Sexual differentiation of the brain: New rules?

Testosterone exposure during development organizes brain structure and chemistry, resulting in male typical behaviors and neuroendocrine functions. The aromatization hypothesis was proposed to explain how testosterone exerts its masculinizing effects on the brain of rodents. This hypothesis states that a defined perinatal critical period exists during which testosterone is converted to estradiol in the brain, and, through activation of estrogen receptors, not androgen receptors (ARs), allows the survival of some neurons and the death of others. Once organized, this structural differentiation was thought to be passively maintained for life. New evidence both supports and challenges specific aspects of this hypothesis. First, studies on AR regulation and function demonstrate that estradiol upregulates ARs in the developing brain and that ARs are indeed involved in the organization and full expression of male‐typical behaviors. Second, neurogenesis and gliogenesis occur in sexually differentiated cell groups during puberty, and are region‐ and sex‐specific and regulated by hormones: the process of sexual differentiation therefore actively continues well past the perinatal period. Thus, although the original aromatase hypothesis is not entirely overturned, these newly identified mechanisms inform our understanding of the complexity of the sexual differentiation process. Supported by MH090091.