Reversal of normal cerebral sexual dimorphism in schizophrenia: evidence and speculations

Sex differences in epidemiology, clinical course and symptomatology of schizophrenia have been widely documented, but still relatively little is known about the brain sexual dimorphism in this psychiatric disorder. While some neuroanatomical and neuropsychological studies have reported existence of differences between male and female patients in a direction of normal sexual dimorphism, others did not find any effect. A few recent reports point to a peculiar disturbance of normal sexual dimorphism in brain regions implicated in the processing of emotions, including amygdala, orbitofrontal cortex and anterior cingulate. Prompted by these findings we compared cerebral activations between the sexes during performance of two emotion processing tasks and found overall much more extensive and intense cerebral activations in men than in women with schizophrenia. Moreover, the pattern of obtained sex differences in cerebral activation in patients differed significantly from what has been observed in the general population. Based on these preliminary structural and functional neuroimaging data, as well as some clinical reports, it is hypothesized in the present paper that schizophrenia is characterized by a reversed (or at least seriously disturbed) cerebral sexual dimorphism. It is further argued that this phenomenon stems from masculinization and/or un-feminization of females and feminizations and/or un-masculinization of males by sex steroid hormones, such as estrogen and testosterone, during both organizational and activational stages of neurodevelopment.