Epidemiological and clinical studies provide evidence for sex differences in the incidence or severity of certain neurological conditions. For example Parkinson's disease, which is characterised by a progressive degeneration of dopaminergic (DA) neurones in the substantia nigra pars compacta (SNc) and a reduction in DA levels in the striatum, is more prevalent in men than women. Therefore, our work aimed to establish whether physiological levels of sex steroid hormones confer a relative degree of protection against neuronal trauma in the nigrostriatal DA pathway (NSDA) of females compared with males. Using the selective neurotoxin 6-hydroxydopamine (6-OHDA), which produces a lesion similar to that seen in Parkinson's disease, we have shown that lesion size (survival of tyrosine hydroxylase positive cells in the SNc and DA levels in the striatum one week after injection of toxin into the medial forebrain bundle) is significantly reduced if the insult is delivered at proestrous (high circulating levels of estrogen) rather than diestrous. Ovariectomy significantly increased lesion size and this was reversed by estrogen replacement. These hormonal manipulations also resulted in changes in the density of the DA transporter (upon which the 6-OHDA toxicity is dependent) that were inversely proportional to lesion size. Comparative studies have demonstrated that male rats are significantly more sensitive to the neurotoxin than females, but orchidectomy rendered them less susceptible. Interestingly, hormone replacement with estrogen, but not the non-aromatisable androgen, dihydrotestosterone, reversed the effects of Gdx in the male. Thus, unlike the situation in the female where estrogen appears to be neuroprotective, in males it may worsen neurodegeneration resulting from exposure to a low dose of 6-OHDA. Whilst the reasons for these sexually dimorphic responses to NSDA injury and estrogen treatment are unknown, we hypothesize that they may be related to the early organisational events mediated by sex steroid hormones which ultimately result in sexual differentiation of the brain.
22 - 24 Mar 2004
British Endocrine Societies