Gender-specific alterations of cerebral metabolites with aging and cortisol treatment

Excess availability of the adrenocortical glucocorticoid hormone cortisol has been correlated with structural brain changes and a decline of cognitive functions during aging. Pertinent studies need to consider gender as a potential confound because of sexual dimorphism in the regulation of hypothalamus-pituitary-adrenal axis activity. In vivo localized proton magnetic resonance spectroscopy of male and female tree shrews revealed similar concentrations of cerebral metabolites in young adult animals but gender-specific alterations with aging as well as in response to cortisol treatment. In comparison with adult tree shrews, aged males had reduced concentrations of N-acetylaspartate (-33%; P<0.01) and total creatine (-34%; P< 0.01). These findings are in line with the occurrence of neuronal loss. In contrast, aged females exhibited increased concentrations of choline-containing compounds (+27%; P<0.05) which--together with a tendency for increased creatine (+24%) and myo-inositol (+14%)--is indicative of glial proliferation. After chronic administration of cortisol (4 mg/day for 28 days), male but not female tree shrews showed a specific reduction of the choline-containing compounds (-29%; P< 0.05). The observed sex differences with age are likely to result from differences in the regulation of stress-related hormones which is further supported by the gender-specific responses to cortisol.