Estrogen Receptors: Mechanism of Action and Relevance to Schizophrenia

Abstract

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 the estrogen receptors in schizophrenia. This narrative review describes estrogen receptor subtypes including the distribution of these receptors in the brain, with a particular focus on the two main subtypes: estrogen receptor-alpha (ERα, or ESR1) and -beta (ERβ, or ESR2). This review highlights the research on estrogen receptors in schizophrenia. Given that this literature is limited, particularly with respect to ERβ, we argue for a more considered effort of future studies to further understand the role of estrogen and its receptors in schizophrenia and to further elucidate the mechanisms underlying the therapeutic effect of estrogen and estrogen receptor modulation in schizophrenia. Such an effort may lead to more targeted novel therapeutic approaches as well as enhance our understanding of the sex differences observed in schizophrenia and other psychiatric disorders.