Developmental profile and regulation of brain estrogen synthesis by aromatase

Aromatase cytochrome P450 enzyme catalyzes the formation of estrogen from androgen in distinct regions of the vertebrate brain. During neural development, local estrogen synthesis is required for the sexual differentiation of male brain characteristics and the differentiation of neural circuits Involved in sex-specific behaviors and neuroendocrine functions. A common phenomenon in all species studied so far is that the male brain displays much higher and brain region-specific aromatase expression during distinct periods of brain development than the female one. An important question arising from these findings is which factor(s) play a role in regulating estrogen formation in a sex- and brain region-specific fashion. Among the factors investigated, androgens have been found to be the most powerful regulators of brain aromatase. In vitro experiments using primary cell cultures of embryonic mouse brains showed that sex differences in aromatase activity in hypothalamic cells develop, at first, independently of gonadal steroids. Later during embryonic development, aromatase expression is regulated in a region- and sex-specific way by circulating androgens. Hypothalamic aromatase neurons are most sensitive to androgen exposure whereas cortical and midbrain ones are insensitive. Moreover, androgens affect morphological maturation of aromatase-immunoreactive cells by stimulating neurite outgrowth and dendritic arborization. These findings suggest that androgens function as major morphogenetic factors during the differentiation of the mammalian hypothalamic aromatase system. During late embryonic development and perinatally, androgen levels differ between sexes, being significantly higher in males. This time period corresponds exactly to the developmental stage when aromatase activities are highest in the male hypothalamus. It seems plausible therefore that higher androgen concentrations in the male circulation during ontogenesis are causally connected with the observed sex differences in hypothalamic aromatase activity.Biomedical Reviews 1997; 7: 41-50