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Contents lists available at ScienceDirect

Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne

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Editorial

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Sex differences in neurological and psychiatric disorders

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1. Introduction to the Special Issue

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Sexual dimorphisms in structure and physiology are widespread in the animal kingdom, including humans. Extreme examples of dimorphic secondary sexual characteristics arise from sexual selection where they are used as indicators of fitness of potential mates (e.g. tail feathers in peacocks and birds of paradise). Some sexual dimorphisms arise from intrasexual competition for resources, such as territory and mates, and include increased body size and weaponry (e.g. antlers) in males of many species. Other sexual dimorphisms are necessitated by sex differences in reproductive physiology, including genitalia, and mammary glands. Accompanying these obvious sexually dimorphic features, sex differences in the brain ensure the expression of male- or female-typical behaviors to maximize the fitness of each sex. The vast majority of sex differences in neuroanatomy, neurochemistry and neuronal structure and connectivity are established by the organizational influences of gonadal sex steroids or genes found on sex chromosomes. Sex differences in adult steroid hormone secretion also contribute to sex differences in the brain. Sex differences in the brain are likely more pervasive than many appreciate. A recent study reported that up to 2.5% of genes are differentially expressed or spliced in the brains of men and women (Trabzuni et al., 2013). Despite these sex differences, most biomedical research is carried out in only one sex, typically males, and therefore fails to identify many of the consequences of sex differences in brain in relation to disease (Beery and Zucker, 2011; McCarthy et al., 2012). Unfortunately there has been resistance in some circles to accept that sex differences in the human brain exist or have any biological relevance (Fine, 2010). This stance is somewhat puzzling given the vast documentation of brain sexual dimorphisms in animal models. It is highly unlikely that sexual dimorphisms in the brain disappeared in early hominids or more recent ancestors. Indeed there is a remarkable conservation in the genes that are differentially expressed between the sexes in humans and rhesus macaques (Reinius et al., 2008). Sex differences in several aspects of human behavior and cognition are commonly reported, but the extent that these differences arise from biology versus societal influences is rarely clear. Unfortunately the debate about sex differences in the human brain often takes on a political nature, as some believe that these differences may be used to imply superiority or inferiority of either gender for cognitive abilities, or to be an excuse for sex differences in less than complimentary behavior (Fine, 2010). However, we feel that sex differences in the brain should be embraced for enriching humanity, rather than being ignored for denigrating one sex or the other. Sex differences in the brain, where they exist, they are rarely absolute. They imply differences in means, often with considerable

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http://dx.doi.org/10.1016/j.yfrne.2014.05.005 0091-3022/Ó 2014 Published by Elsevier Inc.

overlap between males and females. Nevertheless, it is critical to explore sexual dimorphisms in the brain for their impact and therapeutic implications for disease. This is particularly the case for many neurological and psychiatric diseases. As noted by one of the contributors of this issue, Thomas Insel, Director of the National Institute of Mental Health was quoted as saying ‘‘It’s pretty difficult to find any single factor that’s more predictive for (psychiatric) disorders than gender’’ (Davies, 2014). With that knowledge it is irresponsible to ignore sexual dimorphisms in the human brain, as insights from these differences may help us better understand the etiology of sex biased diseases and ultimately may lead to better therapeutic approaches. In this special issue we explore the sexually dimorphic nature of several psychiatric and neurological disorders with reviews of both preclinical animal studies and clinical data.

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2. Sex differences in specific neurological and psychiatric disorders

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Autism Spectrum Disorder (ASD) is perhaps the prototypical sex biased neurodevelopmental disorder, with a sex ratio of four males for every female. In high functioning autism, the ratio is even higher, with a male to female ratio of eleven to one. In this issue, Schaafsma and Pfaff explore the potential genetic, hormonal, and environmental mechanisms underlying ASD’s male bias (Schaafsma and Pfaff, 2014). ASD is a highly genetic disorder, but the majority of genes implicated in the disorder are not located on sex chromosomes. However, it remains possible that genes on the Y chromosome interact with ASD susceptibility genes to contribute to the autistic phenotype. Likewise, genes located on the X chromosome that escape X-inactivation or are susceptible to skewed or mosaic inactivation, or imprinting are candidates for contributing to the male sex bias. Developmental exposure to steroid hormones is also a potential contributor to ASD phenotypes in males, but the data are inconsistent and suggest that increased steroid exposure alone is unlikely to be responsible for the male bias in ASD. The authors also explore the intriguing possibility of an interaction between sex steroids, immune factors or prenatal stressors, and susceptibility genes in predisposing males to develop ASD. This plausible explanation may indeed be common in other psychiatric and neurological disorders characterized by a male sex bias, including Attention Deficit Hyperactivity Disorder. Sex differences in the patterns of drug use and addition have been widely described, but the underlying mechanisms leading to these sex differences may be generalizable to other types of addictive behaviors. In this issue, Fattore and Fratta review the evidence of sex differences not only in abuse of addictive drugs, but

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also in food addiction, compulsive sexual activity, pathological gambling, internet addiction, and physical exercise addition (Fattore et al., 2014). They then provide an overview of potential risk factors and brain mechanisms, with a particular focus on the role of sex steroid hormone in creating sex differences in prevalence. Both biological and sociocultural factors likely contribute to the sex differences in addictive behaviors. For drug and alcohol addiction, sex differences in metabolism, pharmacodynamics and pharmacokinetics likely play roles in the observed sex differences, which may be mediated in part by the organizational and activational effects of gonadal steroids. Far less is known about the neuroendocrine factors contributing to other behavioral addictions and this is an area that deserves further investigation. Women are roughly twice as likely to suffer from anxiety disorders, such as panic disorder, and trauma-related disorders, such as posttraumatic stress disorder (PTSD) and are more likely to suffer from major depression than men. Three reviews in this issue explore various aspects of sex differences in stress response, anxiety and mood disorders from both preclinical and clinical perspectives. First Panagiotakopoulou and Neigh provide a detailed overview of the development and regulation of the hypothalamus–pituitary-stress axis and discuss the mechanisms that mediate the increased sensitivity and activity of female stress axis compared to males, with an overview of both preclinical and clinical studies (Panagiotakopoulos and Neigh, 2014). Then Bangasser and Valentino discuss how sex differences at the molecular and cellular level can contribute to sex differences in disease vulnerability and severity, with a focus trauma-related disorders and major depression (Bangasser and Valentin, 2014). Finally Altemus, Epperson and Sarvaiya, review sex differences in anxiety and depressive disorders from a clinical perspective using developmental stages across the lifespan as an organizing principal (Altemus et al., 2014). These authors propose that sex differences that promote reproductive success also result in differential risk for psychopathology. Attention Deficit Hyperactive Disorder (ADHS) affects 6% of children with a ten-fold higher prevalence of diagnosis in males than in females. In this issue, Davies explores fundamental biological mechanisms that have been shown to, or may, contribute to the sex bias in this disorder (Davies, 2014). This review focuses largely on potential genetic factors giving rise to the sex differences, yielding many of the same considerations put forth by Schaafsma and Pfaff for autism (Schaafsma and Pfaff, 2014). Attention Deficit Hyperactive Disorder (ADHS) affects 6% of children with a ten-fold higher prevalence of diagnosis in males than in females. In this issue, Davies explores fundamental biological mechanisms that have been shown to, or may, contribute to the sex bias in this disorder (Davies, 2014). This review focuses largely on potential genetic factors giving rise to the sex differences, yielding many of the same considerations put forth by Schaafsma and Pfaff for autism (Schaafsma and Pfaff, 2014). Autoimmune diseases arise from immune responses to self and can affect a number of organ systems. In this issue, Ngo, Steyn and McCombe survey gender differences several autoimmune diseases, including, but not limited to those affecting the nervous system (Ngo et al., 2014). Most autoimmune diseases display sex differences in prevalence, with a female bias found in most cases. Ngo et al., summarize the prevalence of common autoimmune diseases specific to adult males and females in many countries where data is available and discuss possible mechanisms for sex specific differences, including gender differences in immune response and organ vulnerability, reproductive physiology including pregnancy and sex hormones, genetic factors, and epigenetics. The authors conclude gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease. Parkonson’s disease has a higher prevalence and earlier onset in men compared to women. In this issue, Gillies and colleagues

describes the sex differences in Parkinson’s disease and explores the interaction of genetic, hormonal and environmental influences on the nigrastriatal dopamine system that may contribute to this sex difference (Gillies et al., 2014). There is intriguing evidence that the Y-chromosome gene, SRY, may directly influence the nigrastriatal dopamine system and therefore contribute to the sex differences in Parkinson’s disease. Furthermore, the authors suggest that while estrogens may have a neuroprotective effect in females, while testicular steroids may increase neurodegeneration. While many may find the data reporting sex differences in cognitive performance disconcerting, sex differences in cognitive decline with aging is a serious issue that must be clearly understood. In this issue, Li explores the evidence of differences in cognitive performance in males and females, and reviews the literature of sex differences in cognitive decline (Li, 2014). As in several other reviews in this issue, the contribution of both organizational and activational effects of sex steroid hormones is discussed. Women have a higher prevalence of Alzheimer’s Disease and a faster rate of cognitive decline with the disease than men. This difference may be related to the reduced concentrations of sex steroid hormones in aging women compared to men. Li presents evidence of the neuroprotective effects of sex steroids with respect to Alzheimer’s Disease as well as clinical data suggesting that hormone replacement therapy may have beneficial effects in the treatment of this debilitating disease. Each of the reviews in this Special Issue highlight the significance of understanding the biological bases of sex differences in neurological and psychiatric disorders for understanding the etiology of the disorder, but more importantly, improve therapeutic strategies for improving the disorders. It is our hope that this special issue will stimulate interest in sexual dimorphisms in the brain and lead to more research of the implications of sex differences for treating these devastating conditions.

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References

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Altemus, M., Epperson, C.N., et al., 2014. Sex differences in mood and anxiety disorders: clinical perpectives. Front. Neuroendocrinol. (in press). Bangasser, D.A., Valentino, R.J., 2014. Sex differences in stress-related psychiatric disorders: Neurobiological Perspectives. Front. Neuroendocrinol. (in press). Beery, A.K., Zucker, I., 2011. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35 (3), 565–572. Davies, W., 2014. Sex differences in Attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms. Front. Neuroendocrinol. (in press). Fattore, L., Melis, M., et al., 2014. Sex difference in addictive disorders. Front. Neuroendocrinol. (in press). Fine, C., 2010. Delusions of Gender: The Real Science behind Sex-Differences. Icon Books Ltd.. Gillies, G.E., Pienaar, I.S., et al., 2014. Sex differences in Parkinson’s disease. Front. Neuroendocrinol. (in press). Li, R., 2014. Sex differences in cognitive impairment and Alzheimer’s disease. Front. Neuroendocrinol. (in press). McCarthy, M.M., Arnold, A.P., et al, 2012. Sex differences in the brain: the not so inconvenient truth. J. Neurosci. 32 (7), 2241–2247. Ngo, S.T., Steyn, F.J., et al., 2014. Gender differences in autoimmune disease. Front. Neuroendocrinol. (in press). Panagiotakopoulos, L., Neigh, G.N., 2014. Origins of sex differences in the stress response: focus on the HPA axis. Front. Neuroendocrinol. (in press). Reinius, B., Saetre, P., et al, 2008. An evolutionarily conserved sexual signature in the primate brain. PLoS Genet. 4 (6), e1000100. Schaafsma, S.M., Pfaff, D.W., 2014. Etiologies underlying sex differences in autism spectrum disorders. Front. Neuroendocrinol. (in press). Trabzuni, D., Ramasamy, A., et al, 2013. Widespread sex differences in gene expression and splicing in the adult human brain. Nat. Commun. 4, 2771.



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Larry J. Young Q2 Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, United States ⇑ Address: 954 Gatewood Rd., Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, United States Fax: +1 404 727 8070. E-mail address: [email protected]

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Donald W. Pfaff Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10021, United States

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Sex differences in neurological and psychiatric disorders.

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