Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders

doi:10.1016/S0301-0082(00)00059-9

Progress in Neurobiology

Volume 64, Issue 3, June 2001, Pages 251-267

https://doi.org/10.1016/S0301-0082(00)00059-9 Get rights and content

Abstract

The steroid hormone estrogen influences brain function and neuropsychiatric disorders, but neuroanatomical information about the estrogen receptors (ERs) are rather limited. The main focus of this article is to provide an overview of the current status of the ER distribution and possible function in the human brain. The ERs are ligand activated transcription factors that belong to the steroid hormone receptors, included in the nuclear receptor superfamily. To date, there are two known ER subtypes, α and β. In the human forebrain, both estrogen receptor subtypes are predominantly expressed in limbic-related areas, although they show distinct distribution patterns. The ERα mRNA expression appears to dominate in the hypothalamus and amygdala, indicating that the α-subtype might modulate neuronal cell populations involved in autonomic and reproductive neuroendocrine functions as well as emotional interpretation and processing. In contrast, the hippocampal formation, entorhinal cortex, and thalamus appear to be ERβ dominant areas, suggesting a putative role for ERβ in cognition, non-emotional memory and motor functions. Clinical observations of estrogenic effects together with the information available today regarding ER expression in the primate brain provide important clues as to the functional aspects of the two ER subtypes. However, further characterization of the different phenotypes of the ER expressing cells in the human brain is needed as well as the delineation of the genes which are regulated by the ERs and how this transcriptional control correlates with human behavior and mental status.

Introduction

Although clinical evidence has suggested for many years that estrogen affects mood, cognition, and mental state, the knowledge about estrogen actions in the central nervous system (CNS), especially in humans, has been very limited. The discovery of a new estrogen receptor (ER), ERβ (Kuiper et al., 1996, Mosselman et al., 1996) in 1996 opened new possibilities and interest about the diverse actions of estrogen. The aim of this article is to give an overview of what is known about ERs and their distribution and possible functions in the human brain. Moreover, the influence of estrogen in neuropsychiatric disorders is also reviewed.

Section snippets

Physiological effects and synthesis of estrogens

Estrogens are steroid hormones that exert a wide range of effects throughout the body, including the CNS. Estrogens are required for normal female sexual maturation, they promote growth and differentiation of the breast, uterus, fallopian tubes, vagina, and ovaries (Carr, 1998). Male reproductive tissues, such as testis and prostate, are also estrogen target tissues (Clark et al., 1992). Moreover, estrogens are important for bone maintenance (Turner et al., 1994) and have a protective role in

The estrogen receptors

The presence of estrogen-binding receptors was discovered in the sixties by the work of Jensen and colleagues (Jensen and Jacobsen, 1962, Jensen and DeSombre, 1972). In the mid-1980s the first ER cDNA was cloned (Walter et al., 1985, Green et al., 1986) and this receptor, now referred to as ERα, was thought to be the only existing ER. It was not until recently that a new ER subtype, ERβ, was discovered and cloned, (Kuiper et al., 1996, Mosselman et al., 1996). Different isoforms have been found

Estrogen receptor distribution in the CNS

Although mammalian species differences are evident (see Section 4.2 below), both ER subtypes are predominantly localized in limbic related areas of the brain such as the amygdala, hypothalamus, and septum (Pfaff and Keiner, 1973, Keefer and Stumpf, 1975, Shughrue et al., 1997, Österlund et al., 2000a, Österlund et al., 2000b, Blurton-Jones et al., 1999, Donahue et al., 2000). The limbic system is suggested to be involved in mechanisms of emotional processing, cognition, and procreation. The

Regulation of estrogen receptor expression

ERs are expressed in various tissues such as the breast, ovaries, testis, lung, uterus, bone, liver, and brain, but the two ER subtypes display distinct distribution patterns (Ciocca and Vargas Roig, 1995, Kuiper et al., 1997, Saunders et al., 1997, Shughrue et al., 1997, Österlund et al., 1998). Not only is the regulation of the ERs cell- and tissue-specific, but it is also under developmental control (Huo and Gorski, 1993). The cellular response to estrogens seems to be correlated to the

Estrogen influence in neuropsychiatric disorders

Natural fluctuations in gonadal hormones occurring in the menstrual cycle, postpartum, and at menopause have for a long time been suggested to influence mood, well-being, and affective disorders. In addition, estrogens are hypothesized to have a protective role in schizophrenia and Alzheimer's disease. Since the detailed pathophysiology of these neuropsychiatric disorders is not well defined, the mechanisms of estrogen mediated actions in these diseases are also unclear. The fact that estrogens

Conclusions

1.
Both ER subtypes (α and β) are expressed in restricted areas of the human forebrain, predominantly limbic structures, but they exhibit distinct mRNA expression patterns. In humans, the ERα mRNA subtype is predominantly expressed in the hypothalamus and amygdala indicating a main role of the ERα in estrogen modulation of neuroendocrine and autonomic events as well as emotive functions and associative and emotional memory processing. In contrast, the ERβ appears to dominate in areas known to be

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Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders

Abstract

Introduction

Section snippets

Physiological effects and synthesis of estrogens

The estrogen receptors

Estrogen receptor distribution in the CNS

Regulation of estrogen receptor expression

Estrogen influence in neuropsychiatric disorders

Conclusions

Ann. Epidemiol.

Psychoneuroendocrinology

J. Steroid Biochem. Mol. Biol.

Cell

Mol. Cell. Endocrinol.

Neuroscience

Brain Res.

Cell

Schizophr. Res.

Biol. Psychiatry

Cell

J. Psychiatr. Res.

Mol. Cell. Endocrinol.

Int. J. Biochem. Cell Biol.

TIG

Neuroscience

Lancet

Mol. Brain Res.

Biol. Psychiatry

Psychoneuroendocrinology

FEBS Lett.

Biochem. Biophys. Res. Commun.

J. Biochem. Mol. Biol.

Steroids

FEBS Lett.

FEBS Lett.

Cell

Cell

Horm. Behav.

Cell

Biochem. Biophys. Res. Commun.

Some cytarchitectural abnormalities of the entorhinal cortex in schizophrenia

Arch. Gen. Psychiatry

5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor

Arch. Gen. Psychiatry

Regulation of gene expression by alternative promoters

FASEB J.

Receptor-associated nuclear proteins and steroid/antisteroid action

Ann. N.Y. Acad. Sci.

Neuroprotection against oxidative stress by estrogens: structure-activity relationship

Mol. Pharmacol.

Women's increased vulnerability to mood disorders: intergrating psychobiology and epidemiology

Depression

Estrogen receptor immunoreactivity in the adult primate brain: neuronal distribution and association with p75, trkA, and cholinacetyltransferase

J. Comp. Neurol.

Estrogen receptor-β mRNA expression in rat ovary: down-regulation by gonadotropins

Mol. Endocrinol.

Effect of chloropromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain

Acta Pharmacol. Toxicol.

Disorders of the ovaries and female reproductive tract

Steroid receptor family: structure and functions

Endocrine Rev.

Psychosis and pregnancy

Compr. Ther.

Estrogen receptors in human nontarget tissues: biological and clinical implications

Endocrine Rev.

Mechanisms of action of steroid hormones

A hypothesis on the pathophysiological mechanisms that underlie Levodopa- or dopamine agonist-indyced dyskinesia in Parkinson's disease: implications for future strategies in treatment

Movement Disord.

Modulation of brain dopamine transmission by sex steroids

Rev. Neurosci.

A functional anatomical study of unipolar depression

J. Neurosci.

Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern

J. Clin. Endocrinol. Metab.

The steroid and thyroid hormone receptor superfamily

Science