Sexual dimorphism in the developmental regulation of brain aromatase

Steroid sex hormones have an organizational role in gender-specific brain development. Aromatase (cytochrome P450_AR), converting testosterone (T) to estradiol-17β (E₂) is a key enzyme in brain development and the regulation of aromatase determines the availability of E₂ effective for neural differentiation. Gender differences in brain development and behaviour are likely to be influenced by E₂ acting during sensitive periods. This differentiating action has been demonstrated in rodent and avian species, but also probably occurs in primates including humans. In rodents, E₂ is formed in various hypothalamic areas of the brain during fetal and postnatal development. The question considered here is whether hypothalamic aromatase activity is gender-specific during sensitive phases of behavioural and brain development, and when these sensitive phases occur. In vitro preoptic and limbic aromatase activity has been measured in two strains of wild mice, genetically selected for behavioural aggression based on attack latency, and in the BALB/c mouse. Short attack latency males show a different developmental pattern of aromatase activity in hypothalamus and amygdala to long attack latency males. Using primary brain cell cultures of the BALB/c mouse, sex differences in hypothalamic aromatase activity during both early embryonic and later perinatal development can be demonstrated, with higher E₂ formation in males. The sex dimorphisms are brain region specific, since no differences between male and female are detectable in cultured cortical cells. Immunoreactive staining with a polyclonal aromatase antibody identifies a neuronal rather than an astroglial localization of the enzyme. T increases fetal brain aromatase activity and numbers of aromatase-immunoreactive hypothalamic neuronal cell bodies. T appears to influence the growth of hypothalamic neurons containing aromatase. Differentiation of sexually dimorphic brain mechanisms may involve maturation of a gender-specific network of estrogen-forming neurons which are steroid-sensitive in early development.