Sexual differentiation of the brain related to gender identity: beyond hormones

Abstract

The sexual differentiation of the brain starts in the second semester of pregnancy, which is, after the development of the genitals which differentiate in the second month of pregnancy. Because these two processes have different timetables, it could be that these are initiated through different pathways. Male gonads synthesize testosterone, which can be converted into estrogen by aromatase in the brain. In humans, the exact mechanism of male and female brain development has still to be elucidated. Based on clinical evidence from genetic men (XY) suffering from a mutation in the androgen receptor gene (complete androgen-insensitivity syndrome) and who show a female phenotype of the external genitals as well as the brain, it can be proposed that direct action of testosterone is probably causing the brain to differentiate in the male direction. However, when the process of genital development and of brain sexual development does not match the same sex, females with a male brain and vice versa can arise. These transsexual people have problems with their gender identity and have the conviction of being born in the wrong body. Twin and family studies show that there are genetic factors influencing the chances of a gender identity problem. Genetic factors could play a large role in the sexual differentiation of the brain, as can be shown from studies where differential genetic expression is found before development of the gonads. These genes could also function in other tissues than gonads and influence the sexual differentiation of the brain. The DMRT gene family which encodes transcription factors or the amount of sex hormone binding globulin (SHBG) is possibly influencing the development of sex differences, just as sex-biased differential splicing. Epigenetic mechanisms such as X-inactivation and genomic imprinting are also good candidates for causing differences in the sexual differentiation of the brain. These observations indicate that probably many processes operate together in the sexual differentiation of the brain and that diverse mutations can lead to gender identity problems.