**6. Androgens and cognitive functions**

It is known that during certain developmental stages- especially during the first years of life, during adolescence, girls surpass in boys several verbal skills. Males excel after about the tenth year of life in non-verbal skills in adulthood, especially in spatial orientation and manipulation (82).

Evidence of a link between sex hormones and spatial abilities came from studies of individuals with Turner syndrome (XO karyotype, no gonadal hormones) or testicular feminization syndrome- (XY karyotype, the tissues are refractory to normal levels of TST). These patients have female external genitalia, they are raised as girls. In these patients verbal skills surpass their spatial abilities, which is a typical pattern of cognitive abilities of women (83).

Studies on men with idiopathic or acquired hypogonadotrophic hypogonadism confirm the importance of TST for spatial abilities. Short-term androgen supplementation did not restore spatial function, suggesting that low levels of sex hormones during the intrauterine and neonatal period have a lifelong impact (84).

Direct sex hormones manipulation supports the conclusion that androgens play an important role in cognition. The first experiments with direct hormonal manipulation can be traced back to 1941 when Simonson et al. (85) published their experiment using methyl TST that was administered to eunuchoids, castrated males, and elderly men. The result was an improved ability to perceive the flicker (critical flicker frequency), a measure of attention and alertness, as long as the androgen treatment lasted (86).

Androgen therapy was also administered to female to male transsexuals in high doses as a preparation before gender reassignment. Their spatial skills have significantly improved, while verbal skills declined considerably (87).

For ethical reasons, nowadays the manipulation of gonadal hormones is restricted to patients in clinical studies. Thus, the last such study was conducted in 1971. Klaiber et al. (88) studied the effect of infused TST on mental abilities in healthy male students. After a 4-

Androgen Deprivation Therapy for Prostate Cancer 345

compared with the control group (17%; odds ratio, 4.412; P < .05) at the 3-month time point. There were no significant differences between the groups at the 9-month time point. On specific domain analysis, the tasks most impacted at the 3 month time point

Joly et al compared physical and cognitive function in a cross-sectional study of 57 patients who were receiving ADT for nonmetastatic PCa and 51 healthy, age-matched controls. Thirty patients received ADT as adjuvant treatment after prostatectomy or radiotherapy, and 27 patients received ADT for increasing levels of PSA. The median duration on ablation therapy was 1.8 years (range, 0.4-7.4 years). To assess cognitive functioning, the researcher administered the Sensitivity Cognitive Screen and a self-reported assessment on cognitive deficits (the Functional Assessment of Cancer Treatment-Cognitive Scale [FACT-COG]). In contrast to other studies cited above, Joly and colleagues observed that, although men with nonmetastatic PCa who received ADT experienced more treatment-related symptoms, no differences in cognitive function on either the High Sensitivity Cognitive Screen or the FACT-COG. The authors suggested that the High Sensitivity Cognitive Screen may not be sensitive enough to detect the subtle cognitive changes that occur after ADT. In addition, self-report of cognitive function has not been correlated consistently with actual

In conclusion, the data show that androgen ablation does have cosequences for cognitive

Male hypogonadism (of any etiology) results in a decline in lean body mass (LBM) and an increase in fat mass, which is reversed with TST replacement (98). A cross-sectional study showed that men undergoing long-term ADT (12–101 months) have increased fat mass in the trunk and all extremities- measured by dual-energy x-ray absorptiometry (DXA), compared with eugonadal men with PCa not undergoing ADT (treated with prostatectomy

Another case control study examined the prevalence and magnitude of obesity and fat mass in a group of 62 men with PCa receiving ADT for 1–5 yr (100). Healthy men (n = 47) with a PSA of less than 4.0 ng/ml were recruited as controls. The study showed that men with PCa had significantly higher body weight (86.5 vs. 80.6 kg) and percent body fat (30 vs. 26%)

Meta-analysis of sixteen studies showed that ADT increased percentage of body fat by on average 7.7% (95% CI 4.3, 11.2, from seven studies, P < 0.0001) and decreased % LBM by on average -2.8% (95% CI -3.6, -2.0, from six studies, P < 0.0001) but for both there was marked heterogeneity between studies (I2 = 99% I2 = 73%, respectively). Similarly, body weight (2.1%, P < 0.0001 from nine studies) and BMI (2.2%, P < 0.0001, from eight studies) increased significantly. More extensive changes were seen with longer duration of

These studies prove that ADT results in an unfavorable body composition. The increase of fat mass in patients on ADT correlates positively with rising insulin levels (102). Hence, this increasing adiposity may be the primary event leading to these metabolic complications (possibly via elaboration of adipokines and inflammatory cytokines). Similarly, it is possible that a decrease in muscle mass may result in decreased glucose uptake by the muscle. These changes may ultimately lead to insulin resistance and diabetes in this population, hence

were spatial memory and ability (96).

neuropsychological testing (97).

than controls.

treatment (101).

functioning. Larger longitudinal studies are warranted.

and/or radiation therapy) and age-matched eugonadal controls (99).

**6.3 ADT and changes in body composition** 

hour infusion of TST or saline in the control group, performance of the control group (saline infusion) showed a significant decline in mental performance when compared to TST infused group.

#### **6.1 Potential mechanisms of action**

TST may impact cognition through several mechanisms. For example, activation of calcium channels in the brain occurs through rapid, nongenomic methods of action on G-proteincoupled, agonist sequestrable testosterone membrane receptors that initiate a transcription-independent signal pathway (89). TST also may impact cognitive performance directly through modulating neurotransmitters and stimulating neuronal connectivity, decreasing β-amyloid peptide production, and preventing N-methyl-Daspartate excitotoxicity (90) mechanisms implicated in cognitive disorders such as Alzheimer disease or dementia. Furthermore, some estrogen studies have highlighted several possible mechanisms through which this hormone can impact cognitive functioning (91). These include increasing cholinergic activity through its action of choline acetyltransferase, maintenance of dendritic spine density on CA1 pyramidal cells of the hippocampus and facilitating induction of long-term potentiation in the hippocampus, increasing serotonergic and cholinergic activity to maintain neural circuitry, altering lipoprotein, and decreasing risk of cerebral ischemia (92, 93).

#### **6.2 Cognitive functions and ADT**

Green et al were the first to systematically research the impact of androgen-ablation therapy on the cognitive functioning of men with PCa. Sixty-five men (mean age, 73 years) with advanced PCa were assigned randomly to 1 of 4 groups: leuprolide (N = 19), goserelin (N = 20), cyproterone acetate (N = 11), and monitoring without hormone treatment (N = 15). All men participated in a battery of neuropsychological assessments at baseline (ie, 1 week before treatment) and then 6 months later. PSA and TST levels decreased significantly from baseline to 6 months for the 3 hormonally treated groups. Conflicting results emerged in the memory domain; men in the goserelin group surprisingly improved on 2 measures of memory (verbal [Wechsler Memory Scale-Revised] and visual [Rey-Osterrieth Complex Figure test]) but declined in another measure of verbal memory (Auditory Verbal Learning Test). The goserelin group also declined in a measure of executive functioning (Trails B). Of the 50 men on active treatments, 24 men showed a reliable decline (ie, >1 standard deviation) on at least 1 cognitive task, and 7 men showed a reliable change on 2 tasks, whereas the monitoring-only group showed no decline on any of the tasks (94).

Salminen et al researched the cognitive effects of ADT on 26 men who were diagnosed recently with PCa and who began ADT 2 months before radiotherapy. From baseline to 12 months, tests of visuomotor speed and of reaction time saw significant decreases. The decline in TST coincided with a decline in visuomotor processing (digit symbol), reaction time (10-choice reaction time), working memory speed (subtraction), sustained attention (vigilance), and recognition speed (recognition of letters) (95).

Jenkins et al assessed 32 men with standard neuropsychological assessments at 3 time intervals: at baseline, 3 months, and 9 months. The average age of these men was 67.5 years, and they used ADT for 3 to 5 months. Twenty-five healthy men, similar in age, served as the control group. Although there was no overall group effect, a greater percent of men in the ablation group reported a significant cognitive decline in 1 task (47%)

hour infusion of TST or saline in the control group, performance of the control group (saline infusion) showed a significant decline in mental performance when compared to TST

TST may impact cognition through several mechanisms. For example, activation of calcium channels in the brain occurs through rapid, nongenomic methods of action on G-proteincoupled, agonist sequestrable testosterone membrane receptors that initiate a transcription-independent signal pathway (89). TST also may impact cognitive performance directly through modulating neurotransmitters and stimulating neuronal connectivity, decreasing β-amyloid peptide production, and preventing N-methyl-Daspartate excitotoxicity (90) mechanisms implicated in cognitive disorders such as Alzheimer disease or dementia. Furthermore, some estrogen studies have highlighted several possible mechanisms through which this hormone can impact cognitive functioning (91). These include increasing cholinergic activity through its action of choline acetyltransferase, maintenance of dendritic spine density on CA1 pyramidal cells of the hippocampus and facilitating induction of long-term potentiation in the hippocampus, increasing serotonergic and cholinergic activity to maintain neural circuitry, altering

Green et al were the first to systematically research the impact of androgen-ablation therapy on the cognitive functioning of men with PCa. Sixty-five men (mean age, 73 years) with advanced PCa were assigned randomly to 1 of 4 groups: leuprolide (N = 19), goserelin (N = 20), cyproterone acetate (N = 11), and monitoring without hormone treatment (N = 15). All men participated in a battery of neuropsychological assessments at baseline (ie, 1 week before treatment) and then 6 months later. PSA and TST levels decreased significantly from baseline to 6 months for the 3 hormonally treated groups. Conflicting results emerged in the memory domain; men in the goserelin group surprisingly improved on 2 measures of memory (verbal [Wechsler Memory Scale-Revised] and visual [Rey-Osterrieth Complex Figure test]) but declined in another measure of verbal memory (Auditory Verbal Learning Test). The goserelin group also declined in a measure of executive functioning (Trails B). Of the 50 men on active treatments, 24 men showed a reliable decline (ie, >1 standard deviation) on at least 1 cognitive task, and 7 men showed a reliable change on 2 tasks,

whereas the monitoring-only group showed no decline on any of the tasks (94).

(vigilance), and recognition speed (recognition of letters) (95).

Salminen et al researched the cognitive effects of ADT on 26 men who were diagnosed recently with PCa and who began ADT 2 months before radiotherapy. From baseline to 12 months, tests of visuomotor speed and of reaction time saw significant decreases. The decline in TST coincided with a decline in visuomotor processing (digit symbol), reaction time (10-choice reaction time), working memory speed (subtraction), sustained attention

Jenkins et al assessed 32 men with standard neuropsychological assessments at 3 time intervals: at baseline, 3 months, and 9 months. The average age of these men was 67.5 years, and they used ADT for 3 to 5 months. Twenty-five healthy men, similar in age, served as the control group. Although there was no overall group effect, a greater percent of men in the ablation group reported a significant cognitive decline in 1 task (47%)

infused group.

**6.1 Potential mechanisms of action** 

**6.2 Cognitive functions and ADT** 

lipoprotein, and decreasing risk of cerebral ischemia (92, 93).

compared with the control group (17%; odds ratio, 4.412; P < .05) at the 3-month time point. There were no significant differences between the groups at the 9-month time point. On specific domain analysis, the tasks most impacted at the 3 month time point were spatial memory and ability (96).

Joly et al compared physical and cognitive function in a cross-sectional study of 57 patients who were receiving ADT for nonmetastatic PCa and 51 healthy, age-matched controls. Thirty patients received ADT as adjuvant treatment after prostatectomy or radiotherapy, and 27 patients received ADT for increasing levels of PSA. The median duration on ablation therapy was 1.8 years (range, 0.4-7.4 years). To assess cognitive functioning, the researcher administered the Sensitivity Cognitive Screen and a self-reported assessment on cognitive deficits (the Functional Assessment of Cancer Treatment-Cognitive Scale [FACT-COG]). In contrast to other studies cited above, Joly and colleagues observed that, although men with nonmetastatic PCa who received ADT experienced more treatment-related symptoms, no differences in cognitive function on either the High Sensitivity Cognitive Screen or the FACT-COG. The authors suggested that the High Sensitivity Cognitive Screen may not be sensitive enough to detect the subtle cognitive changes that occur after ADT. In addition, self-report of cognitive function has not been correlated consistently with actual neuropsychological testing (97).

In conclusion, the data show that androgen ablation does have cosequences for cognitive functioning. Larger longitudinal studies are warranted.

#### **6.3 ADT and changes in body composition**

Male hypogonadism (of any etiology) results in a decline in lean body mass (LBM) and an increase in fat mass, which is reversed with TST replacement (98). A cross-sectional study showed that men undergoing long-term ADT (12–101 months) have increased fat mass in the trunk and all extremities- measured by dual-energy x-ray absorptiometry (DXA), compared with eugonadal men with PCa not undergoing ADT (treated with prostatectomy and/or radiation therapy) and age-matched eugonadal controls (99).

Another case control study examined the prevalence and magnitude of obesity and fat mass in a group of 62 men with PCa receiving ADT for 1–5 yr (100). Healthy men (n = 47) with a PSA of less than 4.0 ng/ml were recruited as controls. The study showed that men with PCa had significantly higher body weight (86.5 vs. 80.6 kg) and percent body fat (30 vs. 26%) than controls.

Meta-analysis of sixteen studies showed that ADT increased percentage of body fat by on average 7.7% (95% CI 4.3, 11.2, from seven studies, P < 0.0001) and decreased % LBM by on average -2.8% (95% CI -3.6, -2.0, from six studies, P < 0.0001) but for both there was marked heterogeneity between studies (I2 = 99% I2 = 73%, respectively). Similarly, body weight (2.1%, P < 0.0001 from nine studies) and BMI (2.2%, P < 0.0001, from eight studies) increased significantly. More extensive changes were seen with longer duration of treatment (101).

These studies prove that ADT results in an unfavorable body composition. The increase of fat mass in patients on ADT correlates positively with rising insulin levels (102). Hence, this increasing adiposity may be the primary event leading to these metabolic complications (possibly via elaboration of adipokines and inflammatory cytokines). Similarly, it is possible that a decrease in muscle mass may result in decreased glucose uptake by the muscle. These changes may ultimately lead to insulin resistance and diabetes in this population, hence

Androgen Deprivation Therapy for Prostate Cancer 347

profile, especially elevated total cholesterol, LDL cholesterol, and triglycerides (115). Furthermore, interventional studies have shown that TST replacement in hypogonadal men

During long-term ADT, triglycerides rise by approximately 26% and total cholesterol approximately 10%. (117, 118, 119) In addition, high-density lipoprotein (HDL) rises approximately 8% to 11%. The net effect of these changes on cardiovascular risks is unknown. Significant changes can be observed within the first 3 months of treatment, with

Metabolic syndrome (MS) is a known risk factor for cardiovascular disease (CVD) (120). According to the Adult Treatment Panel III guidelines (121), a man is considered to have MS if he meets 3 of the following 5 criteria: fasting plasma glucose level >110 mg/dL, serum triglyceride level 150 mg/dL, serum high-density lipoprotein level <40 mg/dL, waist circumference >102 cm, and blood pressure ≥ 130/85 mmHg. Subjects on antihypertensive and antilipid medications are also considered positive for the respective criteria. Recently, male hypogonadism has surfaced as an independent risk factor for MS. Cross-sectional studies have shown that men with hypotestosteronemia have a higher prevalence of MS (122). Longitudinal studies also show that lower androgen levels in men independently

These observations suggest that profound hypogonadism due to ADT imparts increased metabolic burden. Long-term prospective studies are needed to determine the time of onset

Since MS is associated with CVD, large studies were conducted to assed the CV risk and ADT. A large SEER-Medicare–based analysis of 73,196 men aged 66 years and older with PCa identified significant GnRH agonist-associated elevations in risk for myocardial infarction (HR, 1.11; p= .03), sudden cardiac death (HR, 1.16; p = .004), and new diagnosis of coronary heart disease (HR, 1.16; p< .001) (123). Similarly, a second SEER-Medicare–based study of 23,000 men with PCa found a 20% ADT-attributable rise in CV morbidity at 1 year (124). In contrast, a recently reported matched cohort analysis of approximately 20,000 men in an On-tario database found no association between ADT and acute myocardial infarction (HR,

A smaller population-based observational study of 3262 men who had undergone prostatectomy for PCa found that ADT was significantly associated with CV mortality, although only in the subset of men aged 65 years and older (126). This analysis failed to validate baseline coronary artery disease and diabetes as risk factors for CV mortality. Finally, combined analysis of 3 randomized trials involving men with localized PCa found that in the subset of men aged 65 years and older, 6 months of treatment with a GnRH

Three large randomized, controlled trials by the Radiation Therapy Oncology Group (RTOG) have been retrospectively analyzed for an association between neoadjuvant/ concomitant/adjuvant ADT and CV mortality. These analyses have not found convincing evidence of an association (128-130). Secondary analyses of a randomized controlled trial from the EORTC found no association between ADT and CV mortality. The RTOG and EORTC trials were randomized, featured large enrollments, and had long-term follow-up.

agonist led to earlier onset of fatal myocardial infarction (127).

results in an improvement in lipid profile (116).

**9. ADT, metabolic syndrome and cardiovascular disease** 

more modest subsequent change (110).

predict the development of MS (105).

0.91; 95% CI, 0.84–1.00) (125).

of various metabolic alterations in these men.

predisposing them to cardiovascular disease. Lifestyle changes or suitable interventions to minimize the effect of ADT on body composition need to be investigated.
