The aim of this study was to investigate further the hormone-dependent processes underlying sex differences in neurotoxic responses within the rat nigrostriatal dopaminergic (NSDA) pathway after partial lesioning with 6-OHDA, a state thought to mimic the early stages of Parkinson's disease where, in humans and animal models alike, males appear to be more susceptible. Contrary to our hypotheses, hormone manipulations (gonadectomy +/- oestrogen or androgen treatment) failed to alter survival of tyrosine hydroxylase immunoreactive cells in the substantia nigra pars compacta (SNc) after lesioning; this indicates that, unlike inherent sex differences in toxin-induced striatal dopamine depletion, sex differences in cell loss were not hormonally generated, and that hormone-dependent changes in dopamine depletion can occur independently of cell survival. In addition, hormonally induced changes in striatal expression of the dopamine transporter (DAT), an important factor for 6-OHDA toxicity, did not correlate with hormonal influences on striatal dopamine loss and, in males, central inhibition of aromatase prior to 6-OHDA infusion exacerbated striatal dopamine loss with no effect on SNc tyrosine hydroxylase-immunoreactive survival, suggesting locally generated oestrogen is neuroprotective. These results support the novel view that sex steroid hormones produced peripherally and centrally play a significant, sex-specific role within the sexually dimorphic NSDA pathway to modulate plastic, compensatory responses aimed at restoring striatal dopamine functionality, without affecting cell loss.