Estrogen masculinizes neural pathways in mice

A 2010 study in the Proceedings of the National Academy of Sciences found that estrogen masculinizes the developing mouse brain, not testosterone. Male mice produce testosterone in their testes, but the hormone converts to estradiol (a form of estrogen) in the brain via aromatase enzymes. The researchers blocked this conversion and watched male mice develop female-typical neural circuits. When they gave estrogen to female pups, those mice developed male-typical brain structures. The distinction matters because the estrogen receptor pathway activates different genes than the androgen receptor pathway. The study measured dendritic spine density in the preoptic area, a region that controls mating behavior. Males normally have twice the spine density of females. Blocking aromatase dropped male spine counts to female levels. Adding estrogen to females doubled their spine counts. This challenges the default assumption that testosterone alone drives male brain development. The conversion step means that blocking estrogen receptors can prevent masculinization even when testosterone levels are normal. The paper notes that alpha-fetoprotein in female blood binds circulating estrogen, preventing it from entering the brain before birth. The findings are specific to rodents. Primate brain development follows different timing and may not rely on the same aromatization pathway. The authors tested newborn mice during a critical window of the first few postnatal days. Adult hormone exposure does not rewire these circuits. I expected testosterone to act directly on androgen receptors. The estrogen conversion step adds a regulatory layer that changes which interventions would or would not block sexual differentiation of the brain.

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Source: Estrogen masculinizes neural pathways and sex-specific behaviors