Effects of a luteinizing hormone-releasing hormone agonist on cognitive, sexual, and hormonal functions in patients with prostate cancer: relationship with testicular and adrenal androgen levels

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. 9] summarized nine studies on this matter, and stated that ADT impaired cognitive functions
subtly, especially the visuospatial abilities and executive functioning. Alibhai et al. 10] 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. 11] 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. 12] 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
5]. 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 5]. 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 5].

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. 13] 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 14]. 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. 14] 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 4]. The decreases in T and E2 were associated with cognitive functions 15]. However, the association of adrenal androgen levels with cognitive or sexual/hormone
functions has not been examined. Furthermore, cortisol levels and stress are related
16], 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. 17], 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 18]. ADT causes a change in body composition, and the fat mass generally increases 13]. 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 16]. 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 19]. Abiraterone acetate significantly reduced the serum adrenal and testicular androgen
levels 20]. 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.