Oestrogen - A new treatment approach for schizophrenia?

Alfred Psychiatry Research Centre, Monash University and Alfred Hospital, Melbourne, VIC.
The Medical journal of Australia (Impact Factor: 4.09). 03/2009; 190(4 Suppl):S37-8.
Source: PubMed


The oestrogen protection hypothesis proposes that oestrogen has a protective effect against onset of schizophrenia. In support of this: Epidemiological studies have shown that young women are less likely to develop schizophrenia than men of the same age, and women are more likely to develop late-onset schizophrenia after menopause. Clinical studies have shown higher psychotic symptoms in perimenopausal women, and women at the low oestrogen phase of the menstrual cycle. Animal studies provide further evidence in support of the oestrogen protection hypothesis. Three randomised double-blind placebo-controlled trials and an open-label study showed that adding oestradiol to women's usual antipsychotic medications was associated with significant abatement of schizophrenia symptoms. A small study of men with schizophrenia who received oral oestradiol valerate also showed a significant abatement in psychotic symptoms. Although oestrogen appears to be a useful treatment for schizophrenia, further research is required to determine the correct dose and duration of use of oestradiol. New types of oestrogen compounds may provide a safer, non-feminising approach for the treatment of schizophrenia.

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    • "Furthermore, estrogens are associated with the symptomatology of bipolar disorder , anxiety disorders, depression, schizophrenia, migraine, catamenial epilepsy, and stroke (Walf and Frye, 2006; Milad et al., 2010; Begemann et al., 2012; Marsh et al., 2012; Reddy, 2013; Sohrabji and Williams, 2013). Although E 2 's neuroprotective, anti-depressant, mood-stabilizing, and memory enhancing properties (Walf and Frye, 2006; Sherwin and Henry, 2008; Kulkarni, 2009; Liu et al., 2010; Luine and Frankfurt, 2013) might support its use to reduce memory dysfunction in several brain disorders, estrogen therapy has been associated with potentially life-threatening side effects including breast and uterine cancer (Rossouw et al., 2002; Chlebowski et al., 2003). On the other hand, several histone deacetylase inhibitors have been FDA-approved to treat various cancers (Wagner et al., 2010), so epigenetic treatments might afford a mechanism for providing the cognitive benefits of estrogens without their carcinogenic effects. "
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    ABSTRACT: Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement.
    Frontiers in Neuroendocrinology 05/2014; 35(4). DOI:10.1016/j.yfrne.2014.05.001 · 7.04 Impact Factor
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    • ", 2008 ; Hughes et al . , 2009 ; Kulkarni , 2009 ; Sanchez et al . , 2010b ) . "
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    ABSTRACT: Converging evidence from cellular, electrophysiological, anatomic, and behavioral studies suggests that the remodeling of synapse structure and function is a critical component of cognition. This modulation of neuroplasticity can be achieved through the actions of numerous extracellular signals. Moreover, it is thought that it is the integration of different extracellular signals regulation of neuroplasticity that greatly influences cognitive function. One group of signals that exerts powerful effects on multiple neurologic processes is estrogens. Classically, estrogens have been described to exert their effects over a period of hours to days. However, there is now increasing evidence that estrogens can rapidly influence multiple behaviors, including those that require forebrain neural circuitry. Moreover, these effects are found in both sexes. Critically, it is now emerging that the modulation of cognition by rapid estrogenic signaling is achieved by activation of specific signaling cascades and regulation of synapse structure and function, cumulating in the rewiring of neural circuits. The importance of understanding the rapid effects of estrogens on forebrain function and circuitry is further emphasized as investigations continue to consider the potential of estrogenic-based therapies for neuropathologies. This review focuses on how estrogens can rapidly influence cognition and the emerging mechanisms that underlie these effects. We discuss the potential sources and the biosynthesis of estrogens within the brain and the consequences of rapid estrogenic-signaling on the remodeling of neural circuits. Furthermore, we argue that estrogens act via distinct signaling pathways to modulate synapse structure and function in a manner that may vary with cell type, developmental stage, and sex. Finally, we present a model in which the coordination of rapid estrogenic-signaling and activity-dependent stimuli can result in long-lasting changes in neural circuits, contributing to cognition, with potential relevance for the development of novel estrogenic-based therapies for neurodevelopmental or neurodegenerative disorders.
    Pharmacological reviews 07/2013; 65(4):1318-1350. DOI:10.1124/pr.111.005272 · 17.10 Impact Factor
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    • "The protective effect of estrogen in schizophrenia is well researched and is hypothesised to be the result of its neuroleptic-like effect on the dopamine system (19, 60-63). Dopamine overproduction is a pathophysiological feature of the illness and estrogen appears to blunt this effect by reducing dopamine receptor sensitivity and increasing the threshold for vulnerability (64, 65). "
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    ABSTRACT: 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.
    International Journal of Endocrinology and Metabolism 07/2013; 11(3):129-136. DOI:10.5812/ijem.6615
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