Estrogen Hypothesis Research Articles

Estradiol driven change in hallucination proneness across the menstrual cycle as studied with a white noise paradigm

The estrogen hypothesis for schizophrenia suggests neuroprotective effects of estrogen for the development of the disorder and for symptom severity, including auditory hallucinations. Furthermore, estrogen has shown enhancing effects on cognitive control, a function that is also implicated in auditory hallucinations. Whether estrogen affects the tendency to hallucinate in healthy participants, and the potential mediating role of cognitive control, has not yet been studied. Therefore, the current study aimed to test these relationships by using a white noise paradigm in combination with a N-back working memory task in which cognitive load could be manipulated. The paradigm used simulates a hallucinatory state by induction of negative emotions and drainage of cognitive resources. The simultaneous exposure to white noise elicit experiences of hearing voices (false alarms). In a between-subject design, forty-two participants were tested during the menstrual cycle in either the early follicular phase (low estradiol) or late follicular phase (high estradiol). A 2(Cycle Phase) x2(N-back task) ANOVA showed a main-effect of cycle phase on number of experienced hallucinations in the white noise task, with a significantly higher number of reported hallucinations in the early follicular phase. Furthermore, estradiol was found to predict number of hallucinations. No interaction effect of cycle phase and available cognitive resources was found. The results suggest an estradiol-related change in hallucination proneness across the menstrual cycle, but the idea that cognitive functioning mediates this relationship was not supported. Overall, the study supports protective effects of estradiol on hallucination proneness in line with the estrogen-hypothesis of schizophrenia, and that such effects are not specific to the disease.

Estrogen – A key neurosteroid in the understanding and treatment of mental illness in women

The commentary is an invited brief about my contribution to Psychiatry Research. My work has built on the “estrogen hypothesis”, as stated by Hafner, Riecher-Rossler and Seeman in the 1990’s. This hypothesis was that estrogen provides ‘protection’ against the early onset of severe schizophrenia in women, and with decreasing brain estrogens at the menopause, mental ill health worsens in women. In this paper, results from clinical trials conducted over many decades, that involved administering exogenous estrogen in different types and doses, show an overall positive impact - with improved symptoms of schizophrenia in women. This led to the conduct of further successful clinical trials of gonadal hormone treatment in women with PMDD and menopausal depression, plus understanding more about depression caused by hormone contraceptives. The role of estrogens in stress vulnerability is reflected in the sex-dependent reaction to childhood trauma, which has led to our new work in the neurobiological effects of early life trauma in women.

Estrogens and development of the rete testis, efferent ductules, epididymis and vas deferens

Estrogen has always been considered the female hormone and testosterone the male hormone. However, estrogen's presence in the testis and deleterious effects of estrogen treatment during development have been known for nearly 90 years, long before estrogen receptors (ESRs) were discovered. Eventually it was learned that testes actually synthesize high levels of estradiol (E2) and sequester high concentrations in the reproductive tract lumen, which seems contradictory to the overwhelming number of studies showing reproductive pathology following exogenous estrogen exposures. For too long, the developmental pathology of estrogen has dominated our thinking, even resulting in the “estrogen hypothesis” as related to the testicular dysgenesis syndrome. However, these early studies and the development of an Esr1 knockout mouse led to a deluge of research into estrogen's potential role in and disruption of development and function of the male reproductive system. What is new is that estrogen action in the male cannot be divorced from that of androgen. This paper presents what is known about components of the estrogen pathway, including its synthesis and target receptors, and the need to achieve a balance between androgen- and estrogen-action in male reproductive tract differentiation and adult functions. The review focuses on what is known regarding development of the male reproductive tract, from the rete testis to the vas deferens, and examines the expression of estrogen receptors and presence of aromatase in the male reproductive system, traces the evidence provided by estrogen-associated knockout and transgenic animal models and discusses the effects of fetal and postnatal exposures to estrogens. Hopefully, there will be enough here to stimulate discussions and new investigations of the androgen:estrogen balance that seems to be essential for development of the male reproductive tract.

T141. EFFECTS OF MENSTRUAL CYCLE ON RESTING STATE FUNCTIONAL CONNECTIVITY IN SCHIZOPHRENIA: A FUNCTIONAL MRI STUDY

BackgroundThe menstrual cycle is a favorable model for examining the influence of ovarian hormones on cognition, emotion and brain functions. Ovarian hormones have substantial effects on task-related brain activity, but their impacts on functional connectivity at rest have been investigated by a few studies conducted with healthy individuals and these pre-existing findings are inconsistent. As for schizophrenia, different influences of ovarian hormones were reported. For instance, the estrogen hypothesis of schizophrenia has suggested that estrogen plays a neuroprotective role in the pathophysiology of this disorder. The present study investigates resting state functional connectivity (RS-FC) alterations related to menstrual cycle phase and/or hormone levels in patients with schizophrenia and healthy controls and aims to contribute to the understanding of the effects of ovarian hormones on the pathogenesis of schizophrenia and brain functions.MethodsThe study was conducted with 13 women with schizophrenia (the mean of age: 32 ± 7.67) and 13 healthy women (the mean of age: 30.08 ± 7.27). Resting state functional Magnetic Resonance Imaging (fMRI) scanning, as well as hormonal and clinical assessments, were applied to each participant twice, during two menstrual cycle phases: early follicular (Days 2–6; low estrogen/progesterone) and mid-luteal (Days 20–22; high estrogen/progesterone). The serum hormone levels of estradiol, progesterone, prolactin (only in the patients), follicle-stimulating and luteinizing were assessed. The clinical assessment interviews included the Brief Psychiatric Rating Scales, the Clinical Global Impression (only for the patients), the Global Assessment of Functioning and the Calgary Depression Rating Scale for Schizophrenia (for both groups).ResultsOur findings revealed that no cycle phase-related alterations existed in RS-FC in both groups. However, specific correlations between each hormone and RS-FC were found in both cycle phases for two groups. In the patients, estrogen was positively correlated with the auditory network (AN) connectivity in the left amygdala at the early follicular phase. In the controls, the positive correlations to progesterone were found in the precuneus for the connectivity of the posterior default mode network (DMN) and the left-frontoparietal network (FPN) during the early follicular phase. Also, progesterone was negatively correlated with the executive control network (ECN) connectivity in the right superior frontal gyrus at the mid-luteal phase in the controls. Furthermore, the patients had lower progesterone levels during the mid-luteal phase compared to the controls (p<0.05). The severity of the psychotic symptoms of the patients didn’t change between the cycle phases.DiscussionTo our knowledge, this is the first study to examine the influence of the menstrual cycle on the brain’s RS-FC in schizophrenia. Our results indicated that the effects of the menstrual cycle on RS-FC were more prominent in the controls rather than the patients with schizophrenia; and that the findings for the patient group may be associated with the additional mechanisms responsible from schizophrenia. This might imply that differentiating the menstrual cycle effects is difficult in a complex disorder such as schizophrenia. The results obtained from the controls are consistent with the previous findings indicating that the menstrual cycle effects might be associated with the connectivity of the DMN and cognition-related networks. Moreover, our results suggested that estrogen might have a modulating effect on the intrinsic functional connectivity changes in the patients, while progesterone, might mediate to that in the controls.

Timing of menarche and abnormal hippocampal connectivity in youth at clinical-high risk for psychosis

The “estrogen hypothesis” suggests that estrogen is a protective factor against psychotic disorders such as schizophrenia. Although the precise protective mechanisms are still unclear, one potential explanation lies in the role that increased estrogens play in mediating hippocampal plasticity, as this may reduce hippocampal dysconnectivity that is characteristically observed in psychosis. In support of this view, later age at menarche- less available estrogen during critical early adolescent development- is related to earlier onset of psychosis and increased symptom severity. Furthermore, if estrogens have protective effects, then we should see this effect in the psychosis risk period in those at clinical high-risk (CHR) for psychosis — i.e., individuals showing attenuated symptoms at imminent risk for transitioning to a psychotic diagnosis. This study examined whether earlier age at menarche would result in more normative hippocampal connectivity in CHR youth; menarche is an easily assessed, developmental marker associated with the availability of estrogens. Resting-state connectivity was examined in sixty female participants (26 CHR and 34 healthy control; age 12–21) using a cross-sectional approach; hippocampal connectivity was found to relate to age at menarche. Later age at menarche in the CHR group related to increased hippocampal dysconnectivity to the occipital cortex (a region with a neurotrophic response to estrogen) compared to the controls. Results suggest that earlier availability of estrogens may have neuroprotective effects on hippocampal plasticity. Findings have relevance for understanding sex differences and etiology, as well as guiding novel treatments.

Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks

Research indicates that after advanced age, the major risk factor for late-onset Alzheimer’s disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex- and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the “estrogen hypothesis.” This posits that sex hormones, 17β-estradiol in particular, exert a neuroprotective effect by shielding females’ brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17β-estradiol during the menopause transition (MT) as key underlying mechanisms.

Estrogens and SERMS as adjunctive treatments for schizophrenia.

More than thirty years have passed since sex and gender differences were noted in the age of onset, course and outcomes for schizophrenia. The 'estrogen hypothesis" was coined in the 1990's to describe neuroprotective effects of estrogen. Intervention studies in schizophrenia patients with estradiol and selective estrogen receptor modulators (SERMs) are promising but psychiatrists and other health practitioners do not generally take up this useful adjunctive treatment for their female patients with schizophrenia. The reasons for this are manifold, but overall a cultural shift in the practice of psychiatry is needed to recognise the specific needs of women with schizophrenia and tailor treatments, such as hormone adjuncts to improve the outcomes for this significant population. The two main aims of this article are to review the evidence and theory of estrogen treatments in schizophrenia and to recommend translation of adjunctive estrogen treatment into clinical practice for women with schizophrenia.

Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424).

To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided. In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-β (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [β], or differences in H-scores = -15.8, P = .003) and nuclear ER-β (β = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (β = 45.0, P < .001) and ER-β (β = 25.9, P < .001) but lower total PR (β = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-β were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1). Lower expression of nuclear ER-β in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-β and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.

Estrogen Receptors: Mechanism of Action and Relevance to Schizophrenia

Background: Sex differences are observed in schizophrenia, with women exhibiting an overall better disease outcome, leading to the estrogen hypothesis of schizophrenia that postulates a protective role of estrogen against the development and severity of the disorder. Estrogen (17β- estradiol) is a sex steroid hormone; its primary mechanism of action is via binding to estrogen receptors and initiating gene expression. While there has been significant attention placed on the impact of estrogen in schizophrenia, less is known about the importance of estrogen receptors in schizophrenia. Keywords: 17β-estradiol, sex steroid, ERα, ESR1, ERβ, ESR2, brain, CNS.

Early life risk factors for testicular cancer: a case-cohort study based on the Copenhagen School Health Records Register

Purpose: One established risk factors for testicular cancer is cryptorchidism. However, it remains unclear whether cryptorchidism is a risk factor in itself or whether the two conditions share common causes in early life (estrogen hypothesis), such as birth weight and birth order. The objective of this study is to utilize data from the Copenhagen School Health Records Register (CSHRR) to evaluate cryptorchidism, birth weight and birth order as risk factors for testicular cancer.Methods: The study population consisted of 408 cases of testicular cancer identified by a government issued identification number linkage of the entire CSHRR with the Danish Cancer Registry and a random subsample of 4819 males from the CSHRR. The study design was case-cohort and the period of follow-up between 2 April 1968 and 31 December 2003.Results: Cryptorchidism was significantly associated with testicular cancer in crude analyses [hazard ratio (HR) = 3.60, 95% CI 2.79–4.65]. Birth weight was inversely associated with testicular cancer and no clear association with birth order was observed. The positive association between cryptorchidism and testicular cancer was only slightly attenuated controlling for birth weight and birth order and stratified on birth cohort (HR = 3.46, 95% CI 2.67–4.48).Conclusion: This study confirmed the robustness of the association between cryptorchidism and testicular cancer even after adjustment for birth weight and birth order. Furthermore, the study showed an inverse association between birth weight and testicular cancer.

A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings.

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.

The estrogen hypothesis of obesity.

The explanation of obesity as a simple result of positive energy balance fails to account for the scope of variable responses to diets and lifestyles. It is postulated that individual physiological and anatomical variation may be responsible for developing obesity. Girls in poor families develop greater adiposity than their male siblings, a trend not present in richer environments. This indicates strong influence of estrogen on fat accumulation irrespective of poor socioeconomic conditions. Obesity rates in males and females of developed nations are similar, while in poorer nations obesity is much more prevalent in females. Female to male ratio of obesity correlates inversely with gross domestic product. Therefore, the parity of male and female obesity in developed countries may result from male exposure to environmental estrogen-like substances associated with affluence. These hormonally driven mechanisms may be equally active within both sexes in more developed areas, thereby increasing overall obesity.

Testing the estrogen hypothesis of schizophrenia: Associations between cumulative estrogen exposure and cerebral structural measures

BackgroundBone mineral density (BMD), as an indicator of cumulative estrogen exposure, may be reduced in female patients with psychotic disorder (van der Leeuw et al., 2013), possibly reflecting reduced cerebral exposure to estrogen and alterations in neuroprotective effects. To the degree that BMD is a marker of cumulative (endogenous) estrogen exposure, we hypothesized that BMD would be positively associated with cerebral gray and white matter indices. MethodsDual X-ray absorptiometry (DEXA) and magnetic resonance (MRI) scans were acquired in fourteen female patients diagnosed with a psychotic disorder. BMD was expressed in total BMD (g/cm2), Z- and T-scores. Cerebral cortical thickness (CT) (as indicator of gray matter status) and fractional anisotropy (FA) (as indicator of white matter integrity) were measured and served as the dependent variables in multilevel random regression models. BMD measures were the independent variables. ResultsFemoral BMD measures were positively associated with CT at trend significance (total BMD: B=0.266, 95% CI: −0.019–0.552, p=0.067; Z-score: B=0.034, 95% CI: 0.001–0.067, p=0.046; T-score: B=0.034, 95% CI: 0.000–0.068, p=0.052). There were no significant associations between femoral BMD measures and FA. ConclusionsThe data suggest that in women with psychotic disorder, alterations in the neuroprotective effect of estrogen (as measured by BMD) impact cortical gray matter, but not white matter integrity. These findings merit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia.

The Role of Estrogen in the Treatment of Men with Schizophrenia

Schizophrenia is a debilitating and pervasive mental illness with devastating effects on many aspects of psychological, cognitive and social wellbeing. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women, suggesting that estrogen plays a “protective” role . Adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia in women. In men, consideration of estrogen therapy has been impacted by concerns of feminisation, however, clinical trials using estrogen to treat prostate cancer, bone density loss and even aggression in men with dementia or traumatic brain injury, show estrogen to be a safe and effective therapy. Findings do, however, suggest that further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted. The development of the new estrogen compounds - Selective Estrogen Receptor Modulators (SERMs) which do not cause feminisation - opens up the possibility of using a different type of estrogen for a longer period of time at higher doses. Estrogen could therefore prove to be an important component in the treatment of psychotic symptoms in men with schizophrenia. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilised to address concerns unique to the care of men with schizophrenia.

Special biological issues in the management of women with schizophrenia

Schizophrenia is a debilitating and pervasive mental illness with devastating effects on psychological, cognitive and social wellbeing, and for which current treatment options are far from ideal. Gender differences and the influence of the female reproductive life cycle on the onset, course and symptoms of schizophrenia and the discovery of estrogen’s remarkable psychoprotective properties in animal models led to the proposal of the ‘estrogen protection hypothesis’ of schizophrenia. This has fueled the recent successful investigation of estradiol as a potential adjuvant therapeutic agent in the management of schizophrenia in women. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilized to address concerns unique to the care of women with schizophrenia.

A Case of Repeated Brief Psychotic Episodes Secondary to Discontinuation of Non-Prescription Estrogen Replacement Therapy

The estrogen hypothesis of psychosis indicates that estrogen contributes a protective effect against the development of psychotic disorders. Conversely, hypoestrogenic states have been shown to be associated with the occurrence of psychotic disorders in women. We present the case of a 53-year-old woman who experienced repeated brief psychotic episodes on two occasions in the context of discontinuation of non-prescription estrogen replacement therapy.

Psychosis and Gender

Psychosis, mainly schizophrenia, is a heterogeneous disorder with a great variability in its clinical presentation. This heterogeneity may be explained by the role of gender; thus a gender-based approach could help us to better define the disease. Gender differences in social functioning, age of onset, course of the illness, and other domains have been described by several authors, showing better functioning and improved outcome in women with schizophrenia. Moreover, several treatments are gender sensitive, with differences in treatment response depending upon gender. The estrogen hypothesis is one of the most interesting explanations for this gender difference. Estrogens could be useful for understanding the pathophysiology of the illness or tailoring specific gender-related treatments.

P-1463 - Menopause and schizophrenia: wich links?

In the past, some authors postulated that many women with schizophrenia showed signs of “hypoestrogenism”, suggesting that women became psychotic mainly before or during menstruation. Kraepelin created the diagnostic category “Menstrual Psychosis”. Understand a possible relationship between menopause/estrogens and the development of schizophrenia. Bibliographic search in Pubmed and textbooks. Several authors observed a relationship between estrogen levels and psychotic symptoms. Some facts contribute to this hypothesis like late-onset schizophrenia being more frequent in women, a second peak for onset of the disease, psychosis in temporal relationship with ovary surgery, puerperium and oscillations throughout the menstrual cycle, lower doses of antipsychotics during pregnancy. For some authors, estrogens also exert a “protective” effect over psychotic symptoms, beyond other several known effects on various psychopathological aspects, namely through antidopaminergic actions as well as modulation of apoptosis and improvement of depressive and negative symptoms. Although some evidence confirms this theory, the estrogen hypothesis is not universally accepted, some authors claiming the existence of other biological, emotional and social factors that should be considered in menopause. The etiology of the gender differences in schizophrenia is not yet well understood, but hormone-gene interactions may explain part of the mechanism. The psychiatric interview should explore menstrual irregularities or galactorrhoea, and, with increasing evidence, serum levels of prolactin and estrogens may become part of the routine tests. In the future, treatment with hormone replacement therapy may be a possibility for these patients.

Abnormally rapid reversal learning and reduced response to antipsychotic drugs following ovariectomy in female rats

Epidemiological and clinical life cycle studies indicate that favorable illness course and better response to antipsychotic drugs (APDs) in women with schizophrenia are positively correlated with estrogen levels. Accordingly, the estrogen hypothesis of schizophrenia proposes a neuroprotective role of estrogen in women vulnerable to schizophrenia. Previously we demonstrated in the rat that low levels of estrogen induced by ovariectomy led to disruption of latent inhibition (LI) reflecting impairment of selective attention, a core deficit of schizophrenia. LI disruption was reversed by 17β-estradiol and the atypical APD clozapine, whereas the typical APD haloperidol was ineffective unless co-administered with 17β-estradiol. Here we aimed to extend these findings by testing ovariectomized rats in another selective attention task, discrimination reversal. Ovariectomy led to a loss of selective attention as manifested in abnormally rapid reversal. The latter was normalized by high dose of 17β-estradiol (150 μg/kg) and clozapine (2.5mg/kg), but not by haloperidol (0.1mg/kg) or lower doses of 17β-estradiol (10 and 50 μg/kg). However, co-administration of haloperidol with 17β-estradiol (50 μg/kg) was effective. In sham rats low 17β-estradiol (10 μg/kg) produced rapid reversal, while high 17β-estradiol (150 μg/kg), haloperidol alone, or haloperidol-17β-estradiol combination reduced reversal speed. Clozapine did not affect reversal speed in sham rats. These results strengthen our previous results in suggesting that schizophrenia-like attentional abnormalities as well as reduced response to APDs in female rats are associated with low level of gonadal hormones. In addition, they support the possibility that estrogen may have an antipsychotic-like action in animal models.

Sex-Dependent Antipsychotic Capacity of 17β-Estradiol in the Latent Inhibition Model: A Typical Antipsychotic Drug in Both Sexes, Atypical Antipsychotic Drug in Males

The estrogen hypothesis of schizophrenia suggests that estrogen is a natural neuroprotector in women and that exogenous estrogen may have antipsychotic potential, but results of clinical studies have been inconsistent. We have recently shown using the latent inhibition (LI) model of schizophrenia that 17β-estradiol exerts antipsychotic activity in ovariectomized (OVX) rats. The present study sought to extend the characterization of the antipsychotic action of 17β-estradiol (10, 50 and 150 μg/kg) by testing its capacity to reverse amphetamine- and MK-801-induced LI aberrations in gonadally intact female and male rats. No-drug controls of both sexes showed LI, ie, reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, if conditioned with two but not five tone-shock pairings. In both sexes, amphetamine (1 mg/kg) and MK-801 (50 μg/kg) produced disruption (under weak conditioning) and persistence (under strong conditioning) of LI, modeling positive and negative/cognitive symptoms, respectively. 17β-estradiol at 50 and 150 μg/kg potentiated LI under strong conditioning and reversed amphetamine-induced LI disruption in both males and females, mimicking the action of typical and atypical antipsychotic drugs (APDs) in the LI model. 17β-estradiol also reversed MK-induced persistent LI, an effect mimicking atypical APDs and NMDA receptor enhancers, but this effect was observed in males and OVX females but not in intact females. These findings indicate that in the LI model, 17β-estradiol exerts a clear-cut antipsychotic activity in both sexes and, remarkably, is more efficacious in males and OVX females where it also exerts activity considered predictive of anti-negative/cognitive symptoms.