A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings

Abstract

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.

Figure 1

Putative mechanisms of estrogen action in the cell. Estrogen can act via either genomic or nongenomic mechanisms. Genomic mechanisms involve activation of the estrogen receptors (ERs) by estrogen, which then translocate to the cell nucleus as hetero- or homodimers to bind to estrogen response elements (EREs) or to activator protein 1 (AP-1) sites, resulting in transcription activation. Nongenomic actions occur via binding of estrogen to ERs or to a G protein coupled receptor GPR30, either intracellularly or at the plasma membrane (mERs) to activate second messenger systems, such as those involving mitogen-activated protein kinase (MAPK) or cyclic adenosine 3′,5′-monophosphate (cAMP) pathways, which can also activate transcription or have other effects.