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Effects of Sex Steroids in the Human Brain

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Abstract

Sex steroids are thought to play a critical developmental role in shaping both cortical and subcortical structures in the human brain. Periods of profound changes in sex steroids invariably coincide with the onset of sex differences in mental health vulnerability, highlighting the importance of sex steroids in determining sexual differentiation of the brain. Yet, most of the evidence for the central effects of sex steroids relies on non-human studies, as several challenges have limited our understanding of these effects in humans: the lack of systematic assessment of the human sex steroid metabolome, the different developmental trajectories of specific sex steroids, the impact of genetic variation and epigenetic changes, and the plethora of interactions between sex steroids, sex chromosomes, neurotransmitters, and other hormonal systems. Here we review how multimodal strategies may be employed to bridge the gap between the basic and clinical understanding of sex steroid-related changes in the human brain.

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Authors and Affiliations

  1. Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, QC, H3A 1A1, Canada

    Tuong-Vi Nguyen & Simon Ducharme

  2. Department of Obstetrics-Gynecology, McGill University Health Centre, McGill University, Montreal, QC, H3A 1A1, Canada

    Tuong-Vi Nguyen

  3. McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada

    Simon Ducharme & Sherif Karama

  4. Department of Psychiatry, Douglas Mental Health University Institute, McGill University, 6875 Boulevard LaSalle, Montreal, QC, H4H 1R3, Canada

    Sherif Karama

Authors
  1. Tuong-Vi Nguyen
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  2. Simon Ducharme
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  3. Sherif Karama
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Correspondence to Sherif Karama.

Glossary

Amniocentesis:

A medical procedure used in the prenatal diagnosis of chromosomal abnormalities and fetal infections and also used for sex determination in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus.

Chromatin:

Chromatin is the combination or complex of DNA and proteins that make up the contents of the nucleus of a cell. The primary protein components of chromatin are histones that are involved in compacting DNA material.

CpG site/island:

CpG sites are locations within the DNA when a cytosine occurs next to a guanine and where they are only separated by one phosphate bond (cytosine-phosphate-guanine). CpG islands are areas rich in CpG sites, usually targeted by DNA methylation processes.

DNA methylation:

DNA methylation is the biochemical process through which a methyl group is added to cytosine rings with the specific sequence “cytosine nucleotide-phosphate-guanine nucleotide.” DNA methylation stably alters the expression of genes in cells not only when they differentiate from embryonic stem cells into specific tissues but also during postnatal life.

Epigenetics:

Epigenetics is the study of potentially heritable changes in gene activity that are not caused by changes in the DNA sequence; it also can be used to describe stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. Examples of epigenetic changes include DNA methylation and histone modifications.

Histone modifications:

Histones are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation. Histone modifications can alter the structure of chromatin and, in turn, alter the transcriptional efficiency of specific genes.

HPA axis:

The hypothalamo-pituitary-adrenal axis is a complex set of interactions among three endocrine glands: the hypothalamus, the pituitary gland, and the adrenal glands. The interactions among these organs constitute the HPA axis, a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, energy storage, and expenditure.

HPG axis:

The hypothalamo-pituitary-gonadal axis is a complex set of interactions among three endocrine glands: the hypothalamus, the pituitary gland, and the gonads (ovaries in females, testes in males). The hypothalamic gonadotropin-releasing hormone (GnRH) stimulates the release of the follicular stimulating hormone (FSH) and luteinizing hormone (LH), and these, in turn, regulate the gonadal production of estradiol, testosterone and progesterone. This axis controls development, reproduction, and aging in animals, with possibly more widespread effects in the human central nervous system and immune system.

MeCP2:

The methyl-CpG-binding protein 2 (or MeCP2) gene is located on the long (q) arm of the X chromosome in band 28 (“Xq28”). This protein binds methylated DNA and is involved in turning off (“repressing” or “silencing“) several other genes.

Metabolomics:

Metabolomics is the systematic study of the unique chemical fingerprints that specific cellular processes leave behind. The metabolome represents the collection of all metabolites, in this case sex steroid metabolites, in a biological cell, tissue, organ or organism, which are the end products of hormonal-related cellular processes.

microRNA:

A microRNA is a small non-coding RNA molecule (containing about 22 nucleotides) found in plants, animals, and some viruses, which functions in RNA silencing and post-transcriptional regulation of gene expression.

Oxytocin:

Oxytocin is a mammalian neurohypophysial hormone (secreted by the posterior pituitary) that acts primarily as a neuromodulator in the brain. Oxytocin plays an important role in the neuroanatomy of intimacy, specifically in sexual reproduction, in particular during and after childbirth.

Polymorphisms:

A genetic polymorphism is the occurrence in the same population of two or more alleles at one locus, each with appreciable frequency (the minimum frequency typically taken as 1 %).

Post-translational:

Translation is the process whereby an mRNA is processed by ribosomes, which in turn, leads to protein synthesis. Post-translational changes usually refer to any changes at the protein level, such as protein modifications and degradation processes.

Pre-transcriptional:

Transcription is the first step of gene expression, in which a particular segment of DNA is copied into RNA by the enzyme RNA polymerase. Modifications that occur before the transcription from DNA to mRNA are pre-transcriptional and commonly target the transcriptional process through DNA methylation or histone modifications.

Pre-translational:

Modifications that occur after the transcription from DNA to RNA and before the translation from mRNA to protein are called pre-translational and commonly target the translational process through modifications of the mRNA (e.g., through microRNA regulation) and mRNA degradation processes.

Proteomics:

Proteomics is the large-scale study of proteins, particularly their structures and functions. The proteome is the entire set of proteins, produced or modified by an organism or system. This varies with time and distinct requirements, or stresses, that a cell or organism undergoes. One of the challenges of systems biology and functional genomics is to integrate proteomic, transcriptomic, and metabolomic information to give a more complete picture of living organisms.

Sex chromosome complement:

The pair of XX or XY sex chromosomes, which is usually counted as the 23rd pair of chromosomes in humans.

SRY gene:

The sex-determining region Y (or SRY) gene leads to the expression of a specific transcription factor, altering gene expression such that a functional male reproductive system is formed (including functional testes) and is directly responsible for the second-trimester surge of testosterone in male fetuses.

Transcriptomics:

The transcriptome is the set of all RNA molecules produced in one or several population of cells and includes the amount or concentration of each RNA molecule in addition to their molecular identities.

Vasopressin:

Vasopressin, also known as arginine vasopressin (AVP), is a neurohypophysial hormone found in most mammals (secreted by the posterior pituitary). Its two primary functions are to retain water in the body and to constrict blood vessels. However, accumulating evidence suggests that it plays an important role in social behavior, sexual motivation and pair bonding, as well as maternal responses to stress.

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Nguyen, TV., Ducharme, S. & Karama, S. Effects of Sex Steroids in the Human Brain. Mol Neurobiol 54, 7507–7519 (2017). https://doi.org/10.1007/s12035-016-0198-3

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