The effects of fasting compared to eating a meal or snack during simulated night shift on changes in metabolism associated with circadian misalignment: a protocol and methods paper.

Study Objectives: This protocol paper outlines the methods that will be used to examine the impact of altering meal timing on metabolism, cognitive performance, and mood during the simulated night shift. Methods: Participants (male and female) will be recruited according to an a priori selected sample size to complete a 7-day within and between participant's laboratory protocol. Participants will be randomly assigned to one of the three conditions: meal at night or snack at night or no meal at night. This protocol includes an 8-hour nighttime baseline sleep, followed by 4 consecutive nights of simulated nightshift (7 hours day sleep; 10:00-17:00 hours), and an 8-hour nighttime sleep (return to dayshift). During the simulated night shift, meals will be provided at ~06:30, 09:30, 14:10, and 19:00 hours (no eating at night); ~06:30, 19:00, and 00:30 hours (meal at night); or ~06:30, 14:10, 19:00, and 00:30 hours (snack at night). Meal composition will be strictly controlled throughout the study (45%-65% carbohydrates, 15%-25% protein, and 20%-35% fat per day) with daily energy provided to meet individual needs using the Harris-Benedict equation (light/sedentary activity). The primary outcome measures are serum concentrations of blood glucose, insulin, and free fatty acids area under the curve in response to the oral glucose tolerance test. Mixed-effect ANOVAs will be conducted. Conclusions: This protocol paper describes a methodology to describe an innovative approach to reduce the metabolic disease impact associated with shift work.

Translation of culturally and contextually informed diabetes training for Aboriginal primary health care providers on Aboriginal client outcomes: Protocol of a cluster randomized crossover trial of effectiveness.

BACKGROUND: Indigenous populations globally have significantly high rates of type 2 diabetes compared to their non-Indigenous counterparts. This study aims to implement and evaluate the effectiveness of a culturally and contextually informed Aboriginal Diabetes Workforce Training Program on Aboriginal primary health care workforce knowledge, attitude, confidence, skill and practice relating to diabetes care. METHODS: A Cluster Randomised Crossover Control Trial with two arms (Group A and Group B) will be conducted with Aboriginal primary health care services in South Australia. These services primarily provide primary health care to Aboriginal and Torres Strait Islander people. All healthcare service sites will be randomised into groups A and B to receive the training program. The training program consists of three components: 1) Peer support network, 2) E-Learning modules and 3) onsite support. Aboriginal Health Workers of participating sites will be invited to participate in the monthly online peer support network and all chronic disease staff are eligible to participate in the E-Learning modules and onsite support. The Peer Support Network runs for the entirety of the study, 17 months. Training components 2 and 3 occur simultaneously and are 2.5 months in length, with a six-month washout period between the two randomised groups undertaking the training. All primary outcomes of the study relate to diabetes management in a primary health care settings and measure participants' knowledge, attitude, confidence, practice and skills. These will be collected at seven time points across the entire study. Secondary outcomes measure satisfaction of the peer support network using a survey, interviews to understand enablers and barriers to participation, health service systems characteristics through focus groups, and medical record review to ascertain diabetes patients' care received and their clinical outcomes up to 12 months post training intervention. DISCUSSION: The findings will explore the effectiveness of the training program on Aboriginal primary health care provider knowledge, attitude, confidence, skill and practice relating to diabetes care. The final findings will be published in 2027. TRIAL REGISTRATION: The study was prospectively registered in The Australian New Zealand Clinical Trials Registry (ANZCTR), with registration number ACTRN12623000749606 at ANZCTR - Registration. Universal Trial Number (UTN) U1111-1283-5257.

Testosterone in prevention and treatment of type 2 diabetes in men: Focus on recent randomized controlled trials.

In epidemiological studies, lowered serum testosterone concentrations are common in men with obesity, prediabetes, and established type 2 diabetes (T2D). In men with prediabetes, lowered serum testosterone also predicts a future risk of T2D in men. Administration of testosterone consistently reduces fat mass and increases skeletal muscle mass-body compositional changes expected to be metabolically favorable. In men with established T2D, the effects of testosterone treatment on glycemic measures are inconsistent. Irrespective of baseline serum testosterone concentration in men with prediabetes or newly diagnosed early-onset T2D, testosterone treatment prescribed in conjunction with a lifestyle program has been reported to reduce the risk of T2D by 40% after 2 years, suggesting that either a lifestyle program is required to facilitate the glycemic benefit of testosterone treatment and/or that testosterone treatment has more favorable effects on glycemia in men early in the evolution or onset of the disease. The durability of the benefit and longer-term safety of testosterone treatment have not been established. Therefore, more studies are required before testosterone treatment can be recommended for the prevention and/or treatment of men with or at elevated risk of T2D who do not have hypogonadism due to an established disease of the hypothalamic-pituitary-testicular axis.

Supporting best practice in the management of chronic diseases in primary health care settings: a scoping review of training programs for Indigenous Health Workers and Practitioners.

Background To improve diabetes management in primary health care for the Aboriginal and Torres Strait Islander peoples population, training programs that are culturally and contextually relevant to the local context are required. Using a scoping review methodology, the aim of this review was to describe the characteristics of chronic disease management training programs for Aboriginal Health Workers and Practitioners, their effectiveness on knowledge and skills, and client-related outcomes, and the enablers, barriers to delivery and participation. Methods Following protocol parameters, a systematic search was conducted in relevant databases and grey literature. Two independent reviewers screened the title and abstract of each paper to determine if the study met the inclusion criteria. Results Of the 23 included studies, most were developed with stakeholders, profession facilitated and delivered by cultural facilitators. All training programs included content knowledge, two included a professional support network, four provided on-the-job support and six had follow-up support post-training. Modes of delivery ranged from didactic, storytelling and hands-on learning. Two studies reported significant improvement in participants' knowledge and confidence; one reported improvement in knowledge (12.7% increase pre-post training), and an increase in confidence in both clinical and non-clinical skills. Enablers (relevance, modes of learning, power of networking, improved knowledge, confidence and clinical practice) and barriers (adult learning capabilities, competing work-family commitments) were reported. Few studies reported on knowledge transfer into clinical practice and client-related outcomes. Conclusions Multifaceted training programs for Aboriginal health workers are well received and may improve workforce capability.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Testosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial.

OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year randomized controlled testosterone therapy trial for prevention or reversal of newly diagnosed type 2 diabetes, enrolling men ≥ 50 years at high risk for type 2 diabetes from 6 Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomized into the Testosterone for Type 2 Diabetes Mellitus (T4DM) trial, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and 2 years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and fewer depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSION: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

Impact of bariatric surgery, lifestyle change, and pharmacotherapy on fertility in men with obesity: a systematic review protocol.

OBJECTIVE: This review will determine whether various health interventions designed to reduce weight (lifestyle change, bariatric surgery, pharmacotherapy) in men with obesity are associated with improved fertility markers. The review will also establish whether the degree of weight loss achieved through these methods is associated with improvement. INTRODUCTION: Current preconception guidelines provide limited information for men with obesity. Small studies implementing lifestyle changes in men are associated with improvement in sperm quality, whereas bariatric surgery has not been associated with improvements in sperm quality. Determining the benefit of different interventions and the relationship to weight lost is necessary to optimize male fertility. INCLUSION CRITERIA: The population will be men younger than 50 years with overweight (BMI >25 kg/m 2 ) or obesity (BMI >30 kg/m 2 ). The exposure of interest will be an intervention undertaken to improve health or reduce weight, categorized as lifestyle change, bariatric surgery, or pharmacotherapy. Outcomes will include time to conception, fecundity rate, assisted reproduction outcomes, and semen quality measures. Secondary analysis will determine whether degree of weight loss achieved is associated with degree of improvement. METHODS: This review will follow the JBI methodology for systematic reviews of etiology and risk. Databases to be searched will include PubMed, Embase (Ovid), Cochrane Central Register of Controlled Trials, Web of Science Core Collection, and Scopus. Articles not published or translated into English will be excluded. Methodological quality will be assessed using the JBI critical appraisal tools. Data will be extracted using a tool developed by the reviewers. Statistical meta-analysis will be performed where possible to synthesize outcomes of similar methods. REVIEW REGISTRATION: PROSPERO CRD42022349665.

Are e-Health Interventions Effective in Reducing Diabetes-Related Distress and Depression in Patients with Type 2 Diabetes? A Systematic Review with Meta-Analysis.

Background: e-Health refers to any health care service delivered through the internet or related technologies, to improve quality of life. Despite the increasing use of e-health interventions to manage type 2 diabetes (T2D), there is a lack of evidence about the effectiveness on diabetes distress and depression, which are common issues in those living with T2D. Purpose: To synthesize and determine the effects of e-health interventions on diabetes distress and depression among patients with T2D. Methods: We systematically searched PubMed, Scopus, Cochrane CENTRAL, and Web of Science for randomized controlled trials (RCTs), non-RCTs and observational cohort studies for the effects of e-health interventions on diabetes distress and depression in patients with T2D up to September 14, 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 recommendations were followed. The risk of bias was assessed according to the Risk-of-Bias 2 tool (RCTs), the Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) (non-RCTs) and the National Institute of Health tool (observational). The standardized mean difference (SMD) and its related 95% confidence intervals (CIs) were estimated with the DerSimonian-Laird method through random-effect models. A pooled raw mean difference (MD) meta-analysis was conducted for RCTs comparing the effects of e-health versus control on diabetes distress screening to display the clinical impact. Results: A total of 41 studies (24 RCTs, 14 non-RCTs, and 3 observational) involving 8,667 individuals were included. The pooled SMD for the effect of e-health versus the control group on diabetes distress was -0.14 (95% CI = -0.24 to -0.04; I2 = 23.9%; n = 10 studies), being -0.06 (95% CI = -0.15 to 0.02; I2 = 7.8%; n = 16 studies) for depression. The pooled raw MD on diabetes distress screening showed a reduction of -0.54 points (95% CI = -0.81 to -0.27; I2 = 85.1%; n = 7 studies). Conclusion: e-Health interventions are effective in diminishing diabetes distress among adults with T2D, inducing clinically meaningful reductions.

Approach the Patient With Obstructive Sleep Apnea and Obesity.

Obstructive sleep apnea (OSA) and obesity are highly prevalent and bidirectionally associated. OSA is underrecognized, however, particularly in women. By mechanisms that overlap with those of obesity, OSA increases the risk of developing, or having poor outcomes from, comorbid chronic disorders and impairs quality of life. Using 2 illustrative cases, we discuss the relationships between OSA and obesity with type 2 diabetes, dyslipidemia, cardiovascular disease, cognitive disturbance, mood disorders, lower urinary tract symptoms, sexual function, and reproductive disorders. The differences in OSA between men and women, the phenotypic variability of OSA, and comorbid sleep disorders are highlighted. When the probability of OSA is high due to consistent symptoms, comorbidities, or both, a diagnostic sleep study is advisable. Continuous positive airway pressure or mandibular advancement splints improve symptoms. Benefits for comorbidities are variable depending on nightly duration of use. By contrast, weight loss and optimization of lifestyle behaviors are consistently beneficial.

Facilitators of, barriers to, and preferences for e-mental health interventions for depression and anxiety in men: Metasynthesis and recommendations.

BACKGROUND: Little is known about men's use of online mental health (eMH) interventions and factors that promote their engagement or attrition. We aimed to synthesise the qualitative literature on men's preferences for, attitudes towards, and experiences of using eMH interventions for depression and anxiety, and develop recommendations from the findings. METHOD: Systematic searches were conducted (Jan 2000-Oct 2020) in six databases; study quality was assessed using Qualsyst with a minimum total of 0.55 required for inclusion. Extracted data were synthesised using meta-aggregation. RESULTS: Eight studies met inclusion criteria and three synthesised findings were generated. (1) Facilitators of men's eMH use: finding apps and technology motivating and convenient, support and encouragement from important others, and interventions allowing men to take action, gain control over their mental health, and resulting in positive outcomes; (2) Barriers to men's eMH use: lack of free time, predicted or experienced lack of benefit from use, and technical difficulties; (3) What men want in eMH: personalised, tailored, relevant interventions that are bright and easy to use, with information presented in multiple formats, psychoeducation, exercises, self-monitoring, information on further resources, and the option of clinician involvement, without any repetitive questioning, boring tools, or negative feedback. LIMITATIONS: All included studies were conducted in high income, 'Western' countries; most data related to experiences of using an existing eMH intervention within a trial, rather than in 'real world' settings where eMH acceptability is generally lower and experiences may differ. CONCLUSIONS: Practice, research, and policy recommendations are presented.

Does obstructive sleep apnea increase the risk of cancer and cancer mortality in combined community-based cohorts?

Obstructive sleep apnea (OSA) has been linked to cancer in several clinical and community-based cohorts. The effect in community-based studies free of clinical referral bias needs to be replicated. In this observational prospective cohort study, we pooled data from three community-based prospective cohorts (Uppsala Sleep and Health in Men cohort [UMEN]; Sleep and health in women [SHE]; Men Androgen Inflammation Lifestyle Environment and Stress Cohort [MAILES]; nTotal = 1467). All cohorts had objective data on obstructive sleep apnea and registry linkage data on cancer and cancer mortality. Analyses for different obstructive sleep apnea measures (apnea-hypopnea index [AHI], oxygen desaturation index [ODI], and minimal saturation) as risk factors for cancer incidence (all cancers) were performed using Cox proportional hazards models (follow-up 5-16 years). We did not find an overall increased risk of cancer after adjustment for age, sex, and BMI (HRAHI [95% CI] = 1.00 [0.98; 1.01] and HRODI [95% CI] = 0.99 [0.97; 1.01]). Stratifying by daytime sleepiness did not influence the association. Cancer mortality was not significantly associated with obstructive sleep apnea. Taken together, we did not observe an overall increased risk of cancer or cancer mortality in relation to obstructive sleep apnea, however, our confidence limits remain wide for important diagnostic categories of sleep apnea severity. The relationship between obstructive sleep apnea and cancer needs further investigation in a comprehensive multi-cohort approach with greater statistical precision. For future studies we may need to find and then combine every community-based cohort study that can provide a definitive answer to the question on the risk of cancer from obstructive sleep apnea in the general population.

Associations of baseline obstructive sleep apnea and sleep macroarchitecture with cognitive function after 8 years in middle-aged and older men from a community-based cohort study.

Previous prospective studies examining associations of obstructive sleep apnea and sleep macroarchitecture with future cognitive function recruited older participants, many demonstrating baseline cognitive impairment. This study examined obstructive sleep apnea and sleep macroarchitecture predictors of visual attention, processing speed, and executive function after 8 years among younger community-dwelling men. Florey Adelaide Male Ageing Study participants (n = 477) underwent home-based polysomnography, with 157 completing Trail-Making Tests A and B and the Mini-Mental State Examination. Associations of obstructive sleep apnea (apnea-hypopnea index, oxygen desaturation index, and hypoxic burden index) and sleep macroarchitecture (sleep stage percentages and total sleep time) parameters with future cognitive function were examined using regression models adjusted for baseline demographic, biomedical, and behavioural factors, and cognitive task performance. The mean (standard deviation) age of the men at baseline was 58.9 (8.9) years, with severe obstructive sleep apnea (apnea-hypopnea index ≥30 events/h) in 9.6%. The median (interquartile range) follow-up was 8.3 (7.9-8.6) years. A minority of men (14.6%) were cognitively impaired at baseline (Mini-Mental State Examination score <28/30). A higher percentage of light sleep was associated with better Trail-Making Test A performance (B = -0.04, 95% confidence interval [CI] -0.06, -0.01; p = 0.003), whereas higher mean oxygen saturation was associated with worse performance (B = 0.11, 95% CI 0.02, 0.19; p = 0.012). While obstructive sleep apnea and sleep macroarchitecture might predict cognitive decline, future studies should consider arousal events and non-routine hypoxaemia measures, which may show associations with cognitive decline.

Recommendations for culturally safe clinical kidney care for First Nations Australians: a guideline summary.

INTRODUCTION: First Nations Australians display remarkable strength and resilience despite the intergenerational impacts of ongoing colonisation. The continuing disadvantage is evident in the higher incidence, prevalence, morbidity and mortality of chronic kidney disease (CKD) among First Nations Australians. Nationwide community consultation (Kidney Health Australia, Yarning Kidneys, and Lowitja Institute, Catching Some Air) identified priority issues for guideline development. These guidelines uniquely prioritised the knowledge of the community, alongside relevant evidence using an adapted GRADE Evidence to Decision framework to develop specific recommendations for the management of CKD among First Nations Australians. MAIN RECOMMENDATIONS: These guidelines explicitly state that health systems have to measure, monitor and evaluate institutional racism and link it to cultural safety training, as well as increase community and family involvement in clinical care and equitable transport and accommodation. The guidelines recommend earlier CKD screening criteria (age ≥ 18 years) and referral to specialists services with earlier criteria of kidney function (eg, estimated glomerular filtration rate [eGFR], ≤ 45 mL/min/1.73 m2 , and a sustained decrease in eGFR, > 10 mL/min/1.73 m2 per year) compared with the general population. CHANGES IN MANAGEMENT AS RESULT OF THE GUIDELINES: Our recommendations prioritise health care service delivery changes to address institutional racism and ensure meaningful cultural safety training. Earlier detection of CKD and referral to nephrologists for First Nations Australians has been recommended to ensure timely implementation to preserve kidney function given the excess burden of disease. Finally, the importance of community with the recognition of involvement in all aspects and stages of treatment together with increased access to care on Country, particularly in rural and remote locations, including dialysis services.

Effects of the antipsychotic quetiapine on sleep and breathing: a review of clinical findings and potential mechanisms.

Quetiapine is an antipsychotic medication indicated for schizophrenia and bipolar disorder. However, quetiapine also has hypnotic properties and as such is increasingly being prescribed at low doses 'off-label' in people with insomnia symptoms. Pharmacologically, in addition to its dopaminergic properties, quetiapine also modulates multiple other transmitter systems involved in sleep/wake modulation and potentially breathing. However, very little is known about the impact of quetiapine on obstructive sleep apnoea (OSA), OSA endotypes including chemosensitivity, and control of breathing. Given that many people with insomnia also have undiagnosed OSA, it is important to understand the effects of quetiapine on OSA and its mechanisms. Accordingly, this concise review covers the existing knowledge on the effects of quetiapine on sleep and breathing. Further, we highlight the pharmacodynamics of quetiapine and its potential to alter key OSA endotypes to provide potential mechanistic insight. Finally, an agenda for future research priorities is proposed to fill the current key knowledge gaps.

Long-term Outcomes of Testosterone Treatment in Men: A T4DM Postrandomization Observational Follow-up Study.

CONTEXT: The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with testosterone (T) treatment reducing diabetes diagnosis by 40%. BACKGROUND: The long-term effects on new diagnosis of diabetes, cardiovascular and prostate disease, sleep apnea, weight maintenance trajectory and androgen dependence were not yet described. METHODS: A follow-up email survey after a median of 5.1 years since last injection obtained 599 (59%) completed surveys (316 T, 283 P), with participants in the follow-up survey compared with nonparticipants in 23 anthropometric and demographic variables. RESULTS: Randomization to was TU associated with stronger belief in study benefits during (64% vs 49%, P < .001) but not after the study (44% vs 40%, P = .07); there is high interest in future studies. At T4DM entry, 25% had sleep apnea with a new diagnosis more frequent on TU (3.0% vs 0.4%, P = .03) during, but not after, the study. Poststudy, resuming prescribed T treatment was more frequent among TU-treated men (6% vs 2.8%, P = .03). Five years after cessation of TU treatment there was no difference in self-reported rates of new diagnosis of diabetes, and prostate or cardiovascular disease, nor change in weight maintenance or weight loss behaviors. CONCLUSION: We conclude that randomized T treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism was associated with higher levels of self-reported benefits and diagnosis of sleep apnea during, but not after, the study as well as more frequent prescribed poststudy T treatment consistent with androgen dependence in some men receiving prolonged injectable TU.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial.

OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant hand-grip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥95 cm, serum total testosterone ≤14 nmol/L (immunoassay), and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle programme and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2 years (OGTT ≥ 11.1 mmol/L and change in 2-h glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG, were performed. RESULTS: For type 2 diabetes at 2 years, the unadjusted OR for treatment was 0.53 (95% CI:.35-.79), which became 0.48 (95% CI:.30-.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; P < .001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.

Association of alcohol and bone mineral density dependent on type of alcohol consumed.

INTRODUCTION: Osteoporosis prevalence will increase in coming decades, with significant financial and economic implications. Whilst alcohol excess has significant detrimental impacts on bone mineral density (BMD), knowledge of low-volume consumption is inconsistent. Type of alcohol may mediate impact on BMD and warrants further investigation. MATERIALS AND METHODS: Participants were drawn from the Florey Adelaide Male Aging Study, a cohort of community dwelling men from Adelaide, Australia (n = 1195). The final cohort (n = 693) provided information regarding alcohol consumption and undertook BMD scan at wave one (2002-2005) and wave two (2007-2010). Cross-sectional and longitudinal multivariable regression was performed for whole-body and spine BMD. To assess change in exposure over time, change in BMD was compared to change in covariates between waves. RESULTS: Cross-sectionally, whole-body BMD was positively associated with obesity (p < 0.001), exercise (p = 0.009), prior smoking (p = 0.001), oestrogen concentration (p = 0.001), rheumatoid arthritis (p = 0.013) and grip strength (p < 0.001). No association was identified with volume of differing types of alcohol consumed. Spinal BMD was inversely associated with low-strength beer consumption (p = 0.003). The volume of alcohol consumed at Wave 1 did not predict change in whole-body or spinal BMD; however, increases in full-strength beer consumption between waves were associated with reduced spinal BMD (p = 0.031). CONCLUSION: When consumed at quantities in the usual social range, alcohol was not associated with whole-body BMD. However, low-strength beer consumption was inversely related to spinal BMD.