Interaction of sex chromosome complement, gonadal hormones and neuronal steroid synthesis on the sexual differentiation of mammalian neurons.

Female mouse hippocampal and hypothalamic neurons growing in vitro show a faster development of neurites than male mouse neurons. This sex difference in neuritogenesis is determined by higher expression levels of the neuritogenic factor neurogenin 3 in female neurons. Experiments with the four core genotype mouse model, in which XX and XY animals with male gonads and XX and XY animals with female gonads are generated, indicate that higher levels of neurogenin 3 in developing neurons are determined by the presence of the XX chromosome complement. Female XX neurons express higher levels of estrogen receptors than male XY neurons. In female XX neurons, neuronal derived estradiol increases neurogenin 3 expression and neuritogenesis. In contrast, neuronal-derived estradiol is not able to upregulate neurogenin 3 in male XY neurons, resulting in decreased neuritogenesis compared to female neurons. However, exogenous testosterone increases neurogenin 3 expression and neuritogenesis in male XY neurons. These findings suggest that sex differences in neuronal development are determined by the interaction of sex chromosomes, neuronal derived estradiol and gonadal hormones.

Neuroprotective and neurotoxic effects of estrogens.

The ovarian hormone 17beta-estradiol (E2) is neuroprotective in animal models of neurodegenerative diseases. Some studies suggest that the neuroprotective effects of 17beta-estradiol are a consequence of its antioxidant activity that depend on the hydroxyl group in the C3 position of the A ring. As in other tissues, 17beta-estradiol is metabolized in the brain to 2-hydroxyestradiol (2OHE2) and 2-methoxyestradiol (2MEOHE2). These two molecules present the hydroxyl group in the A ring and have a higher antioxidant activity than 17beta-estradiol. To test the hypothesis that conversion to 2-hydroxyestradiol and 2-methoxyestradiol may mediate neuroprotective actions of 17beta-estradiol in vivo, we have assessed whether these molecules protect hilar hippocampal neurons from kainic acid toxicity. Ovariectomized Wistar rats received an i.p. injection of 1, 10 or 100 microg 17beta-estradiol, 2-hydroxyestradiol or 2-methoxyestradiol followed by an i.p. injection of kainic acid (7 mg/kg) or vehicle. Treatment with kainic acid resulted in a significant loss of hilar neurons. Only the highest dose tested of 17beta-estradiol (100 microg/rat) prevented kainic acid-induced neuronal loss. 2-Hydroxyestradiol and 2-methoxyestradiol did not protect hilar neurons from kainic acid, suggesting that the mechanism of neuroprotection by 17beta-estradiol in vivo is not mediated by its metabolism to catecholestrogens or methoxycatecholestrogens. Furthermore, 2-methoxyestradiol (100 microg/rat), by itself, resulted in a significant neuronal loss in the hilus that was detected 96 h after the treatment with the steroid. This finding suggests that endogenous metabolism of 17beta-estradiol to 2-methoxyestradiol may counterbalance the neuroprotective effects of the hormone.