Biologic sex influences many variables that are important to brain health in general, and to stroke or cerebral ischemia in particular, such as general health status, cerebrovascular anatomy and function, unique risk factors such as pregnancy and preeclampsia, symptomatology, and therapeutic response. A more complete understanding of the scale and depth of sexual dimorphism in the brain and the role of more general sex-based factors is crucial to reducing the burden of stroke in women and men. This focused review highlights recent findings in stroke, including sex differences in epidemiology, risk factor reduction, comparative use of stroke therapeutics in both sexes, the importance of frailty in women, and the biologic basis for sex differences in stroke. Such findings show tremendous promise for the future of personalized medicine in stroke prevention and treatment.

https://journals.sagepub.com/doi/pdf/10.1177/0271678X18793324

Sex differences in stroke: Challenges and opportunities:

Men and women exhibit significant differences in obesity, cardiovascular disease, and diabetes. To provide better diagnosis and treatment for both sexes, it is important to identify factors that underlie the observed sex differences. Traditionally, sex differences have been attributed to the differential effects of male and female gonadal secretions (commonly referred to as sex hormones), which substantially influence many aspects of metabolism and related diseases. Less appreciated as a contributor to sex differences are the fundamental genetic differences between males and females, which are ultimately determined by the presence of an XX or XY sex chromosome complement. Here, we review the mechanisms by which gonadal hormones and sex chromosome complement each contribute to lipid metabolism and associated diseases, and the current approaches that are used to study them. We focus particularly on genetic approaches including genome-wide association studies in humans and mice, -omics and systems genetics approaches, and unique experimental mouse models that allow distinction between gonadal and sex chromosome effects.

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Genetic Basis for Sex Differences in Obesity and Lipid Metabolism.

New attention to sexual dimorphism in normal mammalian physiology and disease has uncovered a previously unappreciated breadth of mechanisms by which females and males differentially exhibit quantitative phenotypes Thus, in addition to the established modifying effects of hormones, which prenatally and postpubertally pattern cells and tissues in a sexually dimorphic fashion, sex differences are caused by extragonadal and dosage effects of genes encoded on sex chromosomes Sex differences in immune responses, especially during autoimmunity, have been studied predominantly within the context of sex hormone effects More recently, immune response genes have been localized to sex chromosomes themselves or found to be regulated by sex chromosome genes Thus, understanding how sex impacts immunity requires the elucidation of complex interactions among sex hormones, sex chromosomes, and immune response genes In this Brief Review, we discuss current knowledge and new insights into these intricate relationships in the context of viral infections

Sex drives dimorphic immune responses to viral infections

A Guide for the Design of Pre-clinical Studies on Sex Differences in Metabolism

A sex- and gender-informed perspective increases rigor, promotes discovery, and expands the relevance of biomedical research. In the current era of accountability to present data for males and females, thoughtful and deliberate methodology can improve study design and inference in sex and gender differences research. We address issues of motivation, subject selection, sample size, data collection, analysis, and interpretation, considering implications for basic, clinical, and population research. In particular, we focus on methods to test sex/gender differences as effect modification or interaction, and discuss why some inferences from sex-stratified data should be viewed with caution. Without careful methodology, the pursuit of sex difference research, despite a mandate from funding agencies, will result in a literature of contradiction. However, given the historic lack of attention to sex differences, the absence of evidence for sex differences is not necessarily evidence of the absence of sex differences. Thoughtfully conceived and conducted sex and gender differences research is needed to drive scientific and therapeutic discovery for all sexes and genders.

Sex and Gender Differences Research Design for Basic, Clinical, and Population Studies: Essentials for Investigators

The “four core genotypes” (FCG) mouse model has emerged as a major model testing if sex differences in phenotypes are caused by sex chromosome complement (XX vs. XY) or gonadal hormones or both. The model involves deletion of the testis-determining gene Sry from the Y chromosome and insertion of an Sry transgene onto an autosome. It produces XX and XY mice with testes, and XX and XY mice with ovaries, so that XX and XY mice with the same type of gonad can be compared to assess phenotypic effects of sex chromosome complement in cells and tissues. We used PCR to amplify the Sry transgene and adjacent genomic sequences, to resolve the location of the Sry transgene to chromosome 3 and confirmed this location by fluorescence in situ hybridization (FISH) of the Sry construct to metaphase chromosomes. Using quantitative PCR, we estimate that 12–14 copies of the transgene were inserted. The anogenital distance (AGD) of FCG pups at 27–29 days after birth was not different in XX vs. XY males, or XX vs. XY females, suggesting that differences between XX and XY mice with the same type of gonad are not caused by difference in prenatal androgen levels. The Sry transgene in FCG mice is present in multiple copies at one locus on chromosome 3, which does not interrupt known genes. XX and XY mice with the same type of gonad do not show evidence of different androgen levels prenatally.

https://link.springer.com/content/pdf/10.1186%2Fs13104-015-0986-2.pdf

Shelly Domadia

Papers

Four core genotypes mouse model: localization of the Sry transgene and bioassay for testicular hormone levels.