin- andapomorphine-induced disruptions of prepulse inhibitioninvolvement of dopamine D

1or D2or serotonin 5-HT

1119860

5-HT2119860 or 5-HT7 receptorsrdquoThe Journal of Pharmacology and

Experimental Therapeutics vol 333 no 1 pp 218ndash227 2010[174] D Madularu W M Shams and W G Brake ldquoEstrogen

potentiates the behavioral and nucleus accumbens dopamineresponse to continuous haloperidol treatment in female ratsrdquoThe European Journal of Neuroscience vol 39 no 2 pp 257ndash265 2014

[175] T D Purves-Tyson D J Handelsman K L Double S J OwensS Bustamante and C S Weickert ldquoTestosterone regulation ofsex steroid-related mRNAs and dopamine-related mRNAs inadolescent male rat substantia nigrardquo BMC Neuroscience vol13 article 95 2012

[176] H Y Meltzer ldquoThe importance of serotonin-dopamine interac-tions in the action of clozapinerdquoTheBritish Journal of PsychiatrySupplement no 17 pp 22ndash29 1992

[177] C A Stockmeier J J DiCarlo Y Zhang PThompson andH YMeltzer ldquoCharacterization of typical and atypical antipsychoticdrugs based on in vivo occupancy of serotonin2 and dopamine2receptorsrdquo The Journal of Pharmacology and ExperimentalTherapeutics vol 266 no 3 pp 1374ndash1384 1993

[178] P W J Burnet S L Eastwood and P J Harrisonldquo5-HT1A5-HT2A receptor mRNAs and binding site den-sities are differentially altered in schizophreniardquo Neuropsy-chopharmacology vol 15 no 5 pp 442ndash455 1996

[179] P W J Burnet S L Eastwood and P J Harrison ldquo[3H]WAY-100635 for 5-HT

1119860receptor autoradiography in human brain

A comparison with [3H]8-OH-DPAT and demonstration ofincreased binding in the frontal cortex in schizophreniardquoNeurochemistry International vol 30 no 6 pp 565ndash574 1997

[180] T Sumiyoshi C A Stockmeier J C Overholser G E Dilleyand H Y Meltzer ldquoSerotonin

1119860receptors are increased in post-

mortemprefrontal cortex in schizophreniardquoBrain Research vol708 no 1-2 pp 209ndash214 1996

[181] B Dean and W Hayes ldquoDecreased frontal cortical serotonin2A

receptors in schizophreniardquo Schizophrenia Research vol 21 no3 pp 133ndash139 1996

[182] B Dean W Hayes C Hill and D Copolov ldquoDecreasedserotonin2A receptors in brodmannrsquos area 9 from schizophrenicsubjects A pathological or pharmacological phenomenonrdquoMolecular and Chemical Neuropathology vol 34 no 2-3 pp133ndash145 1998

[183] L Zhang W Ma J L Barker and D R Rubinow ldquoSex differ-ences in expression of serotonin receptors (subtypes 1A and 2A)in rat brain a possible role of testosteronerdquo Neuroscience vol94 no 1 pp 251ndash259 1999

[184] T Inagaki C Gautreaux and V Luine ldquoAcute estrogen treat-ment facilitates recognition memory consolidation and altersmonoamine levels in memory-related brain areasrdquo Hormonesand Behavior vol 58 no 3 pp 415ndash426 2010

[185] A Kugaya C N Epperson S Zoghbi et al ldquoIncrease inprefrontal cortex serotonin

2119860receptors following estrogen

treatment in postmenopausal womenrdquo American Journal ofPsychiatry vol 160 no 8 pp 1522ndash1524 2003

[186] E L Moses W C Drevets G Smith et al ldquoEffects ofestradiol and progesterone administration on human serotonin2A receptor binding a PET Studyrdquo Biological Psychiatry vol 48no 8 pp 854ndash860 2000

[187] G S Kranz C Rami-Mark U Kaufmann et al ldquoEffects of hor-mone replacement therapy on cerebral serotonin-1A receptorbinding in postmenopausal women examined with [carbonyl-11C]WAY-100635rdquo Psychoneuroendocrinology vol 45 pp 1ndash102014

[188] I Blum Y Vered A Lifshitz et al ldquoThe effect of estrogenreplacement therapy on plasma serotonin and catecholaminesof postmenopausal womenrdquo Israel Journal of Medical Sciencesvol 32 no 12 pp 1158ndash1162 1996

[189] C N Epperson Z Amin K Ruparel R Gur and J Loug-head ldquoInteractive effects of estrogen and serotonin on brainactivation during working memory and affective processing inmenopausal womenrdquo Psychoneuroendocrinology vol 37 no 3pp 372ndash382 2012

[190] V G Frokjaer D Erritzoe A Juul et al ldquoEndogenous plasmaestradiol in healthy men is positively correlated with cere-bral cortical serotonin 2A receptor bindingrdquo Psychoneuroen-docrinology vol 35 no 9 pp 1311ndash1320 2010

[191] R Hiroi and R J Handa ldquoEstrogen receptor-120573 regulates humantryptophan hydroxylase-2 through an estrogen response ele-ment in the 51015840 untranslated regionrdquo Journal of Neurochemistryvol 127 no 4 pp 487ndash495 2013

[192] C L Bethea A W Smith M L Centeno and A P ReddyldquoLong-term ovariectomy decreases serotonin neuron numberand gene expression in free ranging macaquesrdquo Neurosciencevol 192 pp 675ndash688 2011

[193] C L Bethea ldquoRegulation of progestin receptors in rapheneurons of steroid-treated monkeysrdquo Neuroendocrinology vol60 no 1 pp 50ndash61 1994

[194] A Gogos and M van den Buuse ldquoEstrogen and progesteroneprevent disruption of prepulse inhibition by the serotonin-1a receptor agonist 8-hydroxy-2-dipropylaminotetralinrdquo TheJournal of Pharmacology and Experimental Therapeutics vol309 no 1 pp 267ndash274 2004

[195] A Gogos P J Nathan V Guille R J Croft and M VanDen Buuse ldquoEstrogen prevents 5-HT1A receptor-induced dis-ruptions of prepulse inhibition in healthy womenrdquo Neuropsy-chopharmacology vol 31 no 4 pp 885ndash889 2006

[196] V Guille A Gogos P J Nathan R J Croft and M van denBuuse ldquoInteraction of estrogen with central serotonergic mech-anisms in human sensory processing loudness dependence ofthe auditory evoked potential andmismatch negativityrdquo Journalof Psychopharmacology vol 25 no 12 pp 1614ndash1622 2011

[197] G Juckel ldquoSerotonin from sensory processing to schizophre-nia using an electrophysiological methodrdquo Behavioural BrainResearch vol 277 pp 121ndash124 2015

[198] C Wyss K Hitz M P Hengartner et al ldquoThe loudnessdependence of auditory evoked potentials (LDAEP) as an indi-cator of serotonergic dysfunction in patients with predominantschizophrenic negative symptomsrdquo PLoS ONE vol 8 no 7Article ID e68650 2013

[199] D C Javitt and S R Zukin ldquoRecent advances in the phen-cyclidine model of schizophreniardquo The American Journal ofPsychiatry vol 148 no 10 pp 1301ndash1308 1991


[200] A C Lahti B Koffel D LaPorte and C A Tamminga ldquoSub-anesthetic doses of ketamine stimulate psychosis in schizophre-niardquo Neuropsychopharmacology vol 13 no 1 pp 9ndash19 1995

[201] G Northoff A Richter F Bermpohl et al ldquoNMDA hypo-function in the posterior cingulate as a model for schizophre-nia an exploratory ketamine administration study in fMRIrdquoSchizophrenia Research vol 72 no 2-3 pp 235ndash248 2005

[202] J H Meador-Woodruff A J Hogg Jr and R E Smith ldquoStriatalionotropic glutamate receptor expression in schizophreniabipolar disorder andmajor depressive disorderrdquo Brain ResearchBulletin vol 55 no 5 pp 631ndash640 2001

[203] E Scarr M Beneyto J H Meador-Woodruff and B DeanldquoCortical glutamatergic markers in schizophreniardquo Neuropsy-chopharmacology vol 30 no 8 pp 1521ndash1531 2005

[204] B Dean E Scarr R Bradbury andD Copolov ldquoDecreased hip-pocampal (CA3) NMDA receptors in schizophreniardquo Synapsevol 32 no 1 pp 67ndash69 1999

[205] N Matosin E Frank C Deng X-F Huang and K ANewell ldquoMetabotropic glutamate receptor 5 binding and pro-tein expression in schizophrenia and following antipsychoticdrug treatmentrdquo Schizophrenia Research vol 146 no 1ndash3 pp170ndash176 2013

[206] E Frank K A Newell and X-F Huang ldquoDensity ofmetabotropic glutamate receptors 2 and 3 (mGluR23) in thedorsolateral prefrontal cortex does not differ with schizophre-nia diagnosis but decreases with agerdquo Schizophrenia Researchvol 128 no 1ndash3 pp 56ndash60 2011

[207] M Beneyto L V Kristiansen A Oni-Orisan R E McCullum-smith and J HMeador-Woodruff ldquoAbnormal glutamate recep-tor expression in themedial temporal lobe in schizophrenia andmood disordersrdquo Neuropsychopharmacology vol 32 no 9 pp1888ndash1902 2007

[208] X-MGao K Sakai R C Roberts R R Conley B Dean andCA Tamminga ldquoIonotropic glutamate receptors and expressionof N-methyl-D-aspartate receptor subunits in subregions ofhuman hippocampus effects of schizophreniardquo The AmericanJournal of Psychiatry vol 157 no 7 pp 1141ndash1149 2000

[209] M Cyr O Ghribi C Thibault M Morissette M Landry andT Di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[210] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[211] S G Kohama V T Garyfallou and H F Urbanski ldquoRegionaldistribution of glutamate receptor mRNA in the monkeyhippocampus and temporal cortex influence of estradiolrdquoMolecular Brain Research vol 53 no 1-2 pp 328ndash332 1998

[212] M Kajta and W Lason ldquoOestrogen effects on kainate-inducedtoxicity in primary cultures of rat cortical neuronsrdquo ActaNeurobiologiae Experimentalis vol 60 no 3 pp 365ndash369 2000

[213] K Kurata M Takebayashi S Morinobu and S Yamawakildquo120573-estradiol dehydroepiandrosterone and dehydroepiandros-terone sulfate protect against N-methyl-D-aspartate-inducedneurotoxicity in rat hippocampal neurons by different mech-anismsrdquoThe Journal of Pharmacology and Experimental Thera-peutics vol 311 no 1 pp 237ndash245 2004

[214] C Galvin and I Ninan ldquoRegulation of the mouse medialprefrontal cortical synapses by endogenous estradiolrdquo Neu-ropsychopharmacology vol 39 no 9 pp 2086ndash2094 2014

[215] J W Phillis D Song and M H OrsquoRegan ldquoTamoxifen achloride channel blocker reduces glutamate and aspartaterelease from the ischemic cerebral cortexrdquo Brain Research vol780 no 2 pp 352ndash355 1998

[216] P Karki A Webb K Smith et al ldquoCAMP response element-binding protein (CREB) and nuclear factor 120581B mediate thetamoxifen-induced up-regulation of glutamate transporter 1(GLT

minus1) in rat astrocytesrdquo The Journal of Biological Chemistry

vol 288 no 40 pp 28975ndash28986 2013[217] P Karki A Webb A Zerguine J Choi D-S Son and E Lee

ldquoMechanism of raloxifene-induced upregulation of glutamatetransporters in rat primary astrocytesrdquo Glia vol 62 no 8 pp1270ndash1283 2014

[218] E Lee M Sidoryk-Wegrzynowicz N Wang et al ldquoGPR30regulates glutamate transporterGLT-1 expression in rat primaryastrocytesrdquoThe Journal of Biological Chemistry vol 287 no 32pp 26817ndash26828 2012

[219] J Pawlak V Brito E Kuppers and C Beyer ldquoRegulationof glutamate transporter GLAST and GLT-1 expression inastrocytes by estrogenrdquo Molecular Brain Research vol 138 no1 pp 1ndash7 2005

[220] J S Sutcliffe F Rhaman K M Marshall and J C NeillldquoOestradiol attenuates the cognitive deficit induced by acutephencyclidine treatment in mature female hooded-Lister ratsrdquoJournal of Psychopharmacology vol 22 no 8 pp 918ndash922 2008

[221] A S Roseman C McGregor and J E Thornton ldquoEstradiolattenuates the cognitive deficits in the novel object recognitiontask induced by sub-chronic phencyclidine in ovariectomizedratsrdquo Behavioural Brain Research vol 233 no 1 pp 105ndash1122012

[222] G Hermes N Li C Duman and R Duman ldquoPost-weaningchronic social isolation produces profound behavioral dysreg-ulation with decreases in prefrontal cortex synaptic-associatedprotein expression in female ratsrdquo Physiology amp Behavior vol104 no 2 pp 354ndash359 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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EndocrinologyInternational Journal of



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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


onset symptom severity and outcome of schizophrenia arenow thought to support the hypothesis that sex hormonesmay also have a role in the aetiology as well as treatment ofschizophrenia

Estrogen is a gonadal hormone that can exert powerfuleffects in numerous regions of the brain consequently affect-ing mood cognition and behaviour [15] Research over thelast two decades has established a clear neuromodulatory roleof estrogen in the pathogenesis and therapeutics of neuropsy-chiatric disorders including schizophrenia Estrogen is oftenconsidered the primary ldquofemalerdquo sex hormone although it ispresent in both sexes [16] Reference to estrogen can broadlyrefer to numerous estrogenic compounds including estradiolestrone estriol equilin and ethinylestradiol In this reviewreference to estrogen refers to the most potent endogenousform 17120573-estradiol unless otherwise stated 17120573-estradiol hasa role in the development of secondary sex characteristicsin women and reproduction in men and in both sexes hasperipheral effects in areas including the liver and bone [17]While 17120573-estradiol is primarily produced in the ovaries toregulate menstrual cycle in females it is also created bynonendocrine tissues including fat breast and importantlythe brain [18] Estrogen has neuroprotective properties and ithas been suggested that it can exert its effects over the entirelifetime protecting the brain from certain insults [19] Accu-mulating evidence has led to the hypothesis that recurringhormone influxes in women serve as a protective factor inthe initial development of schizophrenia [14] Thus in recentyears an increasing amount of literature has explored estrogentherapy as a potential form of treatment for schizophrenia[20 21]

This literature review aims to critically analyse therelevance of estrogen in relation to the pathogenesis andtherapeutics of schizophrenia in a clinical settingThis reviewwill also report on preclinical research and the molecularmechanisms that may underlie the therapeutic effects ofestrogen in schizophrenia

2 Clinical Findings

21 Gender Differences in Schizophrenia A rich literatureelaborately describes gender differences in schizophreniarelating to disease risk course and outcome [22ndash24] Thereis a difference in the age-at-onset of schizophrenia betweenthe sexes whereby men reach a peak onset at the ages of 18ndash24 years whereas for women it occurs up to 4 years later[25 26]This is awell-replicated finding and occurs regardlessof the definition of onset used it is consistent across culturesand is not due to differences in symptoms or social roleFurthermore only in females with schizophrenia is there asecond peak age-at-onset at 45ndash50 years of age [27] There isan increased incidence rate in men (14 1 ratio) which hasbeen verified by 2 independent meta-analyses and remainseven after controlling for various confounding factors suchas age range diagnostic criterion and hospital bias [28 29]There is a plethora of studies based in different countries andcultures supporting the notion that women with schizophre-nia present with a less severe course of the illness comparedto men [24 30 31] For example women with schizophrenia

present with less severe negative symptoms but exhibit morepositive and affective symptoms [32] In women a laterage-at-onset and presentation of affective symptoms havepredicted a better prognosis whereas in men an earlier onsetand presentation of primarily negative symptoms predict aworse course of illness and outcome [22] Females showa more favourable antipsychotic treatment response thanmales [33 34] have fewer hospitalisations better adapt tothe illness and present less disability (particularly with self-care) Women also have an improved outcome and improvedquality of life for example they aremore likely to bemarriedremain employed and keep in contact with family andfriends [24] Men have more brain structural abnormalitiesthan females including enlarged ventricles and decreasedtemporal lobe volume [35ndash37]

22 Estrogen Hypothesis of Schizophrenia In light of thegender differences described above it has been hypothesizedthat gonadal steroids may play a role in buffering femalesagainst the development of schizophrenia [32 38] This isconsistent with the existence of a second peak of onset infemales after the age of 40 which may be associated withmenopause a time of rapidly declining sex hormone levels[25 39] Further premenopausal women with schizophreniaexperience a better course of illness with less negativesymptoms and respond better to antipsychotic treatment(ie require lower doses) than older women [34] The mostcommon interpretation of these gender differences is thewell-described ldquoestrogen hypothesisrdquo which postulates thatestrogen plays a protective role against schizophrenia [14 40]However it is important to note that the studies describinggender differences in schizophrenia suggest sex steroid dys-function not necessarily only estrogen dysfunction A num-ber of reproductive hormones may be implicated includingtestosterone progesterone or luteinising hormone and thusit is important to acknowledge that there is a complexinterplay of hormones occurring For example progesteroneand estrogen naturally vary with each other over endogenoushormonal cycles therefore the influence of progesterone oran interaction between the two hormones on the observedphenomena cannot be excluded However this review willfocus on estrogen as the estrogen hypothesis has been well-supported by molecular animal and clinical studies [41ndash43]

23 Evidence for Estrogen Dysfunction in Patients withSchizophrenia An early study reported that of the sam-ple of 276 women admitted to psychiatric hospitals 46were admitted during or immediately before menstruationa period of low circulating estrogen levels [44] Furtherpsychotic symptoms were reported to improve during preg-nancy [45] but worsened postpartum [46] More recentlycase reports and clinical studies have shown that womenwith schizophrenia demonstrate increased symptom severitygreater relapse rates and more hospital admissions duringtimes of low circulating sex hormones including the earlyfollicular phase of the menstrual cycle postpartum andpostmenopause [47ndash50] In contrast rates of relapse areless frequent and symptom severity is reduced during timesof high circulating sex hormones including pregnancy and



















ER120572 ER120573or


EREAP-1


Second messengers

Genomic actions

Nongenomicactions

MAPKcAMP

GPR30

Estrogen

mERs

































References
























































































































































































1119860



































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































ER120572 ER120573or


EREAP-1


Second messengers

Genomic actions

Nongenomicactions

MAPKcAMP

GPR30

Estrogen

mERs

































References
























































































































































































1119860



































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































References
























































































































































































1119860



































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































































































































































1119860



































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings

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Transcript of A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings