Differenziamento sessuale del cervello: ruolo degli ormoni sessuali e degli enzimi implicati nel loro metabolismo

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 konwn that testosterone, secreted by the fetal testes, plays a key role in the permanent organization of the developing CNS toward masculine patterns in rodents. Two main aspects concerning the mechanism of action of testosterone have emerged in the last 30 years: 1) that the hormone is converted in target cells into compounds which amplify or differentiate its action; 2) that CNS, and in particular the hypothalamus, possesses the enzymatic machinery involved in these conversions (namely the enzymes 5alpha-reductase and aromatase). The interaction of testosterone metabolites (DHT and estradiol respectively) with specific intracellular receptors leads to the activation of responsive genes which are responsible for the masculinization of the brain during development. In this review the present knowledge concerning the mechanism of action of testosterone metabolites and the main characteristics of the two enzymatic pathways involved in their formation in the developing CNS are described. Specific attention has been devoted to the discussion of the experimental data, obtained mainly in rodents, concerning the effects of androgen-derived estrogens on the sex-differentiation of the brain. Moreover, some results obtained in our and other laboratories regarding the cellular localization, the ontogenesis and the possible mechanisms which control aromatase, the enzyme involved in estrogen formation, have been reviewed. Finally, the potential influence of testosterone metabolites on the sexual differentiation of the human brain has been discussed on the basis of some pathologies in which a modification of the normal levels and/or of the mechanism of action of gonadal hormones during embryogenesis is present.