Marielle H. Emmelot-Vonk

Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial.

CONTEXT Serum testosterone levels decline significantly with aging. Testosterone supplementation to older men might beneficially affect the aging processes. OBJECTIVE To investigate the effect of testosterone supplementation on functional mobility, cognitive function, bone mineral density, body composition, plasma lipids, quality of life, and safety parameters in older men with low normal testosterone levels. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled trial of 237 healthy men between the ages of 60 and 80 years with a testosterone level lower than 13.7 nmol/L conducted from January 2004 to April 2005 at a university medical center in the Netherlands. INTERVENTION Participants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for 6 months. MAIN OUTCOME MEASURES Functional mobility (Stanford Health Assessment Questionnaire, timed get up and go test, isometric handgrip strength, isometric leg extensor strength), cognitive function (8 different cognitive instruments), bone mineral density of the hip and lumbar spine (dual-energy x-ray absorptiometry scanning), body composition (total body dual-energy x-ray absorptiometry and abdominal ultrasound of fat mass), metabolic risk factors (fasting plasma lipids, glucose, and insulin), quality of life (Short-Form Health 36 Survey and the Questions on Life Satisfaction Modules), and safety parameters (serum prostate-specific antigen level, ultrasonographic prostate volume, International Prostate Symptom score, serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, hemoglobin, and hematocrit). RESULTS A total of 207 men completed the study. During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P = .07). Quality-of-life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected. CONCLUSION Testosterone supplementation during 6 months to older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN23688581.

Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies

BACKGROUND Accumulating evidence suggests a sex-dependent role of circulating testosterone in the metabolic syndrome (MetS). METHODS We conducted a meta-analysis of observational studies (PubMed and EMBASE-1 May 2010) relating MetS to determinants of testosterone status [total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG)]. RESULTS A total of 52 studies were identified, comprising 22 043 men and 7839 women and presenting relative risk (RR) estimates or hormone levels for subjects with and without MetS. Endogenous TT and FT levels were lower in men with MetS [TT mean difference = -2.64 nmol/l, 95% confidence interval (CI) -2.95 to -2.32; FT standardized mean difference = -0.26 pmol/l, 95% CI -0.39 to -0.13] and higher in women with MetS (TT mean difference = 0.14 nmol/l, 95% CI 0.07-0.20; FT standardized mean difference = 0.52 pmol/l, 95% CI 0.33-0.71) compared with those without. Similarly, men with higher TT levels had a lower MetS risk (RR estimate = 0.38, 95% CI 0.28-0.50) whereas higher TT levels increased the risk of MetS in women (RR estimate = 1.68, 95% CI 1.15-2.45). In both sexes, higher SHBG levels were associated with a reduced risk (men: RR estimate = 0.29, 95% CI 0.21-0.41; women: RR estimate = 0.30, 95% CI 0.21-0.42). CONCLUSION This meta-analysis supports the presence of a sex-dependent association between testosterone and MetS: TT and FT levels are lower in men with MetS, whereas they are higher in women with MetS. There are no indications for a sex-specific association between SHBG and MetS. In both men and women, MetS is associated with lower SHBG levels.

The association between vitamin D and cognition: A systematic review

Vitamin D insufficiency and deficiency are a major health care problem. The association between vitamin D levels and cognitive function is still under debate. We conducted a systematic review to assess the association between levels of vitamin D and cognition. Therefore, the databases of Embase and Pubmed were searched through June 2012 for observational studies relating vitamin D levels to cognition. Our initial search yielded 2182 articles. After applying exclusion criteria, there were 28 studies eligible for inclusion: 25 cross-sectional and 6 prospective studies (3 studies show cross-sectional as well as prospective data). The main finding of the 25 cross-sectional studies was a statistically significant worse outcome on one or more cognitive function tests or a higher frequency of dementia with lower vitamin D levels or intake in 18 out of 25 (72%) studies, whereas 7 (28%) studies failed to show an association. Four out of 6 (66.7%) prospective studies showed a higher risk of cognitive decline after a follow-up period of 4-7 years in participants with lower vitamin D levels at baseline. In conclusion, this review supports the hypothesis that hypovitaminosis D is associated with worse outcome on one or more cognitive function tests or a higher frequency of dementia in cross-sectional as well as prospective studies. Further studies should focus on the role of vitamin D supplementation in the prevention of cognitive decline in participants with low vitamin D levels.

Psychotropic medications, including short acting benzodiazepines, strongly increase the frequency of falls in elderly

OBJECTIVES Falls in the elderly are common and often serious. The aim of this study was to examine the association between the use of different classes of psychotropic medications, especially short acting benzodiazepines, and the frequency of falling in elderly. Study design This retrospective cohort study was performed with patients who visited the day clinic of the department of geriatric medicine of the University Medical Center Utrecht in the Netherlands between 1 January 2011 and 1 April 2012. Measurements Frequencies of falling in the past year and medication use were recorded. Logistic regression analysis was performed to assess the relationship between the frequency of falling in the past year and the use of psychotropic medications. RESULTS During this period 404 patients were included and 238 (58.9%) of them had experienced one or more falls in the past year. After multivariate adjustment, frequent falls remained significantly associated with exposure to psychotropic medications (odds ratio [OR] 1.96; 95% confidence interval [CI] 1.17-3.28), antipsychotics (OR 3.62; 95% CI 1.27-10.33), hypnotics and anxiolytics (OR 1.81; 95% CI 1.05-3.11), short-acting benzodiazepines or Z-drugs (OR 1.94; 95% CI 1.10-3.42) and antidepressants (OR 2.35; 95% CI 1.33-4.16). CONCLUSIONS This study confirms that taking psychotropic medication, including short-acting benzodiazepines, strongly increases the frequency of falls in elderly. This relation should be explicitly recognized by doctors prescribing for older people, and by older people themselves. If possible such medication should be avoided for elderly patients especially with other risk factors for falling.

Raloxifene improves verbal memory in late postmenopausal women: a randomized, double-blind, placebo-controlled trial.

Objective: The aim of this study was to examine the effects of raloxifene compared with those of placebo on verbal memory, mental processing speed, depression, anxiety, and quality of life. Methods: A randomized, double-blind, placebo-controlled trial of 213 healthy women 70 years or older was conducted between July 2003 and January 2008 at the University Medical Centre Utrecht, the Netherlands. Participants were randomly assigned to receive raloxifene (60 mg) or placebo daily for 12 months. Measurements were taken at baseline and after 3, 6, and 12 months. The change in scores from baseline was calculated. The main outcome measures were direct and delayed verbal memory (Groningen 15 Words test), mental processing speed (Trails B test), mood/depression (Geriatric Depression Scale), anxiety (State-Trait Anxiety Inventory 1 and 2), and quality of life (Womens Health Questionnaire and EuroQol-5 dimensional questionnaire). Results: Direct verbal memory improved significantly with raloxifene compared with placebo: the women receiving raloxifene repeated more words in the words A + B test than did the women receiving placebo (P = 0.025). At 12 months, the change from baseline was 16 words in the raloxifene group and 10 words in the placebo group. In the words A test, direct repetition was also significantly better among women receiving raloxifene than among women receiving placebo (P = 0.023), with the change from baseline in the number of words repeated being nine words in the raloxifene group and six words in the placebo group at 12 months. Conclusions: In postmenopausal women, raloxifene gave significantly improved verbal memory when compared with placebo.

The influence of vascular risk factors on cognitive decline in patients with dementia: A systematic review

BACKGROUND AND OBJECTIVE Vascular risk factors (VRF) are associated with a higher incidence of dementia. However, the relationship with disease progression is unclear. This review examined the association of VRF (hypertension, hypercholesterolemia, diabetes mellitus, overweight, smoking or multiple VRF) and cognitive decline in patients suffering from dementia. METHODS Literature was searched in four databases (Pubmed, Embase, Cochrane, PsychInfo) and 1779 articles were identified. This resulted in a total of 20 articles which were included. RESULTS Twelve studies on hypertension (HT) were inconsistent about the association with cognitive decline. For hypercholesterolemia (HC) 2 (out of 7) studies were associated with increased cognitive decline, as were both (2/2) studies which researched LDL-cholesterol. Articles were inconclusive about the effect of diabetes mellitus (DM): five (out of 13) found less cognitive decline, 2 found more cognitive decline, and 6 found no significant effect of DM. Overweight (BMI>25 kg/m(2)) was associated in 2/4 studies with a slower rate of cognitive decline, while the other 2 studies found no effect. All studies (5/5) that researched smoking did not find a significant effect. Four studies (out of 7) that looked at multiple VRF found faster cognitive decline, and 3/7 found no effect. DISCUSSION The results of this review suggest an association between LDL-cholesterol and the progression of dementia, while inconsistent results were found for other VRF. Additional prospective cohort studies and experimental studies should be performed to better understand the causal contribution of VRF on cognitive decline in dementia.

The association of chronic kidney disease with brain lesions on MRI or CT: A systematic review

BACKGROUND AND PURPOSE This review reports on the association between chronic kidney disease (CKD) established with glomerular filtration rate (GFR) and brain lesions established with MRI or CT. METHODS Literature was searched combining synonyms of kidney function, brain lesions and terms for the definitions thereof, and MRI or CT. This resulted in 1507 articles, of which 20 were finally included. RESULTS Cross-sectional studies found an association between GFR and white matter lesions (WML) with 7 out of 11 associations significant (odds ratios (OR) GFR, continuous variable: 0.84-0.89 per 10 ml/min/1.73 m(2)). Most significant results were found in studies including subjects from the general population. GFR was associated with silent cerebral infarcts (SCI) with 9 out of 12 associations significant (OR GFR, continuous variable: 0.96-0.99 per ml/min/1.73 m(2)). Brain atrophy was reported significant 4 out of 5 associations (OR GFR, continuous variable: 0.64 per 10 ml/min/1.73 m(2)). Additionally, 2 follow up studies were included. One established that serum creatinine at baseline is a significant predictor of the presence of SCI; the other that the presence of SCI at baseline is a significant predictor of a decrease in GFR. CONCLUSION The results from this review show that CKD is associated with brain lesions. These brain lesions include WML, SCI and brain atrophy. This finding is of clinical importance because these brain lesions are predictive of stroke, cognitive decline and dementia. Additional follow up studies should be performed to better understand the causative pathway and to establish whether screening and preventive programs are beneficial.

Incidence, Predictive Factors, and Effect of Delirium After Transcatheter Aortic Valve Replacement

OBJECTIVES The purpose of this study was to investigate the incidence, predictive factors, and effect of post-operative delirium (POD) among patients treated by transcatheter aortic valve replacement (TAVR). BACKGROUND Patients undergoing operations that involve valve replacement appear at higher risk of POD than patients subjected to coronary artery bypass surgery alone. In patients with severe aortic stenosis undergoing TAVR, little is known regarding the potential impact of POD on the clinical outcomes. METHODS A retrospective observational cohort study of 268 consecutive patients who underwent TAVR at our institute was conducted. Delirium was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorder, 4th Edition criteria. The primary outcome of this study was the presence of in-hospital POD after TAVR. RESULTS The incidence of POD after TAVR was 13.4% (n = 36). Of these cases, 18 were associated with post-procedural complications, including major vascular complications/bleeding (n = 4), stroke (n = 3), acute kidney injury (n = 3), atrial fibrillation (n = 4), and infectious disease (n = 4). POD was most frequently diagnosed on the second day after TAVR (interquartile range [IQR]: 1 to 5 days) and was associated with prolonged in-hospital stay regardless of complications (in uncomplicated TAVR: 6 days [IQR: 5 to 10 days] vs. 5 days [IQR: 4 to 5 days]; p < 0.001; and in complicated TAVR: 9 days [IQR: 8 to 15 days] vs. 6 days [IQR: 5 to 9 days]; p < 0.001). Predictors of POD were nontransfemoral (transapical/transaortic) access (odds ratio [OR]: 7.74; 95% confidence interval [CI]: 3.26 to 18.1), current smoking (OR: 3.99; 95% CI: 1.25 to 12.8), carotid artery disease (OR: 3.88; 95% CI: 1.50 to 10.1), atrial fibrillation (OR: 2.74; 95% CI: 1.17 to 6.37), and age (OR: 1.08; 95% CI: 1.00 to 1.17, per year increase). After a median follow-up of 16 months (IQR: 6 to 27 months), POD remained an independent predictor of mortality in patients undergoing transfemoral TAVR compared with the nontransfemoral TAVR (hazard ratio: 2.81; 95% CI: 1.16 to 6.83 vs. hazard ratio: 0.43; 95% Cl: 0.10 to 1.76), adjusted for possible confounders in a time-dependent Cox-regression model (i.e., age, sex, Logistic EuroSCORE and the occurrence of complications). CONCLUSIONS POD after TAVR has an incidence of around 13% and occurs early in the post-operative course. Nontransfemoral access is strongly associated with the occurrence of POD. Patients who develop POD show prolonged in-hospital stay and impaired long-term survival.

Effect of testosterone supplementation on sexual functioning in aging men: a 6-month randomized controlled trial

Serum testosterone levels decline significantly with aging and this has been associated with reduced sexual function. We have conducted a double-blind, randomized, placebo-controlled trial to investigate the effect of testosterone supplementation on sexual function in 237 elderly men with a testosterone level <13.7 nmol l−1. Participants were randomly assigned to receive oral testosterone undecanoate or a placebo for 6 months. A total of 207 men completed the study. After treatment, there were no differences in scores on sexual function between the groups. Subanalysis showed that although a baseline testosterone level in the lowest tertile was associated with significantly lower scores for sexual fantasies, desire of sexual contact and frequency of sexual contact, supplementation of testosterone did not result in improvement on any of these items in this group. In conclusion, the findings do not support the view that testosterone undecanoate supplementation for 6 months to elderly men with low-normal testosterone concentrations favorably affects sexual function.

Vitamin D and muscle function: is there a threshold in the relation?

OBJECTIVES First, to determine the association between serum 25 hydroxyvitamin D (25OHD) concentration and muscle mass, strength, and performance. Second, to explore if there is a threshold in the association. DESIGN Cross-sectional, single-center study. SETTING The central part of the Netherlands (52° Northern latitude). PARTICIPANTS A total of 802 independently living men and postmenopausal women 40 to 80 years of age. MEASUREMENTS Health-related and lifestyle factors, including physical activity, 25OHD concentration, lean mass, handgrip strength, knee extension strength, and physical performance were determined. RESULTS Overall, higher 25OHD level was significantly associated with higher lean mass (22.6 g per nmol/L, 95% CI 7.3-37.9), handgrip strength (0.020 kg per nmol/L, 95% CI 0.001-0.038), and physical performance (0.006 points per nmol/L, 95% CI 0.001-0.012), after adjustment for various confounders. This association was most pronounced below a 25OHD level of 60 nmol/L, with lean mass increase 79.6 g per nmol/L (95% CI 40.8-118.4, P < .01), handgrip strength 0.09 kg per nmol/L (95% CI 0.045-0.141, P < .01), and physical performance 0.02 points per nmol/L (95% CI 0.005-0.032, P < .01), and these significant associations attenuated to null above this threshold. CONCLUSION In middle-aged men and (postmenopausal) women, a higher 25OHD level was significantly associated with higher lean mass, muscle strength, and performance. These associations were most pronounced below 60 nmol/L and absent above 60 nmol/L, indicating a ceiling effect.