The strong male prevalence of autism spectrum disorders represents a challenge to any neurobiological theory of autism. Current genetics does not offer clues to this phenomenon. The authors argue that understanding the mechanisms by which male and female sex hormones act during brain development to organize brain circuits that are involved in sexually dimorphic and/or lateralized cognitive, social and emotional functioning, will yield important clues to understand the etiology of autism. The internal environment of the foetus and the newborn baby is characterized by constantly changing sex hormone levels: although in the past decades important insights have been gained into the effect of hormonal exposure on the organization of brain circuits, there are still many contradictory findings that need to be reconciled. Some apparent difficulties are the differences in sex hormone metabolism between animal species, and the fact that androgen and estrogen pathways are metabolically linked together. It is possible that altered androgen and estrogen levels could both lead, via different pathways, to alterations of cognitive, linguistic, social and emotional circuits. For example, testosterone has important effects on development of callosal connections, thus leading to differences in hemispheric specialization between males and females, while recent research suggests a strong link between estrogen pathways and pathways of the "social hormones", oxytocin and vasopressin. In conclusion, we think that in the years to come the challenge will be to gain a deeper understanding of the complex relationships between androgens/estrogens and development/plasticity of specific neural circuits that appear to be critical in autism, in particular reciprocal connections between the cerebral cortex and structures such as the amygdala and the cerebellum.
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