- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
International Journal of Endocrinology
Volume 2015 (2015), Article ID 615356, 16 pages
A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings
1Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia
2School of Psychology and Public Health, La Trobe University, Bundoora, VIC 3086, Australia
Received 1 July 2015; Revised 21 August 2015; Accepted 23 August 2015
Academic Editor: Haifei Shi
Copyright © 2015 Andrea Gogos et al. This is an open access article distributed under the Creative Commons Attribution License, which 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 steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17β-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol’s underlying protective mechanisms is also substantially discussed, with particular focus on estradiol’s impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems.
Schizophrenia is a complex neuropsychiatric disorder, which will affect approximately 0.7% of the population during their lifetime . Schizophrenia is a profoundly debilitating illness currently ranking among the top 10 causes of long-term disability worldwide , which imposes a significant financial burden on public health services as it is one of the most financially costly psychiatric disorders to manage . The profound impact of the disorder is reflected in the fact that approximately 70–92% of patients with schizophrenia are unemployed . Additionally, people with schizophrenia are 13-fold more likely to die by suicide than are members of the general population , and also have a life expectancy 10–25 years less, even after accounting for suicide . Schizophrenia is a disorder characterised by severe impairment of cognition, emotions, and behaviour  with symptomatology being classified within three main clusters: positive symptoms, negative symptoms, and cognitive deficits . Positive symptoms (additive to normal, healthy function) include hallucinations and delusions whilst negative symptoms (deficits) include blunted drive and affect (i.e., asociality, alogia, and avolition) . The heterogeneity of symptoms reflects the diagnosis of schizophrenia defined as a syndrome of disorders, thereby signifying that there may be a need to identify differing aetiologies for different diseases within the syndrome of schizophrenia, which currently remain largely unknown .
The numerous neurotransmitter systems implicated in schizophrenia (e.g., dopaminergic, glutamatergic, and serotonergic systems) add to the difficulty in effectively treating the disorder . Presently, the primary treatment for schizophrenia is antipsychotic medications , which predominantly target the dopaminergic system . However, antipsychotics have reduced efficacy on the negative and cognitive symptoms of schizophrenia  and with respect to the positive symptoms are not efficacious for 20–30% of patients with the disorder [10, 13]. This has led to the exploration of potential adjunctive treatments, such as treatment with estrogen , to extend the current therapeutic benefits of antipsychotic drugs. Importantly the gender differences in onset, symptom severity, and outcome of schizophrenia are now thought to support the hypothesis that sex hormones may also have a role in the aetiology, as well as treatment, of schizophrenia.
Estrogen is a gonadal hormone that can exert powerful effects in numerous regions of the brain, consequently affecting mood, cognition, and behaviour . Research over the last two decades has established a clear neuromodulatory role of estrogen in the pathogenesis and therapeutics of neuropsychiatric disorders including schizophrenia. Estrogen is often considered the primary “female” sex hormone, although it is present in both sexes . Reference to estrogen can broadly refer to numerous estrogenic compounds including estradiol, estrone, estriol, equilin, and ethinylestradiol. In this review, reference to estrogen refers to the most potent endogenous form, 17β-estradiol, unless otherwise stated. 17β-estradiol has a role in the development of secondary sex characteristics in women and reproduction in men and in both sexes has peripheral effects in areas including the liver and bone . While 17β-estradiol is primarily produced in the ovaries to regulate menstrual cycle in females, it is also created by nonendocrine tissues, including fat, breast, and importantly the brain . Estrogen has neuroprotective properties and it has been suggested that it can exert its effects over the entire lifetime, protecting the brain from certain insults . Accumulating evidence has led to the hypothesis that recurring hormone influxes in women serve as a protective factor in the initial development of schizophrenia . Thus, in recent years an increasing amount of literature has explored estrogen therapy as a potential form of treatment for schizophrenia [20, 21].
This literature review aims to critically analyse the relevance of estrogen in relation to the pathogenesis and therapeutics of schizophrenia in a clinical setting. This review will also report on preclinical research and the molecular mechanisms that may underlie the therapeutic effects of estrogen in schizophrenia.
2. Clinical Findings
2.1. Gender Differences in Schizophrenia
A rich literature elaborately describes gender differences in schizophrenia relating to disease risk, course, and outcome [22–24]. There is a difference in the age-at-onset of schizophrenia between the sexes, whereby men reach a peak onset at the ages of 18–24 years, whereas for women it occurs up to 4 years later [25, 26]. This is a well-replicated finding and occurs regardless of the definition of onset used; it is consistent across cultures and is not due to differences in symptoms or social role. Furthermore, only in females with schizophrenia is there a second peak age-at-onset at 45–50 years of age . There is an increased incidence rate in men (1.4 : 1 ratio), which has been verified by 2 independent meta-analyses, and remains even after controlling for various confounding factors such as age range, diagnostic criterion, and hospital bias [28, 29]. There is a plethora of studies based in different countries and cultures supporting the notion that women with schizophrenia present with a less severe course of the illness compared to men [24, 30, 31]. For example, women with schizophrenia present with less severe negative symptoms but exhibit more positive and affective symptoms . In women, a later age-at-onset and presentation of affective symptoms have predicted a better prognosis, whereas in men an earlier onset and presentation of primarily negative symptoms predict a worse course of illness and outcome . Females show a more favourable antipsychotic treatment response than males [33, 34], have fewer hospitalisations, better adapt to the illness, and present less disability (particularly with self-care). Women also have an improved outcome and improved quality of life; for example, they are more likely to be married, remain employed, and keep in contact with family and friends . Men have more brain structural abnormalities than females, including enlarged ventricles and decreased temporal lobe volume [35–37].
2.2. Estrogen Hypothesis of Schizophrenia
In light of the gender differences described above, it has been hypothesized that gonadal steroids may play a role in buffering females against the development of schizophrenia [32, 38]. This is consistent with the existence of a second peak of onset in females after the age of 40 which may be associated with menopause, a time of rapidly declining sex hormone levels [25, 39]. Further, premenopausal women with schizophrenia experience a better course of illness with less negative symptoms and respond better to antipsychotic treatment (i.e., require lower doses) than older women . The most common interpretation of these gender differences is the well-described “estrogen hypothesis,” which postulates that estrogen plays a protective role against schizophrenia [14, 40]. However, it is important to note that the studies describing gender differences in schizophrenia suggest sex steroid dysfunction, not necessarily only estrogen dysfunction. A number of reproductive hormones may be implicated, including testosterone, progesterone, or luteinising hormone, and thus it is important to acknowledge that there is a complex interplay of hormones occurring. For example, progesterone and estrogen naturally vary with each other over endogenous hormonal cycles; therefore the influence of progesterone or an interaction between the two hormones on the observed phenomena cannot be excluded. However, this review will focus on estrogen as the estrogen hypothesis has been well-supported by molecular, animal, and clinical studies [41–43].
2.3. Evidence for Estrogen Dysfunction in Patients with Schizophrenia
An early study reported that, of the sample of 276 women admitted to psychiatric hospitals, 46% were admitted during or immediately before menstruation, a period of low circulating estrogen levels . Further, psychotic symptoms were reported to improve during pregnancy  but worsened postpartum . More recently, case reports and clinical studies have shown that women with schizophrenia demonstrate increased symptom severity, greater relapse rates, and more hospital admissions during times of low circulating sex hormones, including the early follicular phase of the menstrual cycle, postpartum, and postmenopause [47–50]. In contrast, rates of relapse are less frequent and symptom severity is reduced during times of high circulating sex hormones, including pregnancy and the mid-luteal stage of the menstrual cycle [47, 51]. For example, Hallonquist et al.  assessed the variation in symptom severity in female outpatients with schizophrenia during two phases of the menstrual cycle. The authors found that symptom scores as measured by the Abbreviated Symptom Checklist were distinctly low during the mid-luteal phase but high during the early follicular phase . Similarly, Rubin et al.  reported that female patients with chronic schizophrenia showed less severe positive symptoms and general psychopathology (measured using the Positive and Negative Syndrome Scale, PANSS) during the mid-luteal phase versus the early follicular phase, whereas negative symptom severity did not change across the cycle . Some studies have specifically shown that there is a negative correlation between circulating estrogen levels and symptoms of schizophrenia, particularly the positive symptoms [39, 53]. In 125 premenopausal women with schizophrenia, Bergemann and colleagues  assessed psychopathology scores three times during the menstrual cycle. Using the PANSS and Brief Psychiatric Rating Scale, they found a significant improvement in psychotic symptoms during the luteal phase, which was associated with estradiol plasma levels . A positive relationship has also been discovered between later menarche, higher negative symptom scores (as measured by the Scales for Assessment of Negative Symptoms), and greater functional impairment in women with schizophrenia, suggesting that earlier puberty might predict improved clinical outcome . Similarly, a negative association has been discovered between age at menarche and first psychotic symptoms and first hospitalisation; more specifically, a relationship has been identified between earlier puberty and later onset of illness in women with schizophrenia .
Women with schizophrenia are often hypoestrogenic; that is, their circulating levels of estrogen are much lower than the normal reference range and they tend to experience menstrual irregularities [48, 49, 55]. Importantly, some studies showing reduced estrogen levels in women with schizophrenia were conducted during the preantipsychotic era [56, 57]. Since the introduction of antipsychotic drug treatment, reduction in estrogen levels is correlated with an increased risk of symptoms and is found regardless of the type of antipsychotic treatment [47, 58]. This is important as some antipsychotics can cause hyperprolactinaemia, which leads to a reduction in estrogen levels . Hyperprolactinaemia is mainly associated with antipsychotics, such as risperidone, which predominantly block the dopamine D2 receptor, the receptor that modulates prolactin release from the pituitary .
An important question is whether estrogen dysfunction occurs prior to or after the onset of schizophrenia. Early puberty has been associated with a late onset of the disorder , suggesting that physiological estrogens might delay the onset of schizophrenia . Many clinical studies examining plasma estrogen levels and symptomatology in schizophrenia patients require their participants to have a history of regular menstrual cycles; therefore it cannot be inferred from these samples whether gonadal dysfunction is merely a state or a trait of the disorder. Schepp  attempted to explore this question by investigating premenopausal first-episode schizophrenia patients. In comparison to age-matched healthy controls, schizophrenia patients had later menarche, mid-cycle bleeding, mild bleeding, hirsutism, and more tendency to be infertile [56, 61]. This study demonstrates evident gonadal dysfunction in a sample of first-time admitted patients; however, a longitudinal experiment examining endocrinological function, inclusive of prepubescent participants, is necessary to sufficiently answer whether premorbid hypoestrogenism occurs.
2.4. Clinical Trials of Adjunctive Estrogen in Schizophrenia
A growing body of double-blind, placebo-controlled, randomized trials provides evidence that estrogen treatment administered in conjunction with antipsychotics is beneficial for schizophrenia, particularly in reducing the positive symptoms [20, 62, 63]. An initial pilot study by Kulkarni et al.  discovered that the synthetic 17β-estradiol derivative, ethinylestradiol, taken orally daily for eight weeks significantly improved positive symptoms in premenopausal women with schizophrenia. Later trialling a transdermal method of administration, Kulkarni et al. [20, 63] found that women with schizophrenia receiving adjunctive estradiol had significant improvements in the positive symptoms and general psychopathology (PANSS) ratings [20, 63]. In their largest study to date, Kulkarni and colleagues  tested 183 premenopausal women with schizophrenia who were receiving transdermal 17β-estradiol (100 μg/day or 200 μg/day for 8 weeks) together with their prescribed antipsychotic. The largest effect was found in the women receiving 200 μg of estradiol, who showed reduced scores on the positive subscale of the PANSS . Another group found similar beneficial effects, where 8 weeks of adjunctive haloperidol and ethinylestradiol treatment resulted in reduced positive, general, and total PANSS scores, compared to the haloperidol-only group . On the other hand, a study by Bergemann and colleagues  failed to replicate the beneficial effect of estradiol in their placebo-controlled, double-blind study with 46 hypoestrogenic women, finding there was no difference in PANSS scores, relapse rates, or antipsychotic dose between treatment and placebo. This may be due to the use of a combined 17β-estradiol (1–4 mg) and progestin treatment, with doses varying dependent on the phase of menstrual cycle . In comparison, Kulkarni et al. [20, 63] administered only estrogen treatment and at a consistent daily dose for the duration of the experiment.
One cross-sectional study compared postmenopausal women with schizophrenia who were either users or nonusers of hormone replacement therapy. They found that the women taking hormones required a lower dose of antipsychotics and had less severe negative symptoms . Research thus far has primarily concerned females, evidently due to the premise for estrogen therapy relying on observation of hypoestrogenism in women. One study that examined the effects of estradiol in men with schizophrenia found that after two weeks of oral estradiol treatment in conjunction with antipsychotics, the estrogen group experienced more rapid reduction in general psychopathology compared to the placebo group . Although there is concern regarding the potentially feminising side effects of estradiol, estrogen therapy is currently used in males for other clinical conditions (e.g., prostate cancer), and the results of the Kulkarni et al.  study suggest exploration of estrogen treatment in men with schizophrenia is warranted.
Other forms of estrogen have also shown some beneficial effects on schizophrenia symptoms, although perhaps not as potent as the effects of 17β-estradiol. In a double-blind, randomized, placebo-controlled trial, 32 premenopausal women with chronic schizophrenia were treated with conjugated estrogens for 4 weeks, in addition to their antipsychotic treatment. Participants experienced a significant decrease in positive, negative, general, and total PANSS scores . In a similar study, however, Louzã et al.  found no significant difference between the treatment and placebo groups, although there was a trend for the conjugated estrogen group to show greater improvement . The selective estrogen receptor modulator raloxifene has also been trialled in women with schizophrenia with favourable results for the positive [70, 71], negative , and cognitive symptoms [73, 74].
Clinical research specifically concerning the influence of estradiol on cognition in schizophrenia patients is limited. With relevance to endogenous estrogen, research has found estradiol can improve certain cognitive functions in women with schizophrenia. Hoff et al.  determined there was a positive correlation with serum estradiol levels and a global cognitive score including six cognitive domains, with verbal and spatial memory, and perceptual motor speed being the most strongly related. Ko and colleagues  stratified their sample of women with schizophrenia into low or high estrogen groups by using the normal serum reference ranges for estradiol during the follicular phase of the menstrual cycle. Similar to the results of Hoff et al. , they found diminished performance in verbal memory and executive function in the low estradiol group, compared to the high estradiol group. Studies administering estradiol treatment provide less consistent results. Bergemann and colleagues  found oral 17β-estradiol and adjunctive antipsychotic treatment for women with schizophrenia improved metaphoric speech but had no effect on word fluency and verbal ability. In an experiment examining transdermal 17β-estradiol, Kulkarni et al.  found there were no significant differences between or within groups in cognitive domains including attention, language, visuospatial/constructional ability, and memory. These studies employed different neurocognitive batteries and different methods of administering estradiol, which may account for dissimilar outcomes.
The diverse results in the aforementioned estradiol trials may be due to a variety of inconsistent factors including dissimilar measures, severity of symptoms, variable treatment duration, additional pharmacotherapy (i.e., antipsychotics, benzodiazepines), oral versus transdermal administration, and pharmacological and pharmacokinetic variation in estrogen. Additionally, despite its putative effect on the positive symptoms of schizophrenia, estradiol at the efficacious dose is unfortunately not feasible for long-term management of schizophrenia due to the associated health risks (e.g., thromboembolism, endometrial hyperplasia). Evidently, estradiol treatment in men with schizophrenia also remains controversial due to potential feminising side effects [20, 67]. Nevertheless, overall the epidemiological and clinical data presented provide strong support for the notion that estradiol is protective in women with schizophrenia, particularly for the positive symptoms.
3. Mechanisms of Estrogen Action in Schizophrenia
The molecular mechanisms of how estrogen may affect schizophrenia symptoms remain largely unknown. Perhaps the simplest explanation is that estrogen can regulate the dopaminergic system of the central nervous system (CNS) by affecting the expression and function of dopamine receptors and transporters [78, 79]. However, there are several other possible mechanisms by which estradiol can exert the effects in the CNS, some of which have been well defined and others are yet to be characterised. Estradiol actions are generally categorised as either genomic or nongenomic. Genomic actions are delayed in onset and prolonged in duration, such as those likely to occur after chronic estradiol treatment. These effects occur through binding of intracellular estradiol to the estrogen receptor (ER), which belongs to the nuclear receptor superfamily. Upon binding, the receptors dimerise and then translocate to the nucleus where they bind to specific DNA sequences called estrogen response elements (EREs) found in the promotor region of estrogen-responsive genes or to activator protein 1 (AP-1) sites via Fos/Jun interactions, resulting in transcriptional activation of many different genes. The nongenomic actions occur through activation of intracellular second messenger pathways, such as the MAP kinase and cAMP, to elicit a more rapid response, including cell-excitability, synaptic transmission, and antioxidant effects [80–82]. These are believed to be mediated via either ERs interacting with other proteins to form a large complex anchored to the plasma membrane or an alternative G protein coupled receptor, GPR30 [83, 84] (see Figure 1).
Gene profiling of the mouse brain after treatment with estradiol has revealed changes in genes associated with biosynthesis, growth, synaptic potentiation and myelination, lipid synthesis and metabolism, cell signalling pathways, and epigenetic modifications [85, 86]. In the primate prefrontal cortex, estrogen treatment caused changes in genes involved in transcription regulation, neurotransmission, cell signalling, cell cycle control, and proliferation and differentiation . These effects could be a result of either genomic or nongenomic actions . Thus estrogen can have far-reaching and diverse effects on the brain. Interestingly, one group studied the gene expression profile of a cell line treated with 18 different antipsychotics and found a common signature shared by antipsychotics and estrogen receptor modulators: lipid homeostasis . It is theorised that the estrogen pathway may be involved in the therapeutic effect of antipsychotics .
3.1. Estrogen Receptors
The first ER, ERα, was cloned in 1986 , and the second subtype, ERβ, was not discovered until 1996 . The two receptor subtypes are encoded by separate genes, ESR1 and ESR2, respectively. A splice variant of ERβ was later identified, ERβ2 , which shows a much lower affinity to 17β-estradiol than ERα and ERβ1 , but can competitively bind at EREs and as such can act as a negative regulator of estrogen-dependent transcriptional activation . As expected, ERα is highly expressed in areas of the CNS that are implicated in the control of reproductive functions, such as the hypothalamus and preoptic areas , and receptor levels tend to be higher in the female rats than in males [95–97]. ERβ expression shows much overlap with ERα but appears to be more widely distributed, showing strong expression in areas such as the hippocampus in mice, rats, and humans [91, 98], while ERα mRNA is abundantly found in the prefrontal cortex of nonhuman primates [87, 99, 100], indicating both these receptors are involved in potentiating the nonreproductive estrogen actions such as learning and memory.
For many years there was uncertainty surrounding the role of ERs in nongenomic actions of estrogen. While ERα and ERβ were shown to activate nongenomic signalling through crosstalk with other signal transduction proteins , these receptors could not fully account for observed downstream effects of estrogen, such as its antioxidant properties , and it was speculated that another receptor could be involved. GPR30, previously an orphan receptor, was recently renamed G protein coupled estrogen receptor 1 (GPER) following evidence that estrogen can bind to and activate the receptor [102, 103]. It is found to be expressed in multiple regions of the rat CNS , including the hippocampus, frontal cortex, and substantia nigra [94, 104]. Several studies indicate that this receptor is localised to the cytoplasm , specifically the endoplasmic reticulum and Golgi apparatus [90, 105, 106]. However there is also evidence that it is expressed at the plasma membrane and dendritic spines of rat hippocampal neurons [104, 107–109], suggesting that localisation may be cell type-specific or influenced by state. This receptor can rapidly activate multiple kinase pathways involved in nongenomic estrogen actions  and appears to mediate many of the effects of estrogen in neuronal cells , including calcium oscillations and luteinising hormone-releasing activity in primate neurons . While CNS expression patterns do not appear to differ between the adult male and female rat [104, 105, 113], the receptor is implicated in sexual dimorphism of immune response in the GPER knock-out mouse . Importantly, there is emerging evidence for GPERs role in learning and memory [115–117] as well as neuronal plasticity . Several new members and isoforms of estrogen receptors have also recently been identified, some of which are expressed in the CNS, such as ER-X, which could be involved in the nongenomic actions of estrogen ; however these have yet to be well characterised .
3.2. Estrogen Receptors and Cognition
The role of estrogen on cognition is of particular importance for schizophrenia as the cognitive deficits associated with the disease are considered the most debilitating symptoms for patients to assimilate into society , and these symptoms are poorly treated using current antipsychotics . Sinopoli and colleagues  showed that a low dose of estradiol injected directly into the hippocampus, or a high dose injected into the prefrontal cortex, could improve radial arm maze performance (spatial working memory task) in rats . Several studies have demonstrated contradicting findings on the roles of ERα and ERβ on cognition. Viral delivery of ERα into the hippocampus has been shown to rescue memory deficits in ERα knock-out mice . In contrast, another study has shown a negative effect of ERα on memory, where estradiol treatment impaired acquisition of spatial memory, but not cue discrimination, in the Morris water maze in ovariectomised wild-type mice but not ERα knock-out mice . This suggests an ERα-dependent mechanism of estradiol in impairing spatial task performance . Recently, mice with ERβ knock-down showed improved spatial learning, which could be reversed by viral delivery of ERβ to the hippocampus . By contrast, treatment with selective ERβ agonist, diarylpropionitrile (DPN), in female ovariectomised rats enhanced recognition memory but had no effect following treatment with ERα-selective agonist, propyl pyrazole triol (PPT) . Results suggest that ERβ mediates the subchronic and acute effects of estrogen on recognition memory. Molecular work by the same authors showed that memory enhancements via DPN are likely to occur through alterations in monoamines in the hippocampus and prefrontal cortex . In a different species, Phan et al.  found that acute PPT treatment enhanced object and place recognition in ovariectomised mice, whilst DPN at the same dose did not affect object recognition and only slightly facilitated place recognition . Collectively, research demonstrates that different estrogen agonists, estrogen receptors, and brain regions have the ability to mediate dissimilar forms of learning and memory. It is currently difficult to isolate specific actions of ERs in relation to cognitive function. Not only does function change dependent on the cognitive task, but factors such as age, sex, and treatment duration can also alter outcomes. The latter is of particular importance due to the influence of treatment period on genomic versus nongenomic outcomes and consequently mediation via different estrogen receptors . More preclinical research is necessary to further clarify the specific role of ERs in relation to cognition, especially with specific relevance to schizophrenia.
3.3. Estrogen Effects on Brain Structure
Schizophrenia is associated with various structural brain changes, such as progressive decline in global gray and white matter volume in multiple brain regions followed by continuous ventricular enlargement . Abnormal cytoarchitecture also commonly occurs, including neuronal soma and neuropil volume reductions, irregular synaptic organization, and ectopic neurons [131, 132]. The effects of estrogen treatment on brain structure have been well documented, including the modulation of neurogenesis, synaptic density, plasticity and connectivity, and axonal sprouting (reviewed in ). Of particular relevance to cognition, estradiol treatment has been shown to enhance hippocampal synaptic plasticity in young ovariectomised rats , induce dendritic spine formation in CA1 pyramidal neurons , and stimulate neurogenesis of granule cells in the dentate gyrus of adult female rats . Estrogen can also modulate neurotrophic factors  as well as neurotransmission [15, 137], which can secondarily promote neuronal survival and proliferation. Thus, in women with schizophrenia, lower circulating estradiol levels [51, 65] may contribute to the observed brain pathology associated with the disorder. Based on these findings we would expect to see sex differences in brain abnormalities in people with schizophrenia. Indeed, two MRI studies reported more severe abnormalities in males than in females with the disorder when compared to age- and sex-matched controls, particularly in regard to ventricular enlargement  and temporal lobe volume . However there are some conflicting reports, where a similar MRI study showed no difference . Overall these studies suggest that estrogen levels could influence the brain structure differences that occur in the CNS of people with schizophrenia.
3.4. Neuroprotection by Estrogen
Neuroprotective effects are another key component of estrogen action that is relevant to schizophrenia . Early cell culture studies showed increased neuronal survival upon treatment with estrogen under serum deprivation [139–142] and subsequent studies have shown estrogen protection against injury from excitotoxicity [143–145], oxidative stress [101, 146], inflammation [147, 148], and apoptosis . Some of these protective actions have been attributed to the ability of estrogen to reduce the generation of free radicals . More recently, it has been suggested that the neuroprotective actions of estrogen are mediated through maintaining mitochondria function , and there is growing evidence of mitochondrial dysfunction playing a role in schizophrenia . Taken together, these findings indicate that low estrogen levels may leave the brain vulnerable to insult or age-related changes, leading to development of schizophrenia or increased symptom severity, and could explain the observed differences in disease onset and severity between males and females. Treatment with estrogen may therefore help to protect the brain from disease progression.
3.5. Changes in Estrogen Signaling in Schizophrenia
In 2005, Perlman and colleagues showed that while ERα mRNA was not different in the dorsolateral prefrontal cortex of people with schizophrenia, in the dentate gyrus region of the hippocampus ERα expression levels were lower in schizophrenia compared to healthy controls . This has implications in estrogen driven synaptic plasticity and neurogenesis, as this region of the hippocampus is important for control of these activities. Further, lower receptor levels are unlikely to be the result of lower circulating estradiol levels as low levels of hormone would be expected to upregulate receptor expression . Perlman et al.  study also detected a negative correlation between ERα mRNA expression in the dentate gyrus and age-at-onset, suggesting ERα levels may confer vulnerability to the disease. Furthermore, their finding appeared to be diagnosis specific, as people with major depressive disorder and bipolar disorder showed no difference in ERα expression compared to control . On the other hand, ERα mRNA levels were lower in the amygdala in major depressive disorder and bipolar disorder, but not in schizophrenia, compared to control, while sex differences were detected in the dorsolateral prefrontal cortex of people with major depressive disorder that was not present in control. These findings illustrate that alterations in ERα expression in the CNS across major mental illnesses are specific to sex, region, and diagnosis . More recently, ER gene variation has also been implicated in schizophrenia risk. Weickert et al.  showed a SNP in intron 1 of the ESR1 gene was more prevalent in people with schizophrenia. Moreover, this SNP was associated with lower expression levels of ERα in the prefrontal cortex among people with the disorder . Thus, ERα expression levels in the CNS appear to play an important role in schizophrenia pathophysiology and may explain some of the cognitive deficits associated with disorder, particularly in those CNS regions that are implicated in cognition such as the hippocampus  and prefrontal cortex .
3.6. Estrogen Effects on Major Neurotransmitter Systems Targeted by Antipsychotics
Several converging lines of evidence from clinical and animal studies suggest that estrogen can act to modulate the activity of the neurotransmitter systems targeted by current antipsychotics [30, 79, 83, 158]. Understanding the nature of these interactions is important for addressing the therapeutic potential of estrogen and of compounds that target estrogen signalling. Researchers have labelled estradiol as neuroprotective and antipsychotic, implicating numerous neurotransmitter systems in this mechanism . The strongest evidence for estrogen modulation of neurotransmitter systems comes from studies examining the dopamine, serotonin, and glutamate systems; examples of these studies are described below.
3.6.1. Estrogen Interaction with Dopamine
As stated earlier the most direct route by which estrogen could influence symptom severity in schizophrenia could be by modulating dopaminergic activity in the CNS as hyperactivation of the dopamine signalling system is thought to be a central mechanism affected in schizophrenia [12, 159]. Central to this hypothesis are observations that typical antipsychotics, such as haloperidol, are potent antagonists of dopamine D2 receptors  and can reduce positive symptoms of schizophrenia . The stimulatory effect of estrogen on the activity of dopaminergic neurons, particularly those in the striatum and nucleus accumbens, is well documented (see ). Rodent studies have demonstrated that phases of dopaminergic transmission vary during the estrous cycle . Removal of the primary source of estradiol via ovariectomy evokes a permanent loss of dopamine neuron density in the substantia nigra in nonhuman primates . Estradiol treatment can modulate the levels of dopamine transporters and receptors (pre- and postsynaptic) and dopamine synthesis, release, and turnover in both cortical and striatal regions [162, 164–167]. For example, ovariectomy in rats has been shown to reduce protein levels of the dopamine active transporter (which reuptakes dopamine into the neuron for recycling or degradation) and increase levels of dopamine D2 receptor in the nucleus accumbens and caudate nucleus . Subsequent treatment in ovariectomised rats with 17β-estradiol reversed the loss of dopamine transporter levels and reduced dopamine D2 receptor levels below that of intact control levels . Chronic 17β-estradiol treatment of ovariectomised monkeys increased dopamine transporter expression levels in the caudate putamen compared to vehicle-treated monkeys  and also led to a downstream activation of the Akt/GSK3 signalling pathway, which is thought to be impaired in schizophrenia . Ovariectomised macaques showed increased numbers of neurons expressing dopamine β hydroxylase (DBH), an enzyme involved in metabolising dopamine, across all layers of the dorsolateral prefrontal cortex. Treating ovariectomised macaques with 17β-estradiol returned the number of DBH-immunoreactive neurons to levels comparable to intact animals. Furthermore, cotreating ovariectomised macaques with 17β-estradiol and progesterone did not produce a greater effect than 17β-estradiol alone, suggesting this effect is primarily mediated by estrogen . One study treated ovariectomised rats with an ERβ-selective agonist and found increased brain monoamine levels in the prefrontal cortex, including a marked increase in dopamine levels, its metabolite homovanillic acid (HVA), and HVA/dopamine ratio . In humans, a PET study did not show any significant variation in striatal D2 receptor density throughout the menstrual cycle . However, postmenopausal women receiving estrogen replacement therapy following hysterectomy or oophorectomy showed increased dopamine responsiveness to apomorphine .
Rodent behaviour studies also show marked protective effects of estrogen on the dopaminergic system. For example, we measured a behavioural endophenotype of schizophrenia, prepulse inhibition, in ovariectomised female rats treated with estrogen and its analogues . We showed that 17β-estradiol, raloxifene, and tamoxifen prevented the disruption of prepulse inhibition induced by the dopamine D1/D2 receptor agonist, apomorphine . In another animal behaviour relevant to schizophrenia, 17β-estradiol treatment in combination with chronic antipsychotic haloperidol reduced amphetamine-induced locomotor hyperactivity in ovariectomised amphetamine-sensitized female rats . Interestingly, this effect of estradiol was not observed when paired with saline treatment, suggesting that estradiol exerts antipsychotic properties that further potentiate the functional efficacy of haloperidol. However, the lack of a haloperidol treatment-only group in this study makes it difficult to ascertain this facilitatory effect. In contrast to these studies in female rats, the treatment of male rats with 17β-estradiol following gonadectomy has not been shown to effect the mRNA expression of enzymes involved in dopamine synthesis and metabolism . This is in contrast to the increased expression of these enzymes seen in response to testosterone, suggesting that estrogen’s effect on dopamine signalling may be sex-specific . Overall, these studies suggest a protective action of estrogen, particularly in females, on the dopaminergic system.
3.6.2. Estrogen Interaction with Serotonin
The advent of clinically effective atypical antipsychotics which have a higher affinity for serotonin receptors compared to typical antipsychotics, has highlighted a role for the serotonergic system in schizophrenia [160, 176, 177]. Further, postmortem studies have reported altered levels of several serotonin receptors in cortical and subcortical regions of the CNS in people with schizophrenia [178–182]. Sex differences in the regulation of serotonin signalling have been reported by some, where serotonin 5-HT1A receptor mRNA levels were lower in the amygdala and hypothalamus of female rats compared to males, whilst 5-HT2A receptor binding was higher in the female hippocampus . Treating female rats with 17β-estradiol has been found to improve spatial working memory and increase the levels of serotonin in the prefrontal cortex . PET studies of postmenopausal women showed that estradiol replacement therapy increased serotonin 5-HT2A receptor levels in the prefrontal cortex [185, 186]. However, serotonin 5-HT1A receptor levels were not altered following estradiol replacement therapy , suggesting estradiol’s selective action on serotonin receptor subtypes. Another study reported a trend toward elevated plasma serotonin levels in postmenopausal women following estradiol replacement therapy, although this effect failed to reach statistical significance . Furthermore, clinical studies in postmenopausal women showed that removing tryptophan (a biochemical precursor for serotonin synthesis) from the diet prior to, but not after, estradiol treatment can reduce dorsolateral prefrontal and cingulate cortex activation during working memory tasks . Interestingly, a PET study conducted in healthy men found a positive correlation between the levels of the serotonin 5-HT2A receptor ligand [18F]altanserin and plasma levels of estradiol .
The effects of estradiol on serotonin receptor signalling may result from its capacity to modulate serotonin biosynthesis. In vitro studies in raphe cells have shown that ERβ acts as a transcription factor for the tryptophan hydroxylase-2 gene, which encodes the enzyme involved in biosynthesis of serotonin from tryptophan . Interestingly, it has been suggested that changes in serotonin biosynthesis in response to estradiol may vary following a prolonged disruption of estradiol signalling. Studies in macaques ovariectomised for 3 years report reductions in neurons positive for serotonin 5-HT1A receptor, serotonin transporter, and tryptophan hydroxylase-2 gene expression . These changes were largely absent in macaques 5 months after ovariectomy, while another study reported increased numbers of serotonin positive neurons in macaques 4–7 months after ovariectomy , suggesting reduced serotonergic signalling may become more pronounced with chronic loss of estradiol . Using the behavioural paradigm prepulse inhibition, we found that treatment of female ovariectomised rats with 17β-estradiol prevented a serotonin 5-HT1A receptor agonist-induced disruption of prepulse inhibition [21, 173, 194]. Similarly, we found that in healthy women pretreatment with estradiol prevented the disruption of prepulse inhibition induced by a partial serotonin 5-HT1A receptor agonist, buspirone . Further, in these same women, we found that estradiol pretreatment prevented a further buspirone-induced potentiation in loudness dependence of the auditory evoked potential (LDAEP) . This is a measure of early sensory processing that is thought to be primarily mediated by central serotonin function (reviewed in ). A high LDAEP, which is indicative of low serotonin neurotransmission, has been found to be tightly associated with the negative symptoms of schizophrenia . These results are therefore suggestive of a protective role of estradiol against the sensory processing or gating deficits typically observed in schizophrenia patients. Overall, the above studies collectively substantiate the idea of estradiol interacting with multiple facets of the serotonergic system, through which it might exert protective actions against the cognitive, positive, and negative symptom domains of schizophrenia.
3.6.3. Estrogen Interaction with Glutamate
Glutamate signals through two classes of receptors: the ionotropic receptors, which include the NMDA receptor, kainate receptor, and AMPA receptor subtypes; the metabotropic receptors, which include mGluR1-mGluR8 subtypes. The psychomimetic actions of drugs such as ketamine and phencyclidine, which are antagonists of the NMDA receptor, implicate the glutamatergic system in the pathophysiology of schizophrenia [199, 200]. Thus, glutamate’s role in schizophrenia has been proposed to involve NMDA receptor hypofunction . Postmortem studies of brains from people with schizophrenia show regionally discrete increases and decreases in both the levels of NMDA receptor [202–204] and the levels of other ionotropic and metabotropic glutamate receptors [202, 203, 205, 206]. Furthermore, regionally specific differences in the expression of the subunit components of these receptors are also reported in people with schizophrenia, which could affect receptor activity [202, 207, 208]. Chronic treatment with 17β-estradiol has been shown to modulate glutamate NMDA and AMPA receptor density in the rat brain . Further, studies showing treatment with 17β-estradiol or selective estrogen modulators can alter the NMDA receptor subunit levels in the rat hippocampus [209, 210] suggest that estrogen may have varying effects on different areas of the brain in schizophrenia. However, these findings are contrasted by studies in macaques, showing treating ovariectomised animals with 17β-estradiol does not alter hippocampal AMPA receptor or NMDA receptor subunit expression . Studies examining estradiol’s effects on neurodegeneration and damage in cortical and hippocampal neuron cultures have shown that estradiol can be neuroprotective against the effects of glutamate mediated neurotoxicity, further supporting a role for estradiol in the modulation of glutamate signalling [212, 213]. Endogenous estradiol has been shown to enhance basal glutamatergic transmission and facilitate synaptic plasticity in the mouse medial prefrontal cortex .
Our understanding of how estradiol regulates glutamate signalling in the CNS has been advanced by recent in vitro studies examining how the glutamate pathways are affected by selective estrogen receptor modulators. Tamoxifen, which has both agonist and antagonist properties on ERs in different tissues, has been shown to increase glutamate reuptake , suggesting that estradiol could affect the broad changes in ionotropic and metabotropic glutamate receptor activity in schizophrenia by regulating the availability of glutamate in the synaptic cleft. Excitatory amino acid transporters (EAAT) control the uptake of surplus glutamate from the synaptic cleft. In primary astrocyte cultures, tamoxifen and raloxifene are both able to upregulate the mRNA and protein expression of the astrocytic glutamate transporters, EAAT1 and EAAT2, via NFkB mediated pathways . The increase in EAAT2 expression in response to raloxifene has been shown to correspond to an increase in glutamate uptake, suggesting that the increase in EAAT levels results in a functional increase in EAAT activity [217, 218]. This upregulation of glutamate transporter gene expression by tamoxifen and raloxifene is mediated via ERα and ERβ receptors as well as GPER via extracellular signal-regulated kinases, the epidermal growth factor receptor, and cAMP response element-binding protein-mediated regulation of the NF-κB pathway [217, 218]. Treating astrocytic cells with estradiol has also been shown to increase EAAT1 and EAAT2 mRNA and protein expression, an effect that is attenuated by the estrogen receptor antagonist, ICI. Therefore, the effects of tamoxifen and raloxifene on astrocytic glutamate uptake are likely to result from the activation of the estrogen receptors and thus are comparable to the actions of estradiol .
Animal behavioural studies suggest estradiol’s effects on glutamatergic signalling may be involved in behaviours relevant to schizophrenia. Estradiol is protective against NMDA receptor antagonist-induced impairments in the novel object recognition task [220, 221], suggesting that estradiol has the potential to affect glutamatergic dysfunction in schizophrenia. Postweaning social isolation in rats has been shown to result in increased prepulse inhibition and startle response as well as cognitive rigidity, which is reflective of schizophrenia-like symptoms. In male rats, these symptoms are associated with a dysregulation of the serotonin and dopaminergic system in the CNS. By contrast, social isolation in female mice has been shown to downregulate the expression of the NR1 NMDA receptor subunit and the GluR1 AMPA receptor subunit and PSD95 as well as synapsin, which is involved in glutamate release . Whilst such studies suggest that estradiol plays a role in glutamatergic dysfunction in schizophrenia, estradiol treatment has not been shown to reduce deficits in prepulse inhibition in rats, caused by the NMDA receptor antagonist, MK-801 . Thus, further evidence is needed to support a therapeutic effect of estradiol on glutamate dysfunction in schizophrenia. Overall, whilst substantial evidence supports the role of estradiol in modulating the glutamatergic system at the molecular level, how these mechanisms make an impact at the phenotypic level remains elusive and thus requires more in-depth investigation.
4. Summary and Conclusions
In summary, schizophrenia is a neuropsychiatric disorder that has shown robust gender differences in numerous aspects of the illness, including an earlier age of onset, a more severe course of illness, poorer antipsychotic treatment response, and adaptability to illness in male patients with schizophrenia compared to that of women. This review has highlighted the research that has been invested to understand the potentially protective effects of estradiol with respect to these gender differences in schizophrenia. The extent of this research ranges from molecular investigations that have clearly evidenced estradiol’s intricate interactions with the major neurotransmitter systems in the brain, and especially those implicated in schizophrenia, to preclinical models of the illness that have shown estradiol’s potential in either enhancing cognition and memory or reversing deficits that are reflective of the positive, negative, and cognitive symptoms of schizophrenia. Recent clinical trials have provided a promising outlook on the use of estradiol and the more recent use of selective estradiol receptor modulators, as an adjunctive treatment to antipsychotics for schizophrenia patients of both genders. Future studies investigating the mechanism underlying estradiol’s protective action in schizophrenia are warranted; such research is also necessary in other psychiatric disorders where gender differences are observed, including depression and anxiety.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
- J. McGrath, S. Saha, D. Chant, and J. Welham, “Schizophrenia: a concise overview of incidence, prevalence, and mortality,” Epidemiologic Reviews, vol. 30, no. 1, pp. 67–76, 2008.
- K. T. Mueser and D. V. Jeste, Clinical Handbook of Schizophrenia, Guilford Press, New York, NY, USA, 2011.
- M. Knapp, “Schizophrenia costs and treatment cost-effectiveness,” Acta Psychiatrica Scandinavica, vol. 102, no. 407, pp. 15–18, 2000.
- M. S. Ritsner, Handbook of Schizophrenia Spectrum Disorders: Therapeutic Approaches, Comorbidity, and Outcomes, Springer, New York, NY, USA, 2011.
- S. Saha, D. Chant, and J. McGrath, “A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time?” Archives of General Psychiatry, vol. 64, no. 10, pp. 1123–1131, 2007.
- T. J. R. Lambert and J. W. Newcomer, “Are the cardiometabolic complications of schizophrenia still neglected? Barriers to care,” Medical Journal of Australia, vol. 190, no. 4, article 39, 2009.
- K. T. Mueser and S. R. McGurk, “Schizophrenia,” The Lancet, vol. 363, no. 9426, pp. 2063–2072, 2004.
- R. Tandon, W. Gaebel, D. M. Barch et al., “Definition and description of schizophrenia in the DSM-5,” Schizophrenia Research, vol. 150, no. 1, pp. 3–10, 2013.
- C. A. Tamminga, “Accelerating new knowledge in schizophrenia,” The American Journal of Psychiatry, vol. 165, no. 8, pp. 949–951, 2008.
- H. Steeds, R. L. Carhart-Harris, and J. M. Stone, “Drug models of schizophrenia,” Therapeutic Advances in Psychopharmacology, vol. 5, no. 1, pp. 43–58, 2015.
- F. J. Acosta, E. Chinea, J. L. Hernández et al., “Influence of antipsychotic treatment type and regimen on the functionality of patients with schizophrenia,” Nordic Journal of Psychiatry, vol. 68, no. 3, pp. 180–188, 2014.
- P. Seeman, “All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors,” CNS Neuroscience & Therapeutics, vol. 17, no. 2, pp. 118–132, 2011.
- H. Y. Meltzer, “Treatment-resistant schizophrenia—the role of clozapine,” Current Medical Research and Opinion, vol. 14, no. 1, pp. 1–20, 1997.
- M. V. Seeman, “The role of estrogen in schizophrenia,” Journal of Psychiatry and Neuroscience, vol. 21, no. 2, pp. 123–127, 1996.
- G. Fink, B. E. H. Sumner, R. Rosie, O. Grace, and J. P. Quinn, “Estrogen control of central neurotransmission: effect on mood, mental state, and memory,” Cellular and Molecular Neurobiology, vol. 16, no. 3, pp. 325–344, 1996.
- Y. Sayed and P. Taxel, “The use of estrogen therapy in men,” Current Opinion in Pharmacology, vol. 3, no. 6, pp. 650–654, 2003.
- J. Cui, Y. Shen, and R. Li, “Estrogen synthesis and signaling pathways during aging: from periphery to brain,” Trends in Molecular Medicine, vol. 19, no. 3, pp. 197–209, 2013.
- M. J. Legato, Principles of Gender-Specific Medicine, Academic Press, New York, NY, USA, 2009.
- M. L. Rao and H. Kölsch, “Effects of estrogen on brain development and neuroprotection—implications for negative symptoms in schizophrenia,” Psychoneuroendocrinology, vol. 28, supplement 2, pp. 83–96, 2003.
- J. Kulkarni, E. Gavrilidis, W. Wang et al., “Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age,” Molecular Psychiatry, vol. 20, pp. 695–702, 2015.
- A. Gogos, P. Kwek, and M. van den Buuse, “The role of estrogen and testosterone in female rats in behavioral models of relevance to schizophrenia,” Psychopharmacology, vol. 219, no. 1, pp. 213–224, 2012.
- K. M. Abel, R. Drake, and J. M. Goldstein, “Sex differences in schizophrenia,” International Review of Psychiatry, vol. 22, no. 5, pp. 417–428, 2010.
- J. A. Markham, “Sex steroids and schizophrenia,” Reviews in Endocrine & Metabolic Disorders, vol. 13, no. 3, pp. 187–207, 2012.
- S. Ochoa, J. Usall, J. Cobo, X. Labad, and J. Kulkarni, “Gender differences in schizophrenia and first-episode psychosis: a comprehensive literature review,” Schizophrenia Research and Treatment, vol. 2012, Article ID 916198, 9 pages, 2012.
- H. Häfner, “Gender differences in schizophrenia,” Psychoneuroendocrinology, vol. 28, no. 2, pp. 17–54, 2003.
- S. V. Eranti, J. H. MacCabe, H. Bundy, and R. M. Murray, “Gender difference in age at onset of schizophrenia: a meta-analysis,” Psychological Medicine, vol. 43, no. 1, pp. 155–167, 2013.
- H. Häfner, A. Riecher-Rössler, W. an Der Heiden, K. Maurer, B. Fatkenheuer, and W. Loffler, “Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia,” Psychological Medicine, vol. 23, no. 4, pp. 925–940, 1993.
- A. Aleman, R. S. Kahn, and J.-P. Selten, “Sex differences in the risk of schizophrenia: evidence from meta-analysis,” Archives of General Psychiatry, vol. 60, no. 6, pp. 565–571, 2003.
- J. McGrath, S. Saha, J. Welham, O. El Saadi, C. MacCauley, and D. Chant, “A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology,” BMC Medicine, vol. 2, article 13, 2004.
- C. M. Canuso and G. Pandina, “Gender and schizophrenia,” Psychopharmacology Bulletin, vol. 40, no. 4, pp. 178–190, 2007.
- M. Hambrecht, K. Maurer, H. Häfner, and N. Sartorius, “Transnational stability of gender differences in schizophrenia? An analysis based on the WHO study on determinants of outcome of severe mental disorders,” European Archives of Psychiatry and Clinical Neuroscience, vol. 242, no. 1, pp. 6–12, 1992.
- J. M. Goldstein and B. G. Link, “Gender and the expression of schizophrenia,” Journal of Psychiatric Research, vol. 22, no. 2, pp. 141–155, 1988.
- M. J. H. Begemann, C. F. Dekker, M. van Lunenburg, and I. E. Sommer, “Estrogen augmentation in schizophrenia: a quantitative review of current evidence,” Schizophrenia Research, vol. 141, no. 2-3, pp. 179–184, 2012.
- M. V. Seeman, “Interaction of sex, age, and neuroleptic dose,” Comprehensive Psychiatry, vol. 24, no. 2, pp. 125–128, 1983.
- N. L. Bryant, R. W. Buchanan, K. Vladar, A. Breier, and M. Rothman, “Gender differences in temporal lobe structures of patients with schizophrenia: a volumetric MRI study,” American Journal of Psychiatry, vol. 156, no. 4, pp. 603–609, 1999.
- K. L. Narr, P. M. Thompson, T. Sharma et al., “Three-dimensional mapping of temporo-limbic regions and the lateral ventricles in schizophrenia: gender effects,” Biological Psychiatry, vol. 50, no. 2, pp. 84–97, 2001.
- P. Nopoulos, M. Flaum, and N. C. Andreasen, “Sex differences in brain morphology in schizophrenia,” The American Journal of Psychiatry, vol. 154, no. 12, pp. 1648–1654, 1997.
- R. Z. Cohen, M. V. Seeman, A. Gotowiec, and L. Kopala, “Earlier puberty as a predictor of later onset of schizophrenia in women,” The American Journal of Psychiatry, vol. 156, no. 7, pp. 1059–1064, 1999.
- R. Halari, V. Kumari, R. Mehrotra, M. Wheeler, M. Hines, and T. Sharma, “The relationship of sex hormones and cortisol with cognitive functioning in schizophrenia,” Journal of Psychopharmacology, vol. 18, no. 3, pp. 366–374, 2004.
- H. Häfner, W. an der Heiden, S. Behrens et al., “Causes and consequences of the gender difference in age at onset of schizophrenia,” Schizophrenia Bulletin, vol. 24, no. 1, pp. 99–113, 1998.
- E. Hayes, E. Gavrilidis, and J. Kulkarni, “The role of oestrogen and other hormones in the pathophysiology and treatment of schizophrenia,” Schizophrenia Research and Treatment, vol. 2012, Article ID 540273, 8 pages, 2012.
- J. Kulkarni, E. Gavrilidis, R. Worsley, and E. Hayes, “Role of estrogen treatment in the management of schizophrenia,” CNS Drugs, vol. 26, no. 7, pp. 549–557, 2012.
- A. Wieck, “Oestradiol and psychosis: clinical findings and biological mechanisms,” Current Topics in Behavioral Neurosciences, vol. 8, pp. 173–187, 2011.
- K. Dalton, “Menstruation and acute psychiatric illnesses,” British Medical Journal, vol. 1, no. 5115, pp. 148–149, 1959.
- S. S. Chang and D. C. Renshaw, “Psychosis and pregnancy,” Comprehensive Therapy, vol. 12, no. 10, pp. 36–41, 1986.
- R. E. Kendell, J. C. Chalmers, and C. Platz, “Epidemiology of puerperal psychoses,” The British Journal of Psychiatry, vol. 150, pp. 662–673, 1987.
- N. Bergemann, P. Parzer, I. Nagl et al., “Acute psychiatric admission and menstrual cycle phase in women with schizophrenia,” Archives of Women's Mental Health, vol. 5, no. 3, pp. 119–126, 2002.
- N. Bergemann, C. Mundt, P. Parzer et al., “Plasma concentrations of estradiol in women suffering from schizophrenia treated with conventional versus atypical antipsychotics,” Schizophrenia Research, vol. 73, no. 2-3, pp. 357–366, 2005.
- A. Riecher-Rössler, H. Rössler, M. Stumbaum, K. Maurer, and R. Schmidt, “Can estradiol modulate schizophrenic symptomatology?” Schizophrenia Bulletin, vol. 20, no. 1, pp. 203–214, 1994.
- L. H. Rubin, C. S. Carter, L. Drogos, H. Pournajafi-Nazarloo, J. A. Sweeney, and P. M. Maki, “Peripheral oxytocin is associated with reduced symptom severity in schizophrenia,” Schizophrenia Research, vol. 124, no. 1–3, pp. 13–21, 2010.
- T. J. Huber, M. Borsutzky, U. Schneider, and H. M. Emrich, “Psychotic disorders and gonadal function: evidence supporting the oestrogen hypothesis,” Acta Psychiatrica Scandinavica, vol. 109, no. 4, pp. 269–274, 2004.
- J. D. Hallonquist, M. V. Seeman, M. Lang, and N. A. Rector, “Variation in symptom severity over the menstrual cycle of Schizophrenics,” Biological Psychiatry, vol. 33, no. 3, pp. 207–209, 1993.
- N. Bergemann, P. Parzer, B. Runnebaum, F. Resch, and C. Mundt, “Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia,” Psychological Medicine, vol. 37, no. 10, pp. 1427–1436, 2007.
- K. M. Hochman and R. R. Lewine, “Age of menarche and schizophrenia onset in women,” Schizophrenia Research, vol. 69, no. 2-3, pp. 183–188, 2004.
- T. J. Huber, J. Rollnik, J. Wilhelms, A. von Zur Mühlen, H. M. Emrich, and U. Schneider, “Estradiol levels in psychotic disorders,” Psychoneuroendocrinology, vol. 26, no. 1, pp. 27–35, 2001.
- N. Bergemann and A. Riecher-Rössler, Estrogen Effects in Psychiatric Disorders, Springer, New York, NY, USA, 2005.
- E. Diczfalusy and C. Lauritzen, Oestrogene Beim Menschen, Springer, Berlin, Germany, 1961.
- J. H. Zhang-Wong and M. V. Seeman, “Antipsychotic drugs, menstrual regularity and osteoporosis risk,” Archives of Women's Mental Health, vol. 5, no. 3, pp. 93–98, 2002.
- J. Montgomery, E. Winterbottom, M. Jessani et al., “Prevalence of hyperprolactinemia in schizophrenia: association with typical and atypical antipsychotic treatment,” The Journal of Clinical Psychiatry, vol. 65, no. 11, pp. 1491–1498, 2004.
- D. O. Perkins, “Antipsychotic-induced hyperprolactinemia: pathophysiology and clinical consequences,” Advanced Studies in Medicine, vol. 4, no. 10, pp. S982–S986, 2004.
- A. Schepp, Pilotstudie zur Frage eines überdauernden relativen Hypoöstrogenismus bei schizophrenen Frauen [Inauguraldissertation zur Erlangung des medizinischen Doktorgrades], Universität Heidelberg—Mannheim, Heidelberg, Germany, 1997.
- S. Akhondzadeh, A. A. Nejatisafa, H. Amini et al., “Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 27, no. 6, pp. 1007–1012, 2003.
- J. Kulkarni, A. Riedel, A. R. de Castella et al., “Estrogen—a potential treatment for schizophrenia,” Schizophrenia Research, vol. 48, no. 1, pp. 137–144, 2001.
- J. Kulkarni, A. de Castella, D. Smith, J. Taffe, N. Keks, and D. Copolov, “A clinical trial of the effects of estrogen in acutely psychotic women,” Schizophrenia Research, vol. 20, no. 3, pp. 247–252, 1996.
- N. Bergemann, C. Mundt, P. Parzer et al., “Estrogen as an adjuvant therapy to antipsychotics does not prevent relapse in women suffering from schizophrenia: results of a placebo-controlled double-blind study,” Schizophrenia Research, vol. 74, no. 2-3, pp. 125–134, 2005.
- L. A. Lindamer, D. C. Buse, J. B. Lohr, and D. V. Jeste, “Hormone replacement therapy in postmenopausal women with schizophrenia: positive effect on negative symptoms?” Biological Psychiatry, vol. 49, no. 1, pp. 47–51, 2001.
- J. Kulkarni, A. de Castella, B. Headey et al., “Estrogens and men with schizophrenia: is there a case for adjunctive therapy?” Schizophrenia Research, vol. 125, no. 2-3, pp. 278–283, 2011.
- E. Ghafari, M. Fararouie, H. G. Shirazi, A. Farhangfar, F. Ghaderi, and A. Mohammadi, “Combination of estrogen and antipsychotics in the treatment of women with chronic schizophrenia: a double-blind, randomized, placebo-controlled clinical trial,” Clinical Schizophrenia and Related Psychoses, vol. 6, no. 4, pp. 172–176, 2013.
- M. R. Louzã, A. P. Marques, H. Elkis, D. Bassitt, M. Diegoli, and W. F. Gattaz, “Conjugated estrogens as adjuvant therapy in the treatment of acute schizophrenia: a double-blind study,” Schizophrenia Research, vol. 66, no. 2-3, pp. 97–100, 2004.
- J. Kulkarni, C. Gurvich, H. Gilbert et al., “Hormone modulation: a novel therapeutic approach for women with severe mental illness,” Australian & New Zealand Journal of Psychiatry, vol. 42, no. 1, pp. 83–88, 2008.
- J. Kulkarni, C. Gurvich, S. J. Lee et al., “Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia,” Psychoneuroendocrinology, vol. 35, no. 8, pp. 1142–1147, 2010.
- J. Usall, E. Huerta-Ramos, R. Iniesta et al., “Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial,” The Journal of Clinical Psychiatry, vol. 72, no. 11, pp. 1552–1557, 2011.
- E. Huerta-Ramos, R. Iniesta, S. Ochoa et al., “Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial,” European Neuropsychopharmacology, vol. 24, no. 2, pp. 223–231, 2014.
- T. W. Weickert, D. Weinberg, R. Lenroot et al., “Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia,” Molecular Psychiatry, vol. 20, no. 6, pp. 685–694, 2015.
- A. L. Hoff, W. S. Kremen, M. H. Wieneke et al., “Association of estrogen levels with neuropsychological performance in women with schizophrenia,” The American Journal of Psychiatry, vol. 158, no. 7, pp. 1134–1139, 2001.
- Y.-H. Ko, S.-H. Joe, W. Cho et al., “Estrogen, cognitive function and negative symptoms in female schizophrenia,” Neuropsychobiology, vol. 53, no. 4, pp. 169–175, 2006.
- N. Bergemann, P. Parzer, S. Jaggy, B. Auler, C. Mundt, and S. Maier-Braunleder, “Estrogen and comprehension of metaphoric speech in women suffering from schizophrenia: results of a double-blind, placebo-controlled trial,” Schizophrenia Bulletin, vol. 34, no. 6, pp. 1172–1181, 2008.
- C. Chavez, M. Hollaus, E. Scarr, G. Pavey, A. Gogos, and M. van den Buuse, “The effect of estrogen on dopamine and serotonin receptor and transporter levels in the brain: an autoradiography study,” Brain Research, vol. 1321, pp. 51–59, 2010.
- M. G. Sánchez, M. Bourque, M. Morissette, and T. Di Paolo, “Steroids-dopamine interactions in the pathophysiology and treatment of cns disorders,” CNS Neuroscience and Therapeutics, vol. 16, no. 3, pp. e43–e71, 2010.
- A. P. V. Dantas, R. C. A. Tostes, Z. B. Fortes, S. G. Costa, D. Nigro, and M. H. C. Carvalho, “In vivo evidence for antioxidant potential of estrogen in microvessels of female spontaneously hypertensive rats,” Hypertension, vol. 39, no. 2, pp. 405–411, 2002.
- A. Kumar and T. C. Foster, “17β-estradiol benzoate decreases the AHP amplitude in CA1 pyramidal neurons,” Journal of Neurophysiology, vol. 88, no. 2, pp. 621–626, 2002.
- M. Wong and R. L. Moss, “Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons,” The Journal of Neuroscience, vol. 12, no. 8, pp. 3217–3225, 1992.
- B. McEwen, K. Akama, S. Alves et al., “Tracking the estrogen receptor in neurons: implications for estrogen-induced synapse formation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 13, pp. 7093–7100, 2001.
- B. S. McEwen and S. E. Alves, “Estrogen actions in the central nervous system,” Endocrine Reviews, vol. 20, no. 3, pp. 279–307, 1999.
- K. K. Aenlle, A. Kumar, L. Cui, T. C. Jackson, and T. C. Foster, “Estrogen effects on cognition and hippocampal transcription in middle-aged mice,” Neurobiology of Aging, vol. 30, no. 6, pp. 932–945, 2009.
- G. I. Humphreys, Y. S. Ziegler, and A. M. Nardulli, “17β-estradiol modulates gene expression in the female mouse cerebral cortex,” PLoS ONE, vol. 9, no. 11, Article ID e111975, 2014.
- J. Wang, C. M. Cheng, J. Zhou et al., “Estradiol alters transcription factor gene expression in primate prefrontal cortex,” Journal of Neuroscience Research, vol. 76, no. 3, pp. 306–314, 2004.
- A. Pedram, M. Razandi, M. Aitkenhead, C. C. W. Hughes, and E. R. Levin, “Integration of the non-genomic and genomic actions of estrogen: membrane-initiated signaling by steroid to transcription and cell biology,” The Journal of Biological Chemistry, vol. 277, no. 52, pp. 50768–50775, 2002.
- M. H. Polymeropoulos, L. Licamele, S. Volpi et al., “Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia,” Schizophrenia Research, vol. 108, no. 1–3, pp. 134–142, 2009.
- S. Green, P. Walter, V. Kumar et al., “Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A,” Nature, vol. 320, no. 6058, pp. 134–139, 1986.
- G. G. Kuiper, E. Enmark, M. Pelto-Huikko et al., “Cloning of a novel receptor expressed in rat prostate and ovary,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 12, pp. 5925–5930, 1996.
- S. Chu and P. J. Fuller, “Identification of a splice variant of the rat estrogen receptor β gene,” Molecular and Cellular Endocrinology, vol. 132, no. 1-2, pp. 195–199, 1997.
- B. Hanstein, H. Liu, M. C. Yancisin, and M. Brown, “Functional analysis of a novel estrogen receptor-β isoform,” Molecular Endocrinology, vol. 13, no. 1, pp. 129–137, 1999.
- K. Maruyama, H. Endoh, H. Sasaki-Iwaoka et al., “A novel isoform of rat estrogen receptor beta with 18 amino acid insertion in the ligand binding domain as a putative dominant negative regulator of estrogen action,” Biochemical and Biophysical Research Communications, vol. 246, no. 1, pp. 142–147, 1998.
- P. J. Shughrue, C. D. Bushnell, and D. M. Dorsa, “Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous cycle: a comparison with ovariectomized females and intact males,” Endocrinology, vol. 131, no. 1, pp. 381–388, 1992.
- R. B. Simerly and B. J. Young, “Regulation of estrogen receptor messenger ribonucleic acid in rat hypothalamus by sex steroid hormones,” Molecular Endocrinology, vol. 5, no. 3, pp. 424–432, 1991.
- Y. Zhou, P. J. Shughrue, and D. M. Dorsa, “Estrogen receptor protein is differentially regulated in the preoptic area of the brain and in the uterus during the rat estrous cycle,” Neuroendocrinology, vol. 61, no. 3, pp. 276–283, 1995.
- P. Micevych and R. Dominguez, “Membrane estradiol signaling in the brain,” Frontiers in Neuroendocrinology, vol. 30, no. 3, pp. 315–327, 2009.
- C. Gundlah, S. G. Kohama, S. J. Mirkes, V. T. Garyfallou, H. F. Urbanski, and C. L. Bethea, “Distribution of estrogen receptor beta (ERβ) mRNA in hypothalamus, midbrain and temporal lobe of spayed macaque: continued expression with hormone replacement,” Molecular Brain Research, vol. 76, no. 2, pp. 191–204, 2000.
- T. C. Register, C. A. Shively, and C. E. Lewis, “Expression of estrogen receptor α and β transcripts in female monkey hippocampus and hypothalamus,” Brain Research, vol. 788, no. 1-2, pp. 320–322, 1998.
- C. Behl, T. Skutella, F. Lezoualc'h et al., “Neuroprotection against oxidative stress by estrogens: structure—activity relationship,” Molecular Pharmacology, vol. 51, no. 4, pp. 535–541, 1997.
- C. M. Revankar, D. F. Cimino, L. A. Sklar, J. B. Arterburn, and E. R. Prossnitz, “A transmembrane intracellular estrogen receptor mediates rapid cell signaling,” Science, vol. 307, no. 5715, pp. 1625–1630, 2005.
- P. Thomas, Y. Pang, E. J. Filardo, and J. Dong, “Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells,” Endocrinology, vol. 146, no. 2, pp. 624–632, 2005.
- E. Brailoiu, S. L. Dun, G. C. Brailoiu et al., “Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system,” The Journal of Endocrinology, vol. 193, no. 2, pp. 311–321, 2007.
- K. Matsuda, H. Sakamoto, H. Mori et al., “Expression and intracellular distribution of the G protein-coupled receptor 30 in rat hippocampal formation,” Neuroscience Letters, vol. 441, no. 1, pp. 94–99, 2008.
- C. Otto, B. Rohde-Schulz, G. Schwarz et al., “G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol,” Endocrinology, vol. 149, no. 10, pp. 4846–4856, 2008.
- K. T. Akama, L. I. Thompson, T. A. Milner, and B. S. McEwen, “Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines,” The Journal of Biological Chemistry, vol. 288, no. 9, pp. 6438–6450, 2013.
- T. Funakoshi, A. Yanai, K. Shinoda, M. M. Kawano, and Y. Mizukami, “G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane,” Biochemical and Biophysical Research Communications, vol. 346, no. 3, pp. 904–910, 2006.
- R. Hammond, D. Nelson, and R. B. Gibbs, “GPR30 co-localizes with cholinergic neurons in the basal forebrain and enhances potassium-stimulated acetylcholine release in the hippocampus,” Psychoneuroendocrinology, vol. 36, no. 2, pp. 182–192, 2011.
- H. Tang, Q. Zhang, L. Yang et al., “Reprint of ‘GPR30 mediates estrogen rapid signaling and neuroprotection’,” Molecular and Cellular Endocrinology, vol. 389, no. 1-2, pp. 92–98, 2014.
- M. Maggiolini and D. Picard, “The unfolding stories of GPR30, a new membrane-bound estrogen receptor,” Journal of Endocrinology, vol. 204, no. 2, pp. 105–114, 2010.
- S. D. Noel, K. L. Keen, D. I. Baumann, E. J. Filardo, and E. Terasawa, “Involvement of G protein-coupled receptor 30 (GPR30) in rapid action of estrogen in primate LHRH neurons,” Molecular Endocrinology, vol. 23, no. 3, pp. 349–359, 2009.
- K. Takanami, H. Sakamoto, K.-I. Matsuda et al., “Expression of G protein-coupled receptor 30 in the spinal somatosensory system,” Brain Research, vol. 1310, pp. 17–28, 2010.
- C. Wang, B. Dehghani, I. J. Magrisso et al., “GPR30 contributes to estrogen-induced thymic atrophy,” Molecular Endocrinology, vol. 22, no. 3, pp. 636–648, 2008.
- R. Hammond, R. Mauk, D. Ninaci, D. Nelson, and R. B. Gibbs, “Chronic treatment with estrogen receptor agonists restores acquisition of a spatial learning task in young ovariectomized rats,” Hormones and Behavior, vol. 56, no. 3, pp. 309–314, 2009.
- R. Hammond, D. Nelson, E. Kline, and R. B. Gibbs, “Chronic treatment with a GPR30 antagonist impairs acquisition of a spatial learning task in young female rats,” Hormones and Behavior, vol. 62, no. 4, pp. 367–374, 2012.
- W. R. Hawley, E. M. Grissom, N. M. Moody, G. P. Dohanich, and N. Vasudevan, “Activation of G-protein-coupled receptor 30 is sufficient to enhance spatial recognition memory in ovariectomized rats,” Behavioural Brain Research, vol. 262, pp. 68–73, 2014.
- C. Gabor, J. Lymer, A. Phan, and E. Choleris, “Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice,” Physiology & Behavior, vol. 149, pp. 53–60, 2015.
- C. D. Toran-Allerand, X. Guan, N. J. MacLusky et al., “ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury,” The Journal of Neuroscience, vol. 22, no. 19, pp. 8391–8401, 2002.
- K. Soltysik and P. Czekaj, “Membrane estrogen receptors—is it an alternative way of estrogen action?” Journal of Physiology and Pharmacology, vol. 64, no. 2, pp. 129–142, 2013.
- M. F. Green, “What are the functional consequences of neurocognitive deficits in schizophrenia?” The American Journal of Psychiatry, vol. 153, no. 3, pp. 321–330, 1996.
- R. Tandon, M. S. Keshavan, and H. A. Nasrallah, “Schizophrenia, ‘Just the Facts’: what we know in 2008. Part 1: overview,” Schizophrenia Research, vol. 100, no. 1–3, pp. 4–19, 2008.
- K. J. Sinopoli, S. B. Floresco, and L. A. M. Galea, “Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory,” Neurobiology of Learning and Memory, vol. 86, no. 3, pp. 293–304, 2006.
- T. C. Foster, A. Rani, A. Kumar, L. Cui, and S. L. Semple-Rowland, “Viral vector-mediated delivery of estrogen receptor-α to the hippocampus improves spatial learning in estrogen receptor-α knockout mice,” Molecular Therapy, vol. 16, no. 9, pp. 1587–1593, 2008.
- H. N. Fugger, S. G. Cunningham, E. F. Rissman, and T. C. Foster, “Sex differences in the activational effect of ERα on spatial learning,” Hormones and Behavior, vol. 34, no. 2, pp. 163–170, 1998.
- X. Han, K. K. Aenlle, L. A. Bean et al., “Role of estrogen receptor α and β in preserving hippocampal function during aging,” The Journal of Neuroscience, vol. 33, no. 6, pp. 2671–2683, 2013.
- L. F. Jacome, C. Gautreaux, T. Inagaki et al., “Estradiol and ERβ agonists enhance recognition memory, and DPN, an ERβ agonist, alters brain monoamines,” Neurobiology of Learning and Memory, vol. 94, no. 4, pp. 488–498, 2010.
- A. Phan, K. E. Lancaster, J. N. Armstrong, N. J. MacLusky, and E. Choleris, “Rapid effects of estrogen receptor α and β selective agonists on learning and dendritic spines in female mice,” Endocrinology, vol. 152, no. 4, pp. 1492–1502, 2011.
- V. N. Luine, “Estradiol and cognitive function: past, present and future,” Hormones and Behavior, vol. 66, no. 4, pp. 602–618, 2014.
- L. E. DeLisi, K. U. Szulc, H. C. Bertisch, M. Majcher, and K. Brown, “Understanding structural brain changes in schizophrenia,” Dialogues in Clinical Neuroscience, vol. 8, no. 1, pp. 71–78, 2006.
- L. A. Flashman and M. F. Green, “Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment,” Psychiatric Clinics of North America, vol. 27, no. 1, pp. 1–18, 2004.
- S. Iritani, “Neuropathology of schizophrenia: a mini review,” Neuropathology, vol. 27, no. 6, pp. 604–608, 2007.
- M. M. Adams, R. A. Shah, W. G. M. Janssen, and J. H. Morrison, “Different modes of hippocampal plasticity in response to estrogen in young and aged female rats,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 14, pp. 8071–8076, 2001.
- C. S. Woolley and B. S. McEwen, “Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat,” The Journal of Comparative Neurology, vol. 336, no. 2, pp. 293–306, 1993.
- P. Tanapat, N. B. Hastings, A. J. Reeves, and E. Gould, “Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat,” The Journal of Neuroscience, vol. 19, no. 14, pp. 5792–5801, 1999.
- C. D. Toran-Allerand, “The estrogen/neurotrophin connection during neural development: is co-localization of estrogen receptors with the neurotrophins and their receptors biologically relevant?” Developmental Neuroscience, vol. 18, no. 1-2, pp. 36–48, 1996.
- J. Balthazart and G. F. Ball, “Is brain estradiol a hormone or a neurotransmitter?” Trends in Neurosciences, vol. 29, no. 5, pp. 241–249, 2006.
- J. Lauriello, A. Hoff, M. H. Wieneke et al., “Similar extent of brain dysmorphology in severely ill women and men with schizophrenia,” The American Journal of Psychiatry, vol. 154, no. 6, pp. 819–825, 1997.
- Y. Arimatsu and H. Hatanaka, “Estrogen treatment enhances survival of cultured fetal rat amygdala neurons in a defined medium.,” Brain research, vol. 391, no. 1, pp. 151–159, 1986.
- J. Bishop and J. W. Simpkins, “Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro,” Molecular and Cellular Neurosciences, vol. 5, no. 4, pp. 303–308, 1994.
- J. A. Chowen, I. Torres-Aleman, and L. M. Garcia-Segura, “Trophic effects of estradiol on fetal rat hypothalamic neurons,” Neuroendocrinology, vol. 56, no. 6, pp. 895–901, 1992.
- A. Faivre-Bauman, E. Rosenbaum, J. Puymirat, D. Grouselle, and A. Tixier-Vidal, “Differentiation of fetal mouse hypothalamic cells in serum-free medium,” Developmental Neuroscience, vol. 4, no. 2, pp. 118–129, 1981.
- Y. Goodman, A. J. Bruce, B. Cheng, and M. P. Mattson, “Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons,” Journal of Neurochemistry, vol. 66, no. 5, pp. 1836–1844, 1996.
- P. S. Green, K. E. Gridley, and J. W. Simpkins, “Estradiol protects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cells,” Neuroscience Letters, vol. 218, no. 3, pp. 165–168, 1996.
- C. A. Singer, K. L. Rogers, T. M. Strickland, and D. M. Dorsa, “Estrogen protects primary cortical neurons from glutamate toxicity,” Neuroscience Letters, vol. 212, no. 1, pp. 13–16, 1996.
- C. Behl, M. Widmann, T. Trapp, and F. Holsboer, “17-β estradiol protects neurons from oxidative stress-induced cell death in vitro,” Biochemical and Biophysical Research Communications, vol. 216, no. 2, pp. 473–482, 1995.
- M. Sárvári, I. Kalló, E. Hrabovszky et al., “Estradiol replacement alters expression of genes related to neurotransmission and immune surveillance in the frontal cortex of middle-aged, ovariectomized rats,” Endocrinology, vol. 151, no. 8, pp. 3847–3862, 2010.
- S. Suzuki, C. M. Brown, C. D. Dela Cruz, E. Yang, D. A. Bridwell, and P. M. Wise, “Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 14, pp. 6013–6018, 2007.
- L. M. Garcia-Segura, P. Cardona-Gomez, F. Naftolin, and J. A. Chowen, “Estradiol upregulates Bcl-2 expression in adult brain neurons,” NeuroReport, vol. 9, no. 4, pp. 593–597, 1998.
- A. D. Mooradian, “Antioxidant properties of steroids,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 45, no. 6, pp. 509–511, 1993.
- J. W. Simpkins, K. D. Yi, S.-H. Yang, and J. A. Dykens, “Mitochondrial mechanisms of estrogen neuroprotection,” Biochimica et Biophysica Acta—General Subjects, vol. 1800, no. 10, pp. 1113–1120, 2010.
- M. Manatt and S. B. Chandra, “The effects of mitochondrial dysfunction in schizophrenia,” Journal of Medical Genetics and Genomics V, vol. 3, no. 5, pp. 84–94, 2011.
- W. R. Perlman, E. Tomaskovic-Crook, D. M. Montague et al., “Alteration in estrogen receptor α mRNA levels in frontal cortex and hippocampus of patients with major mental illness,” Biological Psychiatry, vol. 58, no. 10, pp. 812–824, 2005.
- N. G. Weiland, C. Orikasa, S. Hayashi, and B. S. McEwen, “Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats,” The Journal of Comparative Neurology, vol. 388, no. 4, pp. 603–612, 1997.
- C. S. Weickert, A. L. Miranda-angulo, J. Wong et al., “Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia,” Human Molecular Genetics, vol. 17, no. 15, pp. 2293–2309, 2008.
- J. D. Sweatt, “Hippocampal function in cognition,” Psychopharmacology, vol. 174, no. 1, pp. 99–110, 2004.
- A. M. Owen, “The functional organization of working memory processes within human lateral frontal cortex: the contribution of functional neuroimaging,” The European Journal of Neuroscience, vol. 9, no. 7, pp. 1329–1339, 1997.
- M. Cyr, F. Calon, M. Morissette, and T. Di Paolo, “Estrogenic modulation of brain activity: implications for schizophrenia and Parkinson's disease,” Journal of Psychiatry and Neuroscience, vol. 27, no. 1, pp. 12–27, 2002.
- O. D. Howes and S. Kapur, “The dopamine hypothesis of schizophrenia: version III—the final common pathway,” Schizophrenia Bulletin, vol. 35, no. 3, pp. 549–562, 2009.
- F. P. Bymaster, D. O. Calligaro, J. F. Falcone et al., “Radioreceptor binding profile of the atypical antipsychotic olanzapine,” Neuropsychopharmacology, vol. 14, no. 2, pp. 87–96, 1996.
- I. Creese, D. R. Burt, and S. H. Snyder, “Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs,” Science, vol. 192, no. 4238, pp. 481–483, 1976.
- T. Di Paolo, “Modulation of brain dopamine transmission by sex steroids,” Reviews in the Neurosciences, vol. 5, no. 1, pp. 27–41, 1994.
- C. Leranth, R. H. Roth, J. D. Elswoth, F. Naftolin, T. L. Horvath, and D. E. Redmond, “Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson's disease and memory,” Journal of Neuroscience, vol. 20, no. 23, pp. 8604–8609, 2000.
- M. Cyr, F. Calon, M. Morissette, M. Grandbois, S. Callier, and T. Di Paolo, “Drugs with estrogen-like potency and brain activity potential therapeutic application for the CNS,” Current Pharmaceutical Design, vol. 6, no. 12, pp. 1287–1312, 2000.
- C. Pasqualini, V. Olivier, B. Guibert, O. Frain, and V. Leviel, “Acute stimulatory effect of estradiol on striatal dopamine synthesis,” Journal of Neurochemistry, vol. 65, no. 4, pp. 1651–1657, 1995.
- M. Pecins-Thompson, N. A. Brown, S. G. Kohama, and C. L. Bethea, “Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques,” The Journal of Neuroscience, vol. 16, no. 21, pp. 7021–7029, 1996.
- L. Xiao and J. B. Becker, “Quantitative microdialysis determination of extracellular striatal dopamine concentration in male and female rats: effects of estrous cycle and gonadectomy,” Neuroscience Letters, vol. 180, no. 2, pp. 155–158, 1994.
- M. G. Sánchez, M. Morissette, and T. Di Paolo, “Effect of a chronic treatment with 17β-estradiol on striatal dopamine neurotransmission and the Akt/GSK3 signaling pathway in the brain of ovariectomized monkeys,” Psychoneuroendocrinology, vol. 37, no. 2, pp. 280–291, 2012.
- E. S. Emamian, “AKT/GSK3 signaling pathway and schizophrenia,” Frontiers in Molecular Neuroscience, vol. 5, article 33, 2012.
- M. F. Kritzer and S. G. Kohama, “Ovarian hormones differentially influence immunoreactivity for dopamine β- hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys,” Journal of Comparative Neurology, vol. 409, no. 3, pp. 438–451, 1999.
- A.-L. Nordström, H. Olsson, and C. Halldin, “A PET study of D2 dopamine receptor density at different phases of the menstrual cycle,” Psychiatry Research—Neuroimaging, vol. 83, no. 1, pp. 1–6, 1998.
- M. C. Craig, W. J. Cutter, H. Wickham et al., “Effect of long-term estrogen therapy on dopaminergic responsivity in post-menopausal women—a preliminary study,” Psychoneuroendocrinology, vol. 29, no. 10, pp. 1309–1316, 2004.
- A. Gogos, P. Kwek, C. Chavez, and M. van den Buuse, “Estrogen treatment blocks 8-Hydroxy-2-Dipropylaminotetralin- and apomorphine-induced disruptions of prepulse inhibition: involvement of dopamine D1 or D2 or serotonin 5-HT1A, 5-HT2A, or 5-HT7 receptors,” The Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 1, pp. 218–227, 2010.
- D. Madularu, W. M. Shams, and W. G. Brake, “Estrogen potentiates the behavioral and nucleus accumbens dopamine response to continuous haloperidol treatment in female rats,” The European Journal of Neuroscience, vol. 39, no. 2, pp. 257–265, 2014.
- T. D. Purves-Tyson, D. J. Handelsman, K. L. Double, S. J. Owens, S. Bustamante, and C. S. Weickert, “Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra,” BMC Neuroscience, vol. 13, article 95, 2012.
- H. Y. Meltzer, “The importance of serotonin-dopamine interactions in the action of clozapine,” The British Journal of Psychiatry. Supplement, no. 17, pp. 22–29, 1992.
- C. A. Stockmeier, J. J. DiCarlo, Y. Zhang, P. Thompson, and H. Y. Meltzer, “Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors,” The Journal of Pharmacology and Experimental Therapeutics, vol. 266, no. 3, pp. 1374–1384, 1993.
- P. W. J. Burnet, S. L. Eastwood, and P. J. Harrison, “ receptor mRNAs and binding site densities are differentially altered in schizophrenia,” Neuropsychopharmacology, vol. 15, no. 5, pp. 442–455, 1996.
- P. W. J. Burnet, S. L. Eastwood, and P. J. Harrison, “[3H]WAY-100635 for 5-HT1A receptor autoradiography in human brain: A comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia,” Neurochemistry International, vol. 30, no. 6, pp. 565–574, 1997.
- T. Sumiyoshi, C. A. Stockmeier, J. C. Overholser, G. E. Dilley, and H. Y. Meltzer, “Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia,” Brain Research, vol. 708, no. 1-2, pp. 209–214, 1996.
- B. Dean and W. Hayes, “Decreased frontal cortical receptors in schizophrenia,” Schizophrenia Research, vol. 21, no. 3, pp. 133–139, 1996.
- B. Dean, W. Hayes, C. Hill, and D. Copolov, “Decreased receptors in brodmann's area 9 from schizophrenic subjects. A pathological or pharmacological phenomenon?” Molecular and Chemical Neuropathology, vol. 34, no. 2-3, pp. 133–145, 1998.
- L. Zhang, W. Ma, J. L. Barker, and D. R. Rubinow, “Sex differences in expression of serotonin receptors (subtypes 1A and 2A) in rat brain: a possible role of testosterone,” Neuroscience, vol. 94, no. 1, pp. 251–259, 1999.
- T. Inagaki, C. Gautreaux, and V. Luine, “Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas,” Hormones and Behavior, vol. 58, no. 3, pp. 415–426, 2010.
- A. Kugaya, C. N. Epperson, S. Zoghbi et al., “Increase in prefrontal cortex serotonin2A receptors following estrogen treatment in postmenopausal women,” American Journal of Psychiatry, vol. 160, no. 8, pp. 1522–1524, 2003.
- E. L. Moses, W. C. Drevets, G. Smith et al., “Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET Study,” Biological Psychiatry, vol. 48, no. 8, pp. 854–860, 2000.
- G. S. Kranz, C. Rami-Mark, U. Kaufmann et al., “Effects of hormone replacement therapy on cerebral serotonin-1A receptor binding in postmenopausal women examined with [carbonyl-11C]WAY-100635,” Psychoneuroendocrinology, vol. 45, pp. 1–10, 2014.
- I. Blum, Y. Vered, A. Lifshitz et al., “The effect of estrogen replacement therapy on plasma serotonin and catecholamines of postmenopausal women,” Israel Journal of Medical Sciences, vol. 32, no. 12, pp. 1158–1162, 1996.
- C. N. Epperson, Z. Amin, K. Ruparel, R. Gur, and J. Loughead, “Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women,” Psychoneuroendocrinology, vol. 37, no. 3, pp. 372–382, 2012.
- V. G. Frokjaer, D. Erritzoe, A. Juul et al., “Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding,” Psychoneuroendocrinology, vol. 35, no. 9, pp. 1311–1320, 2010.
- R. Hiroi and R. J. Handa, “Estrogen receptor-β regulates human tryptophan hydroxylase-2 through an estrogen response element in the 5′ untranslated region,” Journal of Neurochemistry, vol. 127, no. 4, pp. 487–495, 2013.
- C. L. Bethea, A. W. Smith, M. L. Centeno, and A. P. Reddy, “Long-term ovariectomy decreases serotonin neuron number and gene expression in free ranging macaques,” Neuroscience, vol. 192, pp. 675–688, 2011.
- C. L. Bethea, “Regulation of progestin receptors in raphe neurons of steroid-treated monkeys,” Neuroendocrinology, vol. 60, no. 1, pp. 50–61, 1994.
- A. Gogos and M. van den Buuse, “Estrogen and progesterone prevent disruption of prepulse inhibition by the serotonin-1a receptor agonist 8-hydroxy-2-dipropylaminotetralin,” The Journal of Pharmacology and Experimental Therapeutics, vol. 309, no. 1, pp. 267–274, 2004.
- A. Gogos, P. J. Nathan, V. Guille, R. J. Croft, and M. Van Den Buuse, “Estrogen prevents receptor-induced disruptions of prepulse inhibition in healthy women,” Neuropsychopharmacology, vol. 31, no. 4, pp. 885–889, 2006.
- V. Guille, A. Gogos, P. J. Nathan, R. J. Croft, and M. van den Buuse, “Interaction of estrogen with central serotonergic mechanisms in human sensory processing: loudness dependence of the auditory evoked potential and mismatch negativity,” Journal of Psychopharmacology, vol. 25, no. 12, pp. 1614–1622, 2011.
- G. Juckel, “Serotonin: from sensory processing to schizophrenia using an electrophysiological method,” Behavioural Brain Research, vol. 277, pp. 121–124, 2015.
- C. Wyss, K. Hitz, M. P. Hengartner et al., “The loudness dependence of auditory evoked potentials (LDAEP) as an indicator of serotonergic dysfunction in patients with predominant schizophrenic negative symptoms,” PLoS ONE, vol. 8, no. 7, Article ID e68650, 2013.
- D. C. Javitt and S. R. Zukin, “Recent advances in the phencyclidine model of schizophrenia,” The American Journal of Psychiatry, vol. 148, no. 10, pp. 1301–1308, 1991.
- A. C. Lahti, B. Koffel, D. LaPorte, and C. A. Tamminga, “Subanesthetic doses of ketamine stimulate psychosis in schizophrenia,” Neuropsychopharmacology, vol. 13, no. 1, pp. 9–19, 1995.
- G. Northoff, A. Richter, F. Bermpohl et al., “NMDA hypofunction in the posterior cingulate as a model for schizophrenia: an exploratory ketamine administration study in fMRI,” Schizophrenia Research, vol. 72, no. 2-3, pp. 235–248, 2005.
- J. H. Meador-Woodruff, A. J. Hogg Jr., and R. E. Smith, “Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder,” Brain Research Bulletin, vol. 55, no. 5, pp. 631–640, 2001.
- E. Scarr, M. Beneyto, J. H. Meador-Woodruff, and B. Dean, “Cortical glutamatergic markers in schizophrenia,” Neuropsychopharmacology, vol. 30, no. 8, pp. 1521–1531, 2005.
- B. Dean, E. Scarr, R. Bradbury, and D. Copolov, “Decreased hippocampal (CA3) NMDA receptors in schizophrenia,” Synapse, vol. 32, no. 1, pp. 67–69, 1999.
- N. Matosin, E. Frank, C. Deng, X.-F. Huang, and K. A. Newell, “Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment,” Schizophrenia Research, vol. 146, no. 1–3, pp. 170–176, 2013.
- E. Frank, K. A. Newell, and X.-F. Huang, “Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age,” Schizophrenia Research, vol. 128, no. 1–3, pp. 56–60, 2011.
- M. Beneyto, L. V. Kristiansen, A. Oni-Orisan, R. E. McCullumsmith, and J. H. Meador-Woodruff, “Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders,” Neuropsychopharmacology, vol. 32, no. 9, pp. 1888–1902, 2007.
- X.-M. Gao, K. Sakai, R. C. Roberts, R. R. Conley, B. Dean, and C. A. Tamminga, “Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia,” The American Journal of Psychiatry, vol. 157, no. 7, pp. 1141–1149, 2000.
- M. Cyr, O. Ghribi, C. Thibault, M. Morissette, M. Landry, and T. Di Paolo, “Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors,” Brain Research Reviews, vol. 37, no. 1–3, pp. 153–161, 2001.
- M. M. Adams, S. E. Fink, W. G. M. Janssen, R. A. Shah, and J. H. Morrison, “Estrogen modulates synaptic N-methyl-D-aspartate receptor subunit distribution in the aged hippocampus,” Journal of Comparative Neurology, vol. 474, no. 3, pp. 419–426, 2004.
- S. G. Kohama, V. T. Garyfallou, and H. F. Urbanski, “Regional distribution of glutamate receptor mRNA in the monkey hippocampus and temporal cortex: influence of estradiol,” Molecular Brain Research, vol. 53, no. 1-2, pp. 328–332, 1998.
- M. Kajta and W. Lason, “Oestrogen effects on kainate-induced toxicity in primary cultures of rat cortical neurons,” Acta Neurobiologiae Experimentalis, vol. 60, no. 3, pp. 365–369, 2000.
- K. Kurata, M. Takebayashi, S. Morinobu, and S. Yamawaki, “β-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms,” The Journal of Pharmacology and Experimental Therapeutics, vol. 311, no. 1, pp. 237–245, 2004.
- C. Galvin and I. Ninan, “Regulation of the mouse medial prefrontal cortical synapses by endogenous estradiol,” Neuropsychopharmacology, vol. 39, no. 9, pp. 2086–2094, 2014.
- J. W. Phillis, D. Song, and M. H. O'Regan, “Tamoxifen, a chloride channel blocker, reduces glutamate and aspartate release from the ischemic cerebral cortex,” Brain Research, vol. 780, no. 2, pp. 352–355, 1998.
- P. Karki, A. Webb, K. Smith et al., “CAMP response element-binding protein (CREB) and nuclear factor κB mediate the tamoxifen-induced up-regulation of glutamate transporter 1 (GLT−1) in rat astrocytes,” The Journal of Biological Chemistry, vol. 288, no. 40, pp. 28975–28986, 2013.
- P. Karki, A. Webb, A. Zerguine, J. Choi, D.-S. Son, and E. Lee, “Mechanism of raloxifene-induced upregulation of glutamate transporters in rat primary astrocytes,” Glia, vol. 62, no. 8, pp. 1270–1283, 2014.
- E. Lee, M. Sidoryk-Wêgrzynowicz, N. Wang et al., “GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes,” The Journal of Biological Chemistry, vol. 287, no. 32, pp. 26817–26828, 2012.
- J. Pawlak, V. Brito, E. Küppers, and C. Beyer, “Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen,” Molecular Brain Research, vol. 138, no. 1, pp. 1–7, 2005.
- J. S. Sutcliffe, F. Rhaman, K. M. Marshall, and J. C. Neill, “Oestradiol attenuates the cognitive deficit induced by acute phencyclidine treatment in mature female hooded-Lister rats,” Journal of Psychopharmacology, vol. 22, no. 8, pp. 918–922, 2008.
- A. S. Roseman, C. McGregor, and J. E. Thornton, “Estradiol attenuates the cognitive deficits in the novel object recognition task induced by sub-chronic phencyclidine in ovariectomized rats,” Behavioural Brain Research, vol. 233, no. 1, pp. 105–112, 2012.
- G. Hermes, N. Li, C. Duman, and R. Duman, “Post-weaning chronic social isolation produces profound behavioral dysregulation with decreases in prefrontal cortex synaptic-associated protein expression in female rats,” Physiology & Behavior, vol. 104, no. 2, pp. 354–359, 2011.