Publications by authors named "Frederick C W Wu"

100 Publications

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

J Sex Med 2021 Apr 2. Epub 2021 Apr 2.

Endocrinology Unit, Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. Electronic address:

Background: Few 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.

Aim: To determine the prevalence and clinical correlates of self-reported RE and RE- related distress in middle age and older European men.

Methods: Subjects were recruited from population samples of men aged 40-79 years across 8 European centers.

Outcomes: Self-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.

Results: About 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 Implications: RE 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 & Limitations: This 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.

Conclusion: Self-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;xx:xxx-xxx.
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http://dx.doi.org/10.1016/j.jsxm.2021.01.187DOI Listing
April 2021

Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men.

J Clin Endocrinol Metab 2021 Jan;106(2):e625-e637

School of Population and Global Health, University of Western Australia, Perth, Australia.

Context: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase.

Objective: To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men.

Design, Setting, And Participants: The UK Biobank prospective cohort study of community-dwelling men aged 40-69 years old, followed for 11 years.

Main Outcome Measures: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa.

Results: In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06-1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09-1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63-0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59-0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72-0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results.

Conclusions: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.
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http://dx.doi.org/10.1210/clinem/dgaa743DOI Listing
January 2021

Sociodemographic, lifestyle and medical influences on serum testosterone and sex hormone-binding globulin in men from UK Biobank.

Clin Endocrinol (Oxf) 2021 Feb 10;94(2):290-302. Epub 2020 Oct 10.

School of Population and Global Health, University of Western Australia, Perth, WA, Australia.

Objective: Serum testosterone concentrations are affected by factors unrelated to hypothalamo-pituitary-testicular axis pathology. We evaluated the impact of sociodemographic, lifestyle and medical factors, on serum testosterone and sex hormone-binding globulin (SHBG) in men aged 40-69 years.

Design: Cross-sectional analysis of 208,677 community-dwelling men from the UK Biobank.

Measurements: We analysed associations of different factors with serum testosterone and SHBG (immunoassays) and calculated free testosterone (cFT), using smoothed centile plots, linear mixed models and effect size estimates.

Results: Median (interquartile range) for serum testosterone was 11.6 (9.4-14.1) nmol/L, SHBG 36.9 (27.9-48.1) nmol/L and cFT 213 (178-255) pmol/L. Age and BMI were inversely associated with testosterone and cFT, while SHBG was associated with age and inversely with BMI (all P < .001). Living with a partner, (South) Asian ethnicity, never or previous smoker and some medical conditions were associated with lower testosterone. Poultry or fish eater, and higher physical activity were associated with higher testosterone (all P < .001). Testosterone was lowered by ~0.5 nmol/L across ages, ~1.5 nmol/L for BMI 30 vs 25 kg/m , ~2 nmol/L for (South) Asian ethnicity, living with partner, college/university qualifications, low red meat eater, insufficient physical activity and 0.3-1.0 nmol/L with cardiovascular disease or diabetes. Different combinations of these factors varied serum testosterone by ~4 nmol/L, SHBG by ~30 nmol/L and cFT by ~60 pmol/L.

Conclusions: The identified modifiable risk factors support lifestyle-based interventions in men with low testosterone concentrations. Considering sociodemographic, lifestyle and medical factors facilitates more personalized interpretation of testosterone testing results with respect to existing reference ranges.
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http://dx.doi.org/10.1111/cen.14342DOI Listing
February 2021

Androgens In Men Study (AIMS): protocol for meta-analyses of individual participant data investigating associations of androgens with health outcomes in men.

BMJ Open 2020 05 11;10(5):e034777. Epub 2020 May 11.

School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.

Introduction: This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men.

Methods And Analysis: Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.

Ethics And Dissemination: Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.

Prospero Registration Number: CRD42019139668.
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http://dx.doi.org/10.1136/bmjopen-2019-034777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239545PMC
May 2020

Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty.

Nat Commun 2019 11 5;10(1):5027. Epub 2019 Nov 5.

School of Chemistry, Manchester Institute for Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.

Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty.
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http://dx.doi.org/10.1038/s41467-019-12716-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831565PMC
November 2019

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care.

Clin Endocrinol (Oxf) 2019 01 3;90(1):56-65. Epub 2018 Dec 3.

Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, UK.

US Endocrine Society (ES) published a clinical practice guideline on testosterone therapy in men with hypogonadism, and Endocrine Society of Australia (ESA) a position statement on management of male hypogonadism. Both emphasize the importance of diagnosing men who are androgen deficient due to organic (classical or pathological) hypogonadism arising from disorders of the hypothalamus, pituitary or testes, who assuredly benefit from testosterone therapy. Both recognize that men with an intact gonadal axis may have low testosterone concentrations, for instance older men or men with obesity or other medical comorbidities. ES guidelines classify such symptomatic men as having organic (advanced age) or functional (obesity, medical comorbidities) hypogonadism, giving an option for testosterone therapy as a shared decision between clinicians and individual patients. ESA did not recommend testosterone therapy in these men. ES offers a reference range for total testosterone established in young men, while ESA cites age-standardized reference ranges. ES recommends using free testosterone as well as total testosterone to identify men with hypogonadism in conditions where sex hormone-binding globulin (SHBG) is altered, or when total testosterone is borderline. ESA recommends confirmatory biochemical testing with total testosterone, recognizing that this may be lower than expected if SHBG concentrations are low. Both emphasize the importance of identifying pre-existing prostate and cardiovascular disease prior to initiating testosterone therapy, with ES providing specific recommendations for PSA measurement, deferring testosterone therapy after major cardiovascular events and indications for pituitary imaging. These contrasting approaches highlight gaps in the evidence base where individualized patient management is required.
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http://dx.doi.org/10.1111/cen.13888DOI Listing
January 2019

Large divergence in testosterone concentrations between men and women: Frame of reference for elite athletes in sex-specific competition in sports, a narrative review.

Clin Endocrinol (Oxf) 2019 01 27;90(1):15-22. Epub 2018 Sep 27.

Geriatric Research, Education and Clinical Center, V.A. Puget Sound Health Care System, and Division of Gerontology & Geriatric Medicine, University of Washington School of Medicine, Seattle, Washington.

Objective: The purpose of this narrative review was to summarize available data on testosterone levels in normal, healthy adult males and females, to provide a physiologic reference framework to evaluate testosterone levels reported in males and females with conditions that elevate androgens, such as disorders of sex development (DSD), and to determine the separation or overlap of testosterone levels between normal and affected males and females.

Methods: A literature review was conducted for published papers, from peer reviewed journals, reporting testosterone levels in healthy males and females, males with 46XY DSD, and females with hyperandrogenism due to polycystic ovary syndrome (PCOS). Papers were selected that had adequate characterization of participants, and description of the methodology for measurement of serum testosterone and reporting of results.

Results: In the healthy, normal males and females, there was a clear bimodal distribution of testosterone levels, with the lower end of the male range being four- to fivefold higher than the upper end of the female range(males 8.8-30.9 nmol/L, females 0.4-2.0 nmol/L). Individuals with 46XY DSD, specifically those with 5-alpha reductase deficiency, type 2 and androgen insensitivity syndrome testosterone levels that were within normal male range. Females with PCOS or congenital adrenal hyperplasia were above the normal female range but still below the normal male range.

Conclusions: Existing studies strongly support a bimodal distribution of serum testosterone levels in females compared to males. These data should be considered in the discussion of female competition eligibility in individuals with possible DSD or hyperandrogenism.
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http://dx.doi.org/10.1111/cen.13840DOI Listing
January 2019

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.

Clin Endocrinol (Oxf) 2018 10 23;89(4):459-469. Epub 2018 Jul 23.

Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, Arthritis Research UK Centre for Epidemiology, Manchester Academic Health Science Centre, University of Manchester and NIHR Manchester Musculoskeletal Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK.

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.
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http://dx.doi.org/10.1111/cen.13756DOI Listing
October 2018

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

J Clin Endocrinol Metab 2018 03;103(3):991-1004

Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium.

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.

Objective: To investigate the genetic regulation of serum E2 and E1 in men.

Design, Setting, And Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.

Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.

Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.

Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
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http://dx.doi.org/10.1210/jc.2017-02060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868407PMC
March 2018

Distribution of Salivary Testosterone in Men and Women in a British General Population-Based Sample: The Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

J Endocr Soc 2017 Jan 12;1(1):14-25. Epub 2017 Jan 12.

Andrology Research Unit, Manchester Centre of Endocrinology and Diabetes, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PL, United Kingdom.

Introduction: Measurement of salivary testosterone (Sal-T) to assess androgen status offers important potential advantages in epidemiological research. The utility of the method depends on the interpretation of the results against robustly determined population distributions, which are currently lacking.

Aim: To determine age-specific Sal-T population distributions for men and women.

Methods: Morning saliva samples were obtained from participants in the third National Survey of Sexual Attitudes and Lifestyles, a probability sample survey of the British general population. Sal-T was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Linear and quantile regression analyses were used to determine the age-specific 2.5th and 97.5th percentiles for the general population (1675 men and 2453 women) and the population with health exclusions (1145 men and 1276 women).

Results: In the general population, the mean Sal-T level in men decreased from 322.6 pmol/L at 18 years of age to 153.9 pmol/L at 69 years of age. In women, the decrease in the geometric mean Sal-T level was from 39.8 pmol/L at 18 years of age to 19.5 pmol/L at 74 years of age. The annual decrease varied with age, with an average of 1.0% to 1.4% in men and 1.3% to 1.5% in women. For women, the 2.5th percentile fell below the detection limit (<6.5 pmol/L) from age 52 years onward. The mean Sal-T level was approximately 6 times greater in men than in women, and this remained constant over the age range. The Sal-T level was lowest for men and highest for women in the summer. The results were similar for the general population with exclusions.

Conclusions: To our knowledge, this is the first study to describe the sex- and age-specific distributions for Sal-T in a large representative population using a specific and sensitive LC-MS/MS technique. The present data can inform future population research by facilitating the interpretation of Sal-T results as a marker of androgen status.
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http://dx.doi.org/10.1210/js.2016-1029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677216PMC
January 2017

Association between pain and sexual health in older people: results from the English Longitudinal Study of Ageing.

Pain 2018 03;159(3):460-468

Faculty of Health, Psychology and Social Care, Manchester Metropolitan University, Manchester, United Kingdom.

There is little information on the impact of pain on sexual health in later life. The aim of this analysis was to determine the association between self-reported pain and sexual health in older men and women. Data were collected for the nationally representative English Longitudinal Study of Ageing. Community-dwelling adults aged 50 years and older completed the Sexual Relationships and Activities Questionnaire in Wave 6 (2012/2013). Participants were asked (waves 1-6 [2002-2013]) whether they were "often troubled with pain" and, how severe was their pain; mild, moderate, or severe. The association between pain and sexual health was assessed using logistic regression. Analyses were stratified by sex, with adjustments made for age followed by adjustments for health and lifestyle factors, depressive symptoms, and socioeconomic status. Of the 3916 participants who reported having sexual activity in the past year, 28% of women and 23% of men reported experiencing moderate or severe pain often at Wave 6. After adjusting for age, compared with men experiencing no pain, men with moderate or severe pain reported less frequent intercourse and masturbation, more erectile difficulties, and more concerns about their sexual health. After age adjustment, there were no associations between pain severity and sexual health among women. Of the 1872 participants with a cumulative pain score, there were significant associations between reporting pain and concerns about sexual health in both men and women. Pain was associated with impairment in sexual health in men and women; however, the effect was more marked in men.
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http://dx.doi.org/10.1097/j.pain.0000000000001113DOI Listing
March 2018

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

J Clin Endocrinol Metab 2018 02;103(2):701-709

Andrology Research Unit, Division of Diabetes, Endocrinology, and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

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.
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http://dx.doi.org/10.1210/jc.2017-01172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800832PMC
February 2018

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

Clin Endocrinol (Oxf) 2018 03 25;88(3):479-490. Epub 2017 Dec 25.

Manchester Academic Health Sciences Centre, Faculty of Medical and Human Sciences, Institute of Human Development, Centre for Endocrinology and Diabetes, Andrology Research Unit, University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1111/cen.13524DOI Listing
March 2018

A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications.

Endocr Rev 2017 08;38(4):302-324

Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.

In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution, metabolism, and biological activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Consequently, accurate determination of the partitioning of testosterone between bound and free fractions is central to our understanding of how its delivery to the target tissues and biological activity are regulated and consequently to the diagnosis and treatment of androgen disorders in men and women. Here, we present a historical perspective on the evolution of our understanding of the binding of testosterone to circulating binding proteins. On the basis of an appraisal of the literature as well as experimental data, we show that the assumptions of stoichiometry, binding dynamics, and the affinity of the prevailing models of testosterone binding to sex hormone-binding globulin and human serum albumin are not supported by published experimental data and are most likely inaccurate. This review offers some guiding principles for the application of free testosterone measurements in the diagnosis and treatment of patients with androgen disorders. The growing number of testosterone prescriptions and widely recognized problems with the direct measurement as well as the computation of free testosterone concentrations render this critical review timely and clinically relevant.
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http://dx.doi.org/10.1210/er.2017-00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287254PMC
August 2017

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

J Clin Endocrinol Metab 2017 08;102(8):2798-2806

Andrology Research Unit, Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom.

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.
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http://dx.doi.org/10.1210/jc.2017-00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546856PMC
August 2017

Associations of muscle force, power, cross-sectional muscle area and bone geometry in older UK men.

J Cachexia Sarcopenia Muscle 2017 Aug 4;8(4):598-606. Epub 2017 May 4.

Nutrition & Bone Health, Elsie Widdowson Laboratory, Medical Research Council Human Nutrition Research, Fulbourn Rd CB1 9NL, Cambridge, UK.

Background: Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power-which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross-sectional muscle area (CSMA) with bone outcomes at the radius and tibia.

Methods: White European, Black Afro-Caribbean, and South Asian men aged 40-79 years were recruited from Manchester, UK. Cortical bone mineral content, cross-sectional area, cortical area, cross-sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two-legged jump performed on a ground-reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity.

Results: Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P < 0.0001). There was a significant age-ethnicity interaction for jump power (P = 0.039); after adjustments, this was attenuated (P = 0.088). For every 10 year increase in age, grip strength decreased by 11%. Jump force was positively associated with tibial bone outcomes: a 1 standard deviation greater jump force was associated with significantly higher cortical bone mineral content 3.1%, cross-sectional area 4.2%, cortical area 3.4%, and cross-sectional moment of inertia 6.8% (all P < 0.001). Cross-sectional muscle area of the lower leg was not associated with tibial bone outcomes. Both grip strength and CSMA of the arm were positively associated, to a similar extent, with radius diaphyseal bone outcomes.

Conclusions: Jump force and power are negatively associated with age in UK men. In the lower limb, the measurement of jump force is more strongly related to bone outcomes than CSMA. It is important to consider jump force and power when understanding the aetiology of bone loss and mobility in ageing men.
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http://dx.doi.org/10.1002/jcsm.12198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566651PMC
August 2017

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

Am J Geriatr Psychiatry 2017 Jun 7;25(6):662-671. Epub 2017 Feb 7.

Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium; Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium.

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 (β = -0.42, p < 0.05) and the DSST (β = -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.
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http://dx.doi.org/10.1016/j.jagp.2017.02.004DOI Listing
June 2017

Ethnic differences in male reproductive hormones and relationships with adiposity and insulin resistance in older men.

Clin Endocrinol (Oxf) 2017 May 28;86(5):660-668. Epub 2017 Feb 28.

Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Diabetes Centre, University of Manchester, Manchester, UK.

Objectives: To assess ethnic differences in male reproductive hormone levels and to determine whether any differences are explained by adiposity, insulin resistance (IR) or comorbidities in older men.

Design: Multi-ethnic cross-sectional observational study.

Participants: Community dwelling middle-aged and elderly men residing in the UK aged 40-84 years of South Asian (SA; n = 180), White European (WE; n = 328) or African Caribbean (AC; n = 166) origin.

Observations: Measured testosterone (T), calculated free T (cFT), sex hormone-binding globulin and LH in SA, WE and AC men along with an assessment of body composition, IR, lifestyle factors and medical conditions.

Results: Age-adjusted mean T and cFT levels were lower in SA men when compared to WE and AC men (mean (SEM) T: SA: 14·0 ± 0·4; WE: 17·1 ± 0·3; AC: 17·2 ± 0·5 nmol/l, P < 0·001; cFT: SA: 283 ± 7; WE: 313 ± 5; AC: 314 ± 8 pmol/l, P < 0·006). Compared to WE and AC men, SA men had higher levels of body fat, IR, comorbidities and diabetes. After adjusting for body fat, IR and other confounders, T levels in SA men remained lower than in WE men (P = 0·04) but ethnic differences in cFT became nonsignificant. LH levels were higher in SA than WE men in age-adjusted and fully adjusted models.

Conclusions: T and cFT are lower in SA men than in WE and AC men. Whether ethnic-specific reference ranges for T and cFT might be appropriate in clinical practice requires further investigation. Ethnic differences in cFT, but not T, appear to be, more readily, explained by ethnic differences in adiposity, thus providing insights into potential pathophysiological mechanisms.
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http://dx.doi.org/10.1111/cen.13305DOI Listing
May 2017

Does Pain Predict Frailty in Older Men and Women? Findings From the English Longitudinal Study of Ageing (ELSA).

J Gerontol A Biol Sci Med Sci 2017 03;72(3):403-409

Cathie Marsh Institute for Social Research, School of Social Sciences, University of Manchester, UK.

Background: Pain has been suggested to act as a stressor during aging, potentially accelerating declines in health and functioning. Our objective was to examine the longitudinal association between self-reported pain and the development, or worsening, of frailty among older men and women.

Methods: The study population consisted of 5,316 men and women living in private households in England, mean age 64.5 years, participating in the English Longitudinal Study of Ageing (ELSA). Data from Waves 2 and 6 of ELSA were used in this study with 8 years of follow-up. At Wave 2, participants were asked whether they were "often troubled with pain" and for those who reported yes, further information regarding the intensity of their pain (mild, moderate, or severe) was collected. Socioeconomic status (SES) was assessed using information about the current/most recent occupation and also net wealth. A frailty index (FI) was generated, with the presence of frailty defined as an FI >0.35. Among those without frailty at Wave 2, the association between pain at Wave 2 and frailty at Wave 6 was examined using logistic regression. We investigated whether pain predicted change in FI between Waves 2 and 6 using a negative binomial regression model. For both models adjustments were made for age, gender, lifestyle factors, depressive symptoms, and socioeconomic factors.

Results: At Wave 2, 455 (19.7%) men and 856 (28.7%) women reported they often experienced moderate or severe pain. Of the 5,159 participants who were nonfrail at Wave 2, 328 (6.4%) were frail by Wave 6. The mean FI was 0.11 (standard deviation [SD] = 0.1) at Wave 2 and 0.15 (SD = 0.1) at Wave 6. After adjustment for age, gender, body mass index, lifestyle factors, and depressive symptoms, compared to participants reporting no pain at Wave 2 those reporting moderate (odds ratio [OR] = 3.08, 95% confidence interval [CI] = 2.28, 4.16) or severe pain (OR = 3.78, 95% CI = 2.51, 5.71) were significantly more likely to be frail at Wave 6. This association persisted after further adjustment for either occupational class and/or net wealth level. Compared to those without pain, those with mild, moderate, or severe pain were also more likely to develop worsening frailty, as assessed using the FI, and this association persisted after adjustment for SES. There was no evidence that the association between pain and frailty was influenced by gender.

Conclusion: Pain is associated with an increased risk and intensity of frailty in older men and women. Socioeconomic factors contribute to the occurrence of frailty; though in our study do not explain the relationship between pain and frailty.
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http://dx.doi.org/10.1093/gerona/glw226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861874PMC
March 2017

Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men.

J Clin Endocrinol Metab 2016 12 27;101(12):4779-4788. Epub 2016 Oct 27.

Center for Reproductive Medicine and Andrology (H.M.B.), Martin Luther University, Halle-Wittenberg, D-06120 Halle, Germany; Center of Reproductive Medicine and Andrology (M.Z.), University of Münster, Münster, Germany; Medical Research Council Centre for Reproductive Health (R.A.A.), Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom; Anzac Research Institute (D.J.H.), University of Sydney, and Andrology Department, Concord Hospital, Sydney, Australia; Department of Medical Biology (S.W.L.), Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; Hudson Institute of Medical Research (R.I.M.), Monash Medical Centre, Melbourne, Australia; Clinic of Gynecology and Physiopathology of Reproduction (M.C.M.), University of Bologna, Bologna, Italy; National Institute of Health and Family Welfare (M.M.M.), New Delhi, India; Instituto Chileno de Medicina Reproductiva (G.N.), Santiago, Chile; Department of Endocrinology (F.C.W.W.), Manchester Royal Infirmary, Manchester, United Kingdom; Department of Reproductive Health and Research (M.R.P.F., N.A.H., K.M.V.), World Health Organization, Geneva 1211, Switzerland; and CONRAD (M.M.C., K.A.L., D.S.C.), Arlington, Virginia 22209.

Context: The development of a safe and effective reversible method of male contraception is still an unmet need.

Objective: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone.

Design: Prospective multicentre study.

Setting: Ten study centers.

Participants: Healthy men, aged 18-45 years, and their 18- to 38-year-old female partners, both without known fertility problems.

Intervention: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks.

Main Outcomes Measures: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate.

Results: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8-97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59-4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5-97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early.

Conclusions: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high.
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http://dx.doi.org/10.1210/jc.2016-2141DOI Listing
December 2016

Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME).

Int J Clin Pract 2016 Oct;70(10):843-852

New England Research Institutes, Inc., Watertown, MA, USA.

Aims: The aim of this study was to assess cardiovascular (CV) safety of testosterone replacement therapy (TRT) in a large, diverse cohort of European men with hypogonadism (HG).

Methods: The Registry of Hypogonadism in Men (RHYME) was designed as a multi-national, longitudinal disease registry of men diagnosed with hypogonadism (HG) at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years. Independent adjudication was performed on all mortalities and CV outcomes.

Results: Of 999 patients enrolled with clinically diagnosed HG, 750 (75%) initiated some form of TRT. Registry participants, including both treated and untreated patients, contributed 23 900 person-months (99.6% of the targeted) follow-up time. A total of 55 reported CV events occurred in 41 patients. Overall, five patients died of CV-related causes (3 on TRT, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall CV incidence rate was 1522 per 100 000 person-years. CV event rates for men receiving TRT were not statistically different from untreated men (P=.70). Regardless of treatment assignment, CV event rates were higher in older men and in those with increased CV risk factors or a prior history of CV events.

Conclusions: Age and prior CV history, not TRT use, were predictors of new-onset CV events in this multi-national, prospective hypogonadism registry.
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http://dx.doi.org/10.1111/ijcp.12876DOI Listing
October 2016

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

Endocrine 2017 Feb 13;55(2):456-469. Epub 2016 Oct 13.

Department of Medicine, CIBER de Fisiopatologia Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, Complejo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela University, Santiago de Compostela, Spain.

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/m, 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/m), 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/m) 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.
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http://dx.doi.org/10.1007/s12020-016-1135-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272876PMC
February 2017

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

Eur J Endocrinol 2016 Dec 15;175(6):583-593. Epub 2016 Sep 15.

Faculty of Medical and Human SciencesInstitute of Human Development, Centre for Endocrinology and Diabetes, Andrology Research Unit, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.

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 (E) 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 E 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.
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http://dx.doi.org/10.1530/EJE-16-0447DOI Listing
December 2016

Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men.

BJU Int 2017 Feb 14;119(2):216-224. Epub 2016 Aug 14.

New England Research Institutes, Inc., Watertown, MA, USA.

Objectives: To evaluate the effects of testosterone-replacement therapy (TRT) on prostate health indicators in hypogonadal men, including rates of prostate cancer diagnoses, changes in prostate-specific antigen (PSA) levels and lower urinary tract symptoms (LUTS) over time.

Patients And Methods: The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry of treated and untreated, newly-diagnosed hypogonadal men (n = 999). Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer; PSA and testosterone levels were measured via local and central laboratory assays; and LUTS severity was assessed via the International Prostate Symptom Score (IPSS). Incidence rates per 100 000 person-years were calculated. Longitudinal mixed models were used to assess effects of testosterone on PSA levels and IPSS.

Results: Of the 999 men with clinically diagnosed hypogonadism (HG), 750 (75%) initiated TRT, contributing 23 900 person-months of exposure. The mean testosterone levels increased from 8.3 to 15.4 nmol/L in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. Overall, the proportion of positive biopsies was nearly identical in men on TRT (37.5%) compared to those not on TRT (37.0%) over the course of the study. There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score by TRT status. Lower IPSS irritative sub-scale scores were reported in treated compared to untreated men.

Conclusions: Results support prostate safety of TRT in newly diagnosed men with HG.
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http://dx.doi.org/10.1111/bju.13578DOI Listing
February 2017

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

Clin Endocrinol (Oxf) 2016 Dec 18;85(6):891-901. Epub 2016 Aug 18.

Andrology Research Unit, Centre for Endocrinology & Diabetes, Institute of Human Development, Old St Mary's Building, The University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1111/cen.13152DOI Listing
December 2016

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

Eur J Nutr 2017 Sep 1;56(6):2093-2103. Epub 2016 Jul 1.

Department of Clinical and Experimental Medicine, KU Leuven, Louvain, Belgium.

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)D] 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)D 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)D 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 (<50 nmol/l) showed a greater decline in the CTRM compared to men with higher (≥75 nmol/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)D and decline in cognitive subdomains.

Conclusion: We found no evidence for an independent association between 25(OH)D or 1,25(OH)D 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.
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http://dx.doi.org/10.1007/s00394-016-1247-4DOI Listing
September 2017

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

Age Ageing 2016 07 13;45(4):463-8. Epub 2016 Apr 13.

Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: 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).

Objectives: to compare the FI-Lab with the FI-Clin and to assess their individual and combined relationships with mortality and other adverse health outcomes.

Design And Subjects: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1093/ageing/afw054DOI Listing
July 2016

Interactions Between Depression and Lower Urinary Tract Symptoms: The Role of Adverse Life Events and Inflammatory Mechanisms. Results From the European Male Ageing Study.

Psychosom Med 2016 Jul-Aug;78(6):758-69

From the Sexual Medicine and Andrology Unit (Castellini, Rastrelli, Maggi), Department of Experimental, Clinical and Biomedical Sciences, and Psychiatric Unit (Castellini, Ricca), Department of Neuropsychiatric Sciences, University of Florence, Florence, Italy; Andrology Research Unit (Wu, Rutter), Endocrinology and Diabetes Research Group, Institute of Human Development, Faculty of Medical Human Sciences, The University of Manchester, Manchester, UK; Manchester Royal Infirmary (Wu, Rutter), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; Arthritis Research UK Epidemiology Unit (Finn, O'Neill), The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Department of Human Nutrition (Lean), University of Glasgow, Glasgow, UK; School of Community Based Medicine (Pendleton), The University of Manchester, Salford Royal NHS Trust, Salford, UK; Manchester Diabetes Centre (Rutter), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; Department of Oncology (Gacci), Urology Unit, University Hospital Careggi (AOUC), University of Florence, Florence, Italy.

Objectives: Depression and lower urinary tract symptoms (LUTSs) have been found to co-occur among aging men. The present study attempted to clarify the nature of this relationship, considering adverse life events as potential moderators and the inflammation as an underlying biological mechanism.

Methods: The relationship between depression and LUTS was evaluated using data from the European Male Ageing Study, the largest multicenter population-based study of aging in European men. The sample included 3369 men who were assessed by means of several self-reported questionnaires, including the Beck Depression Inventory-II, the International Prostate Symptom Score, and the Adverse Life Events Scale. Participants were asked to provide information regarding general health and life-style, and medical comorbidities. Biological measures including prostate-specific antigen, testosterone, and C-reactive protein were measured.

Results: LUTS and depressive symptoms were correlated (R = 0.32, β = .10, p < .001), even after adjusting for life-style, psychological, and medical variables. A history of adverse life events was associated with both higher LUTS and Beck Depression Inventory scores. Furthermore, adverse life events moderated the LUTS-depression association (F = 22.62, b = 0.061, p < .001), which increased as a function of the number of life events. C-reactive protein was found to mediate the LUTS-depression association. This mediation effect was moderated by number of adverse life events.

Conclusions: Participants with a history of adverse life events represent a vulnerable population in whom the association between somatic and depressive symptoms is stronger. One of the biological mechanisms underlying this association could be an activation of the central inflammatory signaling pathways.
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http://dx.doi.org/10.1097/PSY.0000000000000328DOI Listing
July 2017

Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone.

J Clin Endocrinol Metab 2016 07 24;101(7):2647-57. Epub 2016 Feb 24.

Department of Clinical and Experimental Medicine (L.A., B.D., D.V.), KU Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium; Department of Cellular and Molecular Medicine (L.A., M.R.L., F.C.), KU Leuven, Laboratory of Molecular Endocrinology, Leuven, Belgium; Department of Endocrinology (L.A., B.D., D.V.), University Hospitals Leuven, Leuven, Belgium; Andrology Research Unit (F.C.W.W., T.B.A.), Endocrinology and Diabetes Research Group, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK; Manchester Royal Infirmary (F.C.W.W.), Central Manchester University Hospitals National Health Services (NHS) Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; Arthritis Research UK Centre of Epidemiology (T.W.O.N., S.R.P.), The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit (T.W.O.N.), Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; Department of Clinical and Experimental Medicine (M.R.L.), KU Leuven, Laboratory of Gerontology and Geriatrics, Leuven, Belgium; Department of Surgery and Cancer, Imperial College London (I.T.H.), Hammersmith Campus, London, UK; Department of Physiology (I.T.H.), Institute of Biomedicine, University of Turku, Turku, Finland; Department of Human Nutrition (M.E.J.L.), University of Glasgow, Glasgow, UK; Department of Clinical Biochemistry (B.G.K.), University Hospital of South Manchester, Manchester, UK; Sexual Medicine and Andrology Unit (G.R.), Department of Experimental Clinical and Biochemical Sciences, University of Florence, Florence, Italy; Endocrinology Unit (G.F.), Department of Experimental Clinical and Biochemical Sciences, University of Florence, Florence, Italy; Department of Obstetrics, Gynaecology and Andrology (G.B.), Albert Szent-György Medica

Context: During aging, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free T (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT.

Objective: Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints.

Methods: A total of 3334 community-dwelling men, aged 40-79 years, were included in this study. Differences in clinical variables between the referent group of men with both normal TT (≥10.5 nmol/liter) and normal cFT (≥220 pmol/liter) with those who had normal TT/low cFT, low TT/normal cFT, and low TT/low cFT were assessed by regression models adjusted for age, center, body mass index, and comorbidities.

Results: A total of 2641 men had normal TT (18.4 ± 5.5 [mean ± SD] nmol/liter)/normal cFT (326 ± 74 pmol/liter), 277 men had normal TT (14.2 ± 3.7)/low cFT (194 ± 23), 96 men had low TT (9.6 ± 0.7)/normal cFT (247 ± 20), and 320 men had low TT (7.8 ± 2.5)/low cFT (160 ± 55). Men with normal TT/low cFT were older and in poorer health. They had higher SHBG and LH and reported more sexual and physical symptoms, whereas hemoglobin and bone ultrasound parameters were lower compared to the referent group. Men with low TT/normal cFT were younger and more obese. They had lower SHBG, but LH was normal, whereas features of androgen deficiency were lacking.

Conclusions: Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms; therefore, cFT levels should be assessed in men with suspected hypogonadal symptoms.
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http://dx.doi.org/10.1210/jc.2015-4106DOI Listing
July 2016

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

Age Ageing 2016 Mar 17;45(2):268-74. Epub 2015 Dec 17.

Arthritis Research UK Centre for Epidemiology, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust-Manchester Academic Health Science Centre, Manchester, UK.

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.
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http://dx.doi.org/10.1093/ageing/afv170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776622PMC
March 2016