madman
Super Moderator
Abstract
Sex steroid hormones (SSHs) play roles in the regulation of various processes in the cardiovascular, immune, muscular, and neural systems. SSHs affect prenatal and postnatal development of various brain structures, including regions associated with important physiological, behavioral, cognitive, and emotional functions. This action can be mediated by either intracellular or transmembrane receptors. While the classical mechanisms of SSHs action are relatively well examined, the physiological importance of the non-classical mechanism of SSHs action through membrane-associated and transmembrane receptors in the brain remains unclear. The most recent summary describing the role of SSHs in different body systems is lacking. Therefore, the aim of this review is to discuss classical and non-classical signaling pathways of testosterone and estradiol action via their receptors at functional, cellular, tissue-level and to describe the effects on various body systems and behavior. Particular emphasis will be on brain regions including the hippocampus, hypothalamus, frontal cortex, and cerebellum.
1. Introduction
The sex steroid hormones (SSHs) are known not only as regulators of sexual differentiation, secondary sex characteristics, sexual behaviors, reproduction, but also affect various systems such as skeletal, immune, muscular, and cardiovascular. In addition, SSHs play a pivotal role in brain structure formation and cognitive function (Bhatia et al., 2014; Campbell & Jialal, 2020; Carson & Manolagas, 2015; dos Santos et al., 2014; McEwen & Milner, 2017). Furthermore, SSHs exert pleiotropic effects in the central nervous system promoting neurogenesis and neuroprotection, as well as learning and memory (Diotel et al., 2018; Frick & Kim, 2018; Sun et al., 2019). These effects are mediated not only via intracellular or membrane-associated receptors (such as the androgen receptor (AR), estrogen receptor alpha (ERα), estrogen receptor beta (ERβ)) but also via transmembrane receptors (such as zinc transporter protein 9 (ZIP9), G protein-coupled estrogen receptor 1 (GPER1)). While the classical effects of SSHs via AR, ERα, ERβ are relatively well described, the physiological importance of rapid, non-classical actions of SSHs via membrane-associated (AR, ERα, ERβ) and transmembrane – GPCR steroid receptors (ZIP9, GPER1) is not well understood.
SSHs shape the brain during the critical prenatal and perinatal periods of development (organizational windows) when hormones interact with an immature neural substrate. In this period of life, exposure to SSHs can cause permanent sex differences in brain structures and their functions, which are responsible for the sexual differentiation of the brain and behavior (Cooke et al., 1998; Williams, 1986). Prenatal and perinatal effects of SSHs determine the brain’s response to steroids later in life. In addition, another “organizational window” during the postnatal period of life exists as well – puberty and adolescence (Schulz & Sisk, 2016a; Vigil et al., 2016). Besides the organizational effects, SSHs also have activational effects on mature brain structures. Activational effects are acute, reversible, and evoke transient behavioral or physiological responses throughout life (Cooke et al., 1998; Williams, 1986). In general, the activational effects of SSHs appear post-puberty and act independently or in combination with organizational effects (Schulz & Sisk, 2016b). Therefore, both activational and organizational effects of SSHs on the brain could affect behavioral outcomes later in life.
However, a current summary of results of experimental or clinical studies describing the role of testosterone (T) and estrogen (E, mostly estradiol (E2)) via classical and non-classical receptors and their role in different body systems is lacking. In this review, we aimed to sum up what is known and update the latest knowledge regarding the role of T and E2 in various tissues and body systems with a specific focus on the brain via classical and non-classical signaling. First, we discuss the specific effects of T and E (E2) via different receptors (AR, ERα, ERβ, ZIP9, GPER1) on various body systems. Subsequently, we describe the role of T and E2 in the hippocampus (HIP), hypothalamus (HYP), frontal cortex (FC), and cerebellum (CER) – selected brain regions associated with important physiological, behavioral, cognitive, and emotional functions.
2. Androgens and estrogens
*2.1 Receptors for androgens and estrogens
2.1.1 Intracellular/membrane-associated AR
2.1.2 Intracellular/membrane-associated ERs
*2.1.3 GPCR receptors for androgens and estrogens
2.1.3.1 ZIP9
2.1.3.2 GPER1
3. The effect of T and E2 on brain structures
*3.1 T and E2 in the hippocampus
*3.2 T and E2 in the hypothalamus
*3.3 T and E2 in the frontal cortex
*3.4 T and E2 in cerebellum
4. Conclusions
SSHs are crucial for the proper development and function of the body in both males and females. The research regarding the effect of SSHs on different organs and body systems, especially the brain, is moving forward very quickly, and it is important to stay abreast of the latest developments. The present review summarizes the latest information on the effects of SSHs (e.g. T and E2) via their classical or non-classical pathways at molecular, cellular, and tissue levels, with the main focus on brain regions involved in cognition, including the HIP, HYP, FC, and CER. The role of SSHs in the modulation of behavior in both humans and laboratory animals is described. SSHs are involved in the regulation of many-body systems such as reproductive, immune, muscular, cardiovascular, skeletal, and neural. SSHs affect these systems differently via different receptors. Although the actions of intracellular AR are central for example for bone healing, glucose and fat metabolism, and β-amyloid plaque reduction, the role of membrane-associated AR is pivotal in process of neuronal apoptosis, cell survival, and cell proliferation. ERα plays an important role in energy metabolism, insulin resistance, fat accumulation, or atherosclerosis. On the other hand, the fast, non-classical actions of ERα result in endothelial NO activation, lipolysis, bone growth, and beiging of adipocytes. Intracellular ERβ is involved in neural differentiation and in oncogenesis and metastasis suppression, whereas non-classical ERβ signaling can reverse pre-existing heart failure or inhibit hypertrophy of cardiomyocytes. Concerning transmembrane GPCR receptors, ZIP9 is crucial for male fertility, spermatogenesis, or apoptosis, whereas GPER1 is responsible for the proper functioning of gonads in both males and females.
Regarding the effects of T or E2 on HIP, HYP, FC, and CER, activation of the appropriate receptor trigger changes in both brain structures and behavior. For example, T increases synaptic spine density and neurogenesis in HIP and increases synaptic plasticity and connectivity. In addition, it modulates the morphological maturation of HYP, cortical density in the FC, and increases the gray matter volume in the CER. In addition, T improves working and spatial or episodic memory (HIP), increases male sexual or aggressive behavior (HYP), modulates executive functions and control of emotions (FC), and decreases neuroticism and regulation of male sexual behavior (CER). E2 increases glutaminergic synapse formation and neurogenesis in HIP modulates synapse formation, increases axodendritic synapses and axogenesis in HYP, and regulates neurotransmission in the FC and cell growth in the CER. E2 also improves object recognition and spatial memory consolidation (HIP, FC), controls aggressive behavior and anorectic actions in females (HYP), and regulates modulates motor memory formation (CER).
Both classical and non-classical actions of T and E2 in the brain confirm the importance of these SSHs in the regulation of structural changes in the brain with an impact on behavior and cognitive function. Plenty of studies have been published describing the molecular signaling pathways of SSHs receptors and their effects on the brain, body systems, and behavior. The results of these studies have brought new insights into the neurobehavioral effects of T and E2. However, additional questions have arisen, such as the sex-, age- and tissue-specific role of rapid, non-classical mechanisms involving the GPCR ZIP9 and GPER1 receptors, mainly the brain. The answers to these questions will provide a more complete picture of how SSHs regulate the function of neural and non-neural systems
Sex steroid hormones (SSHs) play roles in the regulation of various processes in the cardiovascular, immune, muscular, and neural systems. SSHs affect prenatal and postnatal development of various brain structures, including regions associated with important physiological, behavioral, cognitive, and emotional functions. This action can be mediated by either intracellular or transmembrane receptors. While the classical mechanisms of SSHs action are relatively well examined, the physiological importance of the non-classical mechanism of SSHs action through membrane-associated and transmembrane receptors in the brain remains unclear. The most recent summary describing the role of SSHs in different body systems is lacking. Therefore, the aim of this review is to discuss classical and non-classical signaling pathways of testosterone and estradiol action via their receptors at functional, cellular, tissue-level and to describe the effects on various body systems and behavior. Particular emphasis will be on brain regions including the hippocampus, hypothalamus, frontal cortex, and cerebellum.
1. Introduction
The sex steroid hormones (SSHs) are known not only as regulators of sexual differentiation, secondary sex characteristics, sexual behaviors, reproduction, but also affect various systems such as skeletal, immune, muscular, and cardiovascular. In addition, SSHs play a pivotal role in brain structure formation and cognitive function (Bhatia et al., 2014; Campbell & Jialal, 2020; Carson & Manolagas, 2015; dos Santos et al., 2014; McEwen & Milner, 2017). Furthermore, SSHs exert pleiotropic effects in the central nervous system promoting neurogenesis and neuroprotection, as well as learning and memory (Diotel et al., 2018; Frick & Kim, 2018; Sun et al., 2019). These effects are mediated not only via intracellular or membrane-associated receptors (such as the androgen receptor (AR), estrogen receptor alpha (ERα), estrogen receptor beta (ERβ)) but also via transmembrane receptors (such as zinc transporter protein 9 (ZIP9), G protein-coupled estrogen receptor 1 (GPER1)). While the classical effects of SSHs via AR, ERα, ERβ are relatively well described, the physiological importance of rapid, non-classical actions of SSHs via membrane-associated (AR, ERα, ERβ) and transmembrane – GPCR steroid receptors (ZIP9, GPER1) is not well understood.
SSHs shape the brain during the critical prenatal and perinatal periods of development (organizational windows) when hormones interact with an immature neural substrate. In this period of life, exposure to SSHs can cause permanent sex differences in brain structures and their functions, which are responsible for the sexual differentiation of the brain and behavior (Cooke et al., 1998; Williams, 1986). Prenatal and perinatal effects of SSHs determine the brain’s response to steroids later in life. In addition, another “organizational window” during the postnatal period of life exists as well – puberty and adolescence (Schulz & Sisk, 2016a; Vigil et al., 2016). Besides the organizational effects, SSHs also have activational effects on mature brain structures. Activational effects are acute, reversible, and evoke transient behavioral or physiological responses throughout life (Cooke et al., 1998; Williams, 1986). In general, the activational effects of SSHs appear post-puberty and act independently or in combination with organizational effects (Schulz & Sisk, 2016b). Therefore, both activational and organizational effects of SSHs on the brain could affect behavioral outcomes later in life.
However, a current summary of results of experimental or clinical studies describing the role of testosterone (T) and estrogen (E, mostly estradiol (E2)) via classical and non-classical receptors and their role in different body systems is lacking. In this review, we aimed to sum up what is known and update the latest knowledge regarding the role of T and E2 in various tissues and body systems with a specific focus on the brain via classical and non-classical signaling. First, we discuss the specific effects of T and E (E2) via different receptors (AR, ERα, ERβ, ZIP9, GPER1) on various body systems. Subsequently, we describe the role of T and E2 in the hippocampus (HIP), hypothalamus (HYP), frontal cortex (FC), and cerebellum (CER) – selected brain regions associated with important physiological, behavioral, cognitive, and emotional functions.
2. Androgens and estrogens
*2.1 Receptors for androgens and estrogens
2.1.1 Intracellular/membrane-associated AR
2.1.2 Intracellular/membrane-associated ERs
*2.1.3 GPCR receptors for androgens and estrogens
2.1.3.1 ZIP9
2.1.3.2 GPER1
3. The effect of T and E2 on brain structures
*3.1 T and E2 in the hippocampus
*3.2 T and E2 in the hypothalamus
*3.3 T and E2 in the frontal cortex
*3.4 T and E2 in cerebellum
4. Conclusions
SSHs are crucial for the proper development and function of the body in both males and females. The research regarding the effect of SSHs on different organs and body systems, especially the brain, is moving forward very quickly, and it is important to stay abreast of the latest developments. The present review summarizes the latest information on the effects of SSHs (e.g. T and E2) via their classical or non-classical pathways at molecular, cellular, and tissue levels, with the main focus on brain regions involved in cognition, including the HIP, HYP, FC, and CER. The role of SSHs in the modulation of behavior in both humans and laboratory animals is described. SSHs are involved in the regulation of many-body systems such as reproductive, immune, muscular, cardiovascular, skeletal, and neural. SSHs affect these systems differently via different receptors. Although the actions of intracellular AR are central for example for bone healing, glucose and fat metabolism, and β-amyloid plaque reduction, the role of membrane-associated AR is pivotal in process of neuronal apoptosis, cell survival, and cell proliferation. ERα plays an important role in energy metabolism, insulin resistance, fat accumulation, or atherosclerosis. On the other hand, the fast, non-classical actions of ERα result in endothelial NO activation, lipolysis, bone growth, and beiging of adipocytes. Intracellular ERβ is involved in neural differentiation and in oncogenesis and metastasis suppression, whereas non-classical ERβ signaling can reverse pre-existing heart failure or inhibit hypertrophy of cardiomyocytes. Concerning transmembrane GPCR receptors, ZIP9 is crucial for male fertility, spermatogenesis, or apoptosis, whereas GPER1 is responsible for the proper functioning of gonads in both males and females.
Regarding the effects of T or E2 on HIP, HYP, FC, and CER, activation of the appropriate receptor trigger changes in both brain structures and behavior. For example, T increases synaptic spine density and neurogenesis in HIP and increases synaptic plasticity and connectivity. In addition, it modulates the morphological maturation of HYP, cortical density in the FC, and increases the gray matter volume in the CER. In addition, T improves working and spatial or episodic memory (HIP), increases male sexual or aggressive behavior (HYP), modulates executive functions and control of emotions (FC), and decreases neuroticism and regulation of male sexual behavior (CER). E2 increases glutaminergic synapse formation and neurogenesis in HIP modulates synapse formation, increases axodendritic synapses and axogenesis in HYP, and regulates neurotransmission in the FC and cell growth in the CER. E2 also improves object recognition and spatial memory consolidation (HIP, FC), controls aggressive behavior and anorectic actions in females (HYP), and regulates modulates motor memory formation (CER).
Both classical and non-classical actions of T and E2 in the brain confirm the importance of these SSHs in the regulation of structural changes in the brain with an impact on behavior and cognitive function. Plenty of studies have been published describing the molecular signaling pathways of SSHs receptors and their effects on the brain, body systems, and behavior. The results of these studies have brought new insights into the neurobehavioral effects of T and E2. However, additional questions have arisen, such as the sex-, age- and tissue-specific role of rapid, non-classical mechanisms involving the GPCR ZIP9 and GPER1 receptors, mainly the brain. The answers to these questions will provide a more complete picture of how SSHs regulate the function of neural and non-neural systems
