Sex differences in the brain–an interplay of sex steroid hormones and sex chromosomes

Abstract

Although considerable progress has been made in our understanding of brain function, many questions remain unanswered. The ultimate goal of studying the brain is to understand the connection between brain structure and function and behavioural outcomes. Since sex differences in brain morphology were first observed, subsequent studies suggest different functional organization of the male and female brains in humans. Sex and gender have been identified as being a significant factor in understanding human physiology, health and disease, and the biological differences between the sexes is not limited to the gonads and secondary sexual characteristics, but also affects the structure and, more crucially, the function of the brain and other organs. Significant variability in brain structures between individuals, in addition to between the sexes, is factor that complicates the study of sex differences in the brain. In this review, we explore the current understanding of sex differences in the brain, mostly focusing on preclinical animal studies.

Analysis of Human Brain Structure Reveals that the Brain “Types” Typical of Males Are Also Typical of Females, and Vice Versa

“…At its extreme, the interpretation is that brains from females and from males belong to two distinct categories, just as male and female genitals are. This interpretation is very common in popular discussions of sex and the brain (e.g., Sax, 2005 ; Brizendine, 2006 ), but can also be found in scientific publications, as in the following statements: “males and females are biologically different not only with regards to gonads and secondary sexual characteristics but also in the structure and, more importantly, the function of many other organs including the brain” ( Grgurevic and Majdic, 2016 , p. 1481), and “sex-specific differences in dopaminergic, serotonergic, and gamma-aminobutyric acid (GABA)ergic markers indicate that male and female brains are neurochemically distinct” ( Cosgrove et al, 2007 , p. 847). The less extreme interpretation, which is more common in scientific publications and which is the one challenged in the present study, is that although there is overlap between females and males in brain structure, the typical female brain differs from the typical male brain.…”

The Complex Relationships between Sex and the Brain

“…According to this new view, sex effects on the brain are exerted in both females and males throughout life by several steroid hormones (including testosterone, estradiol, and progesterone) as well as by genetic and environmental factors. These effects are exerted via multiple partly independent mechanisms and may vary according to internal and external factors (for review, see Arnold 2012; Forger 2018; Grgurevic and Majdic 2016; McCarthy 2016; McCarthy and others 2018; McEwen and Milner 2017; Sekido 2014).…”

“…Most of the evidence supporting this new understanding of sex effects on the brain derives from studies in laboratory animals and tissue cultures. In vitro studies of neuronal cultures obtained from embryos prior to the development of the gonads revealed some differences between XX and XY neurons in the absence of sex-related hormones (for a recent review, see Grgurevic and Majdic 2016). For example, dopamine content and uptake (but not neuron number) were higher in cultures obtained from the embryonic mesencephalon (but not diencephalon) of female compared with male NMRI mice (Sibug and others 1996).…”

Gender Medicine – the heart and mind of the latest findings in our collection from Clinical Science

“…The brain is the most complicated organ in the human body and the ultimate goal in neuroscience is to understand the connection between brain structure/ function and behavioural outcomes, with sex differences shown to affect the structure and function of the brain. Gregor Majdic and Neza Grgurevic are neuroendocrinologists from the University of Ljubljana, researching the interplay between genes and hormones in neurodevelopment, and they have reviewed the current understanding of sex differences From Portland Press in the brain 12 . The conventional view is that masculine or feminine organization of the brain depends on the presence or absence of early gonadal steroid exposure ( Figure 2), however studies suggest that in addition to the neonatal period, later adolescent periods, sex chromosome complement and the involvement of epigenetic effects may all play a crucial role.…”

“…The progression to immunosenescence characterized by age-related changes in immune cells and inflammatory mediators is faster in men than in women 7 Schematic representation of the conventional theory of brain sexual differentiation12 …”