This study examined the changes in cognitive function using the MMSE and in sexual and hormonal functions using the EPIC questionnaire.
We observed no significant worsening in the MMSE scores in this study. The effects of ADT on cognitive functions are controversial. Nelson et al.  summarized nine studies on this matter, and stated that ADT impaired cognitive functions subtly, especially the visuospatial abilities and executive functioning. Alibhai et al.  compared the cognitive functions of non-metastatic prostate cancer patients treated with ADT with those of prostate cancer patients not receiving ADT and healthy controls. They observed no consistent evidence of adverse effects on cognitive functions. In a similar study, Mohile et al.  focused on the preexisting impairment of cognitive functions in elderly subjects and stated that the baseline prevalence of cognitive impairment affected the results. We stratified the patients according to the baseline MMSE scores and found no significant difference during the study. Recently, Chao et al.  reported a prospective study of the effects of ADT on brain function using functional MRI. In that study, 6 months of ADT clearly impaired brain activations during cognitive control and functional brain connectivity on functional MRI. Interestingly, cognitive function tests showed no significant impairment at this point. Further studies of the association of conventional cognitive function tests with brain function imaging are warranted.
The QOL was assessed using the EPIC questionnaire, which has been validated in Japanese . The summary scores of both sexual and hormonal functions at 6 and 12 months worsened significantly in comparison with those before treatment. Although the sexual functions worsened significantly while on ADT, sexual bother improved during the treatment. This tendency was consistent with the results of the validation study . The exact reason remains unknown; however, the loss of libido might reduce the sexual desire that causes sexual bother. The trends in the hormonal function and bother scores were similar to and consistent with the validation study .
In this study, we focused on the hormone levels and QOL assessments and showed the detailed changes in the hormonal domain scores (Tables 3 and 4). Among hormonal functions, hot flashes and body weight gain were worsened significantly on ADT. Only hot flashes were significantly associated with bother. Body weight gain is one of the important adverse events caused by ADT. In the present study, about one-third of all patients experienced body weight gain after 6 months of ADT. Interestingly, the proportions of patients experiencing body weight gains >5 kg or ≤ 5 kg were very similar at 6 and 12 months. Lee et al.  studied the effect of ADT on body composition changes in prostate cancer patients. On ADT, the fat and lean masses were increased significantly only in patients not receiving ADT. By contrast, a significant loss in bone mineral density occurred in both the patients not receiving ADT or those pretreated with ADT. Our findings regarding body weight changes are consistent with these findings. This information would be helpful when obtaining informed consent from patients who need ADT. Gay et al. reported on the QOL assessment using the EPIC questionnaire in patients with prostate cancer treated with neoadjuvant ADT . The sexual and hormonal summary scores were decreased significantly after 2 months of neoadjuvant ADT. In this study, the question items for hormone bother were summarized. The percentage of patients with bother tended to be higher in the cohort of Gay et al.  in comparison with our study. This might be due to age differences, 70.2 vs. 67.5 years, ethnic differences, or tolerance of ADT.
Finally, we investigated the association of cognitive, sexual, and hormone functions with serum hormone levels. In a previous study, we detected a significant decrease in both testicular and adrenal androgens after LH-RH agonist treatment . The decreases in T and E2 were associated with cognitive functions . However, the association of adrenal androgen levels with cognitive or sexual/hormone functions has not been examined. Furthermore, cortisol levels and stress are related , so we also examined the cortisol levels. In the cognitive function test, low E2 levels were significantly related to worse MMSE scores in our study. This finding was consistent with Salminen et al. , who investigated cognitive functions in 23 patients with ADT-treated prostate cancer. The serum E2 levels before and after 6 and 12 months of treatment were correlated with visual memory and verbal fluency. In our study, the A-dione and cortisol levels were associated with the MMSE scores. The odds ratios of A-dione and cortisol were 1.02 and 0.94, respectively, and the role of hormonal changes was unknown. Regarding sexual and hormone functions, low T levels were the factor most significantly associated with worse sexual and hormone bother. High E2 levels were significantly associated with worse sexual bother and both hormone function and bother. In males, E2 is synthesized from T by aromatization in peripheral tissues, including fat . ADT causes a change in body composition, and the fat mass generally increases . In our series, 33.3% of the patients experienced significant body weight gain during the first 6 months of ADT. High E2 levels might affect the QOL changes via this mechanism. High cortisol levels were associated with worse hormonal bother. Cortisol is the most researched stress hormone . Stress during ADT might be associated with high cortisol levels. We observed that low adrenal androgen A-dione and DHEA-S levels were significantly associated with worse sexual and hormonal functions. No relationship between adrenal androgen levels and these functions has been reported. Recently, a new class of CYP17 inhibitor, abiraterone acetate, was approved for treating castration-resistant prostate cancer . Abiraterone acetate significantly reduced the serum adrenal and testicular androgen levels . Further analyses focusing on sexual and hormonal functions are warranted in patients treated with new hormone agents.
This study had several limitations. The first is the small number of patients subjected to the multivariate analysis. Another is the evaluation of cognitive function. We used only MMSE scores, and this score does not cover details of cognitive functions. However, this is the first study to examine the association of testicular and adrenal androgen levels and ADT with cognitive and sexual/hormonal functions. Further large-scale studies are warranted.