The results of several recent studies suggest that estrogen and testosterone play an important role in the modulation of mood and cognitive function in women, and preliminary evidence indicates that these hormones may also modulate the levels of beta-amyloid (Abeta), a 4 Kilo Dalton peptide that is likely to be involved in the pathogenesis of Alzheimer's disease. However, the physiological and clinical effects of reversible castration remain unclear and no systematic data is currently available for men. We designed the present study to investigate the effects of reversible chemical castration on the mood and cognitive performance of men treated for prostate cancer, as well as its impact on the levels of plasma Abeta. Forty men with prostate cancer were clinically treated with androgen blockade therapy (ftutamide and leuprolide) for 36 weeks and subsequently followed up for another 18 weeks after treatment was discontinued. All subjects received a comprehensive clinical, neuropsychological and biochemical evaluation that included the use of the Beck Depression (BDI) and Anxiety Inventories (BAI), several subtests of the Wechsler Memory and Intelligence Scales (Word Lists-WL, Verbal Paired Associates-VPA, Visual Reproduction-VR and Block Design-BD), and biochemical monitoring of changes in estrogen, testosterone and Abeta levels. Chemical castration was associated with a rapid and marked decline in the Levels of testosterone and estradiol, and significant increase in plasma AP levels. Treatment was associated with increased BDI (p = 0.004) and BAI scores (p < 0.001), although such changes were of questionable clinical significance (i.e., few subjects had scores greater than or equal to 13). CAMCOG (p = 0.046) and WL recall total scores (p < 0.001) improved significantly after androgen blockade treatment was discontinued, but visuospatial abilities, as assessed by BD, was not influenced by the introduction or discontinuation of treatment. There was a significant negative correlation between changes in Abeta levels and subjects' WL total score change between weeks 36 and 54 (r = -0.452, p = 0.012). The results of this naturalistic study indicate that chemical castration is associated with a significant rise in the plasma levels of Abeta and, clinically, with increased depression and anxiety scores. The discontinuation of treatment is associated with better cognitive performance, most noticeably of verbal memory. The performance of subjects on the WL test was negatively correlated with plasma levels of Abeta, but the clinical significance of this finding remains to be determined. (C) 2003 Elsevier Ltd. All rights reserved.