Early Androgen Blockade Influences Longer-Term Brain Metabolism As Assessed By Magnetic Resonance Spectroscopy

Background: Magnetic resonance spectroscopy (MRS) can provide a non-invasive, functional insight into brain metabolism and alterations may predict long-term neurocognitive impairment. A sexually dimorphic pattern of spectroscopy has been reported in humans but there is a need to investigate this further in rodents. Methods: Male and female Sprague Dawley rats (n=32, 16) were treated on postnatal days 1-5 with an antiandrogen (flutamide, 50mg/kg) or corn oil SC and scanned at 6wks and 10wks of age using a small animal 7T MRI scanner. Water-suppressed hydrogen MR spectra were acquired from a voxel placed in the frontal cortex using PRESS sequence and metabolites measured using the LC Model software. Serum testosterone (T) was measured by GCMS. Results were analysed with a repeated measures nested general linear model. Full width at half maximum (FWHM) of the water peak was used as a marker of reliability and was within the optimal range (12-18Hz). Results: Male anogenital distance (AGD) was significantly reduced in the treatment group when compared to controls at both 6 and 10 weeks (p=0.003, p=0.02) and this remained significant when corrected for weight (p=0.001, p=0.02). Phallus length was reduced in the treatment group at both ages (p=0.05, p=0.001). Serum T was higher in the control and treated males at 10 weeks (median 1.9ng/ml, 2.05ng/ml) when compared to the same animals at 6 weeks (0.56ng/ml, 0.61ng/ml, p<0.001). T levels were <0.1ng/ml in all female animals. T levels showed a positive correlation with AGD (p<0.001). On MR spectral analysis, glucose, glutamine, phosphocholine and myo-inositol levels were higher in the treated males compared to control males (p=0.05, p=0.03, p=0.01, p=0.01); these levels were similar to those in age-matched female controls (ns). N-acetylaspartylglutamate(NAAG) levels were lower in older animals from all groups (p=0.05) and glutamine, glutamate and GABA also declined over time (ns). Phosphocholine and myo-inositol increased with age (p=0.05, p=0.01). T levels showed a negative correlation with glutamate (p=0.01) and female animals tended to have higher glutamate levels (ns). Conclusions: MRS based assessment shows that brain metabolites have an age and sex dependency. In addition to undermasculinisation of the male external genitalia, early postnatal androgen blockade alters the pattern of these metabolites. The functional effects of these alterations need further study. - See more at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.NP.15.SUN-0680#sthash.KIrgKFSu.dpu