Testing the estrogen hypothesis of schizophrenia: Associations between cumulative estrogen exposure and cerebral structural measures

article i nfo Background: Bone mineral density (BMD), as an indicator of cumulative estrogen exposure, may be reduced in female patients with psychotic disorder (van der Leeuw et al., 2013), possibly reflecting reduced cerebral exposure to estrogen and alterations in neuroprotective effects. To the degree that BMD is a marker of cu- mulative (endogenous) estrogen exposure, we hypothesized that BMD would be positively associated with cerebral gray and white matter indices. Methods: Dual X-ray absorptiometry (DEXA) and magnetic resonance (MRI) scans were acquired in fourteen fe- male patients diagnosed with a psychotic disorder. BMD was expressed in total BMD (g/cm 2 ), Z- and T-scores. Cerebral cortical thickness (CT) (as indicator of gray matter status) and fractional anisotropy (FA) (as indicator of white matter integrity) were measured and served as the dependent variables in multilevel random regres- sion models. BMD measures were the independent variables. Results: Femoral BMD measures were positively associated with CT at trend significance (total BMD: B = 0.266, 95%CI:�0.019-0.552,p = 0.067;Z-score:B = 0.034,95%CI:0.001-0.067,p = 0.046;T-score:B = 0.034,95% CI: 0.000-0.068, p = 0.052). There were no significant associations between femoral BMD measures and FA. Conclusions: The data suggest that in women with psychotic disorder, alterations in the neuroprotective effect of estrogen (as measuredbyBMD)impact corticalgraymatter, but not white matter integrity.These findingsmerit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia.