Discussion
Androgen deprivation therapy is commonly used in the treatment of locally advanced disease with combination therapies and in metastatic prostatic cancer patients. Androgen suppressing treatments cause side effects such as anemia, flushing, fatigue, gynecomastia, osteoporosis, erectile dysfunction, diabetes, and cardiovascular complications. The present study was designed to evaluate the effect of ADT on cognitive functions in metastatic prostate cancer patients. The study used 4 cognitive tests to interpret 4 main cognitive domains: information processing speed, verbal memory, visuospatial memory, and executive functions. In a large, prospective study about cognitive functions in prostate cancer patients, it has been shown that ADT has no significant effect on cognitive function [16]. However, some studies have demonstrated that patients show greater impairment after ADT in visuomotor functions, visuospatial abilities, and executive functions as compared to healthy patients [8,17]. Furthermore, studies have shown that higher free testosterone levels are positively associated with visuospatial function, visual memory, visuomotor scanning, and episodic memory [18]. Some systematic reviews and meta-analyses have been conducted regarding ADT and cognition in prostate cancer patients [8,17,19]. Nelson et al. show that patients who receive ADT have a deterioration in 1 or more cognitive areas (usually visuospatial skills or executive functions), at rates of 47–69%. Jamadar et al. conclude that spatial memory in particular may be sensitive to ADT. The largest and most up-to-date systematic review, conducted by McGinty et al., evaluates 14 studies (417 patients) and 7 cognitive domains. This review concludes that cognitive functions other than visual skills remain largely unchanged.
Although Gonzalez et al. have reported a significant risk of cognitive impairment with ADT, in a prospective, controlled study conducted by Alibhai et al. in 2010, cognitive impairment is not shown in elderly men with prostate cancer after 12 months of ADT [ 16,20]. However, one finding of the regression analysis is that the use of ADT is associated with worse immediate memory, working memory, and visuospatial ability, although this is not confirmed by other analytical approaches. Alibhai et al. have followed one patient group for 36 months to evaluate the long-term results, again showing that there is no relationship between the use of ADT and cognitive impairment [21].
Preclinical studies have shown that ADT can increase the risk of dementia or Alzheimer’s disease through various mechanisms, such as beta-amyloid accumulation in the central nervous system [22,23]. Androgens have also been associated with neuron growth and axonal regeneration, and low testosterone levels and ADT have been shown to increase the risk of cardiovascular and metabolic diseases [6]. Anatomical studies have shown the wide distribution of androgen receptors in areas related to memory, emotional processing, and libido, mainly in the hippocampus and amygdala. Neurological changes associated with androgen deprivation occur in the same regions affected by the age-related decline and are consistent with our knowledge of the loci of androgen receptor expression [24]. In the population of elderly males without prostate cancer, low levels of free testosterone have been associated with decreased visuospatial memory and abilities, as well as verbal memory and processing speed [25].
Marzouk et al. have investigated the relationship between 12-month ADT and cognitive changes using the functional assessment of cancer therapy - cognitive function (FACT-Cog) assessment tool [7]. However, data from patient-reported outcome (PRO) measurements should be carefully evaluated, as PROs have not been validated as a tool to assess cognition. This is because they are subjective, based on a personal perception of cognitive function, and can be influenced by factors such as mood and fatigue. Objective tests remain the gold standard for measuring cognitive function, as they allow the identification of treatment-related cognitive problems that can affect daily life. However, it should be kept in mind that PROs provide a useful measure of the effect of cognitive functions on the perception and quality of life of the patient; thus, PROs should also be used in studies [26].
In a population-based analysis, 101,089 men (15,748 with PCa receiving ADT, 34,865 with PCa not treated with ADT, and 50,476 without cancer) were evaluated using Medicare data linked to surveillance, epidemiology, and end results data to assess exposure to ADT. The cognition of PCa patients not treated with ADT and men with PCa treated with ADT were compared. In that study, ADT was shown not to be associated with an increased risk of cognitive impairment (hazard ratio 0.99; 95% CI 0.94–1.04) [27]. The present study included 48 patients with metastatic prostate cancer scheduled to undergo ADT and followed them for 6 months, testing 4 main cognitive domains: visuospatial memory, executive functions, information processing speed, and verbal memory. To test cognitive functions, the SDMT, CVLT, TMT, and BVMT-R tests were chosen due to their availablility in Turkish, easy application in daily practice, and ability to measure cognitive functions in a short time frame (i.e., 15 min to conduct all 4 tests). In some studies examining cognitive functions in men who underwent ADT using objective cognitive assessment tools, impairment in verbal memory, spatial abilities, and attention has been shown [28,29]. However, in other studies, no significant change in cognition is observed with ADT, consistent with our study [21,30].
Some methodological differences exist among previous studies, such as intermittent versus continuous ADT, various methods of creating androgen deprivation (i.e., orchiectomy, gonadotropin-releasing hormone agonists, and other treatments), varied timing of cognitive evaluation visits, the presence of concurrent treatments, and the characteristics of the control groups [8,17,19]. Furthermore, some meta-analyses report that the relationship between ADT and cognitive impairment is not reliably confirmed [8,9].
The neuropsychological tests used in the studies in which all cognitive areas are evaluated take about 60 min. This time period is not practicable in daily practice; thus, it is important to evaluate the cognitive states of patients globally in a shorter time. By contrast, the cognitive assessment tests used in this prospective study were short (15 min.) and easy for both the patient and the physician, the reasoning being that they are more viable for daily practice. Developing standardized tools for assessing cognitive impairment and making them applicable in daily practice is thought to be important for comprehensive monitoring of patients.