Masculine sexual behavior is disrupted in male and female mice lacking a functional estrogen receptor α gene

Masculine sexual behavior is regulated by testosterone (T). However, T can be metabolized to form estrogens or other androgens, which then activate their own receptors. We used knockout mice lacking a functional estrogen receptor α (ERα) gene to test the hypothesis that, following aromatization, T acts via the ERα to activate normal masculine sexual behavior. After gonadectomy and T replacement, wild-type (WT) male and female mice displayed masculine behavior. However, given the same T treatment, little masculine behavior was displayed by mice of either sex that lack a normal copy of the ERα gene. In particular, the latency to display masculine sex behavior and the number of mount attempts per trial were significantly reduced in the ERα mice compared to WT littermates (P < 0.05). In addition, we found that in both sexes, ERα mice have a smaller cluster of androgen receptor immunoreactivity in the bed nucleus of the stria terminalis. Using adult ERα mice we were unable to determine whether these genotypic differences are due to organizational or activational effects. However, it is clear that the ERα plays a key role in the expression of masculine sexual behavior and in the regulation of androgen receptors in a neuronal cell population involved in the display of motivated behaviors.