madman
Super Moderator
The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders
Abstract: Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and antiinflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.
1. Introduction
Globally, one in seven people (equivalent to 11–18% of the population) suffers from mental or substance use disorders [1]. Despite many efforts, the prevalence of mental disorders remains high, and interestingly, there exist gender disparities. Women have a higher prevalence than men [1]. Indeed, multiple psychiatric disorders display sex differences in their symptoms, age of onset, and prevalence. In general, males are more susceptible to neurodevelopmental disorders, including schizophrenia, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD), whereas females are more susceptible to depression, anxiety, and eating disorders. Multiple factors, such as social and environmental factors, via various pathways and circuits in the brain, play a role in creating these sex differences. However, accumulated evidence suggests biological factors as one of the strongest candidates underlying this phenomenon and a closer examination of sex hormones—in particular, estrogen.
Estrogens have traditionally been known to have their effects on reproductive behaviors, such as sexual receptivity and maternal behaviors [2]. However, over the past twenty years of extensive research, both in animals and humans, it is now known that estrogens, via their signaling mechanisms and interactions with multiple neurotransmitter systems in our brain, including dopamine, serotonin, and glutamate, have heavy involvement in cognition and mood [3–5]. Recent investigations have revealed pronounced interactions of estrogens with the dopaminergic system, a highly implicated system in the pathophysiology of multiple psychiatric and neurodegenerative disorders, and that they modulate executive functions, such as working memory and reward processing [6–8]. Further, the roles of estrogen receptors and estrogen signaling have been highlighted, with studies reporting their neuroprotective effects on the brain by promoting neurotrophins synthesis and protecting the brain from inflammation and stress [9–11]. To add more, investigations revealed, in animal models of psychiatric disorders and in patients, that estrogen and estrogen signaling is disturbed and that they are associated with not only the cognitive deficits but, also, the manifestations of the symptoms, which could also be reversed with estrogen administration or treatments targeting estrogen-signaling pathways [11–13]. Thus, together with much evidence on estrogen signaling disruptions in psychiatric disorders, recently, their effects have been taken under examination in multiple clinical trials for the critical assessment and evaluation of their efficacy as a new treatment for psychiatric patients [14–18]. Altogether, accumulating evidence suggests that estrogen and estrogen signaling may be highly implicated in the pathophysiology of psychiatric disorders, warranting a comprehensive and integrated understanding of estrogen and estrogen signaling across multiple levels of the brain system architecture from cellular and molecular to systemic to elucidate the mechanisms involved in its therapeutic effects in psychiatric disorders.
In this review, we first describe estrogen receptor signaling by providing summarized information of the literature on estrogen receptor signaling; distributions of estrogen receptors in the brain; their mechanisms of actions on major neurotransmitters of our brain, including dopaminergic, serotonergic, and glutamatergic; and they're cognitive and neuroprotective effects. Next, we critically assess the recent progress of our understanding of the role of estrogen receptor signaling and its therapeutic effects in psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder (MDD), ASD, ADHD, general anxiety disorder (GAD), post-traumatic stress disorder (PTSD), eating disorders, and substance use disorder, with an aim to provide and highlight the importance of estrogen singling in major psychiatric disorders, thereby possibly providing guidance as to finding new therapeutic targets.
2. Estrogen Receptor Signaling
2.1. Estrogen
The estrogen family is a steroid hormone and consists of one benzene ring, a phenolic hydroxyl group, and a ketone group, and, depending on the number of hydroxyl groups, the estrogens are named estrone (zero groups, E1), estradiol (one group, E2), estriol (two groups, E3), and estetrol (three groups, E4). While females produce estrogens all during their lives, however, for the predominance during the reproductive years and high relevance to physiology, the word estrogen in the literature commonly refers to E2 (or 17β-estradiol). Estrogens have been traditionally reported to have physiological functions involved in the development of breast tissue and sexual organs, regulations of the menstrual cycle and reproduction, and maintenance of our bone density. However, recent reports suggest its cognitive [3,19] and neuroprotective effects [10] and anti-inflammatory roles [20]. Estrogens are also present in males at low levels [21], and in men, they are involved in reproduction, such as spermatogenesis, erectile function, and libido [22]. Estrogens are produced primarily in ovaries from testosterone but can also be produced in the liver, adipose tissue, heart, and, most importantly, the brain [23]. In the brain, there exists regional specifics in estrogen production, suggesting their selective involvement of the brain functions. Reports show that estrogens are produced in the hippocampus, cerebellum, hypothalamus, amygdala, and cortex [24] by neurons and astrocytes [25].
2.2. Estrogen Receptors and Their Signaling Mechanisms
Estrogens exert their effects via estrogen receptors. There currently are three known classes of receptors, estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G protein-coupled receptor 30 (GPER). With GPER being relatively recently discovered [26], ERα and ERβ are the most widely studied in the literature.
2.3. Estrogen Receptors in the Brain
Along with estrogens, ERα and ERβ are widely distributed in our brain, including the hippocampus, hypothalamus, amygdala, thalamic connectivity system regions [31] of the thalamus, cerebellum, and cortex, as well as the cortico-striato-thalamo-cortical (CSTC) circuit-related regions of the basal ganglia and striatum. GPERs are also expressed in the hippocampus, cortex, and hypothalamus [32]. Revealed by extensive neuroimaging studies, interestingly, these areas are the most frequently reported regions of deficits in psychiatric patients, and below, we provide a brief description of estrogen receptor distributions.
2.4. Mechanism of Actions on Neurotransmitter Systems
Mounting evidence from both clinical and preclinical studies suggests the modulation of estrogen, via estrogen receptor signaling, on neurotransmitter systems in our brains, such as dopaminergic, serotonergic, and glutamatergic, the key neurotransmitter systems implicated in major psychiatric disorders.
2.5. Estrogen Receptors and Cognition
*Beneficial Effects of Selective Estrogen Receptor Modulators (SERMs) on Cognition
2.6. Estrogen and Its Neuroprotective Effects
3. Estrogen Receptor and Psychiatric Disorders
3.1. Schizophrenia
3.2. Bipolar Disorder
3.3. MDD
3.4. ASD
3.5. ADHD
3.6. Anxiety Disorders
3.6.1. Generalized Anxiety Disorder (GAD)
3.6.2. PTSD
3.7. Eating Disorders
3.8. Substance Use Disorder
Alcohol Use Disorder
4. Conclusions
Extensive literature supports estrogen and estrogen-signaling disruptions across the psychiatric illnesses of schizophrenia, bipolar disorder, MDD, ASD, ADHD, GAD, PTSD, eating disorders, and substance use disorders. Estrogens and estrogen signaling plays a pertinent role in the regulation of neurotransmitter systems, such as dopaminergic, serotonergic, and glutamatergic, and actively participate in cognitive functioning—most importantly, memory. Further, they provide neuroprotective and anti-inflammatory effects. Estrogen and estrogen signaling is disrupted in multiple psychiatric disorders, with varying degrees of disruptions affecting different downstream cell cascades. Future studies elucidating estrogen and estrogen-signaling disruptions and possible novel treatment strategies in major psychiatric disorders are warranted.
Abstract: Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and antiinflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.
1. Introduction
Globally, one in seven people (equivalent to 11–18% of the population) suffers from mental or substance use disorders [1]. Despite many efforts, the prevalence of mental disorders remains high, and interestingly, there exist gender disparities. Women have a higher prevalence than men [1]. Indeed, multiple psychiatric disorders display sex differences in their symptoms, age of onset, and prevalence. In general, males are more susceptible to neurodevelopmental disorders, including schizophrenia, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD), whereas females are more susceptible to depression, anxiety, and eating disorders. Multiple factors, such as social and environmental factors, via various pathways and circuits in the brain, play a role in creating these sex differences. However, accumulated evidence suggests biological factors as one of the strongest candidates underlying this phenomenon and a closer examination of sex hormones—in particular, estrogen.
Estrogens have traditionally been known to have their effects on reproductive behaviors, such as sexual receptivity and maternal behaviors [2]. However, over the past twenty years of extensive research, both in animals and humans, it is now known that estrogens, via their signaling mechanisms and interactions with multiple neurotransmitter systems in our brain, including dopamine, serotonin, and glutamate, have heavy involvement in cognition and mood [3–5]. Recent investigations have revealed pronounced interactions of estrogens with the dopaminergic system, a highly implicated system in the pathophysiology of multiple psychiatric and neurodegenerative disorders, and that they modulate executive functions, such as working memory and reward processing [6–8]. Further, the roles of estrogen receptors and estrogen signaling have been highlighted, with studies reporting their neuroprotective effects on the brain by promoting neurotrophins synthesis and protecting the brain from inflammation and stress [9–11]. To add more, investigations revealed, in animal models of psychiatric disorders and in patients, that estrogen and estrogen signaling is disturbed and that they are associated with not only the cognitive deficits but, also, the manifestations of the symptoms, which could also be reversed with estrogen administration or treatments targeting estrogen-signaling pathways [11–13]. Thus, together with much evidence on estrogen signaling disruptions in psychiatric disorders, recently, their effects have been taken under examination in multiple clinical trials for the critical assessment and evaluation of their efficacy as a new treatment for psychiatric patients [14–18]. Altogether, accumulating evidence suggests that estrogen and estrogen signaling may be highly implicated in the pathophysiology of psychiatric disorders, warranting a comprehensive and integrated understanding of estrogen and estrogen signaling across multiple levels of the brain system architecture from cellular and molecular to systemic to elucidate the mechanisms involved in its therapeutic effects in psychiatric disorders.
In this review, we first describe estrogen receptor signaling by providing summarized information of the literature on estrogen receptor signaling; distributions of estrogen receptors in the brain; their mechanisms of actions on major neurotransmitters of our brain, including dopaminergic, serotonergic, and glutamatergic; and they're cognitive and neuroprotective effects. Next, we critically assess the recent progress of our understanding of the role of estrogen receptor signaling and its therapeutic effects in psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder (MDD), ASD, ADHD, general anxiety disorder (GAD), post-traumatic stress disorder (PTSD), eating disorders, and substance use disorder, with an aim to provide and highlight the importance of estrogen singling in major psychiatric disorders, thereby possibly providing guidance as to finding new therapeutic targets.
2. Estrogen Receptor Signaling
2.1. Estrogen
The estrogen family is a steroid hormone and consists of one benzene ring, a phenolic hydroxyl group, and a ketone group, and, depending on the number of hydroxyl groups, the estrogens are named estrone (zero groups, E1), estradiol (one group, E2), estriol (two groups, E3), and estetrol (three groups, E4). While females produce estrogens all during their lives, however, for the predominance during the reproductive years and high relevance to physiology, the word estrogen in the literature commonly refers to E2 (or 17β-estradiol). Estrogens have been traditionally reported to have physiological functions involved in the development of breast tissue and sexual organs, regulations of the menstrual cycle and reproduction, and maintenance of our bone density. However, recent reports suggest its cognitive [3,19] and neuroprotective effects [10] and anti-inflammatory roles [20]. Estrogens are also present in males at low levels [21], and in men, they are involved in reproduction, such as spermatogenesis, erectile function, and libido [22]. Estrogens are produced primarily in ovaries from testosterone but can also be produced in the liver, adipose tissue, heart, and, most importantly, the brain [23]. In the brain, there exists regional specifics in estrogen production, suggesting their selective involvement of the brain functions. Reports show that estrogens are produced in the hippocampus, cerebellum, hypothalamus, amygdala, and cortex [24] by neurons and astrocytes [25].
2.2. Estrogen Receptors and Their Signaling Mechanisms
Estrogens exert their effects via estrogen receptors. There currently are three known classes of receptors, estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G protein-coupled receptor 30 (GPER). With GPER being relatively recently discovered [26], ERα and ERβ are the most widely studied in the literature.
2.3. Estrogen Receptors in the Brain
Along with estrogens, ERα and ERβ are widely distributed in our brain, including the hippocampus, hypothalamus, amygdala, thalamic connectivity system regions [31] of the thalamus, cerebellum, and cortex, as well as the cortico-striato-thalamo-cortical (CSTC) circuit-related regions of the basal ganglia and striatum. GPERs are also expressed in the hippocampus, cortex, and hypothalamus [32]. Revealed by extensive neuroimaging studies, interestingly, these areas are the most frequently reported regions of deficits in psychiatric patients, and below, we provide a brief description of estrogen receptor distributions.
2.4. Mechanism of Actions on Neurotransmitter Systems
Mounting evidence from both clinical and preclinical studies suggests the modulation of estrogen, via estrogen receptor signaling, on neurotransmitter systems in our brains, such as dopaminergic, serotonergic, and glutamatergic, the key neurotransmitter systems implicated in major psychiatric disorders.
2.5. Estrogen Receptors and Cognition
*Beneficial Effects of Selective Estrogen Receptor Modulators (SERMs) on Cognition
2.6. Estrogen and Its Neuroprotective Effects
3. Estrogen Receptor and Psychiatric Disorders
3.1. Schizophrenia
3.2. Bipolar Disorder
3.3. MDD
3.4. ASD
3.5. ADHD
3.6. Anxiety Disorders
3.6.1. Generalized Anxiety Disorder (GAD)
3.6.2. PTSD
3.7. Eating Disorders
3.8. Substance Use Disorder
Alcohol Use Disorder
4. Conclusions
Extensive literature supports estrogen and estrogen-signaling disruptions across the psychiatric illnesses of schizophrenia, bipolar disorder, MDD, ASD, ADHD, GAD, PTSD, eating disorders, and substance use disorders. Estrogens and estrogen signaling plays a pertinent role in the regulation of neurotransmitter systems, such as dopaminergic, serotonergic, and glutamatergic, and actively participate in cognitive functioning—most importantly, memory. Further, they provide neuroprotective and anti-inflammatory effects. Estrogen and estrogen signaling is disrupted in multiple psychiatric disorders, with varying degrees of disruptions affecting different downstream cell cascades. Future studies elucidating estrogen and estrogen-signaling disruptions and possible novel treatment strategies in major psychiatric disorders are warranted.
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