Sexual differentiation of the brain: role of testosterone and its active metabolites

The sex-related morphological differences of many brain nuclei are mainly determined by the hormonal environment present during embryonic development. These morphological differences are at the basis of the gender-specific secretion of many hypothalamic and pituitary hormones, of sexual and aggressive behavior, etc. It is known that, at least in rodents, testosterone (T) secreted by the fetal testes plays a key role in the permanent organization of the developing central nervous system (CNS) toward masculine patterns. The main aspect concerning the mechanism of action of T is that the brain, and especially the hypothalamus, possesses the enzymes that transforms this hormone into compounds which amplify (dihydrotestosterone) or differentiate (estrogens) its action; these enzymatic systems are the 5alpha-reductase and the aromatase respectively. In this short review are summarized the main results obtained in our and other laboratories concerning some characteristics of the two enzymatic pathways in the developing CNS and the possible dimorphism in their expression during ontogenesis. On the basis of diseases in which alterations of the normal levels and/or of the mechanism of action of gonadal hormones during embryogenesis are present, in the last part of the paper some hypotheses on the possible influence of T metabolites in the sexual differentiation of the human brain are also drawn.