Genetic influences on hippocampal volume differ as a function of testosterone level in middle-aged men.
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ABSTRACT:
SUBMITTER: Panizzon MS
PROVIDER: S-EPMC3230702 | biostudies-literature | 2012 Jan
REPOSITORIES: biostudies-literature
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Genetic influences on hippocampal volume differ as a function of testosterone level in middle-aged men.
Panizzon Matthew S MS Hauger Richard L RL Eaves Lindon J LJ Chen Chi-Hua CH Dale Anders M AM Eyler Lisa T LT Fischl Bruce B Fennema-Notestine Christine C Franz Carol E CE Grant Michael D MD Jacobson Kristen C KC Jak Amy J AJ Lyons Michael J MJ Mendoza Sally P SP Neale Michael C MC Prom-Wormley Elizabeth E Seidman Larry J LJ Tsuang Ming T MT Xian Hong H Kremen William S WS
NeuroImage 20111001 2
The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55.8 years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. Ho ...[more]
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Project description:Testosterone regulates numerous physiological processes, and evidence suggests that it plays a critical role in male aging. It has yet to be determined whether the heritability of testosterone varies in accordance with its diurnal rhythm. Similarly, it is unclear whether changes in testosterone level throughout the day are genetically influenced. The aim of the present study was to determine the degree to which genetic and environmental factors contribute to individual differences in testosterone throughout the day in middle-aged men.Saliva-based measures of free testosterone, sampled at multiple time-points both at-home and in-lab, were collected from 783 male twins (193 monozygotic pairs, 196 dizygotic pairs, 5 unpaired twins) as part of the Vietnam Era Twin Study of Aging (VETSA). The average age of participants was 55.9 years (SD=2.6).Testosterone levels declined substantially over the course of the day, with 32-39% of the change occurring in the first 30min after waking. Heritability estimates for specific time-points ranged from .02 to .39. The heritability of the average at-home and in-lab testosterone values were notably higher (.42 and .47 respectively). Daily rates of change showed some evidence of genetic influence, with heritability estimates ranging from .15 to .29, whereas there were no observable genetic influences on coefficients of variation.Genetic influences account for a significant proportion of the variance in average testosterone levels, while environmental factors account for the majority of intra-individual variability. These results highlight the need to explore both genetic and individual-specific environmental factors as determinants of free testosterone levels in aging men.
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Project description:Age-related changes in testosterone are believed to be a key component of the processes that contribute to cognitive aging in men. The APOE-?4 allele may interact with testosterone and moderate the hormone's association with cognition. The goals of the present study were to examine the degree to which free testosterone is associated with episodic memory in a community-based sample of middle-aged men, and examine the potential interaction between free testosterone and the APOE-?4 allele. Data were used from 717 participants in the Vietnam Era Twin Study of Aging. Average age was 55.4 years (standard deviation = 2.5). Significant positive associations were observed between free testosterone level and verbal episodic memory, as well as a significant interaction between free testosterone and APOE-?4 status. In ?4 carriers free testosterone was positively associated with verbal episodic memory performance (story recall), whereas no association was observed in ?4 noncarriers. Results support the hypothesis that APOE-?4 status increases susceptibility to other risk factors, such as low testosterone, which may ultimately contribute to cognitive decline or dementia.
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Project description:Converging animal findings suggest that higher peripheral levels of inflammation are associated with activation of central inflammatory mechanisms that result in hippocampal neurodegeneration and related impairment of memory function. We have recently shown, consistent with animal findings, an inverse association between peripheral levels of interleukin-6 (IL-6), a relatively stable marker of systemic inflammation, and memory function in mid-life adults. In the current study, we extend this work to test whether systemic inflammation is associated with reduced grey matter volume of the hippocampus.For this purpose, we used a computational structural neuroimaging method (optimized voxel-based morphometry) to evaluate the relationship between plasma IL-6 levels and hippocampal grey matter volume in a sample of 76 relatively healthy community volunteers ages 30-54.Peripheral levels of IL-6 covaried inversely with hippocampal grey matter volume, and this relationship persisted after accounting for several possible confounders, including age, gender, race, years of education, percent body fat, blood pressure, smoking, physical activity, hours of sleep, alcohol use, and total grey matter volume.To our knowledge, this is the first report of a relationship between a peripheral marker of IL-6 and hippocampal grey matter volume, raising the possibility that low-grade systemic inflammation could plausibly presage subclinical cognitive decline in part via structural neural pathways.
| S-EPMC2562462 | biostudies-literature
Project description:ObjectiveTo examine the cross-sectional association between physical activity (PA) and hippocampal volume in middle-aged adults with childhood-onset type 1 diabetes (T1D), and whether hyperglycemia and insulin sensitivity contribute to this relationship.MethodsWe analyzed neuroimaging and self-reported PA data from 79 adults with T1D from the Pittsburgh Epidemiology of Diabetes Complications Study (mean age 50 years, mean duration 41 years) and 122 similarly aged adults without T1D (mean age 48 years). Linear regression models, controlling for intracranial volume, sex, education, and age, tested associations between PA and gray matter volumes of hippocampi and total brain in the 2 groups. For the T1D group, models further controlled for hyperglycemia and glucose disposal rate, a measure of insulin sensitivity.ResultsPA was significantly lower in the T1D than in the non-T1D group (median [interquartile range] 952 kcal [420-2,044] vs 1,614 kcal [588-3,091], respectively). Higher PA was significantly associated with larger hippocampi for T1D, but not for non-T1D (standardized β [p values] from regression models adjusted for intracranial volume, sex, age, and education: 0.270 [p < 0.001] and 0.098 [p = 0.12], respectively). Neither hyperglycemia nor glucose disposal rate substantially modified this association. Relationships between PA and total brain gray matter volume were similar.ConclusionsA cross-sectional association between higher PA and larger hippocampi is already detectable by middle age for these patients with T1D, and it appears robust to chronic hyperglycemia and insulin sensitivity. Proof-of-concept studies should investigate whether increasing PA preserves hippocampal volume and the mechanisms underlying the effects of PA on hippocampal volume.
| S-EPMC5395074 | biostudies-literature
Project description:BackgroundSerum testosterone deficiency increases with aging. Age is also a major risk factor for prostate cancer (PrCa) and PCa tumors are more frequently diagnosed among men >65 years old. We evaluated the relationship between preoperative serum testosterone and clinical/ pathological features of PrCa in middle-aged and elderly patients.MethodsA total of 605 PrCa patients who underwent robotic-assisted radical prostatectomy between September 2010 and January 2013 at the University of Pennsylvania, and who had serum testosterone levels measured using Elecsys Testosterone II Immunoassay were included in this IRB-approved protocol. Androgen deficiency was determined as serum free testosterone (FT) <47 pg/ml and total testosterone (TT) <193 ng/dl. Demographic, clinical and tumor characteristics of men with low vs. normal TT or FT were compared using t-test or chi-square tests. Logistic regression was used to determine associations of clinical and pathological variables with FT or TT levels.ResultsAmong middle-aged men (45-64 years; n = 367), those with low FT and low TT had, on average, a higher BMI (29.7 vs. 27.4, P < 0.01; and 32.2 vs. 27.6; P < 0.01, respectively) and higher proportion of Gleason 8-10 PrCa (13.3% vs. 4.8%, P = 0.011; and 19.2% vs. 5.1%, P = 0.012) compared to men with normal FT and normal TT values. Patients with low FT had also higher number of positive cores on biopsy (3.9 vs. 3.1 P = 0.019) and greater tumor volume (7.9 ml vs. 6.1 ml, P = 0.045) compared to those with normal FT. Among men ≥65 years (n = 135) there was no difference in prostatectomy specimens of PrCa between patients with low or normal FT or TT.ConclusionAmong men aged 45-64 years low serum pretreatment FT and TT predicted more aggressive features of PrCa in prostatectomy specimens. In middle-aged patients low testosterone levels measured pre-operatively may indicate more aggressive disease parameters.
| S-EPMC5357970 | biostudies-literature
Project description:BackgroundLow vitality is a common symptom of testosterone deficiency; however, clinical trial results remain inconclusive regarding the responsiveness of this symptom to hormone replacement.AimThe aim of the present study was to determine if the relationship between circulating testosterone levels and vitality would be moderated by the CAG repeat length in the androgen receptor (AR) gene, which influences the receptor's sensitivity to testosterone.MethodsWe examined 676 men in the Vietnam Era Twin Study of Aging when they were, on average, 55.4 years old (SD = 2.5). Salivary testosterone levels were measured by using 3 samples collected at waking on 3 nonconsecutive days. The average testosterone level was classified as low, normal, or high based on 1-SD cutoffs. Analyses were conducted using multilevel, mixed linear models, which accounted for the nonindependence of the twin data, and adjusted for the effects of age, ethnicity, BMI, chronic health conditions, depressive symptoms, and sleep quality.OutcomesVitality was measured using the 36-item Short Form (SF-36) vitality subscale.ResultsWe observed a significant interaction between salivary testosterone and the AR-CAG repeat length. When the repeat length was short, men with low testosterone had significantly lower vitality. As the AR-CAG repeat length increased, the magnitude of the testosterone effect decreased.Clinical translationThe observed interaction between testosterone and variation in the AR gene suggests that men with more sensitive ARs, as indicated by a shorter AR-CAG repeat, are more likely to experience symptoms of age-related testosterone deficiency.Strengths & limitationsStrengths of the present study include our use of a large community-based sample, the use of multiple testosterone measurements, and the availability of a comprehensive set of covariates that may impact the association of interest. Limitations include the homogeneous nature of the sample with respect to ethnicity, the brevity of the 36-item Short Form vitality subscale, and our inability to establish change in testosterone levels because of the cross-sectional nature of data.ConclusionsThe association between testosterone and vitality appears to be clinically meaningful and is in part dependent on variation in the AR gene. Panizzon MS, Bree K, Hsieh T-C, et al. Genetic Variation in the Androgen Receptor Modifies the Association Between Testosterone and Vitality in Middle-Aged Men. J Sex Med 2020;17:2351-2361.
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Project description:To investigate the impact of metabolic components and body composition indices on prostate volume (PV) in a population of middle-aged men receiving health check-ups.Six hundred and sixteen men receiving health assessments were stratified to large and small prostates based on the cut-off of median PV. Their demographic data, health history, and international prostate symptoms scores (IPSS) were collected. Metabolic components and body composition indices were compared between subjects with large and small prostates. Moreover, the correlations between these parameters and PV were analyzed by multivariate logistic regression.The median PV was 27 mL and mean age was 54.8 years. Subjects with large PV were older (56.5 vs. 52.7 years) and had higher serum prostate specific antigen (PSA) level (1.73 vs. 0.96 ng/mL), higher IPSS score (8.37 vs. 6.16), and higher body fat, body mass, and waist circumference (all p<0.05). In multivariate analysis, age (OR, 2.45; 95%CI, 1.74-3.45), serum PSA (OR, 2.75; 95%CI, 1.96-3.86), waist circumference (OR, 1.45; 95%CI, 1.02-2.07), fatness (OR, 1.47; 95%CI, 1.04-2.09), and body fat mass (OR, 1.43; 95%CI, 1.00-2.03) were significantly correlated with PV of study subjects. In subgroup analysis, raised waist circumference (OR, 1.89; 95%CI, 1.00-3.59) was the independent predictor of PV in subjects with bothersome lower urinary tract symptoms.Several metabolic components and body composition indices are significantly associated with PV of middle-aged men, including raised waist circumference, fatness, and body fat mass. Raised waist circumference is the only independent predictor of PV in middle-aged men with bothersome LUTS.
| S-EPMC4701412 | biostudies-other
Project description:Importance:Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk. Objective:To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume. Design, Setting, and Participants:Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014. Intervention:Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcomes and Measures:The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis). Results:Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P?=?.003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P?=?.006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group. Conclusions and Relevance:Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding. Trial Registration:clinicaltrials.gov Identifier: NCT00799617.
| S-EPMC5465430 | biostudies-literature
Project description:BACKGROUND:Chronic Kidney Disease (CKD), characterized by an impaired kidney function, is associated with low testosterone levels. This study investigated the association between dietary patterns, testosterone levels, and severity of impaired kidney function among middle-aged and elderly men. METHODS:This cross-sectional study used the database from a private health-screening institute in Taiwan between 2008 and 2010. Men aged 40 years old and older (n = 21,376) with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 and proteinuria were selected. Among 21,376 men, 256 men had available measurements of testosterone levels. Dietary assessment was conducted using a food frequency questionnaire and three dietary patterns (fried-processed, vege-seafood, and dairy-grain dietary patterns) were identified using principal component analysis. RESULTS:Men in the lower tertiles (T1 and T2) of eGFR had significantly decreased testosterone levels by 0.8 (95% CI: - 1.40, - 0.20) and 0.9 nmol/L (95% CI: - 1.43, - 0.33). Furthermore, serum triglycerides (TG) levels were inversely associated with testosterone levels (β = - 0.51, 95% CI: - 0.77, - 0.24). Men in the higher tertile of fried-processed dietary pattern scores were associated with decreased testosterone levels by 0.8 nmol/L (95% CI: - 1.40, - 0.16), reduced testosterone-to-TG (T/TG) ratio by 1.8 units (95% CI: - 2.99, - 0.53), and increased risk of moderate/severe impaired kidney function (eGFR < 60 mL/min/1.73 m2) and proteinuria severity by 1.35 (95% CI: 1.15, 1.58) and 1.18 (95% CI: 1.02, 1.37) times respectively. In contrast, the vege-seafood dietary pattern was negatively associated with severity of impaired kidney function and proteinuria after multivariable adjustment, but had no association with testosterone levels and T/TG ratio. CONCLUSIONS:The fried-processed dietary pattern is negatively associated with testosterone levels but positively associated with the severity of impaired kidney function. However, the vege-seafood and dairy-grain dietary patterns appear to have beneficial effects.
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