Reproductive hormone levels, androgen receptor CAG repeat length and their longitudinal relationships with decline in cognitive subdomains in men: The European Male Ageing Study.

OBJECTIVE: It has been proposed that endogenous sex hormone levels may present a modifiable risk factor for cognitive decline. However, the evidence for effects of sex steroids on cognitive ageing is conflicting. We therefore investigated associations between endogenous hormone levels, androgen receptor CAG repeat length, and cognitive domains including visuoconstructional abilities, visual memory, and processing speed in a large-scale longitudinal study of middle-aged and older men. METHODS: Men aged 40-79 years from the European Male Ageing Study (EMAS) underwent cognitive assessments and measurements of hormone levels at baseline and follow-up (mean = 4.4 years, SD ± 0.3 years). Hormone levels measured included total and calculated free testosterone and estradiol, dihydrotestosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulphate and sex hormone-binding globulin. Cognitive function was assessed using the Rey-Osterrieth Complex Figure Copy and Recall, the Camden Topographical Recognition Memory and the Digit Symbol Substitution Test. Multivariate linear regressions were used to examine associations between baseline and change hormone levels, androgen receptor CAG repeat length, and cognitive decline. RESULTS: Statistical analyses included 1,827 and 1,423 participants for models investigating relationships of cognition with hormone levels and CAG repeat length, respectively. In age-adjusted models, we found a significant association of higher baseline free testosterone (ß=-0.001, p=0.005) and dihydrotestosterone levels (ß=-0.065, p=0.003) with greater decline on Rey-Osterrieth Complex Figure Recall over time. However, these effects were no longer significant following adjustment for centre, health, and lifestyle factors. No relationships were observed between any other baseline hormone levels, change in hormone levels, or androgen receptor CAG repeat length with cognitive decline in the measured domains. CONCLUSIONS: In this large-scale prospective study there was no evidence for an association between endogenous sex hormone levels or CAG repeat length and cognitive ageing in men. These data suggest that sex steroid levels do not affect visuospatial function, visual memory, or processing speed in middle-aged and older men.

Erectile dysfunction predicts mortality in middle-aged and older men independent of their sex steroid status.

BACKGROUND: erectile dysfunction is associated with mortality, whereas the association between low testosterone (T) and higher mortality remains controversial. Sexual dysfunction and low T often coexist, but the relative importance of sexual symptoms versus low T in predicting mortality is not known. We studied the interrelationships between sex steroids and sexual symptoms with all-cause mortality in a large prospective cohort of European men. DESIGN: survival status was assessed in 1,788 community-dwelling men, aged 40-79, who participated in the European Male Ageing Study (EMAS). Sexual symptoms were evaluated via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. RESULTS: about 420 (25.3%) men died during a mean follow-up of 12.6 ± 3.1 years. Total T levels were similar in both groups, but free T was lower in those who died. Men with three sexual symptoms (erectile dysfunction, reduced morning erections and lower libido) had a higher mortality risk compared with men with none of these symptoms (adjusted hazard ratio (HR) and 95% confidence intervals: 1.75 (1.28-2.40, P = 0.001)). Particularly, erectile dysfunction and poor morning erections, but not lower libido, were associated with increased mortality (HR 1.40 (1.13-1.74, P = 0.002), 1.28 (1.04-1.59, P = 0.023) and 1.12 (0.90-1.39, P = 0.312), respectively). Further adjusting for total T, free T or oestradiol did not influence the observed risk. CONCLUSIONS: sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of sex steroids and can be an early warning sign of a poor health status.

Aging Men With Insufficient Vitamin D Have a Higher Mortality Risk: No Added Value of its Free Fractions or Active Form.

CONTEXT: Low total 25-hydroxyvitamin D (25(OH)D) has been associated with mortality. Whether vitamin D in its free form or 1,25-dihydroxyvitamin D (1,25(OH)2D), provide any additional information is unclear. OBJECTIVE: To determine what level of 25(OH)D is predictive for mortality and if free 25(OH)D or 1,25(OH) 2 D concentrations have any added value. METHODS: This prospective cohort comprised 1915 community-dwelling men, aged 40 to 79 years. Intervention included determination of association of total and free 25(OH)D and 1,25(OH) 2 D concentrations with survival status. Vitamin D results were grouped into quintiles. For total 25(OH)D, specific cutoff values were also applied. Cox proportional hazard models were used adjusted for center, body mass index, smoking, alcohol, physical activity, season of blood sample, kidney function, and number of comorbidities. RESULTS: A total of 469 (23.5%) men died during a mean follow-up of 12.3 ±â€…3.4 years. Compared to those with normal vitamin D values (> 30 µg/L), men with a total 25(OH)D of less than 20 µg/L had an increased mortality (hazard ratio [HR] 2.03 [95% CI, 1.39-2.96]; P < .001). Likewise, men in the lowest 3 free 25(OH)D quintiles (< 4.43 ng/L) had a higher mortality risk compared to the highest quintile (HR 2.09 [95% CI, 1.34-3.25]; P < .01). Mortality risks were similar across all 1,25(OH)2D and vitamin D binding protein quintiles. CONCLUSION: Aging men with vitamin D deficiency have a 2-fold increased mortality risk. Determinations of either the free fractions of vitamin D or measurement of its active form offer no additional information on mortality risks.

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology.

BACKGROUND: Evidence regarding functional hypogonadism, previously referred to as 'late-onset' hypogonadism, has increased substantially during the last 10 year. OBJECTIVE: To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. METHODS: Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. RESULTS: The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well-validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%-50% represent relative contraindications for TRT. Prostate-specific antigen and digital rectal examination of the prostate should be undertaken in men >40 years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. CONCLUSION: TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long-term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision-making.

Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism: Prospective results from the EMAS.

OBJECTIVE: Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone-binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). DESIGN: Prospective observational study with a median follow-up of 4.3 years. PATIENTS: Three thousand three hundred sixty-nine community-dwelling men aged 40-79 years from eight European centres. MEASUREMENTS: Subjects were categorized according to baseline and follow-up biochemical status into persistent eugonadal (referent group; n = 1880), incident LNSH (eugonadism to LNSH; n = 101) and incident LLSH (eugonadism to LLSH; n = 38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. RESULTS: The cumulative incidence of LNSH and LLSH over 4.3 years was 4.9% and 1.9%, respectively. Baseline obesity predicted both LNSH and LLSH, but the former occurred more frequently in younger men. LLSH, but not LNSH, was associated with new/worsened sexual symptoms, including low desire [OR = 2.67 (1.27-5.60)], erectile dysfunction [OR = 4.53 (2.05-10.01)] and infrequent morning erections [OR = 3.40 (1.48-7.84)]. CONCLUSIONS: These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT.

Reproductive Hormone Levels Predict Changes in Frailty Status in Community-Dwelling Older Men: European Male Ageing Study Prospective Data.

Context: Clinical sequelae of androgen deficiency share common features with frailty. Evidence supporting the role of androgens in the development of frailty is limited and conflicting. Objective: To determine associations between male reproductive hormones and prospective changes in frailty status. Design/Setting: A 4.3-year prospective cohort study of community-dwelling men participating in the European Male Ageing Study. Participants: A total of 3369 men aged 40 to 79 from eight European centers. Intervention: None. Main Outcome Measure: Frailty status was determined using frailty index (FI; n = 2278) and frailty phenotype (FP; n = 1980). Results: After adjusting for baseline frailty, age, center, and smoking, the risk of worsening FI decreased with higher testosterone (T), free T, and dihydrotestosterone (DHT) [percentage change (95% confidence interval) in FI associated with 1 standard deviation higher hormone level: -3.0 (-5.9, -1.0) for total T; -3.9 (-6.8, -2.0) for free T; and -3.9 (-6.8, -2.0) for DHT]. After further adjustment for body mass index, only free T remained a significant predictor of FI change. In fully adjusted models, higher luteinizing hormone and follicle-stimulating hormone were positively related to worsening FI only in men <60 years, and higher estradiol predicted lower likelihood of improving FP [odds ratio: 0.68 (0.52, 0.88)]. Conclusions: These prospective data support the hypothesis that higher androgen levels may protect elderly men from worsening frailty. However, the causal nature of these relationships requires further investigation. Whereas raised gonadotropins in men <60 years might be an early marker of frailty, the role of estradiol in frailty needs further clarification.

Elevated luteinizing hormone despite normal testosterone levels in older men-natural history, risk factors and clinical features.

OBJECTIVE: Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). DESIGN, PATIENTS AND MEASUREMENTS: We conducted a 4.3-year prospective observational study of 3369 community-dwelling European men aged 40-79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. RESULTS: Age >70 years (OR = 4.12 [2.07-8.20]), diabetes (OR = 2.86 [1.42-5.77]), chronic pain (OR = 2.53 [1.34-4.77]), predegree education (OR = 1.79 [1.01-3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24-4.50]) predicted development of HLH. Younger age (40-49 years, OR = 8.14 [1.35-49.13]) and nonsmoking (OR = 5.39 [1.48-19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85-43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. CONCLUSIONS: Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism.

Massive Weight Loss Obtained by Bariatric Surgery Affects Semen Quality in Morbid Male Obesity: a Preliminary Prospective Double-Armed Study.

OBJECTIVES: The aim of this study is to evaluate the effect of massive weight loss on the seminal parameters at 6 months from bariatric surgery. DESIGN: Two-armed prospective study performed in 31 morbidly obese men, undergoing laparoscopic roux-en-Y-gastric bypass (n = 23) or non-operated (n = 8), assessing sex hormones, conventional (sperm motility, morphology, number, semen volume), and non-conventional (DNA fragmentation and seminal interleukin-8), semen parameters, at baseline and after 6 months from surgery or patients' recruitment. RESULTS: In operated patients only, a statistically significant improvement in the sex hormones was confirmed. Similarly, a positive trend in the progressive/total sperm motility and number was observed, though only the increase in semen volume and viability was statistically significant (Δ = 0.6 ml and 10%, P < 0.05, respectively). A decrease in the seminal interleukin-8 levels and in the sperm DNA fragmentation was also present after bariatric surgery, whereas these parameters even increased in non-operated subjects. Age-adjusted multivariate analysis showed that the BMI variations significantly correlated with the changes in the sperm morphology (ß = -0.675, P = 0.025), sperm number (ß = 0.891, P = 0.000), and semen volume (r = 0.618, P = 0.015). CONCLUSION: The massive weight loss obtained with bariatric surgery was associated with an improvement in some semen parameters. The correlations found between weight loss and semen parameter variations after surgery suggest that these might occur early downstream of the testis and more slowly than the changes in the sex hormones.

Nonandrogenic Anabolic Hormones Predict Risk of Frailty: European Male Ageing Study Prospective Data.

Context: Low levels of nonandrogenic anabolic hormones have been linked with frailty, but evidence is conflicting and prospective data are largely lacking. Objective: To determine associations between nonandrogenic anabolic hormones and prospective changes in frailty status. Design/Setting: A 4.3-year prospective observational study of community-dwelling men participating in the European Male Ageing Study. Participants: Men (n = 3369) aged 40 to 79 years from eight European centers. Main Outcome Measures: Frailty status was determined using frailty phenotype (FP; n = 2114) and frailty index (FI; n = 2444). Analysis: Regression models assessed relationships between baseline levels of insulinlike growth factor 1 (IGF-1), its binding protein 3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEA-S), 25-hydroxyvitamin D (25OHD), and parathyroid hormone (PTH), with changes in frailty status (worsening or improving frailty). Results: The risk of worsening FP and FI decreased with 1 standard deviation higher IGF-1, IGFBP-3, and 25OHD in models adjusted for age, body mass index, center, and baseline frailty [IGF-1: odds ratio (OR) for worsening FP, 0.82 (0.73, 0.93), percentage change in FI, -3.7% (-6.0, -1.5); IGFBP-3: 0.84 (0.75, 0.95), -4.2% (-6.4, -2.0); 25OHD: 0.84 (0.75, 0.95); -4.4%, (-6.7, -2.0)]. Relationships between IGF-1 and FI were attenuated after adjusting for IGFBP-3. Higher DHEA-S was associated with a lower risk of worsening FP only in men >70 years old [OR, 0.57 (0.35, 0.92)]. PTH was unrelated to change in frailty status. Conclusions: These longitudinal data confirm the associations between nonandrogenic anabolic hormones and the changes in frailty status. Interventional studies are needed to establish causality and determine therapeutic implications.

Glycemia but not the Metabolic Syndrome is Associated with Cognitive Decline: Findings from the European Male Ageing Study.

OBJECTIVE: Previous research has indicated that components of the metabolic syndrome (MetS), such as hyperglycemia and hypertension, are negatively associated with cognition. However, evidence that MetS itself is related to cognitive performance has been inconsistent. This longitudinal study investigates whether MetS or its components affect cognitive decline in aging men and whether any interaction with inflammation exists. METHODS: Over a mean of 4.4 years (SD ± 0.3), men aged 40-79 years from the multicenter European Male Ageing Study were recruited. Cognitive functioning was assessed using the Rey-Osterrieth Complex Figure (ROCF), the Camden Topographical Recognition Memory (CTRM) task, and the Digit Symbol Substitution Test (DSST). High-sensitivity C-reactive protein (hs-CRP) levels were measured using a chemiluminescent immunometric assay. RESULTS: Overall, 1,913 participants contributed data to the ROCF analyses and 1,965 subjects contributed to the CTRM and DSST analyses. In multiple regression models the presence of baseline MetS was not associated with cognitive decline over time (p > 0.05). However, logistic ordinal regressions indicated that high glucose levels were related to a greater risk of decline on the ROCF Copy (ß = -0.42, p < 0.05) and the DSST (ß = -0.39, p < 0.001). There was neither a main effect of hs-CRP levels nor an interaction effect of hs-CRP and MetS at baseline on cognitive decline. CONCLUSION: No evidence was found for a relationship between MetS or inflammation and cognitive decline in this sample of aging men. However, glycemia was negatively associated with visuoconstructional abilities and processing speed.

DNA fragmentation in two cytometric sperm populations: relationship with clinical and ultrasound characteristics of the male genital tract.

We investigated whether DNA fragmentation in two cytometric sperm populations (PIdimmer and PIbrighter) with different biological characteristics and clinical relevance is related to clinical and color-Doppler ultrasound (CDUS) parameters of the male genital tract. One hundred and sixty males of infertile couples without genetic abnormalities were evaluated for clinical, scrotal, and transrectal CDUS characteristics, presence of prostatitis-like symptoms (with the National Institutes of Health-Chronic Prostatitis Symptom Index) and sperm DNA fragmentation (sDF) in PIdimmer and PIbrighter populations (using TUNEL/PI method coupled with flow cytometry). Data were adjusted for age (Model 1) along with waistline, testosterone levels, smoking habit, and sexual abstinence (Model 2). According to the statistical Model 2, PIdimmer sDF was associated with testicular abnormalities, including lower clinical and ultrasound volume (r = -0.21 and r = -0.20, respectively; P < 0.05), higher FSH levels (r = 0.34, P < 0.0001) and occurrence of testicular inhomogeneity (P < 0.05) and hypoechogenicity (P < 0.05). PIbrighter sDF was associated with prostate-related symptoms and abnormal signs, including higher NIH-CPSI total and subdomain scores, a higher prevalence of prostatitis-like symptoms and of CDUS alterations such as macro-calcifications, severe echo-texture inhomogeneity, hyperemia (all P < 0.05), and higher arterial peak systolic velocity (r = 0.25, P < 0.05). Our results suggest that DNA fragmentation in PIdimmer sperm, which is related to poor semen quality, mainly originates in the testicles, likely due to apoptosis. Conversely, DNA fragmentation in PIbrighter sperm appears to mainly originate during or after transit through the prostate, increasing with the presence of an inflammatory status of the organ. These results could lead to new perspectives for the identification of therapeutic targets to reduce sDF.

Evaluation of cognitive subdomains, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D in the European Male Ageing Study.

PURPOSE: Although lower levels of vitamin D have been related to poor cognitive functioning and dementia in older adults, evidence from longitudinal investigations is inconsistent. The objective of this study was to determine whether 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels are associated with specified measures of cognitive decline in ageing men. METHODS: The European Male Ageing Study (EMAS) followed 3369 men aged 40-79 over 4.4 years. 25(OH)D levels at baseline were measured by radioimmunoassay, and 1,25(OH)2D levels were obtained with liquid chromatography-tandem mass spectrometry. Visuoconstructional abilities, visual memory, and processing speed at baseline and follow-up were assessed using the Rey-Osterrieth Complex Figure Test (ROCF), Camden Topographical Recognition Memory (CTRM), and the Digit Symbol Substitution Test (DSST). RESULTS: Following attritions, a total of 2430 men with a mean (SD) age of 59.0 (10.6) were included in the analyses. At baseline, the mean 25(OH)D concentration was 64.6 (31.5) nmol/l, and mean 1,25(OH)2D level was 59.6 (16.6) pmol/l. In age-adjusted linear regression models, high 25(OH)D concentrations were associated with a smaller decline in the DSST (ß = 0.007, p = 0.020). Men with low 25(OH)D levels (<50 nmol/l) showed a greater decline in the CTRM compared to men with higher (≥75 nmol/l) levels (ß = -0.41, p = 0.035). However, these associations disappeared after adjusting for confounders such as depressive symptoms, BMI, and comorbidities. There was no indication of a relationship between 1,25(OH)2D and decline in cognitive subdomains. CONCLUSION: We found no evidence for an independent association between 25(OH)D or 1,25(OH)2D levels and visuoconstructional abilities, visual memory, or processing speed over on average 4.4 years in this sample of middle-aged and elderly European men.

Sperm DNA fragmentation in cryopreserved samples from subjects with different cancers.

Sperm cryopreservation is widely used by cancer patients undergoing chemo- or radiotherapy. Evidence suggests that IVF outcome with cryopreserved spermatozoa from cancer patients is less successful. To determine whether sperm DNA fragmentation (SDF) is involved in the lower fertilising ability of cryopreserved spermatozoa of cancer patients, SDF was evaluated in thawed spermatozoa from 78 men affected by different cancers and 53 men with non-cancer pathologies. SDF was assessed by the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL), propidium iodide (PI), flow cytometry procedure, which allows determination of two different cell populations (PIbrighter and PIdimmer) and thus to determine the percentage of DNA fragmented sperm in both. PIdimmer spermatozoa are totally unviable, whereas PIbrighter spermatozoa with SDF may be motile and morphologically normal, having higher biological relevance in the reproductive process. We found that the proportion of DNA fragmented PIbrighter cells was significantly higher in thawed spermatozoa from cancer than non-cancer patients. Moreover, a positive correlation was found between the degree of DNA fragmentation and sperm motility in the PIbrighter population of spermatozoa from cancer patients that wasn't seen in non-cancer patients. The results of the present study suggest that higher SDF levels may contribute to the lower IVF success of cryopreserved spermatozoa from cancer patients and that evaluation of SDF could complement genetic counselling as part of the routine management of cancer patients who seek fertility preservation.

Frailty and bone health in European men.

Background: frailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health. Methods: men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Aging Study. Subjects completed a comprehensive assessment which included quantitative ultrasound (QUS) scan of the heel (Hologic-SAHARA) and in two centres, dual-energy bone densitometry (dual-energy x-ray absorptiometry, DXA). Frailty was defined based on an adaptation of Fried's phenotype criteria and a frailty index (FI) was constructed. The association between frailty and the QUS and DXA parameters was determined using linear regression, with adjustments for age, body mass index and centre. Results: in total, 3,231 subjects contributed data to the analysis. Using the Fried categorisation of frailty, pre-frail and frail men had significantly lower speed of sound (SOS), broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) compared to robust men (P< 0.05). Similar results were seen using the FI after categorisation into 'high', 'medium' and 'low' levels of frailty. Using the Fried categorisation, frail men had lower femoral neck bone mineral density (BMD) compared to robust men (P < 0.05), but not lower lumbar spine BMD. Using the FI categorisation, a 'high' level of frailty (FI > 0.35) was associated with lower lumbar spine BMD (P < 0.05) when compared to those with low (FI < 0.2), but not lower femoral neck BMD. When analysed as a continuous variable, higher FI was linked with lower SOS, BUA and QUI (P < 0.05). Conclusions: optimisation of bone health as well as prevention of falls should be considered as strategies to reduce fractures in frail older people.

Changes in prevalence of obesity and high waist circumference over four years across European regions: the European male ageing study (EMAS).

Diversity in lifestyles and socioeconomic status among European populations, and recent socio-political and economic changes in transitional countries, may affect changes in adiposity. We aimed to determine whether change in the prevalence of obesity varies between the socio-politically transitional North-East European (Lódz, Poland; Szeged, Hungary; Tartu, Estonia), and the non-transitional Mediterranean (Santiago de Compostela, Spain; Florence, Italy) and North-West European (Leuven, Belgium; Malmö, Sweden; Manchester, UK) cities. This prospective observational cohort survey was performed between 2003 and 2005 at baseline and followed up between 2008 and 2010 of 3369 community-dwelling men aged 40-79 years. Main outcome measures in the present paper included waist circumference, body mass index and mid-upper arm muscle area. Baseline prevalence of waist circumference ≥ 102 cm and body mass index ≥ 30 kg/m2, respectively, were 39.0, 29.5 % in North-East European cities, 32.4, 21.9 % in Mediterranean cities, and 30.0, 20.1 % in North-West European cities. After median 4.3 years, men living in cities from transitional countries had mean gains in waist circumference (1.1 cm) and body mass index (0.2 kg/m2), which were greater than men in cities from non-transitional countries (P = 0.005). North-East European cities had greater gains in waist circumference (1.5 cm) than in Mediterranean cities (P < 0.001). Over 4.3 years, the prevalence of waist circumference ≥ 102 cm had increased by 13.1 % in North-East European cities, 5.8 % in the Mediterranean cities, 10.0 % in North-West European cities. Odds ratios (95 % confidence intervals), adjusted for lifestyle factors, for developing waist circumference ≥ 102 cm, compared with men from Mediterranean cities, were 2.3 (1.5-3.5) in North-East European cities and 1.6 (1.1-2.4) in North-West European cities, and 1.6 (1.2-2.1) in men living in cities from transitional, compared with cities from non-transitional countries. These regional differences in increased prevalence of waist circumference ≥ 102 cm were more pronounced in men aged 60-79 years than in those aged 40-59 years. Overall there was an increase in the prevalence of obesity (body mass index ≥ 30 kg/m2) over 4.3 years (between 5.3 and 6.1 %) with no significant regional differences at any age. Mid-upper arm muscle area declined during follow-up with the greatest decline among men from North-East European cities. In conclusion, increasing waist circumference is dissociated from change in body mass index and most rapid among men living in cities from transitional North-East European countries, presumably driven by economic and socio-political changes. Information on women would also be of value and it would be of interest to relate the changes in adiposity to dietary and other behavioural habits.

The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men.

CONTEXT: The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive. OBJECTIVE: To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men. DESIGN: Multinational European observational prospective cohort study. PARTICIPANTS: A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic-pituitary-testicular (HPT) axis. MAIN OUTCOME MEASURES: Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6-20; 21-23; 24-39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels. RESULTS: The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels. CONCLUSION: Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.

Natural history, risk factors and clinical features of primary hypogonadism in ageing men: Longitudinal Data from the European Male Ageing Study.

OBJECTIVE: In ageing men, the incidence and clinical significance of testosterone (T) decline accompanied by elevated luteinizing hormone (LH) are unclear. We describe the natural history, risk factors and clinical features associated with the development of biochemical primary hypogonadism (PHG, T < 10·5 nmol/l and LH>9·4U/l) in ageing men. DESIGN, PATIENTS AND MEASUREMENTS: A prospective observational cohort survey of 3,369 community-dwelling men aged 40-79 years, followed up for 4·3 years. Men were classified as incident (i) PHG (eugonadal [EUG, T ≥ 10·5 nmol/l] at baseline, PHG at follow-up), persistent (p) PHG (PHG at baseline and follow-up), pEUG (EUG at baseline and follow-up) and reversed (r) PHG (PHG at baseline, EUG at follow-up). Predictors and changes in clinical features associated with the development of PHG were analysed by regression models. RESULTS: Of 1,991 men comprising the analytical sample, 97·5% had pEUG, 1·1% iPHG, 1·1% pPHG and 0·3% rPHG. The incidence of PHG was 0·2%/year. Higher age (>70 years) [OR 12·48 (1·27-122·13), P = 0·030] and chronic illnesses [OR 4·24 (1·08-16·56); P = 0·038] predicted iPHG. Upon transition from EUG to PHG, erectile function, physical vigour and haemoglobin worsened significantly. Men with pPHG had decreased morning erections, sexual thoughts and haemoglobin with increased insulin resistance. CONCLUSIONS: Primary testicular failure in men is uncommon and predicted by old age and chronic illness. Some clinical features attributable to androgen deficiency, but not others, accompanied the T decline in men who developed biochemical PHG. Whether androgen replacement can improve sexual and/or physical function in elderly men with PHG merits further study.

Variation of DNA Fragmentation Levels During Density Gradient Sperm Selection for Assisted Reproduction Techniques: A Possible New Male Predictive Parameter of Pregnancy?

Predicting the outcome of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) is one main goal of the present research on assisted reproduction. To understand whether density gradient centrifugation (DGC), used to select sperm, can affect sperm DNA integrity and impact pregnancy rate (PR), we prospectively evaluated sperm DNA fragmentation (sDF) by TUNEL/PI, before and after DGC. sDF was studied in a cohort of 90 infertile couples the same day of IVF/ICSI treatment. After DGC, sDF increased in 41 samples (Group A, median sDF value: 29.25% [interquartile range, IQR: 16.01-41.63] in pre- and 60.40% [IQR: 32.92-93.53] in post-DGC) and decreased in 49 (Group B, median sDF value: 18.84% [IQR: 13.70-35.47] in pre- and 8.98% [IQR: 6.24-15.58] in post-DGC). PR was 17.1% and 34.4% in Group A and B, respectively (odds ratio [OR]: 2.58, 95% confidence interval [CI]: 0.95-7.04, P = 0.056). After adjustment for female factor, female and male age and female BMI, the estimated OR increased to 3.12 (95% CI: 1.05-9.27, P = 0.041). According to the subgroup analysis for presence/absence of female factor, heterogeneity in the association between the Group A and B and PR emerged (OR: 4.22, 95% CI: 1.16-15.30 and OR: 1.53, 95% CI: 0.23-10.40, respectively, for couples without, n = 59, and with, n = 31, female factor).This study provides the first evidence that the DGC procedure produces an increase in sDF in about half of the subjects undergoing IVF/ICSI, who then show a much lower probability of pregnancy, raising concerns about the safety of this selection procedure. Evaluation of sDF before and after DGC configures as a possible new prognostic parameter of pregnancy outcome in IVF/ICSI. Alternative sperm selection strategies are recommended for those subjects who undergo the damage after DGC.

The Economic Burden of Hyponatremia: Systematic Review and Meta-Analysis.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality observed in clinical practice. Several studies have demonstrated that hyponatremia is associated with an increased length of hospital stay and of hospital resource utilization. To clarify the impact of hyponatremia on the length of hospitalization and costs, we performed a meta-analysis based on published studies that compared hospital length of stay and cost between patients with and without hyponatremia. METHODS: An extensive Medline, Embase, and Cochrane search was performed to retrieve all studies published up to April 1, 2015 using the following words: "hyponatremia" or "hyponatraemia" AND "hospitalization" or "hospitalisation." A meta-analysis was performed including all studies comparing duration of hospitalization and hospital readmission rate in subjects with and without hyponatremia. RESULTS: Of 444 retrieved articles, 46 studies satisfied the inclusion criteria, encompassing a total of 3,940,042 patients; among these, 757,763 (19.2%) were hyponatremic. Across all studies, hyponatremia was associated with a significantly longer duration of hospitalization (3.30 [2.90-3.71; 95% CIs] mean days; P < .000). Similar results were obtained when patients with associated morbidities were analyzed separately. Furthermore, hyponatremic patients had a higher risk of readmission after the first hospitalization (odds ratio 1.32 [1.18-1.48; 95% CIs]; P < .000). A meta-regression analysis showed that the hyponatremia-related length of hospital stay was higher in males (Slope = 0.09 [0.05-0.12; 95% CIs]; P = .000 and Intercept = -1.36 [-3.03-0.32; 95% CIs]; P = .11) and in elderly patients (Slope = 0.002 [0.001-0.003; 95% CIs]; P < .000 and Intercept = 0.89 [0.83-0.97; 95% CIs]; P < .001). A negative association between serum [Na(+)] cutoff and duration of hospitalization was detected. No association between duration of hospitalization, serum [Na(+)], and associated morbidities was observed. Finally, when only US studies (n = 8) were considered, hyponatremia was associated with up to around $3000 higher hospital costs/patient when compared with the cost of normonatremic subjects. CONCLUSIONS: This meta-analysis confirms that hyponatremia is associated with a prolonged hospital length of stay and higher risk of readmission. These observations suggest that hyponatremia may represent one important determinant of the hospitalization costs.