When is a sex difference not a sex difference?

Brain sexual differentiation in mammals requires activity of gonadal hormones; organizational effects of these steroids on brain development occur early in life while activational ones in adulthood ensure appropriate and timely sex-specific behaviors. This traditional view has long served as a reliable model for sexual differentiation of reproductively relevant brain structures. Here, we take a fresh look at this model but refocused in the context of sexual differentiation of non-reproductive parameters and with an emphasis on the hippocampus, a telencephalic brain structure predominantly involved in cognition and stress regulation. We explore sex differences in morphology, neurochemistry, and hippocampal-dependent behaviors to propose a new prototype that can be used to explain and further investigate the effects of steroid hormones, those synthesized gonadally or intracerebrally, on hippocampal development and function. We also propose that a new vernacular be employed, one that distinguishes hormonally modulated responses from sex differences, and argue these are mechanistically and functionally distinct. Understanding when and how the sexes are different is as important as understanding when and how they are the same, at the biological, social, and cultural level.