Understanding Sex Differences to Inform Studies of Diseases of The Nervous System

We are currently seeing a surge of interest in studying sex differences in human biology. However, historically the effect of sex on biology and disease has been minimized. On the genetic level, we have effectively-rounded an XX genotype to an XY genotype citing X-inactivation to dismiss the effect of the second X chromosome in women and dismissing the Y chromosome as small and primarily involved in sex determination during embryogenesis. However, we now know that well over 100 X-linked genes escape inactivation showing full to partial bi-allelic expression in adult female tissues. In addition, there are at least 26 protein-coding genes as well as many long-non-coding RNAs and miRNAs on the Y chromosome. Quite telling is the fact that 98% of human embryos with Turner Syndrome defined by a 45, XO genotype do not survive gestation  That extraordinary embryonic mortality rate is a direct result of the lack of either an X or a Y chromosome in the second sex chromosome position and underscores the importance of X/Y chromosome complement beyond sex determination

It is worthwhile mentioning that we will use the term sex to mean genetic sex, and it will be assumed that the hormonal environment follows the genetics in the studies referenced. While this is the case with the vast majority of humans, there are people for whom those assumptions do not apply. In cases of sex reversal (XX with male external genitalia and XY with female external genitalia), genital development is unlinked to genetic sex. While sex reversal is thought to be rare, occurring an estimated 1 in 10,000 people, it is a condition that can likely go undiagnosed (and therefore underestimated) as people can live relatively normal lives unaware that their genetics do not match their external genitalia.

More commonly, it is estimated that between 0.1 and 0.7% of the population is transgender or gender non-conforming and up to 25% of these individuals are on cross-hormone therapy. These numbers would imply that more than 100,000 people in the US alone have a sex hormone milieu that fits their gender but is opposite to their genetic sex. Gender, though often erroneously used as a synonym of sex, is a term that combines both the internal and external perception of an individual’s sex (as defined by the World Health Organization). While the influence of gender roles might ultimately impact neural biology, to date there are few major studies that differentiate sex and gender in analyses of diseases of the human brain. Thus, in this review, references to males assumes an XY genotype and a circulating hormonal environment dominated by testosterone while a reference to females assumes an XX genotype and a circulating hormonal environment dominated by estrogen. Finally, we will use the term “sexually dimorphic” to refer to traits that are systematically different between males and females and “sex difference” to refer to measurements that have statistically significant differences in male-female population averages.

To be clear, most of the sex differences observed are differences in the population average of a particular measurement with considerable overlap between men and women. Thus, one way to approach studying sex as a biological variable is to consider sex as a differentiation axis that can be used to evaluate natural variations in human biology. In the case of sex differences, the particular variations would tend to be ones influenced by sex hormones, X and Y chromosomes, differential cultural environments or a combination of those.

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