Sexual Differentiation and the Neuroendocrine Hypothesis of Autism

Abstract

The phenotypic expression of autism spectrum disorders varies widely in severity and characteristics and it is, therefore, likely that a number of etiological factors are involved. However, one finding which has been found consistently is that there is a greater incidence of autism in boys than girls. Recently, attention has been given to the extreme male hypothesis-that is that autism behaviors are an extreme form of typical male behaviors, including lack of empathy and language deficits but an increase in so-called systemizing behaviors, such as attention to detail and collecting. This points to the possibility that an alteration during sexual differentiation of the brain may occur in autism. During sexual differentiation of the brain, two brain regions are highly sexually dimorphicthe amygdala and the hypothalamus. Both of these regions are also implicated in the neuroendocrine hypothesis of autism, wherein a balance between oxytocin and cortisol may contribute to the disorder. We are thus proposing that the extreme male hypothesis and the neuroendocrine hypothesis are in fact compatible in that sexual differentiation of the brain towards an extreme male phenotype would result in the neuroendocrine changes proposed in autism. We have preliminary data, treating developing rat pups with the differentiating hormone 17-b estradiol during a critical time and showing changes in social behaviors and oxytocin, to support this hypothesis. Further studies should be undertaken to confirm the role of extremes of normal sexual differentiation in producing the neuroendocrine changes associated with autism. Anat Rec, 294:1663-1670, 2011. V V C 2011 Wiley-Liss, Inc.Key words: autism; oxytocin; cortisol; sexual differentiation; extreme male TWO HYPOTHESESSimply stated, the hypothesis which we are proposing in this article, and the work currently ongoing in our lab, is that enhanced sexual differentiation of the brain, towards the male phenotype, leads to changes in the neuroendocrine factors, oxytocin and cortisol. These factors are involved in the processing and evaluation of social bonding experiences and any disruption in their typical function can lead to the primary defining characteristic of the autism phenotype-inadequate social bonding. The Extreme Male Hypothesis of AutismAutism is a disorder of brain development and thus any factors which regulate brain development and are known to be altered in autism should be considered as possibly contributing to the phenotype. For example, much of our previous work and work of others, has focused on the known role of serotonin in brain development as well as the well known hyperserotonemia which occurs in autism (Whitaker-Azmitia, 2005). More recently, researchers have proposed a role for sexual differentiation of the brain in the phenotypic behaviors of

Sex Differences in Orienting to Pictures with and without Humans: Evidence from the Cardiac Evoked Response (ECR) and the Cortical Long Latency Parietal Positivity (LPP)

“…The differential contribution of the two orienting responses to the prediction of sex has been supported by logistic regression analysis showing an acceptable percentage of correctly classified men and women only when both responses were entered in the equation as predictor variables. The sex differential pattern of the LPP reflecting women’s greater response to social scenes and the ECR reflecting men’s greater (defense preparatory) response to non-social scenes might support the evolutionary view on the propagation of mammalian species supposing the female gender being responsible for “tending and befriending” and the male gender for “defending” [38] . The stronger cardiac orienting to nonsocial information in males than in females might also be in line with the male brain hypothesis proposing the more systemizing male brain to be more prepared for the processing of nonsocial events and to have a greater need for a predictable environment [39] .…”

Autism spectrum traits in normal individuals: a preliminary VBM analysis

“…According to the EMB individuals with ASD are characterized by impairments in empathizing while having intact or superior systemizing skills. Several studies provide supporting evidence for the empathizing-systemizing theory of psychological sex differences and the related EMB theory ( Baron-Cohen et al, 2003 ; Lawson et al, 2004 ; Wakabayashi et al, 2007 ; Aiello and Whitaker-Azmitia, 2011 ; Brosnan et al, 2012 ). For example, Wheelwright et al (2006) examined the EMB in a large UK sample that compared students (723 males, 1038 females) to adults with ASD (69 males, 56 females) and found that the majority (62%) of adults with ASD had an extreme male brain type (S > > E), compared to only 5% of typical males and 0.9% of typical females.…”

Early life nutrient restriction impairs blood–brain metabolic profile and neurobehavior predisposing to Alzheimer’s disease with aging

“…In contrast both males and females retained normal sociability and spatial learning and memory, despite the enhanced anxiety. These encountered neurobehavioral features were reminiscent of an anxiety disorder and/or attention deficit disorder that constitute neuropsychiatric conditions (Aiello and Whitaker-Azmitia, 2011; Pfaff et al, 2011). Retention of normal sociability and spatial learning and memory perhaps rules out conditions akin to autism spectrum disorders or other cognitive dysfunctional disorders (Mair et al, 1991; Silverman et al, 2011; Tanda et al, 2009).…”