Simply 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 Autism
Autism 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 autism, in large part because of the finding of a 3.9–9-fold increase in the incidence of autism in boys compared to girls (Bertrand et al.,2001; Chakrabarti and Fombonne,2001; Gurney et al.,2003; Chakrabarti and Fombonne,2005).
The extreme male theory of autism, as proposed in most detail by Baron-Cohen, states that the sexually divergent behaviors which are more closely aligned with men are overemphasized in autism, while those behaviors more typically seen as female are deficient in autism. As further described by Baron-Cohen (2002) women have greater language skills, spend more time looking at the eyes and making eye contact and have a greater ability to understand the feelings of others than men do—and all of these characteristics are deficient in autism. Conversely, men have a greater attention to detail, to collecting and a preference for interactions with strict rules or closed systems such as computers—and all of these are overdeveloped in autism. Men have a greater need for a predictable environment while women have a greater facility for responding to novel social situations. According to the extreme male hypothesis, then, the traits of systemizing far outweigh the traits of empathy and social bonding, such that the phenotypic behaviors of autism result (Baron-Cohen,2009).
Social approach or avoidance is regulated by a number of neuropeptides and neurohormones, in particular oxytocin and cortisol, which are found principally in sexually dimorphic brain regions—the hypothalamus and the amygdala.
The paraventricular nucleus (PVN) of the hypothalamus contains cells expressing a number of hormones and neuropeptides, some of which are considered neurosecretory (i.e., project to the pituitary) and some of which project to other brain regions. The cells projecting to other brain regions consist primarily of two neuropeptides, oxytocin and vasopressin, and the neurohormone corticotrophin releasing factor (CRF). Both CRF and oxytocin have been implicated in autism as part of the neuroendocrine hypothesis of Jay Shulkin (2007).
Many human studies have found a role for oxytocin in social memory and memory for faces (Savaskan et al.,2008; Guastella et al., 2009) but not an increased memory for non-social stimuli (Rimmele et al.,2009) increased trust (Kosfield et al.,2005; Zak et al.,2005; Baumgartner et al.,2008; Petrovic et al.,2008), increased security of attachments and partner support (Grewen et al.,2005; Buchheim et al.,2009), increased empathy (Barraza and Zak,2009) and increased ability to read the affective state of others (Theory of mind; Domes et al.,2007; Goldman et al.,2008). Oxytocin levels can be observed to change quickly in response to the social environment, including after warm contact between couples (Grewen et al.,2005; Holt-Lunstad et al.,2008) massage (Carter et al.,2007) or maternal-infant bonding (White-Traut et al.,2009). Oxytocin mediates the effects of social support in dealing with stress and improves communication between couples (Ditzen et al.,2009). The administration of oxytocin has been shown to decrease the fear-induced activity of the amygdala (Kirsch et al.,2005). There are suggestions that some of the therapeutic effects of antidepressants in social anxiety disorders are through oxytocin release in the PVN (Raap and Van de Kar,1999). Many oxytocin-containing cells of the PVN have estradiol receptors in the adult, such that these may be a site of gender based activating (as opposed to organizing) effects of hormones (Bodo and Rissman,2006) and blood levels of oxytocin are higher in women than men (Ozsoy et al.,2009). Oxytocin plays an important role in the sexually dimorphic aspect of human social reciprocity and social brain development (Yamasue et al.,2009).
Uvnas-Moberg has summarized the role of oxytocin as being responsive to changes in the social environment to bring about “calm and connection” (1997,1998). The connection may be due to the direct central effects of oxytocin, and the calm may be produced by oxytocin's ability to decrease levels of the stress-related hormone, cortisol (Heinrichs and Gaab,2007; Ditzen et al.,2009, and below). All of these functions of oxytocin can be seen to be lacking in people with autism and a lower peripheral blood level of oxytocin has been reported (Modahl et al.,1998; Green et al.,2001). Moreover, several studies have shown that administering oxytocin improves symptoms of autism. Intranasal oxytocin improves the ability of young autistics to recognize emotions in the “Reading the Mind in the Eyes” task (Guastella et al.,2010) and increases the positive feelings of interacting socially in a simulated ball toss game and increases preference for reciprocal relationships (Andari et al.,2010).
The amygdala plays a role in interpreting sensory and emotional information and motivating resultant behaviors and is particularly active during fearful events (LeDoux,2000). The amygdala has also been shown to play a role in primates in gaze monitoring, the ability to perceive where someone's eyes are focused and what they are looking at (Perrett et al.,1989; Rolls,1999) and may determine whether or not someone is trustworthy and whether or not social approach should take place (Adolphs,1999). Changes in the function and neuropathology of the amygdala have long been known in autism (Baron-Cohen et al.,2000). Postmortem studies show cell packing changes (Bauman and Kemper,2005) and size changes in MRI studies have been observed (Aylward et al.,1999; Schumann et al.,2009) which can be correlated with the ability to engage in joint attention (Mosconi et al.,2009). fMRI activation when looking at faces is different in autism (Critchley et al.,2000).
Corticotrophin releasing hormone (CRF) cell bodies are found both in the PVN and the amygdala. Cells in the amygdala also project to the hypothalamus, further regulating the release of adrenocorticotrophin hormone (ACTH) and eventually of cortisol, through the HPA axis. CRF is therefore thought to be the principle initiator of endocrine, behavioral and autonomic responses to stress (Shekhar et al.,2005). Specifically, increased CRF in the amygdala leads to heightened vigilance and fear and social withdrawal (Erickson et al.,2005) and the number of corticotrophin-releasing hormone cells are greater in men than women (Bao and Swaab,2007).
There are numerous studies on the role of altered HPA axis in autism. Children with autism do not have the usual morning surge in cortisol but cortisol levels are increased more in children with autism than in typically developing children, when exposed to a novel event (Corbett et al.,2006,2008). This suggests a dysfunction of the HPA axis in autism.
Therefore, a balance exists between oxytocin and cortisol in interpreting social interactions as being supportive and pleasant (oxytocin) or stressful and to be avoided (cortisol) whereby oxytocin blunts the stress responses. This balance can be seen in several studies. Intranasal oxytocin decreases salivary levels of cortisol during conflict (Ditzen et al.,2009) or when subjects are exposed to a psychosocial stress (Heinrichs et al.,2003). In a study of young adults, higher levels of oxytocin were associated with less psychosocial stress but higher levels of cortisol were associated with higher levels of psychosocial distress (Gordon et al.,2008). Administration of oxytocin can also be shown to inhibit release of ACTH (Legros et al.,1982,1984; Suh et al.,1986). Oxytocin may play a general role in balancing the effects of cortisol to maintain homeostasis, as oxytocin decreases the cortisol elevation induced by experimental bacterial toxins (Clodi et al.,2008).
Thus, oxytocin plays a dual role in social responding by being both prosocial and at the same time anti-stress. The neuroendocrine hypothesis of autism proposes a dysregulation of this important cortisol/oxytocin balance.