A randomized controlled trial of add-back estrogen or placebo on cognition in men with prostate cancer receiving an antiandrogen and a gonadotropin-releasing hormone analog.
ABSTRACT: The effects of testosterone (T) and estradiol (E(2)) on cognition in men are confounded in extant studies. This randomized, placebo-controlled trial was undertaken to investigate the possible effects of E(2) on cognition in older men. Twenty-five men with prostate cancer (mean age: 71.0+/-8.8 years) who required combined androgen blockade treatment were enrolled. Performance on cognitive tests was evaluated at pre-treatment baseline and following 12 weeks of treatment with a gonadotropin-releasing hormone analog and the nonsteroidal antiandrogen bicalutamide to determine whether specific cognitive functions would decline when the production of both T and E(2) were suppressed. In the second phase of the study, either micronized E(2) 1mg/day or an oral daily placebo was randomly added to the combined androgen blockade for an additional 12 weeks to determine whether E(2) would enhance performance in specific cognitive domains (verbal memory, spatial ability, visuomotor abilities and working memory). Compared to pretreatment, no differences in scores occurred on any cognitive test following 12 weeks of combined androgen blockade. In the add-back phase of the study (Visit 3), the placebo-treated men, but not the E(2)-treated men, exhibited a trend towards improvement in their scores on both the immediate (p=.075) and delayed recall (p=.095) portions of a verbal memory task compared to baseline. Moreover, at Visit 3, placebo-treated men performed significantly better than the E(2)-treated men on both the immediate (p=.020) and delayed recall (p=.016) portions of the verbal memory task. Thus, combined androgen blockade plus add-back E(2) failed to improve short- or long-term verbal memory performance in this sample of older men being treated for prostate cancer.
Project description:OBJECTIVE:Low-dose hydrocortisone (LDH) enhances aspects of learning and memory in select populations including patients with posttraumatic stress disorder and HIV-infected men. HIV-infected women show impairments in learning and memory, but the cognitive effects of LDH in HIV-infected women are unknown. DESIGN:Double-blind, placebo-controlled, cross-over study examining the time-dependent effects of a single low-dose administration of hydrocortisone (10?mg oral) on cognition in 36 HIV-infected women. Participants were first randomized to LDH or placebo and then received the opposite treatment one month later. METHODS:Cognitive performance was assessed 30?min and 4?h after pill administration to assess, respectively, nongenomic and genomic effects. Self-reported stress/anxiety and salivary cortisol were assessed throughout sessions. RESULTS:LDH significantly increased salivary cortisol levels versus placebo; levels returned to baseline 4-h postadministration. At the 30-min assessment, LDH enhanced verbal learning and delayed memory, working memory, behavioral inhibition, and visuospatial abilities. At the 4-h assessment, LDH enhanced verbal learning and delayed memory compared with placebo. LDH-induced cognitive benefits related to reductions in cytokines and to a lesser extent to increases in cortisol. CONCLUSION:The extended benefits from 30?min to 4?h of a single administration of LDH on learning and delayed memory suggest that targeting the hypothalamic-pituitary-adrenal axis may have potential clinical utility in HIV-infected women. These findings contrast with our findings in HIV-infected men who showed improved learning only at the 30-min assessment. Larger, longer term studies are underway to verify possible cognitive enhancing effects of LDH and the clinical significance of these effects in HIV.
Project description:BACKGROUND:In a previous trial, treatment with soy isoflavones was associated with improved nonverbal memory, construction abilities, verbal fluency, and speeded dexterity compared to treatment with placebo in cognitively healthy older adults. OBJECTIVE:The current trial aimed to examine the potential cognitive benefits of soy isoflavones in patients with Alzheimer's disease. METHODS:Sixty-five men and women over the age of 60 were treated with 100?mg/day soy isoflavones, or matching placebo capsules for six months. APOE genotype was determined for all participants. Cognitive outcomes and plasma isoflavone levels were measured at baseline, and at two additional time points: three and six months after baseline. RESULTS:Of the sixty-five participants enrolled, thirty-four (52.3% ) were women, and 31 (47.7% ) were APOE?4 positive. Average age was 76.3 (SD?=?7.2) years. Fifty-nine (90.8% ) subjects completed all study visits. Plasma isoflavone levels increased in subjects treated with soy isoflavones compared to baseline and to placebo, although intersubject variability in plasma levels was large. No significant differences in treatment effects for cognition emerged between treatment groups or genders. Exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency. CONCLUSIONS:Six months of 100?mg/day treatment with soy isoflavones did not benefit cognition in older men and women with Alzheimer's disease. However, our results suggest the need to examine the role of isoflavone metabolism, i.e., the ability to effectively metabolize soy isoflavones by converting daidzen to equol when attempting to fully clarify the cognitive effects of isoflavones.
Project description:Many prostate cancer (PCa) patients are on androgen deprivation therapy (ADT) as part of their cancer treatments but ADT may lead to cognitive impairments. ADT depletes men of both androgen and estrogen. Whether estradiol supplementation can improve cognitive impairments in patients on ADT is understudied.To summarize data on the effects of estradiol treatment on cognitive function of androgen-deprived genetic male populations (PCa patients and male-to-female transsexuals) and castrated male animals.Publications were identified by a literature search on PubMed and Google Scholar.While some studies showed that estradiol improves cognitive function (most notably, spatial ability) for castrated rats, what remains uninvestigated are: 1) whether estradiol can improve cognition after long-term androgen deprivation, 2) how estradiol affects memory retention, and 3) how early vs. delayed estradiol treatment after castration influences cognition. For androgendeprived genetic males, estradiol treatment may improve some cognitive functions (e.g., verbal and visual memory), but the findings are not consistent due to large variability in the study design between studies.Future studies are required to determine the best estradiol treatment protocol to maximize cognitive benefits for androgen-deprived genetic males. Tests that assess comparable cognitive domains in human and rodents are needed. What particularly under-investigated is how the effects of estradiol on cognitive ability intersect with other parameters; sleep, depression and physical fatigue. Such studies have clinical implications to improve the quality of life for both PCa patients on ADT as well as for male-to-female transsexuals.
Project description:Importance:Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions. Objective:To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). Design, Setting, and Participants:The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n?=?394) or placebo (n?=?394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014. Interventions:Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. Main Outcomes and Measures:The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. Results:Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P?=?.88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P?=?.24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P?=?.14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P?=?.89). Conclusions and Relevance:Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions. Trial Registration:clinicaltrials.gov Identifier: NCT00799617.
Project description:Prior research examining the impact of androgen deprivation therapy (ADT) for prostate cancer on cognitive performance has found inconsistent relationships. The purpose of this study was to systematically review the existing literature and determine the effect of ADT on performance across seven cognitive domains using meta-analysis.A search of PubMed Medline, PsycINFO, Cochrane Library, and Web of Knowledge/Science databases yielded 157 unique abstracts reviewed by independent pairs of raters. Fourteen studies with a total of 417 patients treated with ADT were included in the meta-analysis. Objective neuropsychological tests were categorized into seven cognitive domains: attention/working memory, executive functioning, language, verbal memory, visual memory, visuomotor ability, and visuospatial ability.Separate effect sizes were calculated for each cognitive domain using pairwise comparisons of patients who received ADT with (1) prostate cancer patient controls, (2) noncancer controls, or (3) ADT patients' own pre-ADT baselines. Patients treated with ADT performed worse than controls or their own baseline on visuomotor tasks (g =?-0.67, p =?.008; n = 193). The magnitude of the deficits was larger in studies with a shorter time to follow-up (p =?.04). No significant effect sizes were observed for the other six cognitive domains (p =?.08-.98).Prostate cancer patients who received ADT performed significantly worse on visuomotor tasks compared to noncancer control groups. These findings are consistent with the known effects of testosterone on cognitive functioning in healthy men. Knowledge of the cognitive effects of ADT may help patients and providers better understand the impact of ADT on quality of life.
Project description:a small number of reports exist on the cognitive effects of soy isoflavones, the findings from which are mixed. Isoflavone efficacy is dependent upon conversion of glycosides contained in soy foods and supplements to the biologically active aglycons. Of particular interest is the production of the metabolite, equol, which is dependent upon intestinal microflora and an integrous digestive system, both being altered by age and age-associated conditions. Unfortunately, few studies enrolled adults over the age of 70, and none included older men.we examined safety, feasibility and cognitive efficacy of soy isoflavone administration in older nondemented men and women (age 62-89 years).in this randomised, placebo-controlled, double-blind pilot study, subjects ingested either 100 mg/day soy isoflavones (glycoside weight) or matching placebo tablets for 6 months.active and placebo-treated subjects exhibited a comparable side-effect profile. Plasma levels of genistein and daidzein (P < 0.001), but not equol, increased with isoflavone administration. While similar at baseline, the two groups differed across 6 months of treatment on 8 of 11 cognitive tests administered. Isoflavone-treated subjects improved on tests of visual-spatial memory (P < 0.01) and construction (P = 0.01), verbal fluency (P < 0.01) and speeded dexterity (P = 0.04). Placebo-treated participants were faster than isoflavone-treated subjects on two tests of executive function (P < 0.05).these data suggest that administration of 100 mg/day of isoflavones was well tolerated. Plasma genistein and daidzein levels, but not equol, increased with isoflavone administration. Finally, data support the potential cognitive effects of soy isoflavones in older adults.
Project description:Androgen deprivation (AD) is commonly used in neoadjuvant and adjuvant setting with prostate cancer (PC) radiotherapy. This prospective study assessed whether cognitive functioning is impaired during 12 months of AD therapy. Longitudinal testing of 25 patients treated with AD and curative radiotherapy was undertaken at baseline, and at 6 and 12 months. CogniSpeed software was used for measuring attentional performances. Other cognitive performances were evaluated using verbal, visuomotor and memory tests. The Beck depression inventory was employed to evaluate depressive mood and EORTC QLQ-C30 for quality of life (QoL). During longitudinal testing of the AD group, no impairment in cognitive performances was found. Instead, improvement was observed in object recall (immediate, P=0.035; delayed, P<0.001), and in semantic memory (P=0.037). In QoL, impairment in physical function was observed. Androgen deprivation of 12 months appears to be associated with preserved cognitive functioning, although physical impairment occurs. These results have implications for counseling and psychosocial support of patients in the context of treatment options in PC.
Project description:BACKGROUND:Despite widespread use of multivitamin supplements, their effect on cognitive health-a critical issue with aging-remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons. OBJECTIVE:To evaluate whether long-term multivitamin supplementation affects cognitive health in later life. DESIGN:Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. (ClinicalTrials.gov: NCT00270647) SETTING: The Physicians' Health Study II. PATIENTS:5947 male physicians aged 65 years or older. INTERVENTION:Daily multivitamin or placebo. MEASUREMENTS:A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease. RESULTS:No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU (95% CI, -0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, -0.005 SU [CI, -0.04 to 0.03 SU]). LIMITATION:Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin. CONCLUSION:In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits. PRIMARY FUNDING SOURCE:National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products.
Project description:Cognitive function in older adults may be affected by multiple factors, such as sex hormone levels, metabolic disturbances, and neuropsychiatric illness. However, relatively few studies have tested the associations between these factors and cognitive function in a single sample. A cross-sectional analysis was conducted to examine the association between sex hormones, metabolic parameters, and psychiatric diagnoses with verbal memory in nondemented older men.Participants were 112 men (mean age: 61.3 years) from the Baltimore Epidemiologic Catchment Area Follow-Up Study who completed measures of blood sex hormone levels, metabolic parameters (e.g., lipid profiles), and verbal memory.Higher levels of serum sex hormone binding globulin (SHBG) were associated with lower delayed verbal memory scores (standardized coefficients [beta]=-0.19, t=-2.07, df=1, 105, p=0.04), and higher body mass index (BMI) was associated with better immediate (beta=0.21, t=2.41, df=1,105, p=0.02) and delayed (beta=0.22, t=2.46, df=1,105, p=0.02) verbal memory performance after adjustment for age, education, and psychiatric disorders. There was an inverse correlation between SHBG levels and BMI (Pearson's r=-0.37, N=112, p<0.001). Estimated free testosterone levels revealed curvilinear associations with verbal memory performance.Our data suggest that higher SHBG levels are associated with worse verbal memory, whereas a higher BMI is associated with better verbal memory in older men. Higher SHBG levels due to lower adiposity may be a risk factor for cognitive dysfunction. The mechanisms linking SHBG to cognitive function have yet to be elucidated.
Project description:Cannabis and tobacco have contrasting cognitive effects. Smoking cannabis with tobacco is prevalent in many countries and although this may well influence cognitive and mental health outcomes, the possibility has rarely been investigated in human experimental psychopharmacological research.The individual and interactive effects of cannabis and tobacco were evaluated in 24 non-dependent cannabis and tobacco smokers in a randomized, placebo-controlled, double-blind, 2 (cannabis, placebo) × 2 (tobacco, placebo) crossover design. Verbal memory (prose recall), working memory (WM) performance including maintenance, manipulation and attention (N-back), psychotomimetic, subjective and cardiovascular measures were recorded on each of four sessions.Cannabis alone impaired verbal memory. A priori contrasts indicated that tobacco offset the effects of cannabis on delayed recall. However, this was not supported by linear mixed model analysis. Cannabis load-dependently impaired WM. By contrast, tobacco improved WM across all load levels. The acute psychotomimetic effects and ratings of 'stoned' and 'dizzy' induced by cannabis were not altered by tobacco. Cannabis and tobacco had independent effects on increasing heart rate and interacting effects on increasing diastolic blood pressure.Relative to placebo, acute cannabis impaired verbal memory and WM. Tobacco enhanced performance on WM, independently of cannabis. Moreover, we found some preliminary evidence that tobacco may offset the effects of cannabis on delayed, but not immediate, verbal recall. In contrast, the psychotomimetic and subjective effects of cannabis were unaffected by tobacco co-administration. By reducing the cognitive impairment from cannabis, tobacco co-administration may perpetuate use despite adverse health consequences.