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Handbook of Clinical Gender Medicine


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of the biased sex ratio has, until quite recently, been limited. The androgen-exposure model and the X and Y chromosome models offer interesting potential explanations for the biased sex ratio in ASC and require further research attention. While often conceived as competing theories, they may, in fact, be related as there are genes on the X chromosome which are responsive to testosterone and could modulate the production or sensitivity of an individual to testosterone. Given the possibility that ASC are highly polygenic and/or heterogeneous, it is also possible that multiple independent factors contribute to the biased sex ratio. Ultimately, a better understanding of the mechanisms underlying sex differences in the vulnerability to ASC could significantly improve diagnosis, guide research efforts into environmental risk factors, and generate novel, possibly sex-specific, therapeutic possibilities for individuals with ASC.

      Copyright © 2012 S. Karger AG, Basel

      Epidemiology

      Prevalence

      Pathogenesis

      The Extreme Male Brain Theory of Autism Spectrum Conditions

      It is increasingly suggested that ASC is a spectrum of conditions that blends into the whole of the population. In other words, ASC occurs in the tails of a normal distribution. This model is multifactorial and will include polygenic effects and environmental influences, one of which may be testosterone (for reasons to be discussed). It is also important to understand that, in terms of cognition and brain structure, ‘male’ and ‘female’ are not distinct categories; they too are dimensional. Within each sex, there is individual variability, and there is a substantial overlap between male and female distributions.

      Analogies can also be drawn between sex differences in brain development and neuroanatomical characteristics found in ASC. Although there is a great deal of individual variation in human brain morphometry, the cerebrum as a whole is about 9% larger in men and in boys. One of the most consistent anatomical findings in children with ASC is that young children with autism tend to have larger-than-average heads. Magnetic resonance imaging confirms that these large heads contain abnormally large brains. Reports of regional differences in sexual dimorphism are more controversial, but correcting for the overall larger size of male brains, the amygdala is disproportionately large in boys while the hippocampus and caudate are disproportionately large in girls. Like an exaggeration of typical boys, children with ASC show greater growth of the amygdala [see 4 for review].

      Finally, studies of brain function also reveal similarities between typical sex differences and differences between those with ASC and neurotypicals. The ‘default mode network’ (DMN) is decreased in functional connectivity in males relative to females during resting conditions. In ASC, connectivity within the DMN is even more decreased during rest. Using task-related functional MRI, typical males show decreased activity in the posterior parietal cortex (BA 7) during the EFT and people with ASC show even less activity in BA 7 during this task. Finally, typical males show decreased activity bilaterally in the inferior frontal gyrus (BA 44/45) during the ‘Reading the Mind in the Eyes’ Test relative to typical females, and people with ASC show even less activity in this region during this task [see 4 for review].

      So, which biological mechanisms shape the sex differences described above and is there evidence that these mechanisms are disrupted in individuals