European Male Aging Study Research Articles

Evidence-based definition of hypoprolactinemia in European men aged 40-86 years: the European male ageing study.

Empirical evidence for a low normal or reference interval for serum prolactin (PRL) is lacking for men, while the implications of very low PRL levels for human health have never been studied. A clinical state of "PRL deficiency" has not been defined except in relation to lactation. Using data from the European Male Ageing Study (EMAS), we analyzed the distribution of PRL in 3,369 community-dwelling European men, aged 40-80 years at phase-1 and free from acute illnesses. In total, 2,948 and 2,644 PRL samples were collected during phase-1 and phase-2 (3 to 5.7 years later). All samples were analysed in the same centre with the same assay. After excluding individuals with known pituitary diseases, PRL ≥ 35 ng/ml, and PRL-altering drugs including antipsychotic agents, selective serotonin reuptake inhibitors, or dopamine agonists, 5,086 data points (2,845 in phase-1 and 2,241 in phase-2) were available for analysis. The results showed that PRL declined minimally with age (slope = -0.02) and did not correlate with BMI. The positively skewed PRL distribution was log-transformed to a symmetrical distribution (skewness reduced from 13.3 to 0.015). Using two-sigma empirical rule (2[]SD about the mean), a threshold at 2.5% of the lower end of the distribution was shown to correspond to a PRL value of 2.98ng/ml. With reference to individuals with PRL levels of 5-34.9 ng/ml (event rate = 6.3%), the adjusted risk of developing type 2 diabetes increased progressively in those with PRL levels of 3-4.9 ng/ml: event rate = 9.3%, OR (95% CI) 1.59 (0.93-2.71), and more so with PRL levels of 0.3-2.9 ng/ml: event rate = 22.7%, OR 5.45 (1.78-16.62). There was also an increasing trend in prediabetes and diabetes based on fasting blood glucose levels was observed with lower categories of PRL. However, PRL levels were not associated with cancer, cardiovascular diseases, depressive symptoms or mortality. Our findings suggest that a PRL level below 3 ng/ml (64 mlU/l) significantly identifies European men with a clinically-important outcome (of type 2 diabetes), offering a lower reference-value for research and clinical practice.

Does testosterone influence the association between sleep and frailty in men: results from the European Male Aging Study

BackgroundPrevious studies have suggested an association between sleep disturbance and frailty. The mechanism is unknown, although it has been suggested that hormonal factors may play a role.MethodsThe aim was to determine the association between sleep duration, sleep quality and frailty, and to determine whether testosterone influenced this association. Males aged 40–79 years were recruited from eight European centres to the European Male Aging Study (EMAS). Subjects completed an interviewer-assisted questionnaire including questions regarding sleep quality and duration. Sleep quality was scored 0–20 and categorised as 0–4, 5–9, 10–14, and 15–20, with higher scores indicating poorer quality. A 39-component frailty index (FI) was constructed. Total testosterone levels were measured. The association between sleep duration, sleep quality and the FI was assessed using negative binomial regression, with adjustment for putative confounders including testosterone level.ResultsTwo thousand three hundred ninety-three participants contributed data to the analysis. The mean age was 63.3 years and mean sleep duration was 7.01 h. The mean frailty index was 0.15. Mean testosterone levels declined with decreasing sleep quality. After adjustment, compared to those with a sleep score of 0–4, the FI was 57% (95% CI 38%, 78%) higher among those with a sleep score of 15–20. After adjustment compared to those with normal sleep duration (6–9 h), those with a short (< 6 h) and long (≥ 9 h) sleep duration had a 16% (95% CI 6%, 28%) and 11% (95% CI 0%, 23%) higher FI, respectively. Adjustment for testosterone did not influence the strength of either association.ConclusionFrailty is associated with impaired sleep quality and sleep duration. The association cannot, however, be explained by variation in testosterone levels.

Hyponatremia, hypernatremia and impairment of functional, psychological and sexual domains

ObjectiveTo determine the influence of serum sodium on physical, psychologic and sexual function.MethodsThis is a cross-sectional survey on 3340 community-dwelling men aged 40–79 years from a prospective cohort study in eight European countries, the European Male Ageing Study (EMAS). Participants filled-out the Short Form-36 (SF-36), the Physical Activity Scale for the Elderly (PASE), and the EMAS sexual function questionnaire. For all the analyses, serum sodium corrected for glycaemia ([Na+]G) was used.ResultsThe relationship between [Na+]G and SF-36 physical function score (F = 3.99; p = 0.01), SF-36 mental health score (F = 7.69; p < 0.001), and PASE score (F = 14.95; p < 0.001) were best described by a quadratic equation, with worse scores for [Na+]G in either the lowest or the highest ends of the range. After dividing the sample into [Na+]G < 136 mmol/L (n = 81), 136–147 mmol/L (n = 3223) and > 147 mmol/L (n = 36), linear regression analyses with linear spline functions adjusted for confounders did not confirm these relationships. Similarly, erectile dysfunction and [Na+]G, were in a quadratic relationship (F = 9.00; p < 0.001). After adjusting for confounders, the linear regression with spline functions denoted a significantly worsened erectile function for increases in serum [Na+]G > 147 mmol/L (B = 0.15 [0.04;0.26], p < 0.01) but no relationship with [Na+]G < 136 mmol/L. Likewise, the relationship of [Na+]G with concerns about sexual dysfunction was confirmed only for men with serum [Na+]G > 147 mmol/L.ConclusionsThis is the first study supporting an association between [Na+]G and sexual function. A worsening of erection and concerns about sexual function were observed for the highest values of [Na+]G, independently of other relevant factors.

Number of CAG repeats and mortality in middle aged and older men.

The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association. Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95%CIfor mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats. Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

Abstract #1368352: Significance of LH Estimation While Evaluating Erectile Dysfunction in Male Subjects with Type 2 Diabetes Mellitus

Erectile Dysfunction (ED) is quite common in male subjects with Type 2 Diabetes Mellitus and many of them have Hypogonadism (low testosterone). There are subjects having ED despite having normal testosterone levels and among them some may have Compensated hypogonadism (CH), an entity characterized by normal testosterone with an increase in LH level and is associated with a unique symptomatology. The objective was to determine the prevalence of CH in male subjects with type 2 diabetes having ED and to evaluate its correlations. It was a cross-sectional study among the T2DM subjects attending the OPD of an Endocrinology Specialty Hospital. 500 male subjects with T2DM were screened for ED using International Index of Erectile Function-5 (IIEF-5) questionnaire, which consists of 5 items; a sum score of 21 or less indicates the presence of ED. Out of these 127 (25.4%) subjects were diagnosed as having ED. These subjects underwent clinical and biochemical evaluation including Lipid profile, HbA1c, Testosterone, LH, TSH, Prolactin. Compensated hypogonadism was defined (European Male Aging Study) as total testosterone > 10.5 nmol / L and LH > 9.4 IU /L. The mean age of the participants was 56.4 ± 6.7 years and the mean duration of diabetes was 11.9 ± 7.4 years. Hypertension was present in 51.5% and CAD in 26.6% of subjects. Among the participants 44.2% had hypogonadism (low T) whereas compensated hypogonadism was present in additional 9.5%. CH was positively correlated with older age (>55yrs) (p<0.01), the severity of ED (p-0.02), Hypertension (p-0.02), CAD (p<0.01) and LDL (p-0.012) but not with HbA1c. There was a statistically significant negative correlation between LH level and IIEF-5 score. Hypogonadism is common in males with T2DM and is characterized by clinical and biochemical evidence of testosterone deficiency. Compensated hypogonadism (CH) is a subclinical deficiency of testosterone (normal testosterone and high LH). Symptoms of CH may include ED, low moods, decreased muscle mass, sleep disturbances, mobility issues and fatigue. Our study shows CH to be correlating with sexual dysfunction, hypertension, CAD and LDL in subjects with T2DM. Hypogonadism is treated with testosterone but in CH only limited studies have demonstrated some positive effects of testosterone therapy and the clinical meaningfulness of these findings remains debatable. The present management strategies for CH include healthy lifestyle habits, exercise, nutritious diet, reducing stress and getting good sleep. We suggest larger studies to validate our findings, to essentially include LH estimation in the workup of ED and consider formation of guidelines regarding management of CH in subjects with T2DM including the place of testosterone therapy.

Sarcopenia-defining parameters, but not sarcopenia, are associated with cognitive domains in middle-aged and older European men.

Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross-sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle-aged and older men. This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40-79years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey-Osterrieth Complex Figure (ROCF-Copy and ROCF-Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia-defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow-up of 4.3years. Cross-sectional associations between cognition, sarcopenia-defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia-defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders. In the whole cohort (n=3233), ROCF-Copy (β=0.016; P<0.05), ROCF-Recall (β=0.010; P<0.05), CTRM (β=0.015; P<0.05), DSST score (β=0.032; P<0.05) and fluid cognition (β=0.036; P<0.05) were significantly and independently associated with GS at baseline. In the Leuven+Manchester subcohorts (n=456), ROCF-Copy (β=1.008; P<0.05), ROCF-Recall (β=0.908; P<0.05) and fluid cognition (β=1.482; P<0.05) were associated with HGS. ROCF-Copy (β=0.394; P<0.05), ROCF-Recall (β=0.316; P<0.05), DSST (β=0.393; P<0.05) and fluid cognition (β=0.765; P<0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analysis showed that low ROCF-Copy score at baseline was associated with an increase in CST in men ≥70years (β=-0.599; P<0.05). In addition, a decrease in ROCF-Recall was associated with a decrease in GS, and a decrease in DSST was associated with an increase in CST (β=0.155; P<0.0001, β=-0.595; P<0.001, respectively) in persons with the highest change in both cognition and muscle function. Sarcopenia was not associated with cognitive performance in this population, whereas several components of sarcopenia were associated with domain-specific cognitive performance. Longitudinally, baseline and change in subdomains of cognition predicted change in muscle function in specific subgroups.

Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort.

BackgroundAging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell‐produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin‐like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes.ObjectivesTo characterize insulin‐like peptide 3 as a biomarker to assess gonadal status in aging men.Methods and materialsA large European multicenter (European Male Aging Study) cohort of community‐dwelling men was analyzed to determine how insulin‐like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters.Results and discussionInsulin‐like peptide 3 declines cross‐sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin‐like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin‐like peptide 3 is negatively dependent on luteinizing hormone and sex hormone‐binding globulin and positively dependent on follicle‐stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin‐like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin‐like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European‐wide reference range for insulin‐like peptide 3 (95% confidence interval) adjusted for increasing age.ConclusionInsulin‐like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin‐dependent short‐term regulation and within‐individual variation in testosterone.

The number of androgen receptor CAG repeats and mortality in men

Introduction The androgen receptor (AR) mediates peripheral effects of testosterone. Evidence suggests that the number of CAG repeats in exon-1 of the AR gene negatively correlates with AR transcriptional activity. The aim of this analysis was to determine the association between CAG repeat number and mortality in men. Methods Men aged 40–79 years were recruited from primary care for participation in the UK arm of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios(HR)/95% confidence intervals (CI). Results 312 men were followed up. The mean baseline age was 59.5 years. At follow up, 85/312(27%) men had died. CAG repeat length ranged from 14 to 39, with the highest proportion of CAG repeat number at 21 repeats(16.4%). In a multivariable model, using men with CAG repeat numbers of 22-23 as the reference, men with a lower number of CAG repeats(<22) showed a trend for a higher mortality in the follow-up period (HR 1.46 (0.75, 2.81)) as did men with higher number of repeats (>23) (1.37 (0.65, 2.91)). Conclusion Our data suggest that CAG repeat number may partially influence the risk of mortality in men. Further larger studies are required to quantify the effect.

European male aging study gonadal state related to the outcomes of microsurgical varicocele repair

ABSTRACT Introduction and Objective In European Male Aging Study (EMAS), hypogonadism is classified in four groups as normal or eugonadal [total testosterone (TT) ≥10.5nmol/L and luteinizing hormone (LH) ≤9.4IU/L; N/E group], secondary hypogonadism (TT&amp;lt;10.5nmol/L and LH ≤9.4IU/L; S/H group), primary hypogonadism (TT&amp;lt;10.5nmol/L and LH&amp;gt;9.4IU/L; P/H group), compensated hypogonadism (TT≥10.5nmol/L and LH&amp;gt;9.4IU/L;C/H group). Symptoms and co-morbidities were different among groups. In the present study, incidence of EMAS hypogonadism and the relationship between gonadal state and treatment outcomes of microsurgical varicocele repair. Patients and Methods Enrolled were 88 patients who underwent microsurgical varicocele repair with pretreatment measurement of sex hormones. We retrospectively analyzed incidence of EMAS hypogonadism, presurgical difference in semen quality according to gonadal state, and change in semen parameters after microsurgical varicocele repair. Student T test was used to compare two groups. This study was proved by institutional review board of Chiba University (#2557). Results Seventy-five patients were classified as eugonadal (N/E group, 84.3%), and 13 (15.7%) were hypogonadal [8 in S/H group (9%), 0 in P/H group (0%), and 5 in C/H group (5.7%)]. Mean testicular volume was significantly higher in N/E group than in hypogonadal (S/H, P/H and C/H) groups (mean volume of the right testis 17mL vs. 12mL, p=0.0283; mean volume of the left testis, 16mL vs. 11mL, p=0.0281). Out of 54 patients with male infertility, 44 were in N/E group and 8 (15.4%) were hypogonadal and total sperm count was significantly higher in N/E group than in hypogonadal patients (10.1 × 106 vs.1.3 × 106, p=0.0033). Post-surgical semen analyses were performed after 6.4 months in average. Sperm count, sperm motility and total sperm count were significantly higher in N/E group than in hypogonadal patients (in average, 33.4 × 106/mL vs. 2.8 × 106/mL, p&amp;lt;0.001; 41.4% vs. 22.3%, p=0.003; 116.8 × 106 vs. 7.7 × 106, p&amp;lt;0.001, respectively). Change rate before and after surgery was significantly better in N/E group than in hypogonadal patients (sperm count, 8.1 times increase vs. 2.5 times increase in average, p=0.0242; total sperm count, 10.7 times increase vs. 2.5 times increase in average, p=0.0159). Conclusion Hypogonadism should be evaluated using not only testosterone level but also LH level. EMAS hypogonadal state were related to semen parameters and outcomes of microsurgical varicocelectomy. Disclosure Work supported by industry: no.

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

ObjectiveIt 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. MethodsMen 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. ResultsStatistical 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 (β=-0.001, p=0.005) and dihydrotestosterone levels (β=-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. ConclusionsIn 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.

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. 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. about 420 (25.3%) men died during a mean follow-up of 12.6 ± 3.1years. 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. 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.

Inflammatory markers are associated with quality of life, physical activity, and gait speed but not sarcopenia in aged men (40–79 years)

BackgroundAge‐related chronic low‐grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia‐defining parameters, quality of life (QoL), and physical activity in middle‐aged and older men.MethodsMen aged 40–79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003–2005) and again after a median follow‐up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high‐sensitive C‐reactive protein (hs‐CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF‐36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole‐body dual X‐ray absorptiometry) and strength. In this subgroup, cross‐sectional associations between baseline inflammatory markers and sarcopenia‐defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking.ResultsAt baseline, hs‐CRP and WBC were negatively associated with PASE score (hs‐CRP: β = −7.920, P < 0.001; and WBC: β = −4.552, P < 0.001) and the physical component score of SF‐36 (hs‐CRP: β = −1.025, P < 0.001; and WBC: β = −0.364, P < 0.001). Baseline WBC levels were negatively associated with gait speed (β = −0.013; P = 0.025), quadriceps isometric 90° (β = −5.983; P = 0.035) and isokinetic 60°/s peak torque/body weight (β = −5.532; P = 0.027). The prevalence of sarcopenia at baseline was 18.1% (n = 81). Of those without sarcopenia at baseline, 64 (18.6%) satisfied criteria for sarcopenia at follow‐up. There were no significant associations between baseline inflammatory markers and either prevalent or incident sarcopenia, or change in level of sarcopenia‐defining parameters between baseline and follow‐up.ConclusionsIn middle‐aged and older men, hs‐CRP and WBC were negatively associated with QoL and PASE scores, while WBC was negatively associated with gait speed and knee strength. Associations with hs‐CRP remained significant in all ages, whereas WBC levels were only associated with PASE, gait speed and knee strength in older adults (60–79 years). Baseline inflammatory markers (hs‐CRP, WBC and albumin) did not predict functional decline, decline in physical activity, decreased QoL or incident sarcopenia.

Hypothalamic-pituitary-gonadal axis and sexual functioning in metformin-treated men after discontinuation of testosterone replacement therapy: A pilot study.

Metformin was found to reduce elevated gonadotropin levels. The aim of the present study was to determine whether metformin modulates the impact of discontinuation of testosterone therapy on hypothalamic-pituitary-gonadal axis activity and sexual function in men with low testosterone levels. The study included 28men with late-onset hypogonadism (defined according to the criteria of the European Male Aging Study group) receiving testosterone undecanoate (120mg in three equal doses), 12 of whom had been treated with oral metformin (1.7-3g daily). Both testosterone and metformin had been administered for at least six months before enrolment. In all patients, testosterone replacement required to be discontinued. The control group included 16 testosterone- and metformin-treated men with late-onset hypogonadism who during the entire study period continued their treatment. Glucose homeostasis markers, as well as plasma levels of insulin, gonadotropins, testosterone, calculated bioavailable testosterone, dehydroepiandrosterone-sulphate, oestradiol, thyrotropin, free thyroxine, prolactin, insulin-growth factor-1 and cortisol were measured at the beginning of the study and four months later. Moreover, at the beginning and the end of the study, all enrolled patients completed a questionnaire assessing their sexual functioning (IIEF-15). Discontinuation of testosterone therapy resulted in a decrease in total testosterone and bioavailable testosterone (by 42% and 45% in metformin-treated patients, and by 52% and 54% in metformin-naïve patients), as well as impaired all aspects of male sexual function. Changes in bioavailable testosterone, as well as in erectile function, orgasmic function and sexual desire were less pronounced if subjects received metformin. Only in metformin-naïve men, follow-up FSH and LH levels were higher than at baseline (by 75% and 62%). Moreover, discontinuation of testosterone therapy in metformin-naïve men increased glycated haemoglobin, as well as worsened insulin sensitivity. There were no differences between baseline and follow-up levels of the remaining hormones. In metformin-naïve subjects, the increase in gonadotropin levels correlated with the changes in testosterone levels and insulin sensitivity. No effect on glucose homeostasis markers, hormone levels and sexual functioning was observed in the control group. The obtained results suggest that metformin treatment mitigates the unfavourable effect of discontinuation of testosterone treatment on hypothalamic-pituitary-testicular axis activity and sexual function in men with late-onset hypogonadism.

Self-Reported Shorter Than Desired Ejaculation Latency and Related Distress—Prevalence and Clinical Correlates: Results From the European Male Ageing Study

BackgroundFew data have looked at the occurrence and clinical correlates of self-reported shorter than desired ejaculation latency (rapid ejaculation, RE) and its related distress in the general population. AimTo determine the prevalence and clinical correlates of self-reported RE and RE- related distress in middle age and older European men. MethodsSubjects were recruited from population samples of men aged 40-79 years across 8 European centers. OutcomesSelf-reported RE and its related distress were derived from the European male Aging Study (EMAS) sexual function questionnaire (EMAS-SFQ). Beck's depression Inventory (BDI) was used for the quantification of depressive symptoms, the Short Form 36 health survey (SF-36) for the assessment of the quality of life, the International Prostate Symptom Score (IPSS) for the evaluation of lower urinary tract symptoms. ResultsAbout 2,888 community dwelling men aged 40-79 years old (mean 58.9 ± 10.8 years) were included in the analysis. Among the subjects included, 889 (30.8%) self-reported RE. Among them, 211 (7.3%) claimed to be distressed (5.9% and 1.4% reported mild or moderate-severe distress, respectively). Increasing levels of RE-related distress were associated with a progressive worse sexual functioning, higher risk of ED and with couple impairment, along with a higher prevalence of depressive symptoms (all P < 0.05). Furthermore, a worse quality of life and higher IPSS score were associated with RE-related distress (all P < 0.05). The aforementioned results were confirmed even when patients using drugs possibly interfering with ejaculation or those without a stable relationship were excluded from the analysis. Clinical ImplicationsRE is a frequent condition in men from the general population; however, its related distress is relatively modest. Nonetheless, men with any degree of self-reported RE show increasing levels of depression, worse quality of life and worse couple satisfaction. Strengths & LimitationsThis is the first study estimating the prevalence of self-reported RE and its related distress, along with their biological and psychological correlates, in a population sample of European middle age and older men. However, is should be recognized that the diagnosis of RE was derived from patient reports and not supported by Intra-ejaculatory-Latency-Time (IELT) measurements. ConclusionSelf-reported RE is relatively common in European men aged more than 40 years. The reported limited RE-related distress may explain the relatively low number of medical consultations for RE. RE-related distress is associated with worse sexual function, couple impairment, and more LUTS resulting in a worse quality of life and mood disturbances.Corona G, Rastrelli G, Bartfai G, et al. Self-Reported Shorter Than Desired Ejaculation Latency and Related Distress—Prevalence and Clinical Correlates: Results From the European Male Ageing Study. J Sex Med Rev 2021;18:908–919.

OR02-06 Sexual Symptoms Predict All-Cause Mortality Independently of Sex Steroids in Ageing Men

Background: The association between low testosterone (T) and higher mortality in men remains controversial. Most studies focus only on the association between total T (TT) and mortality. While TT declines with age, free T (FT) shows a greater fall, due to the rise in SHBG. Moreover, higher LH as well as sexual dysfunction, often co-existing with low T, have also been associated with mortality in ageing men. Objective: To study the interrelationships between sex steroids, gonadotrophins and sexual symptoms with all-cause mortality in a large prospective cohort of European men. Methods: 1913 community-dwelling men, aged 40-79, participated in the European Male Ageing Study (EMAS) between 2003-2005. Sexual symptoms were assessed via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. In 5 of 8 EMAS centres, survival status was available until 1 April 2018. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. Because of the wide age range at study entry, age was used as time-scale, instead of years since inclusion adjusting for age. Results were expressed as hazard ratios (HR) with 95% confidence intervals, adjusted for centre, BMI and smoking. Results: 483 (25.3%) men died during a mean follow-up of 12.4±3.3 years. Men who died had a higher BMI (p=0.002), but smoking status did not differ. TT levels were similar in both groups, but FT was lower in those who died (mean±SD: 312±86 pmol/L vs 270±84, p<0.001) and LH was higher (5.7±3.3 U/L vs 7.8±5.8, p<0.001). Men in the lowest FT quartile had higher mortality risk compared to men in the highest quartile (HR 1.43 (1.06-1.95); p=0.021). Also men in the highest FSH quartile had increased mortality risk (HR 1.38 (1.02-1.88); p=0.036). However, there was no association with TT, E2 or LH. Men with 3 sexual symptoms had a higher mortality risk compared to men with no sexual symptoms (HR 1.77 (1.28-2.41); p<0.001). In particular erectile dysfunction and poor morning erections, but not lower libido, were associated with increased mortality (HR 1.40 (1.15-1.73); p=0.001; HR 1.30 (1.06-1.60); p=0.012; HR 1.14 (0.93-1.40); p=0.203 respectively). Further adjusting for TT and FT did not influence the observed HRs. Also in men with normal TT (>12 nmol/L), the presence of sexual symptoms increased mortality risk (HR 1.51 (1.15-1.97); p=0.003). Finally, men with TT<8 nmol/L and sexual symptoms had a higher mortality risk compared to men with normal TT and no sexual symptoms (HR 1.92 (1.05-3.52); p=0.035). Conclusions: Men with the lowest FT and highest FSH levels have an increased mortality risk. Sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of T levels. As both vascular disease and low T can influence erectile function, sexual symptoms can be an early sign for increased cardiovascular risk and mortality, as well as a sequela of low T.

MP09-20 MEN WITH COMPENSATED OR PRIMARY HYPOGONADISM HAVE HIGHER RISK OF ISUP GRADE GROUPS 3-5 PROSTATE CANCER DIAGNOSIS

INTRODUCTION AND OBJECTIVE:Hypogonadism is classified using serum total testosterone and luteinizing hormone levels in the European Male Ageing Study (EMAS). We conducted retrospective study to inv...

Late-onset hypogonadism: a concept comes of age.

The term Late-onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as 'a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)'. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age-related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US-initiated 7T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that 'in men >65years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits'. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.

Risk factors for late-onset hypogonadism.

The European Male Aging Study (EMAS) has recently defined strict diagnostic criteria for late-onset hypogonadism (LOH) including the levels of serum total testosterone (TT), free testosterone (FT) and three sexual symptoms. However, there is no report on risk factors for LOH using these criteria. In this study, we investigated risk factors for LOH based on these criteria. We recruited 277 men (aged 36-80years) who completed both a health check-up and two questionnaires (a health and lifestyle questionnaire, and a sexual function questionnaire). Data on parameters, such as systolic blood pressure (SBP), glucose, triglyceride (TG) and high-density lipoprotein (HDL), were obtained from medical records of the hospital in Shantou. TT and sex hormone-binding globulin (SHBG) were measured by chemiluminescent immunoassay, and FT was calculated. TT, FT, age, waist circumference, SBP and glucose showed significant differences between LOH-positive and LOH-negative individuals. Univariate regression analyses showed that age, waist circumference, SBP, glucose and health status were risk factors for LOH. Pearson's correlation analysis revealed that TT was inversely correlated with waist circumference, glucose and SBP, and FT was inversely correlated with age, SBP and health status. In conclusion, age, waist circumference, SBP, glucose and health status were risk factors for LOH.

Reassessing Free-Testosterone Calculation by Liquid Chromatography–Tandem Mass Spectrometry Direct Equilibrium Dialysis

Assessment of free testosterone (FT) might help evaluate androgen status in patients with borderline total testosterone (T) and/or altered sex hormone-binding globulin (SHBG) levels. However, the validity of different methods to measure FT is debatable. Serum from 183 women and 146 men was analyzed using equilibrium dialysis (ED), with FT directly measured by liquid chromatography-tandem mass spectrometry. FT calculation was re-evaluated for the mass action law-based equation according to Vermeulen (cFT-V), empirical equations according to Ly (cFT-L), and a proposed calculation based on a multistep, dynamic, allosteric model according to Zakharov (cFT-Z). FT level analyzed by ED [median,13 pmol/L (1.2% of T) in women; 248 pmol/L (1.5% of T) in men] was strongly inversely correlated to SHBG level, significantly to albumin level in women, and only weakly to SHBG level in men. The median [percentile (p) range, 2.5 to 97.5] ratios of calculated FT (cFT) over ED-FT (from European Male Aging Study samples) were 1.19 (0.9 to 1.47), 1.00 (0.69 to 1.42), and 2.05 (1.26 to 3.26) for cFT-V, cFT-L, and cFT-Z, respectively. The ratio for cFT-V was not significantly affected by SHBG, T, or albumin levels (ρ range, 0.17 to -0.01); ratios for cFT-L and cFT-Z were affected (P < 0.05 and P < 0.001, respectively) and strongly correlated with SHBG levels (ρ = 0.72 and 0.75, respectively). Rank correlations between cFT% and ED-FT% (for men) were 0.62, 0.74, and 0.89 for cFT-Z, cFT-L, and cFT-V, respectively. FT results by direct ED confirm prior FT data from indirect ED and ultrafiltration methodologies. Calculations have inherent limitations, with clinically important differences among evaluated equations: cFT-V, although overestimating FT level, appears the most robust approximation, largely independent of SHBG, albumin, and T levels.

Testosterone replacement therapy and cardiovascular risk

Late onset hypogonadism (LOH) is the most commonly used term to indicate the age-dependent reduction of testosterone. Sexual dysfunction represents the most important determinant for medical consultation and the most specific symptoms associated with LOH. In particular, data from the European Male Ageing Study (EMAS), a population-based survey on more than 3400 subjects, recognized that a triad of sexual symptoms (low libido and reduced spontaneous and sex-related erections) is the only syndromic association with decreased testosterone levels. Accordingly, a meta-analysis of the available randomized controlled trials documented that testosterone therapy (TTh) is able to improve all aspects of sexual function when compared to placebo. Despite this evidence, however, the relative clinical significance and the potential benefit of TTh in LOH are still the subject of strong criticisms in the scientific community. The debate is further complicated by the recent position statement of the US Food and Drug Administration (FDA) emphasizing a possible increased cardiovascular risk of TTh. However, this position was not endorsed by the European Medicines Association (EMA), which reached an opposite position after a specific review of the available data. In this review, all the conflicting data supporting the different positions of the FDA and EMA will be discussed. In particular, data derived from either population-based studies or interventional trials will be analyzed in detail. Although some evidence suggests an increase in TTh-related cardiovascular risk, the data derived from controlled trials do not support this position especially when the incidence of major adverse cardiovascular events are considered. Symptomatic men with documented reduced testosterone levels can be safely treated with TTh.