European Male Aging Study Research Articles

Testosterone level and endothelial dysfunction in patients with vasculogenic erectile dysfunction.

The association between endothelial dysfunction and late onset hypogonadism (LOH) in patients with vasculogenic erectile dysfunction (ED) is not yet well settled. Our objective was to assess the association between LOH and endothelial dysfunction in patients with vasculogenic ED. Throughout 2014-2015 a total of 90 men were enrolled in this cross-sectional observational study. Of them 60 patients with a clinical diagnosis of ED were further subdivided into two equal groups: patients with vasculogenic ED and LOH (A); patients with vasculogenic ED and euogonadal (B). Thirty age-matched men with no ED or hypogonadism were enrolled as control group (C). All patients were subjected to detailed medical and sexual history, total testosterone (TT), calculated free (FT) and bioavailable testosterone (BT), flow cytometric evaluation for endothelial progenitor cells (EPCs) (CD45negative/CD34positive/CD144positive) and endothelial microparticles (EMPs) (CD45negative/CD144positive/annexin V positive). The mean age ± SD of the three groups A, B and C were 51.3±11.1, 53.6±10.6 and 48.3±5years, respectively, with insignificant age differences (p=0.089). The diagnostic criteria of LOH were adapted according to European male aging study, 2010. The means of TT(ng/mL) were 2.32±0.21, 6.43±0.36 and 5.37±0.30 in groups A, B and C, respectively. There were highly significant differences between group A and groups B and C (p<0.001 for each). The means of EPCs were 0.43±0.070, 0.22±0.05 and 0.032±0.013 in groups A, B and C, respectively. The means of EMPs were 0.15±0.029, 0.056± .013 and 0.014±0.002 in groups A, B and C, respectively. There were significant differences between group C and groups A and B (p<0.05 for each). This study clearly demonstrated that there is a significant association between LOH and the higher expression of EPCs and EMPs in patients with vasculogenic ED.

Clomiphene Citrate in the Treatment of Idiopathic or Functional Hypogonadotropic Hypogonadism In Men: A Case Series and Review of the Literature

Late-onset hypogonadotropic hypogonadism (LOH) is a complex, heterogeneous entity. Whenever treatment is indicated, the endocrine literature has recommend testosterone replacement. We present our experience with clomiphene citrate treatment in patients with LOH and a review of the literature. This retrospective case series included 18 male patients with hypogonadotropic hypogonadism, roughly according to the European Male Aging Study criteria for LOH, attended at an academic hospital outpatient clinic. Data were retrieved from the patients' electronic medical records. The patients' mean age (±SD) was 44.3 ± 6.3 years (range 21-67 years) referred for evaluation of low testosterone together with decreased libido, erectile dysfunction, fatigue or tiredness, anxiety, and osteoporosis. Clomiphene was initially prescribed at doses between 25 mg 3 times a week and 50 mg/day. At 6 to 8 weeks following initiation of treatment, mean basal total-testosterone increased from 7.6 ± 2.6 to 19.3 ± 5.2 nmol/L (P<.0001). Mean basal luteinizing hormone (LH) increased from 2.7 ± 2.1 to 8.3 ± 3.5 nmol/L (P<.0001). Mean basal follicle-stimulating hormone (FSH) increased from 4.2 ± 3.6 to 8.6 ± 6.2 nmol/L (P = .007). Testosterone and LH responses were invariably observed, including 2 patients with history of nonpituitary cranial pathologies, 2 with somewhat elevated FSH, and 1 with an eating disorder. Twelve (67%) patients reported improvement in symptoms. Side effects included transient nipple tenderness in 1 patient. Available data suggest that clomiphene is an efficient and convenient alternative to testosterone replacement therapy in a substantial subset of patients with LOH. Additional long-term controlled studies should further establish the role of clomiphene in LOH. FSH = follicle-stimulating hormone LH = luteinizing hormone LOH = late-onset hypogonadotropic hypogonadism.

Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe.

Reference ranges for testosterone are essential for making a diagnosis of hypogonadism in men. To establish harmonized reference ranges for total testosterone in men that can be applied across laboratories by cross-calibrating assays to a reference method and standard. The 9054 community-dwelling men in cohort studies in the United States and Europe: Framingham Heart Study; European Male Aging Study; Osteoporotic Fractures in Men Study; and Male Sibling Study of Osteoporosis. Testosterone concentrations in 100 participants in each of the four cohorts were measured using a reference method at Centers for Disease Control and Prevention (CDC). Generalized additive models and Bland-Altman analyses supported the use of normalizing equations for transformation between cohort-specific and CDC values. Normalizing equations, generated using Passing-Bablok regression, were used to generate harmonized values, which were used to derive standardized, age-specific reference ranges. Harmonization procedure reduced intercohort variation between testosterone measurements in men of similar ages. In healthy nonobese men, 19 to 39 years, harmonized 2.5th, 5th, 50th, 95th, and 97.5th percentile values were 264, 303, 531, 852, and 916 ng/dL, respectively. Age-specific harmonized testosterone concentrations in nonobese men were similar across cohorts and greater than in all men. Harmonized normal range in a healthy nonobese population of European and American men, 19 to 39 years, is 264 to 916 ng/dL. A substantial proportion of intercohort variation in testosterone levels is due to assay differences. These data demonstrate the feasibility of generating harmonized reference ranges for testosterone that can be applied to assays, which have been calibrated to a reference method and calibrator.

Frailty and bone health in European men.

Backgroundfrailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health.Methodsmen 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.Resultsin 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).Conclusionsoptimisation 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 (Łódź, 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.

Comparison the sexuality of 26 - 36-years-old Lithuanian healthy and type-1 diabetic males with older than 40 years men sexuality of 8 European countries

Aims. Sexuality of 26-36-year-old type 1 diabetes mellitus patients (T1D) was compared with published results of sexuality of healthy men from general population (HM) and sexuality of European Male Ageing Study (EMAS) different age more than 40-year-old men, assessed using EMAS- Sexual Functioning Questionnaire (SFQ).Materials and metods. EMAS-SFQ was answered by 122 T1D patients with different duration of disease. Results were presented as scores of sexuality domains and ratio of percent of specific sexual parameter of Lithuanian HM or T1D divided to percent of different age of EMAS or different cities investigated in EMAS. Results of HM of 26-36-year-old were comparable with these of EMAS 40-49-year-old men, and results of T1D of 26-36-year-old were similar with these of EMAS 50-59 -year- old men.Results. Masturbation (M) score of HM was statistically higher than in T1D males (p &lt; 0, 05). This increase was independent of duration of T1D, but was due to lower number of men who never masturbate (lower number of 0 points in calculating the M score). Comparison of M score between HM and T1D who ever masturbated did not reveal statistically significant result.M did not differ significantly between the groups of males with regular, non-regular sexual partner and without partner at all (p=0.811). The same result appears when T1D and HM groups are analysed separately. When the M of T1D males are compared with HM statistically significant difference of M (p&lt;0.01) was observed from the first 0-5 years of the disease.When males having regular or non-regular sex partner were compared with the ones without partner at all in the groups of HM, T1D males and the group of all participants, statistically significant differences of M was observed only in T1D male group (p=0.048) but not in the groups of healthy males (p=0.773) or all participants (p=0.160)Sexual functioning distress was higher in T1D in all the groups of the duration of disease, including 0-9 -year-duration of diabetes, in comparison with HM and EMAS 40-70 +.Negative changes of sexual functioning were statistically significant only than comparing the whole group of T1D and HM, but differed significantly comparative with EMAS 50-70+ men. Used as single item of erectile dysfunction is also useful and is highly discriminative in most cases. Low incidence of erectile dysfunction is evident in comparison of HM with all the other groups of investigated men.Conclusions. Use of multidomain sexual function questionnaire EMAS-SFQ proved to be useful for sexuality investigation of the males of different ages. Multiple domains have its own prerogatives, but use of single items (masturbation and erection) may be equally important. Since healthy men sexuality of 26-36-years is comparable with EMAS 40-49-year-old men, and 26-36-year-old T1D is similar to EMAS 50-59-year-old men, „plateau“ of HM during 20-60 years is expected and decreased sexuality early in 40-ties may be a sign of aging in males.

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

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. The European Male Ageing Study (EMAS) followed 3369 men aged 40-79 over 4.4years. 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). 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 (β=0.007, p=0.020). Men with low 25(OH)D levels (<50nmol/l) showed a greater decline in the CTRM compared to men with higher (≥75nmol/l) levels (β=-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. 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 4.4years in this sample of middle-aged and elderly European men.

EVALUATION OF 25-HYDROXYVITAMIN D AND 1,25-DIHYDROXYVITAMIN D AND COGNITIVE DECLINE IN THE EUROPEAN MALE AGEING STUDY

EVALUATION OF 25-HYDROXYVITAMIN D AND 1,25-DIHYDROXYVITAMIN D AND COGNITIVE DECLINE IN THE EUROPEAN MALE AGEING STUDY

Sexuality of 26 - 36-Year-Old Lithuanian Healthy and Type-1 Diabetic Males (Comparison with Older than 40 Years Men Sexuality of 8 European Countries)

Objective: To determine the relation of the European Male Ageing Study (EMAS) Sexual function questionnaire (SFQ) parameters in the groups of healthy (H) and type 1 diabetic (T1D) males and in groups of different ages and different centers of EMAS. Design and Method: The evaluation of EMAS SFQ of 204 persons: 82 H and 122 T1D patients was performed. The answers to the questions characterizing various domains of sexual activity were analyzed. Results: Results. Eight sexual parameters were counted. The ratio of H males (%) /40 - 49-year-old EMAS males (%) was above 1, except the frequency of erectile dysfunction which is very low in the group of H males and extremely high in the group of T1D males. The results were similar when the 50 - 59-year-old EMAS group was taken in comparison to H males. The H males group shows even more clear predominance while T1D males are similar to 50 - 59-year-old EMAS males. Comparing the results of H males and EMAS males from various centers the rarity of H erectile dysfunction and higher frequency of masturbation become apparent. Other parameters do not show difference in comparison to EMAS centers. Conclusions: Conclusions. The sexuality of H males is above the one of EMAS 40 - 49-year-old males, while the sexuality of T1D males is similar to the sexuality of EMAS 50 - 59-year-old males. The erectile dysfunction is rare and the frequency of masturbation is higher when H males are compared to the various ages EMAS males from different centers.

P-01-058 Evaluation of sexuality between 26-36-year-old healthy and type 1 diabetic men using European male ageing study sexual functioning questionnaire

P-01-058 Evaluation of sexuality between 26-36-year-old healthy and type 1 diabetic men using European male ageing study sexual functioning questionnaire

A frailty index based on laboratory deficits in community-dwelling men predicted their risk of adverse health outcomes

abnormal laboratory test results accumulate with age and can be common in people with few clinically detectable health deficits. A frailty index (FI) based entirely on common physiological and laboratory tests (FI-Lab) might offer pragmatic and scientific advantages compared with a clinical FI (FI-Clin). to compare the FI-Lab with the FI-Clin and to assess their individual and combined relationships with mortality and other adverse health outcomes. secondary analysis of the eight-centre, longitudinal European Male Ageing Study (EMAS) of community-dwelling men aged 40-79 at baseline. Follow-up assessment occurred 4.4 ± 0.3 (mean ± SD) years later. we constructed a 23-item FI using common laboratory tests, blood pressure and pulse (FI-Lab), compared it with a previously validated 39-item FI using self-report and performance-based measures (FI-Clin) and finally combined both FIs to create a 62-item FI-Combined. Outcomes were all-cause mortality, institutionalisation, doctor visits, medication use, self-reported health, falls and fractures. the mean FI-Lab score was 0.28 ± 0.11, the FI-Clin was 0.13 ± 0.11 and FI-Combined was 0.19 ± 0.09. Age-adjusted models demonstrated that each FI was associated with mortality [HR (CI) FI-Lab: 1.04 (1.03-1.06); FI-Clin: 1.05 (1.04-1.06); FI-Combined: 1.07 (1.06-1.09)], institutionalisation, doctor visits, medication use, self-reported health and falls. Combined in a model with FI-Clin, the FI-Lab remained independently associated with mortality, institutionalisation, doctor visits, medication use and self-reported health. the FI-Lab detected an increased risk of adverse health outcomes alone and in combination with a clinical FI; further evaluation of the feasibility of the FI-Lab as a frailty screening tool within hospital care settings is needed.

Low vitamin D and the risk of developing chronic widespread pain: results from the European male ageing study.

BackgroundThe association between low levels of vitamin D and the occurrence of chronic widespread pain (CWP) remains unclear. The aim of our analysis was to determine the relationship between low vitamin D levels and the risk of developing CWP in a population sample of middle age and elderly men.MethodsThree thousand three hundred sixty nine men aged 40–79 were recruited from 8 European centres for a longitudinal study of male ageing, the European Male Ageing Study. At baseline participants underwent assessment of lifestyle, health factors, physical characteristics and gave a fasting blood sample. The occurrence of pain was assessed at baseline and follow up (a mean of 4.3 years later) by shading painful sites on a body manikin. The presence of CWP was determined using the ACR criteria for fibromyalgia. Serum 25-hydroxyvitamin D (25-(OH) D) was assessed by radioimmunoassay. Logistic regression was used to determine the relationship between baseline vitamin D levels and the new occurrence of CWP.ResultsTwo thousand three hundred thirteen men, mean age 58.8 years (SD = 10.6), had complete pain and vitamin data available and contributed to this analysis. 151 (6.5 %) developed new CWP at follow up and 577 (24.9 %) were pain free at both time points, the comparator group. After adjustment for age and centre, physical performance and number of comorbidities, compared to those in upper quintile of 25-(OH) D ( ≥36.3 ng/mL), those in the lowest quintile (<15.6 ng/mL) were more likely to develop CWP (Odds Ratio [OR] = 1.93; 95 % CI = 1.0-3.6). Further adjustment for BMI (OR = 1.67; 95 % CI = 0.93-3.02) or depression (OR = 1.77; 95 % CI = 0.98-3.21), however rendered the association non-significant.ConclusionsLow vitamin D is linked with the new occurrence of CWP, although this may be explained by underlying adverse health factors, particularly obesity and depression.

Chronic widespread pain is associated with worsening frailty in European men.

Background: we hypothesised that chronic widespread pain (CWP), by acting as a potential stressor, may predispose to the development of, or worsening, frailty.Setting: longitudinal analysis within the European Male Ageing Study (EMAS).Participants: a total of 2,736 community-dwelling men aged 40–79.Methods: subjects completed a pain questionnaire and shaded a manikin, with the presence of CWP defined using the American College of Rheumatology criteria. Physical activity, smoking, alcohol consumption and depression were measured. Repeat assessments took place a median of 4.3 years later. A frailty index (FI) was used, with frail defined as an FI >0.35. The association between CWP at baseline and the new occurrence of frailty was examined using logistic regression; the association between CWP at baseline and change in FI was examined using negative binomial regression.Results: at baseline, 218 (8.3%) men reported CWP. Of the 2,631 men who were defined as non-frail at baseline, 112 (4.3%) were frail at follow-up; their mean FI was 0.12 (SD 0.1) at baseline and 0.15 (SD 0.1) at follow-up, with a mean change of 0.03 (SD 0.08) P ≤ 0.001. Among men who were non-frail at baseline, those with CWP were significantly more likely to develop frailty. After adjustment for age and centre, compared with those with no pain, those with CWP at baseline had a 70% higher FI at follow-up; these associations remained significant after further adjustment for smoking, body mass index, depression, physical activity and FI at baseline.Conclusion: the presence of CWP is associated with an increased risk of frailty in older European men.

Low heel ultrasound parameters predict mortality in men: results from the European Male Ageing Study (EMAS).

Background: low bone mineral density measured by dual-energy x-ray absorptiometry is associated with increased mortality. The relationship between other skeletal phenotypes and mortality is unclear. The aim of this study was to determine the relationship between quantitative heel ultrasound parameters and mortality in a cohort of European men.Methods: men aged 40–79 years were recruited for participation in a prospective study of male ageing: the European Male Ageing Study (EMAS). At baseline, subjects attended for quantitative ultrasound (QUS) of the heel (Hologic—SAHARA) and completed questionnaires on lifestyle factors and co-morbidities. Height and weight were measured. After a median of 4.3 years, subjects were invited to attend a follow-up assessment, and reasons for non-participation, including death, were recorded. The relationship between QUS parameters (broadband ultrasound attenuation [BUA] and speed of sound [SOS]) and mortality was assessed using Cox proportional hazards model.Results: from a total of 3,244 men (mean age 59.8, standard deviation [SD] 10.8 years), 185 (5.7%) died during the follow-up period. After adjusting for age, centre, body mass index, physical activity, current smoking, number of co-morbidities and general health, each SD decrease in BUA was associated with a 20% higher risk of mortality (hazard ratio [HR] per SD = 1.2; 95% confidence interval [CI] = 1.0–1.4). Compared with those in higher quintiles (2nd–5th), those in the lowest quintile of BUA and SOS had a greater mortality risk (BUA: HR = 1.6; 95% CI = 1.1–2.3 and SOS: HR = 1.6; 95% CI = 1.2–2.2).Conclusion: lower heel ultrasound parameters are associated with increased mortality in European men.

Alternatives to testosterone replacement: testosterone restoration.

The European Male Aging Study has demonstrated that the hypogonadism of male aging is predominantly secondary. Theoretically with appropriate stimulation from the pituitary, the aging testis should be able to produce eugonadal levels of testosterone. The strategies for the treatment of late onset hypogonadism (LOH) have focused on replacement with exogenous testosterone versus restoration of endogenous production. The purpose of this article is to review existing peer-reviewed literature supporting the concept of restoration of endogenous testosterone in the treatment of LOH.

Associations of obesity with socioeconomic and lifestyle factors in middle-aged and elderly men: European Male Aging Study (EMAS).

Social and lifestyle influences on age-related changes in body morphology are complex because lifestyle and physiological response to social stress can affect body fat differently. In this study, we examined the associations of socioeconomic status (SES) and lifestyle factors with BMI and waist circumference (WC) in middle-aged and elderly European men. A cross-sectional study of 3319 men aged 40-79 years recruited from eight European centres. We estimated relative risk ratios (RRRs) of overweight/obesity associated with unfavourable SES and lifestyles. The prevalence of BMI ≥ 30 kg/m(2) or WC ≥ 102 cm rose linearly with age, except in the eighth decade when high BMI, but not high WC, declined. Among men aged 40-59 years, compared with non-smokers or most active men, centre and BMI-adjusted RRRs for having a WC between 94 and 101.9 cm increased by 1.6-fold in current smokers, 2.7-fold in least active men and maximal at 2.8-fold in least active men who smoked. Similar patterns but greater RRRs were observed for men with WC ≥ 102 cm, notably 8.4-fold greater in least active men who smoked. Compared with men in employment, those who were not in employment had increased risk of having a high WC by 1.4-fold in the 40-65 years group and by 1.3-fold in the 40-75 years group. These relationships were weaker among elderly men. Unfavourable SES and lifestyles associate with increased risk of obesity, especially in middle-aged men. The combination of inactivity and smoking was the strongest predictor of high WC, providing a focus for health promotion and prevention at an early age.

A multi-step, dynamic allosteric model of testosterone's binding to sex hormone binding globulin

PurposeCirculating free testosterone (FT) levels have been used widely in the diagnosis and treatment of hypogonadism in men. Due to experimental complexities in FT measurements, the Endocrine Society has recommended the use of calculated FT (cFT) as an appropriate approach for estimating FT. We show here that the prevailing model of testosterone's binding to SHBG, which assumes that each SHBG dimer binds two testosterone molecules and that the two binding sites on SHBG have similar binding affinity is erroneous and provides FT values that differ substantially from those obtained using equilibrium dialysis. MethodsWe characterized testosterone's binding to SHBG using binding isotherms, ligand depletion curves, and isothermal titration calorimetry (ITC). We derived a new model of testosterone's binding to SHBG from these experimental data and used this model to determine FT concentrations and compare these values with those derived from equilibrium dialysis. ResultsExperimental data on testosterone's association with SHBG generated using binding isotherms including equilibrium binding, ligand depletion experiments, and ITC provide evidence of a multi-step dynamic process, encompassing at least two inter-converting microstates in unliganded SHBG, readjustment of equilibria between unliganded states upon binding of the first ligand molecule, and allosteric interaction between two binding sites of SHBG dimer. FT concentrations in men determined using the new multistep dynamic model with complex allostery did not differ from those measured using equilibrium dialysis. Systematic error in calculated FT vales in females using Vermeulen's model was also significantly reduced. In European Male Aging Study, the men deemed to have low FT (<2.5th percentile) by the new model were at increased risk of sexual symptoms and elevated LH. ConclusionTestosterone's binding to SHBG is a multi-step dynamic process that involves complex allostery within SHBG dimer. FT values obtained using the new model have close correspondence with those measured using equilibrium dialysis.

Bone turnover markers predict hip bone loss in elderly European men: results of the European Male Ageing Study (EMAS).

The aim of this study was to determine whether bone turnover markers (BTMs) predict changes in areal bone mineral density (aBMD) in middle-aged and elderly European men. Older men with high bone turnover are at a higher risk of accelerated hip bone loss, but the clinical utility of BTMs in individuals is limited. Prospective studies on the value of BTMs to predict changes in aBMD in men are few and conflicting. The aim of this study was to determine whether BTMs predict changes in aBMD in middle-aged and elderly European men. In 487 men aged 40-79 years from the European Male Ageing Study (EMAS), BTMs were assessed at baseline and dual-energy X-ray absorptiometry (DXA) at the lumbar spine (LS), femoral neck (FN) and total hip (TH) was performed at baseline and after a mean follow-up of 4.3 years. The mean aBMD decreased by 0.32%/year at FN and 0.22%/year at TH and increased by 0.32%/year at LS. Higher baseline levels of β C-terminal cross-linked telopeptide (β-CTX) and N-terminal propeptide of type I procollagen (PINP) were significantly associated with higher loss of hip aBMD in the whole cohort and men aged 60-79 years. These associations remained significant after adjustment for age, centre and body mass index (BMI). Men aged 60-79 years with β-CTX in the upper quintile were more likely of being in the upper quintile of annual percentage (%) aBMD loss at FN (OR=4.27; 95% CI=2.09-8.73) and TH (OR=3.73; 95% CI=1.84-7.57). The positive predictive value (PPV) was 46% at both hip sites. Older men with high bone turnover have a higher risk of accelerated hip bone loss, but the PPV is low. BTMs are therefore unlikely to be of clinical utility in predicting accelerated hip bone loss in individual subjects.

Late‐onset hypogonadism in men with systolic heart failure: prevalence, clinical associates, and impact on long‐term survival

Male ageing is characterized by diminished circulating androgens with several adverse psychosomatic consequences and can be aggravated by concomitant chronic diseases. According to the European Male Aging Study (EMAS) Group, late-onset hypogonadism (LOH) refers to testosterone deficiency accompanied by sexual complaints. We investigated the prevalence of LOH in men with systolic heart failure (HF), and its clinical determinants and prognostic consequences. Among 201 men with systolic HF (age: 60 ± 11 years), serum total testosterone (TT) was assessed using an immunoassay, and estimated free testosterone (eFT) was calculated using Vermeulen's formula. LOH was diagnosed when TT &#60; 3.2 ng/mL and eFT &#60; 64 pg/mL were accompanied by three sexual symptoms (decrease in the number of morning erections, reduced potency, and low libido) of at least moderate severity assessed using the Aging Males' Symptoms Scale. Decreased frequency of morning erections, reduced potency, and low libido were experienced by 56%, 62%, and 55% of men with HF, respectively; whereas 67%, 61%, and 44% of subjects complained of at least one, two, and three symptoms, respectively. Hypogonadal TT and eFT were observed in 34% and 47% of patients, respectively; and in 33% subjects, both TT and eFT were reduced. Finally, 30 men with HF (15%) were diagnosed with LOH as compared with 2% in a European male population (EMAS). In a multivariable model, older age and higher serum uric acid were independently associated with greater LOH prevalence (both P &#60; 0.05). Among men aged ≤60 years (but not in those aged >60 years), LOH increased 5-year all-cause mortality in the univariable model; however, when adjusted for HF severity, the association lost its statistical significance. Men with systolic HF commonly report sexual complaints. LOH-the combination of sexual dysfunction and testosterone deficiency-occurs more frequently than in a general male population. LOH does not affect long-term mortality, when adjusted for HF severity.

Andropause – lessons from the European Male Ageing Study

Andropause or late-onset hypogondism (LOH) is a situation where a middle-aged or older man has low serum testosterone (T) in conjunction with diffuse symptoms reminiscent of those of genuine male hypogonadism (e.g. reduced sexual function, loss of vigor, muscle weakness, depression). Opinions about the diagnostic criteria, prevalence and treatment options of andropause vary considerably amongst experts. We review here some salient findings on the prevalence, diagnostic criteria and impact on health of andropause, obtained from the European Male Ageing Study (EMAS), a multicenter study of ageing among community-dwelling middle-aged and older men.