Sexual differentiation of the brain is a complex developmental phenomenon which, influenced by both the genetic background and sex hormone secretions, leads to several genderspecific physiological and behavioral responses. The developing “sex brain” is feminine by default, unless some specific stimuli drive it to a male phenotype: to achieve a male-specific brain, it is necessary to develop neural circuits responsive to testicular hormones (masculinization) loosing those able to respond to ovarian hormones (defeminization). Genetic and hormonal inputs strictly cooperate in the developing brain, especially in some specific brain areas, as the hypothalamus where marked differences also in the volume and morphology of some selected hypothalamic nuclei, differently enlarged between males and females, occur.

The genetic control of brain sexual differentiation is based on recent evidences: some sex differences are already present in tissues before gonadal differentiation; brain cells, that differ in their genetic sex, respond differently to the same hormonal inputs. Even if the “co-primary” role of genes in controlling brain sex differentiation is established, it is generally recognized that the hormonal “milieu”, particularly testosterone, is the leading force controlling this process, at least in rodents. Testosterone is converted in active metabolites by the enzymes 5alpha-reductase (type 1 and 2) and aromatase, giving rise to DHT and estradiol respectively. These two steroids, interacting with specific intracellular receptors, bring about the activation of genes responsible for brain masculinization. Our recent demonstration of a dimorphic expression for aromatase and 5alpha reductase type 2 during embryogenesis, but very likely, not for androgen and estrogen receptors, is consistent with the crucial role of testosterone metabolism in brain differentiation.