Estrogen and the developing mammalian brain

In recent years, the knowledge of how estrogen interferes with mammalian brain functions and development has broadened substantially. In the adult brain, estrogen is not only involved in the neuroendocrine feedback regulation at the hypothalamic and pituitary level but also in the control of motor and cognitive functions. More recently, estrogen was found to act as a protective factor for neurodegenerative disorders such as Parkinson's and Alzheimer's disease. In contrast to these regulatory and protective functions, estrogen plays a different role during neuronal development. After the demonstration that the estrogen-synthesizing enzyme aromatase and both nuclear estrogen receptors are expressed in many brain areas during ontogeny, it was soon realized that estrogen modulates neuronal differentiation, notably by influencing cell migration, survival and death, and synaptic plasticity of neurons. These effects were initially seen in the classical target area for estrogen, the hypothalamus, but successive studies revealed the neurotrophic potential of estrogen also in other brain regions. The focus of this review will be to summarize estrogen formation and the role of estrogen during mammalian brain development. Moreover, cellular mechanisms involved in these neurotrophic effects will be discussed, giving special emphasis to "nongenomic" estrogen signaling and cross-coupling of estrogen signaling with those of growth factors.